@article {pmid42977507,
year = {2026},
author = {Li, M and Xu, D and Li, Y and Zhao, Q},
title = {Mitochondria-Associated Membranes as a Convergent Hub of Brain Aging: From Neurodegeneration to Cerebral Ischemia.},
journal = {The European journal of neuroscience},
volume = {64},
number = {9},
pages = {},
doi = {10.1111/ejn.70746},
pmid = {42977507},
issn = {1460-9568},
support = {CY2024-MS-A05//Lanzhou University Second Hospital/ ; CY2023-MS-A01//Lanzhou University Second Hospital/ ; 82660095//National Natural Science Foundation of China/ ; GSWSQNPY2024-13//Major Scientific and Technological Innovation Project of the Gansu Provincial Health Sector/ ; 2022RCCX0023//Science and Technology Planning Project of Chengguan District/ ; 2025B-017//Gansu Provincial Department of Education/ ; },
mesh = {Humans ; *Aging/metabolism/pathology ; *Mitochondria Associated Membranes/metabolism ; *Brain Ischemia/metabolism/pathology ; Animals ; *Brain/metabolism/pathology ; *Neurodegenerative Diseases/metabolism/pathology ; *Mitochondria/metabolism/pathology ; },
abstract = {Brain aging is the principal risk factor for both neurodegenerative diseases (NDDs) and cerebral ischemic disorders, yet the subcellular mechanisms linking these conditions remain incompletely defined. Mitochondria-associated membranes (MAMs)-specialized contact sites between the endoplasmic reticulum (ER) and mitochondria-sit at the intersection of two well-established hallmarks of aging, mitochondrial dysfunction, and loss of proteostasis, making them an attractive mechanistic node for understanding age-related brain decline. In this review, we propose a MAM-centered framework that unifies neurodegenerative and ischemic brain pathology under the broader paradigm of brain aging. We first summarize the molecular architecture of MAMs and their core functions in neuronal Ca[2+] transfer, mitochondrial dynamics, lipid metabolism, inflammasome assembly, and autophagic quality control, together with emerging evidence from non-neuronal brain cells. We then examine how MAM dysfunction intersects with five hallmarks of aging-mitochondrial dysfunction, loss of proteostasis, disabled macroautophagy, chronic inflammation (inflammaging), and altered intercellular communication-drawing on evidence from physiological aging and cellular senescence models. Next, we discuss disease-specific roles of MAMs in cerebral ischemia and in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. A central theme emerges: Rather than a unidirectional decline of MAMs, brain aging is associated with a loss of MAM homeostasis, in which both insufficient and excessive ER-mitochondria coupling can be pathological and the shared deficit is the failure to maintain contact-site function within an optimal range. Finally, we consider age-relevant therapeutic and biomarker strategies targeting MAMs and their potential translation into geriatric neurology. To our knowledge, this is the first review to integrate MAM biology across physiological brain aging, cerebral ischemia, and the four major NDDs within a single homeostatic framework, offering a unified perspective on the mechanisms of age-related brain decline.},
}

Humans
*Aging/metabolism/pathology
*Mitochondria Associated Membranes/metabolism
*Brain Ischemia/metabolism/pathology
Animals
*Brain/metabolism/pathology
*Neurodegenerative Diseases/metabolism/pathology
*Mitochondria/metabolism/pathology

@article {pmid42978072,
year = {2026},
author = {Zhao, J and Jin, W and Hu, L and Yang, L and Wang, Y and Li, Z and Bai, L},
title = {Multi-omics dissection of interactive cross-stress tolerance to Penoxsulam and salinity in Echinochloa crus-galli.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.71436},
pmid = {42978072},
issn = {1526-4998},
support = {32472586//Natural Science Foundation of China/ ; 2024RC2015//Yuelushan Laboratory Talent Program/ ; 2024JJ2036//Natural Science Foundation of Hunan Province/ ; 2024JJ1005//Natural Science Foundation of Hunan Province/ ; YLS-2025-ZY01003//Yuelushan Laboratory Breeding Program/ ; //Hunan Agriculture Research System (HARS-02)/ ; 2026CX20//Agricultural Science and Technology Innovation Fund Project of Hunan Province/ ; },
abstract = {BACKGROUND: Herbicide resistance and soil salinization increasingly co-occur in rice paddies, yet how evolved penoxsulam resistance shapes the fitness of barnyardgrass (Echinochloa crus-galli) under combined salt and herbicide stress remains poorly understood. This study aimed to resolve the physiological and molecular basis of such cross-stress tolerance.

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

CONCLUSION: Penoxsulam resistance in E. crus-galli operates through constitutive homeostasis maintenance and targeted carbon partitioning rather than amplified defence, providing a mechanistic framework for integrated resistance management in saline paddy fields. © 2026 Society of Chemical Industry.},
}

@article {pmid42979863,
year = {2026},
author = {Choudhury, AK and Rani, P and Gupta, R and Gulati, M and Kapoor, B},
title = {Liposomal Delivery of a Riluzole-Butyric Acid Mutual Prodrug Enhances Neuroprotection and Cognitive Recovery in Experimental Alzheimer's Disease.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/1061186X.2026.2759730},
pmid = {42979863},
issn = {1029-2330},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, impaired synaptic signaling, and persistent neuroinflammation. Current therapies primarily provide symptomatic relief and have limited effects on disease progression. Riluzole, approved for amyotrophic lateral sclerosis, exhibits neuroprotective effects through modulation of glutamatergic signaling, but its poor oral bioavailability limits its therapeutic potential. Butyric acid, a short-chain fatty acid postbiotic produced by gut microbial fermentation, possesses well-established anti-inflammatory and neuroprotective properties. In this study, a mutual prodrug of riluzole and butyric acid was synthesized and encapsulated into liposomes to investigate its effects on drug distribution and preclinical efficacy. The prodrug-loaded liposomes exhibited an average particle size of 322 nm, zeta potential of -7.95 mV, and entrapment efficiency of 43.49%. Oral administration significantly improved cognitive performance and attenuated neuroinflammation and oxidative stress in an AlCl3-induced AD-like rat model. Administration of prodrug-loaded liposomes led to the highest concentrations of riluzole in brain homogenates among the relevant treatment groups. Overall, the prodrug-loaded liposomes demonstrated better therapeutic efficacy than the prodrug suspension, individual drug-loaded liposomes, and their respective conventional formulations. The enhanced therapeutic performance is attributed to the complementary pharmacological actions of riluzole and butyric acid, combined with the ability of the liposomal system to improve drug bioavailability and facilitate cerebral delivery.},
}

@article {pmid42980086,
year = {2026},
author = {Yardimci, BI and Zurel, AG and Biterge, B},
title = {Protein Isoaspartate Repair in Amyotrophic Lateral Sclerosis: An Integrative Bioinformatic Analysis of the PCMT Gene Family.},
journal = {ACS chemical neuroscience},
volume = {17},
number = {21},
pages = {3526-3537},
doi = {10.1021/acschemneuro.6c00479},
pmid = {42980086},
issn = {1948-7193},
support = {THD-2025-47488//Bilimsel Arastirma Projeleri Birimi, Istanbul Teknik ?niversitesi/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/metabolism ; Humans ; Computational Biology/methods ; *Protein D-Aspartate-L-Isoaspartate Methyltransferase/genetics/metabolism ; *Isoaspartic Acid/metabolism ; Animals ; },
abstract = {Protein homeostasis is a fundamental determinant of neuronal survival, and its disruption contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). Protein L-isoaspartate O-methyltransferases (PCMTs) are evolutionarily conserved proteins involved in the recognition and processing of damaged proteins through the repair of isoaspartyl residues and protein quality-control pathways; however, their potential involvement in ALS remains largely unexplored. Here, we performed a comprehensive in silico characterization of the PCMT family (PCMT1, PCMTD1, and PCMTD2) by integrating structural, transcriptomic, single-cell, genetic, and protein modeling analyses. Domain analysis demonstrated that all three proteins share a conserved PCMT domain, while predicted S-adenosylmethionine-binding motifs were identified in PCMT1 and PCMTD2 but not PCMTD1, indicating evolutionary conservation with functional divergence. Expression profiling revealed that PCMT family genes are expressed in ALS-relevant tissues and broadly distributed across neuronal, glial, vascular, and immune cell populations in both healthy and ALS-associated brain single-cell data sets. Analysis of multiple independent ALS transcriptomic cohorts identified consistent upregulation of PCMT family members, with PCMTD1 exhibiting the most reproducible disease-associated expression changes across nervous system tissues and peripheral blood. Gene set correlation analyses further revealed distinct relationships between PCMT expression and neuronal pathways, with PCMT1 showing positive associations with axonal transport and synaptic signaling, whereas PCMTD1 and PCMTD2 displayed largely inverse correlation patterns. Rare missense variants identified in ALS patients were predicted to impair protein function and decrease protein stability, while structural modeling suggested that several substitutions may disrupt conserved residues and the local protein architecture. Collectively, these findings identify the PCMT family as previously underexplored candidates associated with ALS and provide a comprehensive framework for future mechanistic studies investigating their roles in neuronal protein homeostasis and neurodegeneration.},
}

*Amyotrophic Lateral Sclerosis/genetics/metabolism
Humans
Computational Biology/methods
*Protein D-Aspartate-L-Isoaspartate Methyltransferase/genetics/metabolism
*Isoaspartic Acid/metabolism
Animals

@article {pmid42980369,
year = {2026},
author = {Kumar, N and Paruchuri, N and Punshon, T and Jackson, B and Cornell, K and Stommel, E and Deosthali, H and Ravikumar, V and Mostafa, E and Palisoul, S and Vaickus, L and Ho, S and Levy, J},
title = {Integrative spatial metallomics: a tutorial review of multimodal elemental imaging workflows, challenges and opportunities.},
journal = {Analytical methods : advancing methods and applications},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6ay01718e},
pmid = {42980369},
issn = {1759-9679},
abstract = {Spatially resolved molecular assays are increasingly used to study human health and disease, revealing complex tissue organization beyond what is accessible through bulk analyses. While spatial transcriptomic, metabolomic, and proteomic approaches have rapidly matured, quantitative mapping of metals and trace elements in biological tissues and biominerals through elemental imaging remains comparatively nascent. Elemental distributions alone often provide limited biological interpretation without contextualization within the tissue microenvironment. Here, we summarize themes and computational strategies for integrating spatial elemental data with histopathology and complementary spatial molecular assays. We highlight multimodal approaches for tissue alignment, pixel-wise clustering, and correlative analysis, illustrated through limited use cases involving amyotrophic lateral sclerosis (ALS) and kidney stone formation. In the ALS cohort, pixel-level elemental profiles were clustered and compared with annotated tissue structures. In the kidney stone cohort, spatial gradients and correlations in elemental and biomolecular features from the renal papilla through the medulla to cortex were examined. Finally, we discuss key challenges for cross-sample, cohort-level analyses, including differences in spatial resolution, normalization, tissue architecture, and mechanistic inference. Addressing these challenges will require interdisciplinary collaboration, enhanced biobanking practices, and development of computational and statistical frameworks.},
}

@article {pmid42980747,
year = {2026},
author = {He, BH and Yang, W and Yang, M and Lv, X and Zhao, JJ},
title = {Advances in plant polysaccharide research for neurodegenerative diseases therapy.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42980747},
issn = {1573-4978},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Polysaccharides/therapeutic use/pharmacology/chemistry ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Oxidative Stress/drug effects ; *Plants/chemistry ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), represent a growing global public health burden with limited therapeutic options. Plant polysaccharides are natural, biocompatible, and multi-target bioactive macromolecules that have emerged as promising candidates for ND intervention. This review systematically summarizes recent progress in elucidating the structural characteristics, structure-activity relationships, and neuroprotective mechanisms of plant polysaccharides. Key structural features such as molecular weight, monosaccharide composition, glycosidic bond configuration, and spatial conformation critically modulate the biological activity of these molecules. Furthermore, we summarize the numerous protective effects of plant polysaccharides against NDs, including inhibiting abnormal protein aggregation, alleviating oxidative stress via the Nrf2/HO-1 pathway, suppressing neuroinflammation through the NF-κB and MAPK signaling pathways, regulating neuronal apoptosis, and modulating the gut-brain axis. Clinical translation challenges, primarily blood-brain barrier penetration, structural heterogeneity, and insufficient clinical validation, are discussed. Future directions include developing advanced delivery systems, conducting large-scale randomized controlled trials, and exploring synergistic combination therapies. Collectively, plant polysaccharides show considerable promise as potential multi-target candidates for the intervention of NDs, although further studies are needed to clarify their therapeutic potential and facilitate clinical translation.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism
*Polysaccharides/therapeutic use/pharmacology/chemistry
Animals
*Neuroprotective Agents/pharmacology/therapeutic use/chemistry
Oxidative Stress/drug effects
*Plants/chemistry

@article {pmid42981879,
year = {2026},
author = {Sanchez-Santos, C and Madruga, E and Recio, J and Diaz-Palacios, K and Aledavood, E and Lietha, D and Gil, C and Martinez, A},
title = {Targeting the DFG-out conformation of TTBK1 enables the discovery of selective type II neuroprotective inhibitors.},
journal = {European journal of medicinal chemistry},
volume = {321},
number = {Pt 3},
pages = {119468},
doi = {10.1016/j.ejmech.2026.119468},
pmid = {42981879},
issn = {1768-3254},
abstract = {Tau Tubulin Kinase 1 (TTBK1) is an emerging therapeutic target for neurodegenerative diseases because it promotes the pathological phosphorylation of tau and TDP-43, key drivers of Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). However, the development of selective TTBK1 inhibitors is hindered by the high structural similarity between TTBK1 and the essential paralog TTBK2, making ATP-competitive strategies challenging. Here, we report the discovery of computationally supported type II TTBK1 inhibitors by targeting the inactive DFG-out kinase conformation. A druggable DFG-out model was generated using metadynamics and molecular dynamic simulations and employed for virtual screening of the MBC chemical library. This approach identified novel chemotypes that were validated as selective TTBK1 inhibitors with improved discrimination over TTBK2. The most promising compounds also displayed neuroprotective activity in SH-SY5Y neuroblastoma cells. These findings demonstrate that targeting the inactive TTBK1 conformation is a viable strategy to achieve isoform selectivity and establish a new framework for developing disease-modifying therapies for ALS, AD, and other TTBK1-driven neurodegenerative disorders.},
}

@article {pmid42933032,
year = {2026},
author = {Arabinour, M and Sultani, N and Zhou, X and Tayebi, L},
title = {From prediction to design rules: explainable machine learning analysis of cryoprotectant effects in GelMA-based cryobioprinting bioinks.},
journal = {Biomedical physics & engineering express},
volume = {12},
number = {6},
pages = {},
doi = {10.1088/2057-1976/aeb94c},
pmid = {42933032},
issn = {2057-1976},
mesh = {*Cryoprotective Agents/pharmacology/chemistry ; *Machine Learning ; *Cryopreservation/methods ; Random Forest ; },
abstract = {Machine learning has been used to predict cryoprotective-agent (CPA) effects in cryobioprinting, but prediction accuracy alone does not yield experimentally usable formulation rules. Here, we performed a secondary explainable analysis of Qiaoet al's GelMA-HUVEC dataset using formulation-grouped validation, SHAP interpretation, stability metrics, and multi-objective ranking. A compact Random Forest model using permeable CPA identity, sugar CPA identity, permeable CPA concentration, sugar concentration, and storage day achieved MAE = 4.842%, RMSE = 6.106%, andR[2]= 0.649, with bootstrap 95% confidence intervals of 4.418-5.274% for MAE and 0.585-0.710 forR[2]. SHAP analysis identified permeable CPA concentration and storage day as the strongest viability drivers, with directional patterns favoring balanced 15% permeable CPA and 15% sugar CPA rather than simple concentration maximization. Multi-objective ranking identified GL_15_RA_15 as the strongest individual formulation, whereas EG + trehalose showed the highest average CPA-family performance. Cross-domain tests showed limited transfer between EG and GL formulations, indicating that the extracted rules should be treated as local, data-supported design hypotheses rather than universal cryoprotectant principles. Together, these results show that explainable secondary analysis can convert small cryobioprinting datasets into experimentally testable CPA hypotheses while explicitly defining their transferability limits.},
}

*Cryoprotective Agents/pharmacology/chemistry
*Machine Learning
*Cryopreservation/methods
Random Forest

@article {pmid42974963,
year = {2026},
author = {Libonati, L and Cambieri, C and Ceccanti, M and Moret, F and Petrucci, A and Carbone, A and Suppa, A and Inghilleri, M},
title = {Urinary Dysfunction in ALS Patients: Assessment With the Overactive Bladder Awareness Tool.},
journal = {Neurourology and urodynamics},
volume = {},
number = {},
pages = {},
doi = {10.1002/nau.70527},
pmid = {42974963},
issn = {1520-6777},
abstract = {AIMS: To compare urinary symptom bother and overactive bladder screening positivity between patients with amyotrophic lateral sclerosis (ALS) and controls using the Overactive Bladder Awareness Tool (OAB-V8).

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

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

CONCLUSIONS: ALS patients reported modestly greater urinary symptom burden than controls after adjustment for age and sex. These findings support clinical attention to urinary symptoms in ALS but do not establish their underlying urodynamic mechanism.},
}

@article {pmid42975030,
year = {2026},
author = {Ayoubi, R and MacDougall, EJ and McDowell, I and Biddle, MS and Ferreira, BT and Zha, C and Dorion, MF and Ross, JP and Bolivar, SG and Ruiz Moleon, V and Alende, C and Francis, V and Fotouhi, M and Chaineau, M and Chen, CX and Piscopo, VEC and Soubannier, V and Shlaifer, I and You, Z and Nicouleau, M and Keates, T and Lee, WH and Marsden, BD and Koukouflis, L and Wigren, E and Marks, CA and Healy, LM and Dion, PA and Rouleau, GA and Fon, EA and Virk, HS and Gräslund, S and Gileadi, O and Edwards, AM and Durcan, TM and McPherson, PS and Laflamme, C},
title = {A validated antibody toolbox for ALS research.},
journal = {eLife},
volume = {15},
number = {},
pages = {},
pmid = {42975030},
issn = {2050-084X},
support = {ALS-RAP//Motor Neurone Disease Association, Amyotrophic Lateral Sclerosis Association and ALS Society of Canada/ ; OGI-210//Genome Canada, Genome Quebec and Genome Ontario/ ; YCharOS: A platform enabling neuroscience target validation//Québec Consortium for Drug Discovery/ ; NC/NAM0019/1//National Centre for the Replacement Refinement and Reduction of Animals in Research/ ; MRC UKRI076/MRC_/Medical Research Council/United Kingdom ; OGI-196//Genome Canada and Ontario Genomics/ ; grant no. 875510//EUbOPEN/ ; PJT-195804/CAPMC/CIHR/Canada ; Tier 1//Canada Research Chairs/ ; ALS Scholars//Sean M. Healey & AMG Center for ALS/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/immunology/genetics/metabolism ; Humans ; *Antibodies/immunology ; *C9orf72 Protein/immunology/genetics ; Induced Pluripotent Stem Cells/metabolism ; },
abstract = {A substantial fraction of amyotrophic lateral sclerosis (ALS)-associated proteins remains poorly characterized, in part because of the limited availability of validated research antibodies. We established knockout (KO)-based antibody characterization workflows and demonstrated that widely used antibodies against the major ALS-associated protein C9orf72 lacked specificity (Laflamme et al., 2019). We subsequently scaled this framework to systematically benchmark research antibodies, revealing that up to 61% fail to perform as recommended by manufacturers (Ayoubi et al., 2023b). Here, we extend this approach by establishing the ALS-Reproducible Antibody Platform (ALS-RAP), a comprehensive effort to generate a publicly available dataset of KO-validated antibodies targeting proteins encoded by ALS risk genes. In total, we characterized 303 antibodies against 33 ALS-associated proteins to identify high-quality reagents for use in western blot, immunoprecipitation, and immunofluorescence. Using these antibodies, we profiled protein levels across human induced pluripotent stem cell-derived and primary neurological cell types. These analyses revealed diverse cellular distributions and higher levels of several ALS-associated proteins in glial populations, consistent with emerging evidence for immune contributions to ALS. Together, ALS-RAP provides a validated antibody toolbox and protein expression resource to support the study of ALS-associated proteins.},
}

*Amyotrophic Lateral Sclerosis/immunology/genetics/metabolism
Humans
*Antibodies/immunology
*C9orf72 Protein/immunology/genetics
Induced Pluripotent Stem Cells/metabolism

@article {pmid42975041,
year = {2026},
author = {Kuiper, MM and Kruithof, WJ and Broekman-Peters, N and Visser-Meily, JMA and Beelen, A},
title = {Personalizing nutritional care in amyotrophic lateral sclerosis (ALS): a multi-perspective qualitative focus group study of experiences and challenges.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2026.2750614},
pmid = {42975041},
issn = {2167-9223},
abstract = {Background: Proactive, timely nutritional care is important for people living with amyotrophic lateral sclerosis (plwALS), as weight loss and malnutrition are associated with faster disease progression and shorter survival. However, previous studies have shown that there is considerable practice variation in nutritional care, and that care is not always delivered proactively. Objectives: To gain insight into how healthcare professionals (HCPs), plwALS and their primary caregiver experience nutritional care. Methods: A generic qualitative study was conducted using semi-structured focus group discussions. Five focus group discussions were organized: two with HCPs and three with plwALS and their primary caregivers. Data were transcribed verbatim and analyzed inductively using thematic analysis. Results: In total, 14 HCPs, 19 plwALS, and three primary caregivers participated. Analyses resulted in four major themes: (1) A gap between knowing and acting, (2) balancing providing and withholding care, (3) sufficiently informed to participate in shared decision-making? and (4) opportunities for improvement. Conclusion: Findings suggest that improving nutritional care in ALS requires clear and transparent communication to ensure that plwALS and caregivers are well-informed about the importance of nutrition and monitoring of nutritional status, and more involved in clinical decision-making. Clear explanations about the dietitian's role and nutritional care process may improve patient engagement and facilitate shared decision-making.},
}

@article {pmid42975618,
year = {2026},
author = {Xu, Z and Fan, T and Xu, R},
title = {Current findings, application, and diagnosis of magnetic resonance imaging in amyotrophic lateral sclerosis.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42975618},
issn = {2191-0200},
abstract = {Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disorder within the motor neuron disease (MND) spectrum, characterized by progressive degeneration of upper and lower motor neurons. The clinical phenotype ranges from pure motor syndromes to forms with cognitive and behavioral impairment, and the pathological burden extends beyond the motor system. Diagnosis remains primarily clinical, supported by electrophysiology and exclusion of mimics. Therefore, objective imaging biomarkers are urgently needed. Magnetic resonance imaging (MRI) is widely used as an auxiliary and differential diagnostic tool in ALS. T1- and T2-weighted imaging can assess cortical thickness, gray matter atrophy, and signal changes. Diffusion tensor imaging probes white matter microstructure. Magnetic resonance spectroscopy detects neurochemical alterations. Resting-state functional MRI assesses functional connectivity and network organization. Susceptibility-weighted imaging is sensitive to iron and calcium deposition. Ultra-high-field MRI provides higher resolution and improved metabolite quantification. This critical review summarizes current findings on MRI in ALS, but importantly organizes the evidence by the specific question being addressed: pathological/histological correlates, diagnostic or discriminatory performance, and clinical associations with phenotype, severity, progression, and prognosis. We also discuss major limitations, including methodological heterogeneity, limited standardization, small and clinically heterogeneous cohorts, frequent use of healthy rather than disease controls, and scarce multicenter validation. Although advanced MRI has revealed robust group-level alterations, none of these techniques has yet become established in routine clinical diagnosis of ALS. We, therefore, distinguish promising research findings from validated clinical biomarkers and outline priorities for future translation.},
}

@article {pmid42975660,
year = {2026},
author = {Yin, Y and Tu, Y and Wang, B and Chen, Y and Zhao, Y and Tang, J and Zhang, M and Zhang, J},
title = {Subtype and stage inference of tract-level diffusion abnormalities in amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42975660},
issn = {1432-1459},
support = {No.82471967//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/classification/pathology ; Female ; *Diffusion Tensor Imaging ; Male ; Middle Aged ; Retrospective Studies ; Anisotropy ; Aged ; *White Matter/diagnostic imaging/pathology ; Adult ; Severity of Illness Index ; },
abstract = {BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) shows substantial heterogeneity in clinical presentation and white matter involvement, but conventional diffusion tensor imaging analyses provide limited information on whether tract-level abnormalities follow distinct patient level patterns.

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

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

CONCLUSION: Tract-level diffusion SuStaIn identified anatomically interpretable patterns of white matter involvement in ALS and provided patient-level stage estimates associated with clinical disease burden.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/classification/pathology
Female
*Diffusion Tensor Imaging
Male
Middle Aged
Retrospective Studies
Anisotropy
Aged
*White Matter/diagnostic imaging/pathology
Adult
Severity of Illness Index

@article {pmid42976580,
year = {2026},
author = {Jiménez-Villegas, J and Carnicero-Senabre, D and Sicart, A and Van Den Bosch, L and Cuadrado, A and Rojo, AI},
title = {Lack of NRF2 expression alters the dynamics of stress granules promoting the aggregation of ALS disease-associated proteins.},
journal = {Redox biology},
volume = {98},
number = {},
pages = {104462},
doi = {10.1016/j.redox.2026.104462},
pmid = {42976580},
issn = {2213-2317},
abstract = {Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron death. Although ALS pathogenesis is multifactorial, increasing evidence highlights a close interplay between dysfunction of RNA metabolism and redox imbalance in disease progression. Redox perturbation converges with RNA dysregulation at the level of the dynamics of stress granules, transient ribonucleoprotein assemblies implicated in protein aggregation, in ALS. The redox-sensitive transcription factor NRF2 (Nuclear factor erythroid 2-related factor 2) plays a pivotal role in cellular homeostasis, yet its function and regulation remain poorly defined in ALS. In this study, we explore how NRF2 modulates stress granule dynamics under oxidative and non-oxidative stress conditions. Using live-cell imaging, we reveal that NRF2 deficiency enhances the formation of stress granules in response to oxidative and non-oxidative stressors, facilitates their persistence, and promotes increased stress granule recruitment of ALS-linked proteins such as TDP-43 and FUS. Likewise, we uncover a protective role of pharmacological NRF2 activation in limiting exacerbated stress granule responses in iPSC-derived motor neurons from C9orf72-ALS patients and show how NRF2 activation can impact TDP-43 aggregation and loss of function in SH-SY5Y cells. Together, these findings position NRF2 as a crucial integrator of redox signalling and RNA metabolism in ALS pathogenesis. Targeting NRF2 may offer novel therapeutic avenues to counteract the vicious cycle of oxidative stress, dysfunctional stress granule dynamics, and protein aggregation in motor neuron disease.},
}

@article {pmid42977228,
year = {2026},
author = {Mercadante, S and Travia, M and Scimone, P and Dabbene, M and Cascio, AL},
title = {Cancer versus Non-Cancer Patients Admitted to Hospice: a comparison study.},
journal = {Journal of pain and symptom management},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jpainsymman.2026.10.030},
pmid = {42977228},
issn = {1873-6513},
abstract = {CONTEXT: Malignant disease remains the leading reason for hospice admission, and direct, patient-level comparisons of cancer and non-cancer patients within the same residential hospice are scarce.

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

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

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

CONCLUSION: In this single-centre series, non-oncological patients, mostly affected by neurological diseases, were admitted older, more functionally compromised and with higher MDAS scores than oncological patients, despite comparable length of stay and mortality. Apparent differences in symptom burden are confounded by substantial, likely informative, missing data and should be interpreted with caution. Whether these differences reflect later referral or the age profile of the underlying diseases cannot be determined from these data.},
}

@article {pmid42967168,
year = {2026},
author = {Cao, S and Liu, T and Cheng, X and Tian, X and Wei, J},
title = {The "Invisible Killer" of Neurodegeneration: Mitochondrial Dysfunction in Neurodegenerative Disorders, Mechanisms, Emerging Pathways and Therapeutic Strategies.},
journal = {Journal of inflammation research},
volume = {19},
number = {},
pages = {653025},
pmid = {42967168},
issn = {1178-7031},
abstract = {Neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) place substantial burden on global public health. Mounting evidence identifies mitochondrial dysfunction as a central contributor to neuronal damage and progressive brain functional decline. As a narrative review, this work aims to dissect mitochondrial‑associated pathological features across these major neurodegenerative disorders, summarize under‑recognized emerging mechanisms, and highlight translational bottlenecks for mitochondrial‑targeted therapies. Mitochondria sustain neuronal survival by mediating oxidative‑phosphorylation‑driven energy production, biomolecule biosynthesis, calcium homeostasis, reactive oxygen species (ROS) metabolism, and apoptotic regulation. In PD, aggregated α‑synuclein (α‑syn) damages respiratory‑chain complex I, perturbs mitochondrial dynamics and blocks PINK1/Parkin‑dependent mitophagy. In AD, amyloid‑β together with hyper‑phosphorylated tau (p-Tau) impairs respiratory complex activity, axonal mitochondrial trafficking and mitophagic clearance. Mutant huntingtin induces multiple mitochondrial lesions in HD, while inflammation‑triggered oxidative stress secondarily compromises mitochondrial function in MS. Pathogenic mutations in ALS disrupt respiratory‑chain assembly, mitochondrial dynamics and mitophagy. Beyond classic mitochondrial defects including respiratory‑chain impairment, dynamic imbalance and defective mitophagy, emerging mechanisms such as mitocytosis, mitochondrial aminoacyl‑tRNA synthetase (mt‑aaRS) dysfunction and mitochondria‑associated membrane (MAM) disruption are discussed. Mitochondrial dysfunction drives neurodegeneration via energy exhaustion, aggravated oxidative stress, pathological protein aggregation and excessive neuronal apoptosis. We further recapitulate mitochondrial‑oriented therapeutic approaches including small‑molecule regulators, mitophagy activators, mitochondrial biogenesis promoters, gene‑editing strategies and mitochondrial transplantation. Notable translational obstacles remain, including limited blood‑brain‑barrier penetration of candidate drugs, narrow therapeutic time‑window post‑symptom onset, and prominent disease heterogeneity. By synthesizing basic experimental findings and pre‑clinical and clinical trial progress, this review provides updated insights into the pathogenesis of neurodegenerative diseases and facilitates the development of precise mitochondrial‑targeted therapeutic regimens.},
}

@article {pmid42969635,
year = {2026},
author = {Bannwarth, S and Paquis-Flucklinger, V},
title = {[Mitochondria in sporadic amyotrophic lateral sclerosis: actor or initiator?].},
journal = {Medecine sciences : M/S},
volume = {42},
number = {10},
pages = {797-799},
doi = {10.1051/medsci/2026146},
pmid = {42969635},
issn = {1958-5381},
}

@article {pmid42970317,
year = {2026},
author = {Pourhadi, M and LeWitt, PA and Todi, SV},
title = {Ceruloplasmin in Disorders of the Nervous System.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0988},
pmid = {42970317},
issn = {2152-5250},
abstract = {Ceruloplasmin (Cp) is a multicopper ferroxidase that links copper handling, iron export, and redox homeostasis. Within the nervous system, these functions are critical because disruption of iron and copper balance can amplify oxidative stress, neuroinflammation, and neuronal vulnerability. Although Cp has long been studied as a circulating biomarker, most reports characterize it only by protein concentration, leaving its enzymatic and structural status comparatively unexplored. Here, we synthesize human literature on Cp across major neurological disorders, with attention to studies that assess Cp's ferroxidase activity, oxidation, fragmentation, and copper-binding state alongside its circulating levels. The evidence is by far most extensive in Alzheimer's and Parkinson's diseases, which together account for the majority of the reviewed literature: reduced ferroxidase activity, increased Cp oxidation, and altered non-Cp-bound copper are repeatedly linked to disease severity, regional iron accumulation, and biomarker-defined patient subgroups; in several studies, these alterations were independent of total Cp concentration. A smaller but growing body of evidence in amyotrophic lateral sclerosis, multiple sclerosis, essential tremor, and the cerebellar ataxias points to a related pattern of Cp-linked iron mishandling contributing to neuronal vulnerability. Preliminary findings from a few small studies in schizophrenia and a single study in obsessive-compulsive disorder further suggest that circulating Cp levels track systemic inflammatory and oxidative states in these conditions. From these investigations, a picture emerges where Cp's functional and structural integrity, rather than its abundance alone, is the more informative correlate of disease-relevant metal dyshomeostasis, most clearly demonstrated in Alzheimer's and Parkinson's diseases. Based on this body of work, we propose that future studies adopt combined assessments of Cp quantity and function to clarify disease-specific Cp signatures and to evaluate whether correcting Cp activity or copper/iron imbalance can improve outcomes.},
}

@article {pmid42970788,
year = {2026},
author = {Poppe, A and Gruen, E and Butz, C and Meenen, B and Lampe, D and Schmidt, J and Greiner, W and Köberlein-Neu, J and Meyer, I and , },
title = {Using a Living Lab to Refine an Electronic Prescribing Workflow: Insights From the eRIKA Project.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e100362},
doi = {10.2196/100362},
pmid = {42970788},
issn = {2561-326X},
mesh = {*Workflow ; *Electronic Prescribing/standards ; Humans ; Germany ; Digital Health ; },
abstract = {BACKGROUND: The integration of eHealth solutions into routine health care remains challenging despite their potential to improve care quality and efficiency. Living labs (LLs) have emerged as an approach to addressing these challenges by enabling co-design and iterative testing of eHealth tools. LLs promote collaboration among patients, health care professionals, developers, and policy makers. However, systematic insights into their practical implementation remain limited.

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

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

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

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

RR2-10.2196/87277.},
}

*Workflow
*Electronic Prescribing/standards
Humans
Germany
Digital Health

@article {pmid42970872,
year = {2026},
author = {Wang, XC and Wen, YJ and Huang, YJ and Wu, HX and Zhang, XJ and Cui, JY and Yu, YJ and Fu, HY and She, Y},
title = {Roasting-time dependent aroma development in sesame oil: time-resolved VOCs evolution revealed by deconvolution-assisted HS-SPME-GC-MS.},
journal = {Food chemistry},
volume = {532},
number = {Pt 4},
pages = {151826},
doi = {10.1016/j.foodchem.2026.151826},
pmid = {42970872},
issn = {1873-7072},
abstract = {Roasting is essential for developing sesame oil's color, aroma, and texture. This study investigated the effects of roasting time on key volatile organic compounds (VOCs) and sensory profiles. An optimized HS-SPME-GC-MS coupled with DEMCR-ALS-based deconvolution (AntDAS-GCMS) was established to profile VOC dynamics during roasting at 150 °C for 0-40 min. Among 731 resolved differential features, 94 VOCs changed significantly across 30 samples. Volatile composition changed markedly during the first 20 min, when the characteristic roasted aroma emerged. However, odor activity values (OAVs) of key aroma-active compounds continued to change with prolonged roasting, particularly those associated with caramel-sweet and smoky notes. Hydrocarbon-associated signals progressively decreased, whereas nitrogen-containing heterocyclic compounds increased. Sensory and OAV-based analyses showed a shift from fresh, seed-like profile toward a thermally derived flavor system. Roasting for 20-30 min enhanced desirable aromas, whereas longer roasting increased smoky notes and reduced aroma balance.},
}

@article {pmid42972546,
year = {2026},
author = {Zhuang, SP and Cai, ZW and Huang, ZY and Lin, LY and Chen, S and Zou, ZY and Ding, H and Qin, W and Chen, HJ},
title = {Voxel-based texture similarity networks reveal abnormal brain network topology linked to molecular signatures in amyotrophic lateral sclerosis.},
journal = {BMC medicine},
volume = {24},
number = {1},
pages = {},
pmid = {42972546},
issn = {1741-7015},
support = {No. 82572160//National Natural Science Foundation of China/ ; Nos. 2023CXA009//Fujian Provincial Health Technology Project/ ; No.2024J01625//Fujian Provincial Natural Science Foundation of China/ ; Nos. 2024Y9253//Fujian Province Joint Funds for the Innovation of Science and Technology/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/genetics ; Female ; Male ; *Brain/diagnostic imaging/physiopathology/pathology ; Magnetic Resonance Imaging/methods ; Middle Aged ; *Nerve Net/diagnostic imaging/physiopathology ; Aged ; Adult ; Case-Control Studies ; },
abstract = {BACKGROUND: While amyotrophic lateral sclerosis (ALS) is characterized by disrupted brain network function, the abnormal patterns of structural similarity networks and their biological underpinnings remain poorly understood. This study employed voxel-based texture similarity network (vTSN) analysis to identify complex brain network disruptions in ALS, aiming to advance the pathophysiological understanding of the disease.

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

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

CONCLUSIONS: vTSN exhibits excellent performance for detecting network abnormality in ALS and reveals potential molecular signatures of the pathophysiology of disease. These findings underscore the potential of vTSN-derived network measure as a biologically meaningful biomarker for ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/genetics
Female
Male
*Brain/diagnostic imaging/physiopathology/pathology
Magnetic Resonance Imaging/methods
Middle Aged
*Nerve Net/diagnostic imaging/physiopathology
Aged
Adult
Case-Control Studies

@article {pmid42972606,
year = {2026},
author = {Bedarf, L and Neuhaus, D and Bauer, M and Berger, C and Wendebourg, MJ and Schlaeger, R and Birkl, C and Scheurer, E and Lenz, C},
title = {Evidence of White Matter R2* Homogenization After Formalin Fixation.},
journal = {Magnetic resonance in medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/mrm.70646},
pmid = {42972606},
issn = {1522-2594},
support = {//Stiftung zur Foerderung der gastroenterologischen und allgemeinen klinischen Forschung sowie der medizinischen Bildauswertung/ ; 219548//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; //Neuromuscular Research Association Basel/ ; },
abstract = {PURPOSE: Disentangling intrinsic susceptibility-driven R2* characteristics in white matter (WM) from fixation-related effects using in vivo, postmortem (PM) in situ, and formalin-fixed PM ex situ MRI.

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

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

CONCLUSION: While orientation-dependent R2* is reduced but preserved in unfixed PM in situ tissue, it is largely eliminated after prolonged formalin fixation without rehydration, likely due to microstructural reorganization and protein cross-linking. Collectively, these findings indicate that orientation-dependent R2* measured in fixed tissue has limited translational validity, while underscoring its sensitivity to intact microstructural organization in vivo and in unfixed PM tissue.},
}

@article {pmid42974031,
year = {2026},
author = {Wang, M and Yang, J and Gao, C and Qu, S and Mi, H and Guo, Y and Gui, T and Gai, Z},
title = {Utility of extracellular vesicles in the diagnosis of central nervous system diseases.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1959745},
pmid = {42974031},
issn = {1664-2295},
mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Central Nervous System Diseases/diagnosis/metabolism ; Biomarkers/metabolism/cerebrospinal fluid ; Animals ; Parkinson Disease/diagnosis ; Alzheimer Disease/diagnosis/metabolism ; },
abstract = {Central nervous system (CNS) disorders encompass a diverse spectrum of conditions characterized by intricate pathological mechanisms, and the presence of the blood-brain barrier (BBB) has long impeded early diagnosis. Extracellular vesicles (EVs) are lipid bilayer nanoparticles released by living cells that can encapsulate and transport bioactive molecules such as proteins and nucleic acids across the BBB. EVs can be detected in biofluids such as blood and cerebrospinal fluid (CSF) through non-invasive or minimally invasive assays, and have emerged as highly promising vehicles for CNS liquid biopsies. Recent studies demonstrate that specific EV-associated protein cargoes (e.g., phosphorylated tau, α-syn) and non-coding RNAs (e.g., miR-422a, miR-409-3p) exhibit distinct differential expression profiles across various pathologies. These molecular signatures hold promise for early detection, differential diagnosis, and disease staging, with some biomarker panels showing high diagnostic accuracy. However, whether they outperform conventional CSF biomarkers still requires direct comparison and validation within the same cohorts. This review highlights recent research advances in the use of EVs for the diagnosis of Alzheimer's disease and Parkinson's disease, briefly touches upon other CNS disorders including stroke, glioma, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis, and discusses the clinical translational potential and remaining challenges of EV-based diagnostics.},
}

Humans
*Extracellular Vesicles/metabolism
*Central Nervous System Diseases/diagnosis/metabolism
Biomarkers/metabolism/cerebrospinal fluid
Animals
Parkinson Disease/diagnosis
Alzheimer Disease/diagnosis/metabolism

@article {pmid42974758,
year = {2026},
author = {Xue, L and Ma, J and Wan, G and Long, B and Mao, Y and Wang, F and Bai, S},
title = {A Wavelet-ALS-Assisted CNN-BiGRU Method for Peak Recognition in CCD-Based Capillary Electrophoresis Fluorescence Detection.},
journal = {Electrophoresis},
volume = {},
number = {},
pages = {},
doi = {10.1002/elps.70177},
pmid = {42974758},
issn = {1522-2683},
support = {62163006//National Natural Science Foundation of China/ ; 61605153//National Natural Science Foundation of China/ ; },
abstract = {Capillary electrophoresis (CE) is an efficient, rapid, and sensitive separation and analysis technique that has been widely applied in biochemistry, pharmaceutical research, and environmental monitoring. However, charge-coupled device (CCD)-based CE fluorescence signals are susceptible to baseline drift, random noise, and channel crosstalk, which reduce the accuracy of peak recognition. To meet the demand for high-precision signal analysis, this study proposes a convolutional neural network (CNN)-bidirectional gated recurrent unit (BiGRU) peak recognition algorithm on the basis of wavelet transform and one-dimensional asymmetric least squares (ALS). In the proposed system, an FPGA-based platform is used for real-time signal acquisition and data transmission, whereas the host computer performs subsequent processing of the received spectral data. Experimental results show that the proposed method achieves high-accuracy peak recognition on the spectral dataset, with Precision, Recall, and F1-score reaching 98.44%, 99.93%, and 99.18%, respectively. These results demonstrate its good robustness and practical applicability, providing technical support for the miniaturization and intelligent development of portable gene sequencers.},
}

@article {pmid42974926,
year = {2026},
author = {Gangfuß, A and Gowda, VK and Natera-de Benito, D and Munot, P and Vanegas, M and Darling, A and Reutlinger, C and Carrera-Garcia, L and Wunderlich, G and Kölbel, H and Stüve, B and Muhmann, D and Monfort Belenguer, L and Barca, DG and Reddy C, VS and Srinivasan, VM and Anguita, CM and Jungbluth, H and Dafsari, HS and Rossor, T and Böhm, J and Schara-Schmidt, U and Roos, A},
title = {Clinical Variability and Genotype Driven Outcomes in an International Cohort of 14 Pediatric FIG4 Patients.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
pmid = {42974926},
issn = {2328-9503},
support = {//Mediment/ ; //Josepha und Charlotte von Siebold Habilitandinnen-Förderprogramm/ ; //German Society of Muscular Diseases (DGM)/ ; CP22/00141//Miguel Servet program from Instituto de Salud Carlos III, Spain/ ; B2B-RARE//European Regional Development Fund (ERDF)/ ; },
abstract = {BACKGROUND: Biallelic FIG4 variants classically cause distinct conditions characterized by peripheral neuropathy (Charcot-Marie-Tooth disease type 4J) or skeletal dysplasia (Yunis-Varón syndrome). However, central nervous system involvement is increasingly recognized. The prevalence and specific characteristics of movement disorders within FIG4-related disease remain poorly characterized, prompting a need to redefine its clinical continuum.

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

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

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

CONCLUSION: Loss of functional FIG4 causes a broader and more severe disease spectrum with central nervous system involvement, including intellectual disability and movement abnormalities such as dystonia and bradykinesia. Recognizing these features should prompt clinicians to consider FIG4-associated disorders, allowing for optimized patient care and tailored therapeutic strategies.},
}

@article {pmid42963097,
year = {2026},
author = {Hald, K and Fagerström, M and Thomsen, JL and Johnsen, SP and Nilsen, P},
title = {Implementation of artificial intelligence in healthcare: a protocol for a phased mixed-methods multiple case study in the North Denmark Region.},
journal = {BMJ open},
volume = {16},
number = {10},
pages = {e124097},
pmid = {42963097},
issn = {2044-6055},
abstract = {BACKGROUND: Artificial intelligence (AI) is increasingly being implemented across healthcare systems with the potential to improve diagnostic accuracy, support clinical decision-making and enhance healthcare delivery. Despite growing investments in AI, evidence on how AI innovations are successfully implemented, adopted and sustained in routine clinical practice remains limited. Existing research has predominantly focused on technical performance and clinical effectiveness, while implementation-related factors have received less attention. This study aims to evaluate the implementation of AI innovations across multiple healthcare settings over time.

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

ETHICS AND DISSEMINATION: According to Danish legislation, this study does not require approval from a regional research ethics committee. The study has been assessed by the Aalborg University Research Ethics Committee and registered as a research project involving the processing of personal data at Aalborg University. All participants will provide informed consent prior to participation. Findings will be disseminated through peer-reviewed publications, conference presentations and reports targeting relevant stakeholders.},
}

@article {pmid42963841,
year = {2026},
author = {Xu, J and Guo, B and Li, B and Qi, Z and Liu, X and Wang, G and Chen, S and Xu, X},
title = {Ala-205-met mutation in acetolactate synthase (ALS) of Bromus japonicus confers resistance to ALS-inhibiting herbicides.},
journal = {Pest management science},
volume = {},
number = {},
pages = {},
doi = {10.1002/ps.71450},
pmid = {42963841},
issn = {1526-4998},
support = {2024060203//Basic Research Funds of Hebei Academy of Agriculture and Forestry Sciences/ ; 2023LYS03//HAAFS Youth Innovation Fund Project/ ; },
abstract = {BACKGROUND: Acetolactate synthase (ALS)-inhibitor-resistant Bromus japonicus populations are widespread in wheat fields in China. A novel population BD-R has evolved resistance to flucarbazone-sodium, whereas its underlying resistance mechanism remains unclear. The objectives of this study were to (i) determine the resistance and cross-resistance levels to ALS inhibitors; (ii) investigate the resistance mechanisms; (iii) evaluate response to herbicides with other modes of action; and (iv) develop a CAPS molecular marker for rapid resistance detection.

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

CONCLUSION: BD-R conferred high-level resistance and cross-resistance levels to ALS-inhibitors. Haloxyfop-P-methyl and quizalofop-P-ethyl can be used for effective control BD-R. This study is the first report of the Ala-205-Met mutation conferring resistance to ALS inhibitors in weeds, indicating the complexity of the evolution of herbicide resistance in weeds. © 2026 Society of Chemical Industry.},
}

@article {pmid42964735,
year = {2026},
author = {Ghiasvand, K and Meftahi, GH},
title = {Black Myrobalan (Terminalia chebula) as a potential multitarget neuroprotective agent: Translational insights and future directions in neurodegenerative diseases.},
journal = {Biochemistry and biophysics reports},
volume = {48},
number = {},
pages = {102850},
pmid = {42964735},
issn = {2405-5808},
abstract = {Myrobalan or Haritaki (Terminalia chebula Retz.) has been integrated into Ayurvedic, Unani, and even Tibetan medicine systems for over 2000 years. The "King of Medicines" has traditionally been used for diverse ailments such as digestive issues, wound healing, and general body strengthening. Now, modern medicine is focusing on the myrobalan's potential neuroprotective properties and its use in Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis (ALS) neurodegenerative disorders. These ailments are characterized by some combination of enduring oxidative damage, mitochondrial dysfunction, neuroinflammation, irregular protein aggregation, and progressive neuron cell death. Most of the current treatment options revolve around addressing the symptoms of the diseases, which is insufficient as the underlying disease continues to progress. There is an urgent need to devise therapies that work simultaneously on multiple disease pathways. Some of the noted secondary metabolites in T. chebula include hydrolyzable tannins like chebulinic and chebulagic acid as well as corilagin. Others occur as phenolic acids such as gallic and ellagic acid and flavonoids quercetin and kaempferol. Moreover, glycosides, sterols, and a wide range of alkaloids are also present. A number of these compounds are known to possess multifunctional biological properties like scavenging ROS, activating Nrf2/ARE signaling, downregulating pro-inflammatory mediators through blockade of NF-κB, and exerting protective effects on the mitochondria, as well as modulating apoptosis via Bcl-2 and caspases. T. chebula extracts and some isolated compounds have also been shown to improve cognitive function, reduce neuroinflammation, and protect dopaminergic neurons, and ameliorate neurotoxic effects of amyloid-β or α-synuclein through in vitro and in vivo animal studies. A review of the contributions from the phytochemistry, mechanism of action, preclinical, translational, and adjunctive applications of Terminalia chebula in neurodegenerative disease therapy is presented here.},
}

@article {pmid42966163,
year = {2026},
author = {Gao, C and Shi, R and Jiang, X and Chai, H and He, X},
title = {Immunometabolic dysregulation of reactive microglia and astrocytes in neurodegenerative diseases: Mechanistic insights and therapeutic implications.},
journal = {Journal of the neurological sciences},
volume = {491},
number = {},
pages = {126237},
doi = {10.1016/j.jns.2026.126237},
pmid = {42966163},
issn = {1878-5883},
abstract = {Neurodegenerative diseases (NDDs) are increasingly understood as multifactorial disorders characterized by intertwined pathological processes, in which metabolic dysfunction may act as a critical and potentially disease-amplifying contributor to the proteinopathy-driven pathological cascade. Despite growing recognition that microglial and astrocytic metabolism governs central nervous system tissue damage-repair homeostasis, intercellular metabolic crosstalk between glia and neurons remains insufficiently synthesized across major NDDs. This review delineates how core metabolic pathways, including glycolysis, mitochondrial respiration, lipid processing, and amino acid transport, shape glial reactivity in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We highlight glial metabolic reprogramming, a proposed theoretical framework arising from severe glial metabolic dysregulation. Within this framework, persistent pathological stress may drive reactive glia to sequester local energy substrates in excess, which is hypothesized to trigger bioenergetic failure in neighboring neurons. Broad-spectrum anti-inflammatory agents show poor clinical performance because they only block cytokine outputs rather than reverse glial metabolic exhaustion. Therapeutic efforts should therefore shift toward restoring glial metabolic flexibility. Cell-type-specific metabolic reprogramming, instead of pan-metabolic suppression, may circumvent systemic adverse effects. Precision strategies targeting such intercellular metabolic imbalance could provide promising cell-resolved metabolic avenues to retard NDD progression.},
}

@article {pmid42966271,
year = {2026},
author = {D'Antoni, L and Viccaro, F and D'Andria, M and Sanna, A and Cardini, ME and Tomsa, C and Flore, R and Di Meo, F and Fabozzi, A and Baccolini, V and Siena, L and Palange, P and Ceccanti, M},
title = {The impact of diagnostic criteria on the detection of nocturnal hypoventilation in adult amyotrophic lateral sclerosis patients.},
journal = {Sleep medicine},
volume = {149},
number = {},
pages = {109344},
doi = {10.1016/j.sleep.2026.109344},
pmid = {42966271},
issn = {1878-5506},
abstract = {BACKGROUND: Nocturnal hypoventilation (NH) is an early manifestation of respiratory muscle weakness in amyotrophic lateral sclerosis (ALS) and plays a key role in determining the optimal timing for non-invasive ventilation (NIV). However, several diagnostic definitions of NH have been proposed, and their impact on NH prevalence remains unclear.

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

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

CONCLUSIONS: Currently used definitions of NH in ALS show substantial heterogeneity and identify different patient subsets. These findings highlight the need for ALS-specific consensus definitions of NH.},
}

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

CONCLUSIONS: These findings reveal substantial stated willingness among Japanese patients with ALS and their caregivers to contribute to research despite low baseline awareness of PPI. This gap between limited awareness and high stated willingness suggests that targeted educational efforts could meaningfully expand patient engagement in ALS research. Systematic awareness-building initiatives, structured and accessible engagement opportunities, and sustained collaborative relationships between researchers and the patient community are essential for strengthening patient advocacy and accelerating drug development for ALS in Japan.},
}

@article {pmid42957098,
year = {2026},
author = {Kuo, YC and Ting, CH and Lai, HJ and Huang, PY and Shih, YA and Yang, CC and Cheng, LF and Tai, ST and Chao, CC and Chang, HY and Wang, IF and Tsai, LK},
title = {Characterization of plasma misfolded superoxide dismutase 1 in amyotrophic lateral sclerosis.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107669},
doi = {10.1016/j.nbd.2026.107669},
pmid = {42957098},
issn = {1095-953X},
abstract = {OBJECTIVE: To characterize the dynamics of plasma misfolded superoxide dismutase 1 (mSOD1) and evaluate its utility as a state-dependent biomarker for patient stratification and therapeutic monitoring in amyotrophic lateral sclerosis (ALS).

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

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

INTERPRETATION: Approximately 22% of nongenetic ALS patients exhibit elevated plasma mSOD1, primarily during the moderate disease stage. Plasma mSOD1 is a candidate state-dependent biomarker for biological stratification and may have potential for treatment monitoring.},
}

@article {pmid42958460,
year = {2026},
author = {Keskin, I and Sigfridsson, I and Skagerberg Ekhtiari, E and Marklund, M and Mattson, S and Brännström, T and Marklund, SL and Nordström, U and Andersen, PM},
title = {Strain-specific morphology and CNS propagation of template-directed SOD1 aggregation following peripheral nerve inoculation.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42958460},
issn = {2051-5960},
support = {VR-MH 2012-3167; 2015-02804; 2017-03100; 2019-01707//Swedish Research Council/ ; 2012.0091; 2014.0305; 2020.0232//Knut and Alice Wallenberg Foundation/ ; 2015-0234; 2016-0303; 2018-0310; 2019-0320; 2020-0353//Hjärnfonden, Sweden/ ; },
mesh = {Animals ; Mice, Transgenic ; *Superoxide Dismutase-1/metabolism/genetics ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Disease Models, Animal ; *Spinal Cord/pathology/metabolism ; *Sciatic Nerve/pathology/metabolism ; Mice ; Species Specificity ; Female ; Humans ; Mice, Inbred C57BL ; Male ; *Protein Aggregation, Pathological/pathology/genetics/metabolism ; },
abstract = {Accumulation of misfolded SOD1 protein into intracellular aggregates, in the spinal cord (SpC) and brainstem, is a hallmark of amyotrophic lateral sclerosis caused by mutations in the SOD1 gene (SOD1-ALS). Two distinct aggregate conformations, denoted strain A and strain B, were identified in the CNS of SOD1[G85R] and SOD1[D90A] transgenic (Tg) ALS mouse models, respectively. Both strains transmit templated SOD1 aggregation and ALS-like disease in Tg mouse models when inoculated into the SpC, whereas muscle or intraperitoneal inoculations, of up to 300 times more inoculate, did not. Here, we used strain A and strain B aggregate seeds, prepared from SpCs of the Tg mice, to investigate strain-specific differences in transmission of templated aggregation and ALS phenotype via a peripheral nerve. We show that both strains can transmit templated aggregation to the CNS via the sciatic nerve in SOD1[G85R] Tg mice. Strain A resulted in shorter time to disease onset and earlier end-stage disease compared to strain B, and these strain-specific differences were accentuated in the sciatic nerve inoculation model compared to direct SpC inoculations. To further analyse the differences between strain A and strain B, we developed an immunohistochemical method that distinguishes the two SOD1 aggregate strains in tissue sections. This method revealed that strain B adopts an elongated, skein-like morphology, whereas strain A aggregates appear as accumulations of rounded, bead-like structures. These findings suggest that SOD1 aggregates forming in a peripheral nerve might transmit disease to the CNS and that different SOD1 aggregate strains can influence disease onset and progression. Our results warrant further exploratory studies of SOD1 aggregate conformations and their potential role in the manifestation of SOD1 mutant-specific disease phenotypes.},
}

Animals
Mice, Transgenic
*Superoxide Dismutase-1/metabolism/genetics
*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism
Disease Models, Animal
*Spinal Cord/pathology/metabolism
*Sciatic Nerve/pathology/metabolism
Mice
Species Specificity
Female
Humans
Mice, Inbred C57BL
Male
*Protein Aggregation, Pathological/pathology/genetics/metabolism

@article {pmid42959461,
year = {2026},
author = {Dorça, AC and Rocha, EMSS and Marra, MB and Morais, LA and Andersen, TM},
title = {Beyond the Larynx: New Insights Into Upper Airway Responses to Mechanical Insufflation-Exsufflation.},
journal = {Respirology case reports},
volume = {14},
number = {11},
pages = {e70792},
pmid = {42959461},
issn = {2051-3380},
abstract = {This case report describes a 44-year-old man with amyotrophic lateral sclerosis (ALS) and ineffective secretion clearance despite home use of mechanical insufflation-exsufflation (MI-E). He reported upper airway obstruction, respiratory discomfort and recurrent aerophagia during therapy. Dynamic assessments using transnasal flexible laryngoscopy and videofluoroscopy under different MI-E settings showed that upper airway responses were strongly influenced by inspiratory flow, pressure levels, expiratory time and cervical positioning. Higher inspiratory flow and pressure induced supraglottic closure and airflow diversion to the oesophagus. In contrast, lower inspiratory flow combined with reduced expiratory pressure and shorter expiratory time improved glottic opening, maintained airway patency and enhanced cough mechanics. Spontaneously adopted cervical extension optimized airflow and minimized oesophageal insufflation, whereas neutral alignment impaired cough efficiency. These findings emphasize the importance of individualized MI-E settings and patient-specific biomechanics in optimizing therapy in ALS.},
}

@article {pmid42959522,
year = {2026},
author = {Matta, C and Cheon, YH and Vágó, J and Mészár, Z and Kim, EH and Jiang, S and Balogh, A and Zana, M and Dinnyés, A and Jin, EJ},
title = {Engineered peroxisomes and patient-derived iPSC models as potential biomaterial platforms for precision neuroprotection in oxidative stress-driven central nervous system disorders.},
journal = {Materials today. Bio},
volume = {41},
number = {},
pages = {103752},
pmid = {42959522},
issn = {2590-0064},
abstract = {Peroxisomes couple hydrogen peroxide metabolism to lipid homeostasis, making their functions relevant to neurological disease and to the design of intracellular catalytic biomaterials. However, the strength of disease-specific evidence and the functions reproduced by current materials vary substantially. This narrative review distinguishes modified biological peroxisomes from artificial and biomimetic platforms and evaluates how patient-derived induced pluripotent stem cell (iPSC) models could support their development. We examine membrane chemistry, substrate permeability, enzyme retention, catalytic activity, cell targeting, blood-brain barrier transport, three-dimensional tissue penetration, and intracellular fate. We separate the established causal role of peroxisomal defects in primary peroxisomal disorders from associative or unresolved findings in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Kleefstra syndrome is discussed as a hypothesis-generating neurodevelopmental model, without assuming a primary peroxisomal defect. Published artificial-organelle studies establish selected catalytic and delivery capabilities, but do not validate the integrated patient-specific CNS therapeutic strategy proposed here. We therefore outline a staged evaluation framework that combines materials characterization with mechanistic controls, differentiated neural cultures, multicellular models, animal pharmacology, safety, and manufacturing assessment. Comparison with conventional antioxidant carriers, plasmalogen supplementation, and PPAR agonists should determine whether compartmentalized catalysis offers a measurable advantage. We provide a platform classification, a disease-resolved evidence hierarchy, and a set of controls and measurable endpoints intended to make peroxisome-inspired constructs comparable across studies. Clinical development will require evidence of disease-relevant benefit beyond ROS reduction and an acceptable therapeutic window.},
}

@article {pmid42960175,
year = {2026},
author = {},
title = {Corrigendum to From Vision to Validation: The Journey of Tofersen in Superoxide Dismutase 1Gene-Associated Amyotrophic Lateral Sclerosis [Mayo Clinic Proceeding: Innovations, Quality & Outcomes 10(5) (2026) PIQO_100755].},
journal = {Mayo Clinic proceedings. Innovations, quality & outcomes},
volume = {10},
number = {6},
pages = {100775},
doi = {10.1016/j.mayocpiqo.2026.100775},
pmid = {42960175},
issn = {2542-4548},
abstract = {[This corrects the article DOI: 10.1016/j.mayocpiqo.2026.100755.].},
}

@article {pmid42955216,
year = {2026},
author = {Oria, RS and Esomonu, UG and Sunday, KI and Oge, PA},
title = {Microglial perturbation in heavy metal-induced neuroinflammation and neurodegeneration: mechanisms, phenotypic plasticity, and therapeutic prospects.},
journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine},
volume = {},
number = {},
pages = {},
pmid = {42955216},
issn = {1572-8773},
abstract = {Heavy metal exposure has emerged as a significant environmental contributor to neurodegenerative disease, and a substantial body of mechanistic evidence implicates microglia in the pathological cascades that follow. Lead, cadmium, arsenic, manganese, copper, cobalt, mercury, and zinc disrupt central nervous system homeostasis through multiple cellular targets, but the resident innate immune cells of the brain are well placed to translate these insults into sustained neuroinflammation. Evidence for this critical narrative review was assembled through a purposive search of PubMed, MEDLINE, and Google Scholar for mechanistically informative studies reporting glial endpoints, with reference lists searched by hand and no systematic protocol applied. This review synthesizes current understanding of how individual metals engage microglial signaling networks, with particular attention to oxidative stress, NF-κB activation, NLRP3 inflammasome assembly, MAPK cascades, and suppression of the Nrf2 antioxidant axis. We examine the phenotypic spectrum that extends well beyond the classical M1/M2 dichotomy, including disease-associated microglia, lipid-droplet-accumulating microglia, and interferon-responsive states, and consider how metal-specific signatures map onto these transcriptional programs. Manganese-driven inflammasome assembly, cadmium-induced mitochondrial impairment, lead-mediated disruption of calcium homeostasis, and mercury-evoked autophagic dysfunction are discussed as illustrative examples of mechanistic divergence within a common neuroinflammatory framework. Glial responses to metal mixtures, which better represent real exposure than single-element designs, are considered separately, and the evidence for greater-than-additive effects is appraised. Downstream consequences for astrocyte reactivity, blood-brain barrier integrity, synaptic remodeling, and neuronal viability are placed in the context of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Therapeutic avenues are appraised, including chelation, natural antioxidants, NLRP3 inhibitors, TREM2 modulation, and microglial replacement strategies. Methodological constraints, particularly the overreliance on BV-2 cells and acute high-dose exposure paradigms, are critically considered. The review concludes by identifying priorities for translational research, including longitudinal human cohort studies, single-cell transcriptomic profiling of metal-exposed microglia, and the development of region-specific exposure models that better reflect chronic environmental realities.},
}

@article {pmid42955945,
year = {2026},
author = {Setti, A and Stufera Mecarelli, L and Santini, T and D'Angelo, A and Padovano, V and Vitiello, E and Castagnetti, F and Martone, J and Mariani, D and Bozzoni, I},
title = {ALS-linked FUS mutation impairs GEMIN5-dependent mRNA recruitment to neuronal late endosomes.},
journal = {Cell reports},
volume = {45},
number = {11},
pages = {118206},
doi = {10.1016/j.celrep.2026.118206},
pmid = {42955945},
issn = {2211-1247},
abstract = {Neurons depend on tightly regulated positioning of cellular components to maintain long-distance signaling, but the mechanisms guiding specific mRNAs to distant regions remain unclear. Here, we show that late endosomes function as selective RNA carriers in human motor neurons and uncover the molecular logic guiding their loading. Using APEX2-mediated proximity labeling, we identify the external transcriptome of RAB7A-positive endosomes and find a specific population of mRNAs enriched for endosomal, axonal, and synaptic functions. We find that mRNAs enriched in RAB7A endosomes contain evolutionarily conserved 5'UTRs that act as localization signals, and that the RNA-binding protein GEMIN5 interacts with these regions to promote endosomal RNA recruitment. Finally, we show that there is a conspicuous loss of endosome-associated transcripts in amyotrophic lateral sclerosis-associated conditions, accompanied by the mislocalization of GEMIN5 from endosomes. These findings uncover fundamental principles of RNA compartmentalization and highlight endosomal mRNA loading as a vulnerable axis in neuronal homeostasis.},
}

@article {pmid42955954,
year = {2026},
author = {Longo, F and La Spada, AR},
title = {Ataxin-2 loss flips a metabolic switch for neuron health.},
journal = {Cell reports},
volume = {45},
number = {11},
pages = {118128},
doi = {10.1016/j.celrep.2026.118128},
pmid = {42955954},
issn = {2211-1247},
abstract = {Gastaldo et al.[1] report that lowering ataxin-2 protects neurons from TDP-43 toxicity in amyotrophic lateral sclerosis by activating neuronal glycolysis and astrocytic cholesterol synthesis, not by reversing TDP-43-dependent molecular pathology. The downstream effectors, IDH1 and HMGCS1, thus emerge as candidate therapeutic targets.},
}

@article {pmid42956091,
year = {2026},
author = {Helbig, J},
title = {Wissenschaftsgeschichte als Objektarbeit am Museum für Naturkunde Berlin: Lehrtafeln bewahren und erforschen*.},
journal = {Berichte zur Wissenschaftsgeschichte},
volume = {},
number = {},
pages = {},
doi = {10.1002/bewi.70047},
pmid = {42956091},
issn = {1522-2365},
abstract = {Historical teaching charts are often overlooked in museum collections, despite their potential as valuable sources for the history of science. This article examines how the documentation and contextualisation of such objects can generate new perspectives on scientific practice and knowledge production. It presents a collaborative university seminar at the Museum für Naturkunde Berlin in which students from different disciplines systematically documented a dispersed collection of 267 historical teaching charts and developed a documentation framework through object-based research. Using the teaching chart Anatomie von Helix pomatia as an exemplary case study, the article demonstrates how close examination of a single object reveals connections between scientific illustration, institutional practices, teaching, and the material production of knowledge. Rather than serving merely as visual aids, historical teaching charts emerge as material witnesses to scientific work, preserving traces of their production, use, and historical context. The project illustrates how the systematic documentation of neglected museum objects can provide a foundation for future research, collection management, and preservation. More broadly, it argues that the history of science begins with recognising, documenting, and interpreting material evidence as historical sources.},
}

@article {pmid42947858,
year = {2026},
author = {Cerami, C and Panzavolta, A and Faltracco, V and Dalla Bella, E and Riva, N and Telesca, A and Ferrara, F and Dodich, A and Lunetta, C and Consonni, M},
title = {The cost of mentalizing: executive contributions to social cognition performance in amyotrophic lateral sclerosis.},
journal = {Frontiers in psychology},
volume = {17},
number = {},
pages = {1960658},
pmid = {42947858},
issn = {1664-1078},
abstract = {BACKGROUND: Mentalizing deficits are common in amyotrophic lateral sclerosis (ALS). Performance at high-level socio-cognitive tasks may be particularly vulnerable to integrity of basic cognitive processes. However, the extent to which non-social functioning contributes to socio-cognitive impairment in ALS remains poorly understood. In this study, we addressed this question in a large cohort of patients.

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

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

DISCUSSION: Mentalizing impairment in ALS reflects an interaction between executive processes and specialized socio-cognitive systems. The identification of dissociable profiles supports a dual-route, network-based model of ALS, involving socio-affective and inferential pathways, and underscores the importance of integrated cognitive assessment and more targeted interventions addressing both social and non-social cognitive domains.},
}

@article {pmid42948861,
year = {2026},
author = {Lin, H and Li, C and Wu, J and Yin, J},
title = {Longitudinal coagulation-fibrinolysis dynamics are associated with survival in amyotrophic lateral sclerosis: a prospective cohort study.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/21678421.2026.2750602},
pmid = {42948861},
issn = {2167-9223},
abstract = {Background: Amyotrophic lateral sclerosis (ALS) has been associated with thromboembolic risk. However, whether dynamic coagulation-fibrinolysis markers provide prognostic information in ALS remains insufficiently defined. Methods: We conducted a prospective cohort study of 151 patients with ALS, including repeated coagulation measurements in a longitudinal subset (n = 58), and assessed directional validation in the independent Answer ALS (AALS) cohort (n = 270). Survival analyses, longitudinal modeling, and plasma proteomic analyses were used to examine associations between coagulation-fibrinolysis dynamics, functional decline, and survival. Results: Higher baseline fibrinogen (FIB) was independently associated with shorter survival (HR = 2.19; 95% confidence interval (CI), 1.40-3.44). In the longitudinal subset, a steeper increase in D-dimer (DD) was associated with shorter survival (HR = 1.012; 95% CI, 1.001-1.024) and lower ALSFRS-R scores over time (β = -0.013; 95% CI, -0.016 to -0.009). Directionally consistent validation was observed in AALS using rescaled SomaScan-derived DD trajectories (HR = 1.0002; 95% CI, 1.0000-1.0004). Plasma proteomics showed reduced tetranectin, a fibrinolysis-related protein, in ALS; slower tetranectin decline was associated with longer survival using rescaled SomaScan-derived tetranectin trajectories (HR = 0.996; 95% CI, 0.993-0.998). Conclusions: These findings suggest that longitudinal coagulation-fibrinolysis markers may help identify a survival-related biomarker profile in ALS, involving higher baseline FIB, steeper rising DD, and reduced or more rapidly declining tetranectin.},
}

@article {pmid42949499,
year = {2026},
author = {Poddar, K and Wahi, C},
title = {Deep learning models to detect neurodegenerative diseases across different modalities, datasets, and stages: A systematic review.},
journal = {Technology and health care : official journal of the European Society for Engineering and Medicine},
volume = {},
number = {},
pages = {9287329261502060},
doi = {10.1177/09287329261502060},
pmid = {42949499},
issn = {1878-7401},
abstract = {BackgroundNeurodegenerative diseases like Alzheimer's and Parkinson's pose significant diagnostic challenges because they are incurable. Their symptoms often overlap with those of normal ageing and involve progressive neuronal loss. This makes early prediction, proper diagnosis, and ongoing monitoring crucial at every stage of the disease. Deep learning has become a useful tool for handling different types of data. However, the performance of these models relies heavily on the availability and variety of data, making it important to characterize datasets.ObjectiveThis PRISMA-based systematic review looks at 111 studies from 2019 to April 2026, organized into three clinical stages of neurodegenerative diseases: early prediction, diagnosis, and progression.MethodsEach study is assessed across four dimensions: data type (neuroimaging or non-neuroimaging), datasets (open-access, self-created, or hybrid), deep learning model architecture, and the use of explainable AI.ResultsMRI is the only imaging modality that spans all three stages. Speech is the most common non-neuroimaging method for diagnosis, while gait is used only for diagnosis and progression. The ADNI and PPMI datasets are the most commonly used. Self-created datasets introduce new modalities such as ECG and iPSCs, which are not found in open-access datasets. CNNs are the leading models for neuroimaging tasks, while LSTMs and RNNs capture temporal patterns in longitudinal datasets. Survival models are exclusively used for ALS and LATE. Fewer than 6% of the studies used confirmed XAI. Only 2 of the 111 studies validated their results on an independent external cohort.ConclusionThis review is the only one that covers all three disease stages across multiple neurodegenerative diseases.},
}

@article {pmid42951561,
year = {2026},
author = {Pellacani, S and Strani, L and Tanzilli, D and Barbieri, R and Marabottini, R and Martone, F and Napolitano, A and Cocchi, M and Durante, C},
title = {A multiway approach to overcome the peak resolution challenges in gas-chromatography coupled to ion mobility spectrometry.},
journal = {Analytica chimica acta},
volume = {1425},
number = {},
pages = {346326},
doi = {10.1016/j.aca.2026.346326},
pmid = {42951561},
issn = {1873-4324},
abstract = {BACKGROUND: Gas-chromatography coupled to ion mobility spectrometry (GC-IMS) is a powerful platform for untargeted analysis of volatile compounds, combining high sensitivity and short analysis times. However, its practical implementation still presents several analytical and computational challenges. From the instrumental perspective, the high sensitivity of isothermal GC-IMS makes it prone to signal saturation and memory effects, which can compromise the reproducibility of measurements. On the data-analysis side, the nature of GC-IMS outputs produce large and collinear datasets, in which baseline drift, shift in ion mobility and retention time modes, and peak overlap hinder the reliable extraction of relevant chemical information.

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

SIGNIFICANCE: A complete pipeline for the GC-IMS analysis was carefully developed and validated. PARAFAC2, was successfully applied for the deconvolution of GC-IMS data. This approach provided comparable results with previous methods and indicated that the same grade of automation reached in the analysis of GC-MS data with the same approach is feasible.},
}

@article {pmid42951629,
year = {2026},
author = {Inoue, H},
title = {[Disease modeling with iPSCs for pathophysiological elucidation and therapeutic research: establishment of an iPSC-based drug discovery platform centered on drug repositioning].},
journal = {[Rinsho ketsueki] The Japanese journal of clinical hematology},
volume = {67},
number = {9},
pages = {1145-1149},
doi = {10.11406/rinketsu.67.1145},
pmid = {42951629},
issn = {0485-1439},
mesh = {*Induced Pluripotent Stem Cells/cytology ; Humans ; *Amyotrophic Lateral Sclerosis/drug therapy/pathology/genetics ; *Drug Repositioning ; *Drug Discovery/methods ; Animals ; *Models, Biological ; },
abstract = {Advances in induced pluripotent stem cell (iPSC) technology have enabled the establishment of patient-derived disease models, greatly accelerating research on disease mechanisms and drug discovery. Drug repositioning, which applies existing drugs to new indications, has emerged as an efficient therapeutic development strategy that reduces both development time and cost. This review summarizes recent progress in disease modeling and therapeutic research using iPSCs, focusing on amyotrophic lateral sclerosis (ALS). Motor neurons differentiated from ALS patient-derived iPSCs successfully recapitulated disease phenotypes and enabled compound screening. Using this platform, the Src/c-Abl inhibitor bosutinib was identified as a promising therapeutic candidate. Bosutinib promoted autophagy, reduced abnormal protein accumulation, and suppressed motor neuron degeneration in vitro and in vivo. Based on these findings, investigator-initiated clinical trials were conducted, demonstrating acceptable safety and suggesting potential efficacy in ALS patients. Furthermore, integration of iPSC-based analyses with biomarkers such as neurofilament light chain enabled patient stratification and suggested the feasibility of personalized therapeutic approaches. Future integration of iPSC models with artificial intelligence, genomic analysis, and real-world clinical data is expected to further enhance predictive precision and accelerate translational research. iPSC-based drug discovery therefore represents a promising platform for developing novel therapies for neurodegenerative diseases.},
}

*Induced Pluripotent Stem Cells/cytology
Humans
*Amyotrophic Lateral Sclerosis/drug therapy/pathology/genetics
*Drug Repositioning
*Drug Discovery/methods
Animals
*Models, Biological

@article {pmid42952031,
year = {2026},
author = {Lee, SH and Blecha, J and Kim, JM and Nillo, RM and Flavell, RR and Chao, CK and Forsayeth, JR and Gerdes, JM and VanBrocklin, HF and Wilson, DM},
title = {Copper-Mediated Radiofluorination of the Excitatory Amino Acid Transporter 2 (EAAT2)-Targeted PET Tracer [[18]F]RP-115: Alternate Synthetic Method.},
journal = {Journal of labelled compounds & radiopharmaceuticals},
volume = {69},
number = {13-14},
pages = {},
pmid = {42952031},
issn = {1099-1344},
support = {RC-201810-2017455//Alzheimer's Drug Discovery Foundation/ ; 1R01AG072743-01A1/AG/NIA NIH HHS/United States ; },
mesh = {*Fluorine Radioisotopes/chemistry ; *Positron-Emission Tomography ; *Copper/chemistry ; *Radiopharmaceuticals/chemical synthesis/chemistry ; *Excitatory Amino Acid Transporter 2/metabolism ; Chemistry Techniques, Synthetic ; Halogenation ; },
abstract = {Excitatory amino acid transporter 2 (EAAT2) is a key regulator of extracellular glutamate in the central nervous system. Dysregulated EAAT2 is implicated in neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), highlighting EAAT2 as a potential target for PET imaging. We previously reported a multistep radiosynthesis of [[18]F]RP-115, a CNS-permeable prodrug that undergoes esterase-mediated hydrolysis in the CNS to yield the active EAAT2-binding carboxylate. Motivated by recent advances in copper-mediated radiofluorination (CMRF), we sought to develop a more efficient late-stage radiosynthesis of [[18]F]RP-115. A two-step radiosynthesis of [[18]F]RP-115 using CMRF provided [[18]F]RP-115 in high radiochemical yield (52.8% ± 2.1 %, decay-corrected from starting [[18]F]fluoride ion, n = 4), high molar activity (355 ± 61 GBq/μmol), and high radiochemical purity (> 99%) with a total synthesis time of 70 min. Chiral HPLC analysis demonstrated that the configuration of the aspartic acid residue remained intact without racemization during both the CMRF and trifluoroacetic acid mediated deprotection. We developed an efficient radiosynthesis of [[18]F]RP-115 via CMRF, achieving high radiochemical yield and molar activity. This efficient synthesis may serve as a basis for the future implementation of a CMRF-based automated radiosynthesis of [[18]F]RP-115.},
}

*Fluorine Radioisotopes/chemistry
*Positron-Emission Tomography
*Copper/chemistry
*Radiopharmaceuticals/chemical synthesis/chemistry
*Excitatory Amino Acid Transporter 2/metabolism
Chemistry Techniques, Synthetic
Halogenation

@article {pmid42952702,
year = {2026},
author = {Morioka, H and Hirayama, T and Shibukawa, M and Sugisawa, T and Nagasawa, J and Hanashiro, S and Ebina, J and Okamoto, R and Ogawa, M and Okuni, I and Murakami, Y and Kano, O},
title = {Impact of hybrid assistive limb on gait ability and quality of life in patients with amyotrophic lateral sclerosis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1823485},
pmid = {42952702},
issn = {1664-2295},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/complications/physiopathology ; *Quality of Life ; Female ; Male ; Middle Aged ; Aged ; *Gait/physiology ; *Gait Disorders, Neurologic/rehabilitation/etiology ; Robotics ; },
abstract = {OBJECTIVE: Hybrid Assistive Limb (HAL) is a cyborg-type wearable robot that supports gait training based on the wearer's intended motion. This study aimed to evaluate the effects of HAL treatment on gait ability and quality of life (QoL) in patients with amyotrophic lateral sclerosis (ALS).

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

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

CONCLUSION: Although no curative treatment exists for ALS, HAL treatment may provide short-term improvement in gait ability in patients with ALS. However, no significant changes in QoL were observed after one course of treatment.},
}

Humans
*Amyotrophic Lateral Sclerosis/rehabilitation/complications/physiopathology
*Quality of Life
Female
Male
Middle Aged
Aged
*Gait/physiology
*Gait Disorders, Neurologic/rehabilitation/etiology
Robotics

@article {pmid42952712,
year = {2026},
author = {Guha, R and Kim, S and Bandaru, A and Vivek, N},
title = {Biophysics-informed computational framework for predicting antisense oligonucleotide knockdown efficacy under small-data constraints.},
journal = {Frontiers in systems biology},
volume = {6},
number = {},
pages = {1921636},
pmid = {42952712},
issn = {2674-0702},
abstract = {A central strategy in treating neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), is lowering levels of disease-driving proteins. Antisense oligonucleotides (ASOs) offer a direct RNA-targeted approach to reduce protein expression, but experimental discovery and optimization are constrained by small, heterogeneous datasets and target-specific variability. Computational models that predict ASO knockdown efficacy directly from sequence and context could improve candidate selection, yet generalization across gene families and experimental settings remains challenging. In this study, we present a biophysics-based computational framework for predicting RNase H-active ASO knockdown efficacy under small-data constraints. We curate and integrate heterogeneous literature-derived ASO efficacy measurements into a unified dataset and evaluate model transfer using independently generated experimental ASOs targeting ALS-relevant genes DAZAP1 and FAM69C. Knockdown efficacy is defined at the transcript level (%KD), providing a mechanistic measure of RNase H-mediated activity. To our knowledge, this is the first framework that combines ASO feature engineering with one-shot family calibration for prediction under realistic small-data conditions. We integrate sequence representations with physics-based features capturing RNA-DNA hybridization thermodynamics, targeting RNA accessibility. Compared to sequence-only baselines, this mechanistic feature augmentation reduces external wet-lab prediction error, improving generalization to independent experimental data. Despite these gains, uncalibrated predictions exhibit systematic target-family-specific scale bias. We address this challenge by using a minimal one-shot family calibration strategy that applies an additive offset derived from a single experimentally measured reference ASO per new target family. We further assess the model's behavior using a leave-one-family-out simulation on literature-derived ASO families, repeatedly applying one-shot calibration to quantify its expected benefit and variability under controlled small-n conditions. One-shot calibration markedly improves absolute prediction accuracy while preserving within-family ranking, without retraining or increasing model complexity. Out-of-distribution evaluation shows stable performance for DAZAP1 and increased uncertainty for FAM69C, consistent with the expected effects of very small sample sizes. Permutation-based interpretability analyses show that predictive signal is dominated by global sequence architecture, with thermodynamic and accessibility features providing correlated, secondary contributions. Together, these results establish a computational workflow in which literature-trained models can be transferred to new target genes using minimal experimental input, supporting systematic ASO prioritization in small-data models.},
}

@article {pmid42953394,
year = {2026},
author = {Turra, GM and Angonese, PS and Rudell, EC and Tasca, VF and Markus, C and Merotto Junior, A},
title = {Legacy of Recurrent Gene Flow and Evidence of Independent Evolution of ALS Resistance Mutations in Weedy Rice.},
journal = {Evolutionary applications},
volume = {19},
number = {11},
pages = {e70342},
pmid = {42953394},
issn = {1752-4571},
abstract = {Weedy rice (Oryza spp.) provides a unique model for studying adaptive evolution because herbicide resistance can arise through both crop-to-weed gene flow and independent mutational events. In Brazil, nearly two decades of cultivation of imidazolinone (IMI)-resistant rice have imposed intense selection for acetolactate synthase (ALS) inhibitors resistance. This study investigated how historical gene flow and independent evolution have shaped the contemporary landscape of ALS resistance mutations in Brazilian weedy rice. Specifically, we characterized the diversity and distribution of ALS resistance mutations and developed rapid allele-specific molecular markers for major resistance alleles. A total of 200 weedy rice accessions collected from the major rice-growing region of Brazil were screened for IMI resistance and genotyped using newly developed SNAP (single nucleotide amplified polymorphism) qPCR markers targeting the IMI rice-derived mutations Ala122Thr, Ser653Asn, and Gly654Glu. Samples negative for these mutations were sequenced, and dose-response assays were conducted with imazethapyr, penoxsulam, nicosulfuron, and cloransulam-methyl. Ninety-three percent of the accessions were resistant to IMI herbicides. The ALS mutation Gly654Glu, present in rice cultivars used until 2006, was found in 15.5% of weedy rice resistant accessions, Ala122Thr became the dominant mutation (54.5%), whereas Ser653Asn occurred at an intermediate frequency (16.0%), indicating a temporal shift in the genetic basis of ALS resistance. Sequencing further identified the ALS substitutions Ala205Val, Trp574Leu, and Ser653Thr, which were not associated with commercial IMI-resistant rice cultivars, indicating ongoing independent evolution of target-site resistance. Trp574Leu conferred broad cross-resistance to all ALS-inhibiting herbicides evaluated, whereas the remaining mutations displayed mutation-specific resistance spectra. The SNAP markers showed high specificity and sensitivity, enabling reliable high-throughput detection of resistance alleles. Together, our findings demonstrate that the contemporary ALS resistance landscape in Brazilian weedy rice has been shaped mainly by repeated crop-to-weed gene flow, but also ongoing independent mutational events that continue to diversify resistance under herbicide selection.},
}

@article {pmid42953823,
year = {2026},
author = {Chen, HW},
title = {Bypassing the Blood-Central Nervous System (CNS) Barrier: A Dual-Axis Framework for Amyotrophic Lateral Sclerosis (ALS) Utilizing Glymphatic-Lymphatic Clearance and In Situ Chaperone Synthesis.},
journal = {Cureus},
volume = {18},
number = {9},
pages = {e117043},
pmid = {42953823},
issn = {2168-8184},
abstract = {Amyotrophic lateral sclerosis (ALS) is characterized by prion-like propagation of misfolded TAR DNA-binding protein 43 (TDP-43) and superoxide dismutase 1 (SOD1) across motor neuron pools. Because any circulating pharmacological agent must cross the blood-brain and blood-spinal cord barriers (BBB and BSCB), this review proposes active craniospinal tensioning (ACT) as a mechanical, non-pharmacological route to disease modification that acts on cerebrospinal fluid (CSF) and venous pressure dynamics rather than requiring penetration of these barriers. ACT is proposed to engage a single Monro-Kellie/Queckenstedt pressure continuity through two concurrent mechanisms: suboccipital venous occlusion-rebound, hypothesized to transiently raise and release craniospinal CSF pressure via venous compression and thereby accelerate venous-side glymphatic efflux; and dural pull-recoil, hypothesized to generate a reciprocal CSF pressure gradient via spinal elongation, agitating perivascular CSF directly while inducing a coupled venous pressure gradient. Because both mechanisms act concurrently on a shared venous-side target, the combined maneuver is proposed to be more potent than either delivered alone, as in prior work on pelvis-stabilized axial spinal traction (PSAST), which lacks the occlusion-rebound component. A secondary, hypothesis-generating micro-biochemical axis, cerebral venous preconditioning (CVPC), proposes that the same occlusion-rebound cycle produces capillary/venule wall strain sufficient to activate heat shock factor 1 (HSF-1) across the neurovascular unit, independent of oxygen tension, with a possible but uncharacterized contribution from hypoxia-inducible factor 1-alpha (HIF-1α). The two routes are non-exclusive, with the macro-fluidic axis alone proposed as sufficient. This framework is entirely theoretical, requires preclinical and clinical validation, and is intended as a template for related proteinopathy-driven neurodegenerative diseases, including Parkinson's disease, Huntington's disease, spinocerebellar ataxia, and fatal familial insomnia, addressed in forthcoming work.},
}

@article {pmid42953977,
year = {2026},
author = {Zhang, J and Wang, D and Chen, J and Lu, Y and Deng, D and Xu, B and Xu, Y and Jin, K and Xu, J and Liu, B and Ruan, J and Wang, X},
title = {The TBK1-OTUB2-IRF3 signalling complex promotes neuroinflammation and neurodegeneration.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag378},
pmid = {42953977},
issn = {1460-2156},
abstract = {The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway-mediated chronic inflammation drives neurodegeneration in natural aging and various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we identify Otubain-2 (OTUB2) as a pivotal regulator that orchestrates the STING signalosome to amplify inflammatory responses. The function of OTUB2 in neuroinflammation and neurodegeneration was investigated through genetic deletion and pharmacological inhibition of OTUB2 in hTARDBP transgenic mice , adeno-associated virus-mediated TDP43 overexpression mice, and aged mice. Biochemical assays were performed to dissect underlying molecular mechanisms. OTUB2 inhibited K63 ubiquitination of TANK-binding kinase 1 (TBK1), thereby suppressing TBK1 kinase activity and promoting cell death mediated by hyperactivated receptor-interacting serine/threonine-protein kinase 1 (RIPK1). Additionally, OTUB2 functioned as a scaffold facilitating assembly of the TBK1-interferon regulatory factor 3 (IRF3) signalling complex, a prerequisite for IRF3 phosphorylation, and enhanced IRF3 dimerization by reducing its K11 ubiquitination. Genetic deletion or pharmacological inhibition of OTUB2 significantly ameliorated neuroinflammation and neurodegeneration in both ALS and aged mouse models. This study establishes OTUB2 as a critical regulator of cGAS-STING signalling and a potential therapeutic target for neuroinflammation and neurodegeneration.},
}

@article {pmid42954000,
year = {2026},
author = {Geronimo, A and Cao, Q and Elman, L and Simmons, Z and Ackrivo, J},
title = {Feasibility of Longitudinal Home Monitoring of Nocturnal Transcutaneous CO2 and Relationship to Standard Respiratory Measures in Patients With ALS: A Pilot Cohort Study.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70432},
pmid = {42954000},
issn = {1097-4598},
support = {MDA874016//Muscular Dystrophy Association/ ; UL1 TR002014/TR/NCATS NIH HHS/United States ; UL1 TR00045/TR/NCATS NIH HHS/United States ; K23 HL-151879/HL/NHLBI NIH HHS/United States ; //Sentec AG/ ; },
abstract = {INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) results in respiratory muscle weakness causing hypoventilation, retention of carbon dioxide (CO2), and chronic hypercapnic respiratory failure. In this pilot study, we performed a 12-month assessment of daytime and home nocturnal CO2 to track respiratory progression, determine relationships with surrogate respiratory measures, and assess the impact of non-invasive ventilatory support.

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

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

DISCUSSION: Home nocturnal PtcCO2 assessment in ALS may identify respiratory insufficiency prior to FVC. Transcutaneous CO2 may play a role in the respiratory management of patients as a biomarker for hypoventilation risk and NIV titration. However, equipment availability and data quality limitations would benefit from professional assistance rather than independent in-home use.},
}

@article {pmid42954893,
year = {2026},
author = {Young, MJ},
title = {Consciousness in ALS.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-4},
doi = {10.1080/21678421.2026.2739759},
pmid = {42954893},
issn = {2167-9223},
}

@article {pmid42942116,
year = {2026},
author = {Ramadan, S and Panza, E and Orlacchio, A},
title = {Beyond Monogenic Inheritance: Emerging Genetic Architecture of Amyotrophic Lateral Sclerosis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42942116},
issn = {1422-0067},
support = {JALSDGC project to A.O.//Italian research Foundation for ALS/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; *Genetic Predisposition to Disease ; C9orf72 Protein/genetics ; RNA-Binding Protein FUS/genetics ; Superoxide Dismutase-1/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by marked genetic and phenotypic heterogeneity. Although pathogenic variants in major ALS genes, including C9ORF72, SOD1, TARDBP, and FUS, have provided fundamental insights into disease pathogenesis, many familial and most sporadic cases remain without a molecular diagnosis, suggesting a genetic architecture extending beyond coding variants and monogenic inheritance. Advances in genomic technologies have revealed contributions from deep-intronic and regulatory variants, structural rearrangements, repeat expansions, and other forms of genomic variation incompletely captured by standard diagnostic approaches. Evidence also indicates that combinations of rare variants with moderate or incomplete penetrance may contribute to disease susceptibility and clinical variability, supporting a multilayer model of ALS genetics. Population-specific variation and convergence of genetically diverse defects on common molecular pathways further complicate variant interpretation and disease classification. This review examines emerging components of ALS genetic architecture, including non-coding variation, structural variants, repeat expansions, oligogenic burden, ancestry-related gaps, and convergent neurodegenerative pathways. Integrating these genomic layers with functional and transcriptomic evidence may improve variant interpretation, diagnostic yield, patient stratification, and the development of mechanism-based precision therapies.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
*Genetic Predisposition to Disease
C9orf72 Protein/genetics
RNA-Binding Protein FUS/genetics
Superoxide Dismutase-1/genetics

@article {pmid42944613,
year = {2026},
author = {Abbasi Dezfouli, S and Heidenreich, E and Shahrbaf, M and Khajeh, E and Ramouz, A and Klauss, M and Hellbach, K and Öcal, O and Loos, M and Mehrabi, A},
title = {Novel algorithm for the diagnosis and treatment of different types of bile leakage following liver surgery.},
journal = {BJS open},
volume = {10},
number = {5},
pages = {},
pmid = {42944613},
issn = {2474-9842},
mesh = {Humans ; *Anastomotic Leak/diagnosis/therapy/etiology ; *Hepatectomy/adverse effects ; *Algorithms ; Female ; Male ; Bilirubin/analysis/blood ; Aged ; Middle Aged ; Bile ; Anastomosis, Surgical/adverse effects ; Retrospective Studies ; Bile Ducts/surgery ; Drainage ; Postoperative Complications/diagnosis ; },
abstract = {BACKGROUND: Posthepatectomy bile leakage (PHBL) after liver resection with bilioenteric anastomosis may originate from the anastomosis (anastomotic leak (AL)) or the transection surface (surface leak), including leakage from isolated bile ducts (IBDLs). Differentiating these sources remains challenging, and standardized management guidelines are lacking.

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

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

CONCLUSIONS: Distinct diagnostic thresholds help differentiate AL from other PHBL types. AL and IBDL benefit from reoperation, whereas surface leak is better managed without surgery. Timing influences therapeutic success, supporting a novel type- and timing-based management algorithm for PHBL.},
}

Humans
*Anastomotic Leak/diagnosis/therapy/etiology
*Hepatectomy/adverse effects
*Algorithms
Female
Male
Bilirubin/analysis/blood
Aged
Middle Aged
Bile
Anastomosis, Surgical/adverse effects
Retrospective Studies
Bile Ducts/surgery
Drainage
Postoperative Complications/diagnosis

@article {pmid42945473,
year = {2026},
author = {Salmon, K and de Majo, M and Basak, N and Crook, A and Cummings, C and Dratch, L and França, MC and Heckmann, J and Higgins, P and Knight, D and Koo, A and Nalini, A and Rouleau, G and Shahrizaila, N and Sokhi, DS and Son, B and Thomas, P and Trefiak, P and Van Damme, P and , and Roggenbuck, J and Harms, M and Al-Chalabi, A},
title = {Global best practice recommendations for genetic counselling and testing in amyotrophic lateral sclerosis.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag375},
pmid = {42945473},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with substantial clinical and genetic heterogeneity. Advances in ALS genomics, emerging gene-targeted therapies, and genotype-specific clinical trials have increased the importance of genetic counselling and testing for individuals with ALS and their families. However, access to these services remains highly variable globally due to disparities in healthcare infrastructure, laboratory capacity, specialist availability, and funding. Existing guidance has largely been developed in high-resource settings and may not be feasible or equitable worldwide. The International Alliance of ALS/MND Associations convened an international, multidisciplinary Genetics Task Force to develop expert consensus recommendations for genetic counselling, genetic testing, and laboratory practice in ALS across diverse geographic and resource settings. Recommendations were developed through a structured, iterative consensus process incorporating clinical expertise, lived experience perspectives, published evidence, and global representation. Final recommendations were reviewed and approved through anonymous voting at an in-person consensus meeting. The resulting recommendations establish both minimum and aspirational best practices, emphasizing equitable access, informed decision-making, culturally responsive counselling, tiered genetic testing approaches, and context-appropriate laboratory standards. These globally informed recommendations provide a pragmatic framework to support clinicians, laboratories, policymakers, and advocacy organizations in improving access to high-quality ALS genetics services worldwide.},
}

@article {pmid42946239,
year = {2026},
author = {Dale, A and Sattler, R},
title = {TDP-43 dysfunction destabilizes glial homeostatic identity in ALS/FTD.},
journal = {Brain research},
volume = {},
number = {},
pages = {150618},
doi = {10.1016/j.brainres.2026.150618},
pmid = {42946239},
issn = {1872-6240},
abstract = {TAR DNA-binding protein 43 (TDP-43) pathology is a defining feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 dysfunction has traditionally been studied through a neuron-centric framework, increasing evidence demonstrates that astrocytes, microglia, and oligodendrocytes are also directly affected and actively contribute to disease progression. In this review, we examine how TDP-43 dysfunction disrupts lineage-specific glial homeostatic programs and promotes distinct pathological state transitions across major glial populations. In astrocytes, TDP-43 dysfunction impairs neurotransmitter regulation, metabolic and neuronal support, RNA homeostasis, and secretory signaling while promoting inflammatory and antiviral-like states. In microglia, altered TDP-43 disrupts inflammatory regulation, phagocytosis, lysosomal function, lipid metabolism, and stage-dependent protective responses. In oligodendrocytes, TDP-43 dysfunction compromises RNA processing, lineage maintenance, lipid metabolism, myelin integrity, and long-term axonal support. Together, these findings suggest that glial TDP-43 dysfunction cannot be reduced to a single generalized form of reactivity but instead reflects the breakdown of distinct cell type-specific identities required to maintain central nervous system homeostasis. A cross-glial framework integrating cell-autonomous dysfunction, non-cell-autonomous signaling, disease stage, and genetic context may therefore provide a more complete understanding of TDP-43 proteinopathy and its contribution to neurodegeneration across the ALS-FTD spectrum.},
}

@article {pmid42946847,
year = {2026},
author = {Raina, GS and Mehan, S and Das Gupta, G},
title = {Combined melatonin and edaravone therapy attenuates methylmercury-induced amyotrophic lateral sclerosis-like neurodegeneration through GLP-1 modulation and myelin preservation.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42946847},
issn = {1432-1912},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons, resulting in progressive muscle weakness, paralysis, and respiratory failure. Despite the availability of disease-modifying therapies, current treatment options provide only modest clinical benefits, highlighting the need for novel therapeutic strategies targeting multiple pathological mechanisms. Melatonin, a pleiotropic neuroprotective molecule with antioxidant, anti-inflammatory, and anti-apoptotic properties, has emerged as a promising candidate; however, its influence on glucagon-like peptide-1 (GLP-1)-associated neuroprotective signaling and related molecular events in ALS remains poorly understood. Therefore, the present study investigated the neuroprotective efficacy of melatonin in a methylmercury (MTMR)-induced rat model of ALS and explored its effects on GLP-1-associated molecular alterations, neuroinflammation, oxidative stress, apoptosis, neurotransmitter homeostasis, demyelination, and neuronal injury. Molecular docking analysis was performed to predict the interaction of melatonin with proteins implicated in ALS pathology. Adult Wistar rats were exposed to MTMR (5 mg/kg, p.o.) for 21 days to induce ALS-like neurodegeneration, followed by treatment with melatonin (5 or 10 mg/kg, i.p.), edaravone (3 mg/kg, i.p.), or their combination for an additional 21 days. Neurobehavioral performance, biochemical alterations, hematological parameters, molecular biomarkers, and histopathological changes were subsequently evaluated. MTMR administration produced profound motor deficits accompanied by reduced GLP-1 levels, neurotransmitter imbalance, increased neuroinflammatory and apoptotic markers, elevated neurofilament light chain (NEFL), skeletal muscle injury, methylmercury accumulation, and extensive myelin and neuronal damage. Melatonin treatment significantly attenuated these pathological alterations in a dose-dependent manner by increasing GLP-1 levels, improving antioxidant status, reducing inflammatory and apoptotic responses, restoring neurotransmitter balance, preserving myelin integrity, and improving neuronal morphology across multiple brain regions and the spinal cord. Molecular docking further predicted favorable interactions between melatonin and several proteins associated with ALS pathophysiology, supporting its potential as a multitarget therapeutic agent. In most outcome measures, combined treatment with melatonin and edaravone produced greater neuroprotective effects than either intervention alone. Collectively, these findings demonstrate that melatonin substantially attenuates methylmercury-induced ALS-like neuropathology through coordinated modulation of multiple pathological processes associated with neurodegeneration. Although the precise molecular mechanisms require further experimental validation, the observed restoration of GLP-1 levels together with improvements in oxidative stress, neuroinflammation, apoptosis, neurotransmitter homeostasis, and myelin integrity suggests that melatonin may represent a promising adjunctive therapeutic strategy for ALS.},
}

@article {pmid42946878,
year = {2026},
author = {Chen, Z and Mansikkaviita, J and Seitz, C and Yazdani, S and Lehikoinen, J and Deeba, E and Lovik, A and Keszei, M and Grönlund, H and Laaksovirta, H and Fang, F and Tienari, PJ and Ingre, C and Andersson, J},
title = {Persistent and compartmentalized T cell immunity in ALS.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {42946878},
issn = {1546-170X},
support = {802091//EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))/ ; 2023-02428//Vetenskapsrådet (Swedish Research Council)/ ; 2024-02262//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; FS-2023-ESC-S5//Target ALS (Target ALS Foundation)/ ; },
abstract = {Amyotrophic lateral sclerosis is a fatal neurodegenerative disease increasingly linked to T cell responses, although the mechanisms driving T cell activation and disease progression remain unclear. Here we used single-cell RNA and T cell receptor sequencing, longitudinal immune profiling and imaging flow cytometry to identify long-lived intrathecal clonotypes and antigen-presenting cell-T cell complexes displaying features of immunological synapse formation, consistent with intrathecal antigen presentation. Higher frequencies of CD4[+] effector, CD4[+] regulatory and CD8[+] T cells in cerebrospinal fluid (CSF) were associated with slower disease progression, whereas increased circulating CD4[+] effector and regulatory T cells were associated with faster progression. T cell clonotypes shared between blood and CSF exhibited distinct transcriptional states. Finally, frequencies of cytomegalovirus-specific T cells in CSF and anticytomegalovirus serum antibodies were correlated with faster progression and shorter survival in sporadic amyotrophic lateral sclerosis. These findings reveal compartmentalized immune dynamics, largely contrasting protective intrathecal responses with harmful systemic activation.},
}

@article {pmid42946883,
year = {2026},
author = {Lillini, D and Basili, T and Migliorelli, L and Aironi, C and Gabrielli, L and Squartini, S},
title = {Improving dysarthric speech classification with generative AI-based data augmentation.},
journal = {Medical & biological engineering & computing},
volume = {},
number = {},
pages = {},
pmid = {42946883},
issn = {1741-0444},
abstract = {Dysarthria is a neurological speech disorder characterized by impaired motor control of speech production, resulting in reduced intelligibility. It commonly arises in the context of neurodegenerative conditions, including amyotrophic lateral sclerosis and cerebral palsy. The development of deep learning systems for dysarthria assessment is hindered by the scarcity of annotated data, which restricts the ability of models to generalize to unseen speakers. This study proposes a cross-corpus diffusion-based data augmentation strategy for improving automatic speech intelligibility classification from dysarthric speech. A Grad-TTS model is trained on dysarthric speakers from the TORGO dataset and used to synthesize the vocabulary of UA-Speech, producing speaker-conditioned samples intended to transfer pathological acoustic traits across corpora. The proposed strategy is evaluated both independently and in combination with conventional signal-level augmentation using ResNet-50 and ResNet-152 classifiers in binary and four-class intelligibility classification tasks. The results indicate that cross-corpus synthetic augmentation improves average performance and that, in most settings, its integration with conventional augmentation yields further gains, suggesting that the two strategies introduce complementary forms of variability.},
}

@article {pmid42947273,
year = {2026},
author = {Sigfridsson, I and Marklund, M and Andersen, PM and Zetterström, P and Marklund, SL and Brännström, T},
title = {Intracisternal injection of two human SOD1 aggregate strains induces templated aggregation and ALS in transgenic mouse model.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42947273},
issn = {2051-5960},
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism ; Mice, Transgenic ; *Superoxide Dismutase-1/administration & dosage/metabolism/genetics ; Humans ; Disease Models, Animal ; Spinal Cord/pathology/metabolism ; Mice ; *Protein Aggregation, Pathological/pathology ; Female ; Mutation ; Mice, Inbred C57BL ; },
abstract = {Cytosolic aggregates containing misfolded superoxide dismutase-1 (SOD1) protein is an established hallmark of ALS caused by mutations in the SOD1 gene. We have previously identified two structurally distinct strains of human (h) SOD1 aggregates (denoted A and B) in mice transgenic (Tg) for hSOD1. Strain A and B have both been shown to transmit templated aggregation and induce early-onset of fatal ALS-like disease when injected directly into the spinal cord or peripheral nerve of hSOD1 Tg mice. In contrast, peripheral administration of hSOD1 aggregates into the intraperitoneal cavity or skeletal muscle did not induce disease. Collectively, these studies provide insight on the spreading mechanism of SOD1. However, the complete map of propagation routes and underlying mechanisms utilized by SOD1 aggregates in ALS is not fully charted. Here, we investigated whether hSOD1 aggregates may spread to the central nervous system (CNS) via the cerebrospinal fluid (CSF). Mutant hSOD1 aggregate seeds or control samples prepared from spinal cords of hSOD1 Tg mice or non-Tg mice, respectively, were inoculated into the cisterna magna of adult 100-day-old Tg mice expressing the G85R mutated hSOD1 protein. Disease phenotyping as well as biochemical and immunohistochemical analyses were performed and compared across the experimental groups. The mice inoculated with hSOD1 seeds developed early signs of ALS by 90 days after inoculation and reached terminal stage approximately 180 days earlier than mice receiving control seeds. Additionally, both strain A and B were observed to initiate templated aggregation along the neuroaxis. The results show that hSOD1 aggregates are capable of transmitting from the CSF to the CNS where they induce ALS-like pathology and concomitant phenotype. Unraveling the propagation pathways utilized by SOD1 opens new avenues to assess treatment strategies against ALS.},
}

Animals
*Amyotrophic Lateral Sclerosis/pathology/genetics/metabolism
Mice, Transgenic
*Superoxide Dismutase-1/administration & dosage/metabolism/genetics
Humans
Disease Models, Animal
Spinal Cord/pathology/metabolism
Mice
*Protein Aggregation, Pathological/pathology
Female
Mutation
Mice, Inbred C57BL

@article {pmid42947290,
year = {2026},
author = {Meyer, T and Grehl, T and Schumann, P and Weyen, U and Rödiger, A and Smesny, U and Ilse, B and Weydt, P and Bernsen, S and Fabian, R and Göricke, B and Petri, S and Lumi, R and Bjelica, B and Großkreutz, J and Cetin, H and Keritam, O and Haimberger, F and Korsukewitz, C and Löscher, W and Kohl, Z and Regensburger, M and Baum, P and Metelmann, M and Kettemann, D and Norden, J and Steinbach, R and Körtvélyessy, P and Lingor, P and McFarlane, R and Münch, C and Boentert, M and Maier, A},
title = {Anatomically Defined Motor Phenotypes Reveal Dissociated Trajectories of Progression, Neurofilament Profiles, and Survival in ALS.},
journal = {European journal of neurology},
volume = {33},
number = {11},
pages = {},
doi = {10.1111/ene.70798},
pmid = {42947290},
issn = {1468-1331},
support = {//Boris Canessa ALS Stiftung/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/mortality/blood/pathology/physiopathology/classification ; Disease Progression ; *Neurofilament Proteins/blood ; Female ; Phenotype ; Male ; Middle Aged ; *Motor Neurons/pathology ; Aged ; Cohort Studies ; },
abstract = {BACKGROUND: Clinical heterogeneity in amyotrophic lateral sclerosis (ALS) may reflect structured disease trajectories. This study investigated whether anatomically defined motor phenotypes capture reproducible patterns associated with progression, serum neurofilament light chain (NfL), and survival.

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

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

CONCLUSIONS: Anatomically defined motor phenotypes identify reproducible ALS trajectories with distinct clinical and neurofilament profiles. Early propagation provides an actionable risk marker of disease aggressiveness, while combined upper and lower motor neuron dysfunction or lower motor neuron predominance is prognostically unfavorable. These findings support integrating structured phenotyping into prognostic models and clinical trial stratification.},
}

Humans
*Amyotrophic Lateral Sclerosis/mortality/blood/pathology/physiopathology/classification
Disease Progression
*Neurofilament Proteins/blood
Female
Phenotype
Male
Middle Aged
*Motor Neurons/pathology
Aged
Cohort Studies

@article {pmid42947405,
year = {2026},
author = {Agarwal, S and Rehman, SAA and Muñoz, IM and Knebel, A and Hop, PJ and Gourlay, R and Brown, F and Macartney, T and Squires, I and Veldink, JH and Kenna, KP and Rouse, J and Mehta, AR},
title = {NEK1 autophosphorylation is disrupted by amyotrophic lateral sclerosis-associated missense variants: activity biomarkers and structural insights.},
journal = {Open biology},
volume = {16},
number = {10},
pages = {},
doi = {10.1098/rsob.260209},
pmid = {42947405},
issn = {2046-2441},
support = {//Greater Houston Community Foundation/ ; //UK Medical Research Council/ ; //National Institute for Health and Care Research/ ; MR/Z505535/1//Dementias Platform UK/ ; RGS/R2/252027//Royal Society/ ; },
mesh = {*NIMA-Related Kinase 1/genetics/metabolism/chemistry ; *Amyotrophic Lateral Sclerosis/genetics/metabolism ; *Mutation, Missense ; Phosphorylation ; Humans ; Biomarkers/metabolism ; Models, Molecular ; },
abstract = {Rare variants in NEK1, encoding a serine/threonine kinase, are among the most consistently implicated genetic contributors to amyotrophic lateral sclerosis (ALS), reported in approximately 2-3% of cases. Yet, while recent studies have characterized the cell biological consequences of NEK1 loss-of-function, the biochemical effects of ALS-associated missense variants on kinase activity have not been directly investigated. This distinction is mechanistically important, because missense alleles encode mutant proteins rather than simply reducing protein dosage. Here, we provide the most comprehensive cell-based phosphoproteomic map of NEK1 phosphorylation to date, identifying 10 recurrent phosphorylation sites across independent expression and acquisition conditions. We experimentally assign pSer14, pThr156 and pSer418 as NEK1 autophosphorylation sites using kinase-dead controls, targeted extracted ion chromatogram analysis, phosphosite mutagenesis and phosphospecific antibodies. Leveraging activation-loop pThr156 as a read-out of NEK1 activity, we assessed nine ALS-associated missense variants spanning the major functional regions of the protein. Among catalytic-domain variants, R261C produced the most robust reduction in pThr156 autophosphorylation, R232C produced a smaller reduction, and R232H increased pThr156; the basic-region variant, A313T, also showed a smaller reduction. Structural modelling provides a mechanistic framework for understanding these variant-specific effects. Our study establishes the first activity-based framework for functional classification of NEK1 missense variants, and provides direct evidence that ALS-associated missense variants can alter NEK1 autophosphorylation through a mechanism distinct from simple haploinsufficiency. The phosphospecific antibodies, isogenic cell lines and curated phosphoproteomic datasets generated here provide a community resource for future studies of NEK1 regulation, variant interpretation and therapeutic target validation.},
}

*NIMA-Related Kinase 1/genetics/metabolism/chemistry
*Amyotrophic Lateral Sclerosis/genetics/metabolism
*Mutation, Missense
Phosphorylation
Humans
Biomarkers/metabolism
Models, Molecular

@article {pmid42947411,
year = {2026},
author = {Duffy, K and Gwathmey, K and Schneck, D and Arguedas, A and Xenopoulos-Oddsson, A and Heiman-Patterson, T and Ajroud-Driss, S and Arcila-Londono, X and Wymer, J and Olney, N and Hayat, G and Lunetta, C and Cerri, F and Al-Lahham, T and Sherman, A and Ghasemi, M and Cui, E and Fiecas, M and Walk, D},
title = {Time-to-Event Analysis of Clinical Milestones in the ALS Natural History Consortium Dataset.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70440},
pmid = {42947411},
issn = {1097-4598},
support = {FD-R01-007630/FD/FDA HHS/United States ; //Department of Neurology, University of Minnesota/ ; },
abstract = {INTRODUCTION/AIMS: Study of clinical milestones, particularly intermediate events like loss of ambulation, in large amyotrophic lateral sclerosis (ALS) cohorts is limited. Here, we leverage the ALS Natural History Consortium dataset to evaluate the time-to-event for several outcomes and prognostic factors that predict risk.

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

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

DISCUSSION: These findings further inform expectations of time to various outcomes, especially rarely investigated intermediate events, and their risk factors. The importance of progression rate supports other recent findings, highlighting delta-FRS as a key prognostic factor with potential utility in clinical trial designs.},
}

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

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

CONCLUSIONS: BCCs represent a promising yet underexplored therapeutic platform for ALS and related neurodegenerative disorders. Their ROS-responsive, redox-modulating, and neuroprotective properties, combined with favorable CNS drug-like pharmacokinetics, offer a mechanistically distinct approach to disease modification. Emerging preclinical evidence strongly supports further translational investigation.},
}

Humans
*Amyotrophic Lateral Sclerosis/drug therapy/pathology/metabolism
Reactive Oxygen Species/metabolism
Animals
*Neuroprotective Agents/chemistry/pharmacology/therapeutic use
*Boron Compounds/chemistry/pharmacology/therapeutic use
*Neurons/drug effects/metabolism
Blood-Brain Barrier/metabolism/drug effects
*Boron/chemistry/pharmacology
Molecular Structure
Oxidative Stress/drug effects

@article {pmid42933233,
year = {2026},
author = {Lehrer, S},
title = {ALS-associated cytoskeletal and glial gene expression: evidence consistent with developmental pathway re-engagement.},
journal = {Journal of the neurological sciences},
volume = {491},
number = {},
pages = {126231},
doi = {10.1016/j.jns.2026.126231},
pmid = {42933233},
issn = {1878-5883},
abstract = {BACKGROUND: We examined whether amyotrophic lateral sclerosis (ALS) is associated with cytoskeletal and glial transcriptional patterns compatible with developmental pathway re-engagement, while recognizing that similar patterns may arise from injury responses and altered cell composition.

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

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

CONCLUSIONS: ALS was associated with higher expression of selected cytoskeletal and glial genes in bulk postmortem tissue. These cross-sectional associations are compatible with, but do not demonstrate, developmental program reactivation, altered protein activity, or causation. Cell-resolved and functional studies are needed.},
}

@article {pmid42933234,
year = {2026},
author = {Cappelli, J and Hundal, S},
title = {Cost-effectiveness of multidisciplinary care compared with standard neurology care in Amyotrophic Lateral Sclerosis: A model-based cost-utility analysis.},
journal = {Journal of the neurological sciences},
volume = {491},
number = {},
pages = {126235},
doi = {10.1016/j.jns.2026.126235},
pmid = {42933234},
issn = {1878-5883},
abstract = {OBJECTIVE: To evaluate the cost-effectiveness of multidisciplinary clinic (MDC) care compared with standard general neurology care for adults with amyotrophic lateral sclerosis (ALS).

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

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

CONCLUSION: MDC improved survival and quality-adjusted survival but at substantially higher cost. Its ICER remained well above commonly used U.S. willingness-to-pay thresholds across sensitivity analyses, including alternative utility valuations. These findings highlight the distinction between clinical benefit and cost-effectiveness and quantify the long-term economic consequences of survival gains associated with multidisciplinary ALS care.},
}

@article {pmid42933736,
year = {2026},
author = {Chakraborty, W and Anand, A and Kumar, S and Roy, KK},
title = {Circadian aging and neurodegeneration: the emerging role of the melatonin-cortisol axis in brain homeostasis, disease progression, and precision chronomedicine.},
journal = {Frontiers in neuroendocrinology},
volume = {83},
number = {},
pages = {101292},
doi = {10.1016/j.yfrne.2026.101292},
pmid = {42933736},
issn = {1095-6808},
abstract = {Circadian aging may promote neurodegenerative illnesses by dysregulating the melatonin-cortisol axis. Low nighttime melatonin synthesis, blunted cortisol circadian cycles, abnormal clock-gene oscillation patterns, and sleep-wake architecture undermine central and peripheral circadian equilibrium with age. Neuroendocrine alterations produce oxidative stress, mitochondrial failure, pervasive neuroinflammation (CNS immune function loss), and proteostasis. Increasing Alzheimer's, Parkinson's, ALS, Huntington's, frontotemporal dementia, Lewy body disease, PTSD, and vascular cognitive impairment due to impaired glymphatic axonal clearance/blood-brain barrier dysregulation/synaptic degeneration/pathoproteopathic protein We examine how clock genes, melatonin signaling, hypothalamic-pituitary-adrenal axis administration, microglia reactivity, and immune-mediated metabolic dysregulation affect dementia. New endocrine, transcriptomic, multi-omics, and wearable-derived digital biomarkers, chronopharmacology (including melatonin receptor agonists), bright-light therapy, time-restricted eating with exercise chronotherapy guidance/synchronization, sleep optimization, and gut microbiota modulation This study addressed inter-individual circadian variability, genetic susceptibility to therapy timing, biomarker standardization, and clinical trial design. The melatonin-cortisol axis may identify and treat age-related neurodegenerative diseases with tailored treatment.},
}

@article {pmid42933747,
year = {2026},
author = {Gray, EL and McGuiness, O and Menadue, C and Piper, A and Wong, K and Kiernan, MC and Yee, BJ},
title = {Diaphragm reserve utilisation in motor neurone disease: A novel ultrasound-derived physiological index.},
journal = {Respiratory physiology & neurobiology},
volume = {347},
number = {},
pages = {104667},
doi = {10.1016/j.resp.2026.104667},
pmid = {42933747},
issn = {1878-1519},
abstract = {INTRODUCTION: Respiratory involvement is a major determinant of prognosis in motor neurone disease (MND; or amyotrophic lateral sclerosis), yet conventional static respiratory measures provide limited information about how much available diaphragm thickening capacity is recruited during quiet breathing. We evaluated diaphragm reserve utilisation (RU), an ultrasound-derived ratio of tidal diaphragm thickening relative to maximal diaphragm thickening, as a novel physiological descriptor in MND.

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

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

CONCLUSION: Diaphragm reserve utilisation describes the proportion of measured diaphragm thickening capacity recruited during tidal breathing. Patients with MND demonstrated preserved tidal thickening despite reduced maximal thickening capacity, resulting in higher RU than healthy controls. This supports RU as a novel physiological index of relative diaphragm thickening reserve utilisation. The relationship between RU and survival warrants validation in larger prospective cohorts.},
}

@article {pmid42934257,
year = {2026},
author = {Okoshi, K and Aoki, Y},
title = {Neuromuscular junction pathology in amyotrophic lateral sclerosis and emerging molecular therapeutic strategies.},
journal = {Journal of human genetics},
volume = {},
number = {},
pages = {},
pmid = {42934257},
issn = {1435-232X},
abstract = {Traditionally conceptualized as a soma-centric pathology, amyotrophic lateral sclerosis (ALS) is a fatal, heterogeneous neurodegenerative disease. The suboptimal outcomes of central nervous system (CNS)-directed therapeutic strategies have necessitated a shift in focus toward the dying-back hypothesis. This hypothesis contends that synaptic disconnection and axonal retraction at the distal neuromuscular junction (NMJ) are early pathological events that may antedate overt motor neuron loss. This review systematically examines the NMJ as an early vulnerable and therapeutically tractable peripheral niche in ALS pathogenesis, rather than merely a downstream consequence of proximal proteinopathy. Evidence from human clinical samples and ALS mouse models, particularly SOD1-G93A mice, collectively supports the early vulnerability of the NMJ, with the temporal precedence of denervation, synaptic retraction, and mitochondrial dysfunction most clearly demonstrated in experimental models. We highlight how the breakdown of the tripartite synapse-comprising the motor terminal, skeletal muscle, and terminal Schwann cells (tSCs)-may disrupt essential neurotrophic signaling and local metabolic homeostasis. Furthermore, we discuss how advancements in humanized in vitro NMJ models and spatial transcriptomics provide unprecedented resolution into localized RNA dysmetabolism and bioenergetic failure. Finally, we evaluate emerging therapeutic strategies specifically designed to stabilize or restore the NMJ, including MuSK agonists and other NMJ-directed approaches. By recontextualizing the NMJ as a critical early site of vulnerability, we propose that targeting the peripheral synaptic microenvironment may offer a promising strategy for modifying the progression of ALS.},
}

@article {pmid42934377,
year = {2026},
author = {Wu, Y and Zhang, X and Gao, C and Zhang, Z and Liao, X and Kang, Y},
title = {The cGAS-STING Pathway in Neuroinflammation and Neurological Disease: Mechanisms, Disease Contexts, and Periphery-to-Brain Communication.},
journal = {Cellular and molecular neurobiology},
volume = {46},
number = {1},
pages = {},
pmid = {42934377},
issn = {1573-6830},
support = {2024MZFS007//Research Grant of Key Laboratory of Anesthesiology and Resuscitation, Ministry of Education/ ; 82272199//National Natural Science Foundation of China/ ; 2022YFC2504500//Key Technologies Research and Development Program/ ; },
mesh = {Humans ; Animals ; cGAS-STING Signaling Pathway ; *Nucleotidyltransferases/metabolism ; *Nervous System Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; *Neuroinflammatory Diseases/metabolism/pathology ; *Membrane Proteins/metabolism ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; STING Protein ; Signal Transduction ; Inflammation/metabolism/pathology ; },
abstract = {Neurodegenerative disorders involve a strong inflammatory component, yet the underlying inflammatory mechanisms may be heterogeneous across disease stage, cell type, and systemic context. A key unresolved question is how cellular and systemic stress is converted into sustained neuroinflammation. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an innate DNA-sensing hub that translates mislocalized self-DNA - derived from mitochondrial stress and mtDNA leakage, nuclear envelope instability, micronuclei formation, or impaired nucleic-acid disposal - into type I interferon, NF-kB, autophagy-related, and senescence-associated inflammatory programs. Rather than treating cGAS-STING as a universal disease-defining pathway, this review frames it as a context-dependent amplifier that becomes pathogenic when DNA-DAMP burden, defective mitochondrial quality control, neurovascular "leakage", and glial priming converge. We synthesize cell-type-specific evidence in microglia, astrocytes, neurons, and the neurovascular unit; compare mechanistic involvement across Alzheimer's disease, Parkinson's disease dementia and Lewy body disease, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD), vascular and acute brain injury, and systemic inflammatory encephalopathies; and organize periphery-to-brain communication axes using an explicit evidence-grading framework. A distinctive contribution of this review is a two-hit model in which systemic inflammatory stressors and barrier dysfunction first lower cognitive resilience, followed by brain-resident mitochondrial/DNA damage programs that lock in complement-linked synaptopathy. We also evaluate pharmacological and lifestyle-based modulation, emphasizing biomarker-enriched trial design, CNS exposure, compartment-specific target engagement, and immune-safety constraints. This framework aims to clarify when, where, and in whom cGAS-STING modulation may preserve synapses and cognition without unacceptable immune trade-offs.},
}

Humans
Animals
cGAS-STING Signaling Pathway
*Nucleotidyltransferases/metabolism
*Nervous System Diseases/metabolism/pathology
*Brain/metabolism/pathology
*Neuroinflammatory Diseases/metabolism/pathology
*Membrane Proteins/metabolism
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
STING Protein
Signal Transduction
Inflammation/metabolism/pathology

@article {pmid42934615,
year = {2026},
author = {Bakhshi, F and Ashkezari, AD and Heydari, S},
title = {Design and protocol of a randomized assessor-blinded controlled trial evaluating an educational escape room for individual and team cardiopulmonary resuscitation skills among nursing students.},
journal = {BMC nursing},
volume = {25},
number = {1},
pages = {},
pmid = {42934615},
issn = {1472-6955},
support = {18765//Shahid Sadoughi University of Medical Sciences/ ; },
abstract = {BACKGROUND: High-quality cardiopulmonary resuscitation (CPR) depends not only on technical competence but also on effective communication, role clarity, leadership, and coordinated team performance under pressure. However, conventional CPR instruction may not adequately reproduce the collaborative and time-sensitive demands of real resuscitation. Educational escape rooms (EERs), as simulation-based gamified learning strategies, may provide a more immersive and learner-centered approach to strengthening both cognitive and teamwork-related aspects of CPR training. This study protocol was developed to evaluate the effect of a team-based CPR educational escape room (CPR-EER) integrated into advanced life support (ALS) training for undergraduate nursing students.

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

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

TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT), registered on 16 October 2024, IRCT20240815062770N1. Available at: https://irct.behdasht.gov.ir/ .},
}

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

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

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

DISCUSSION: Defining respiratory phenotypes in ALS may allow tailored research within those subgroups, biomarker correlations, more accurate prognostication, and stratification in clinical trials based on phenotype-specific disease progression.},
}

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

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

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

INTERPRETATION: Rate and shape describe partially overlapping aspects of the disease. LCMM-LateDecline, with moderate early decline yet occult respiratory compromise, is clinically challenging, and the 3-visit criterion hides over half of ultrarapid patients. Rate predicts the overall burden of progression, whereas shape predicts the timing of deterioration. ANN NEUROL 2026.},
}

@article {pmid42938002,
year = {2026},
author = {Huang, Z and Zhang, X and Song, WL and Wang, M and Yu, Z and Jiao, S},
title = {Deciphering Electrocatalytic Sulfur Reduction Reactions in Al-S Batteries via Single-Particle Electrodes.},
journal = {Journal of the American Chemical Society},
volume = {148},
number = {37},
pages = {39638-39646},
doi = {10.1021/jacs.6c08648},
pmid = {42938002},
issn = {1520-5126},
support = {52304318//National Natural Science Foundation of China/ ; 2023M740225//China Postdoctoral Science Foundation/ ; BX20230038//National Postdoctoral Program for Innovative Talents/ ; 24RCKA004//Science and Technology Program of Gansu Province/ ; },
abstract = {The kinetically sluggish sulfur reduction reaction (SRR) governs the performance of ultrahigh-capacity aluminum-sulfur batteries, while deciphering the SRR process is critical for rationally electrocatalyzing reaction kinetics to unlock their full energy output. To overcome this challenge, a single-particle electrochemical methodology has been developed to investigate the SRR process on a cobalt/nickel and nitrogen codoped graphene (CoNi-NG) electrocatalyst. The SRR process involves a major route of S8 → Al2S8 → Al2S4 → Al2S3 with a minor route of Al2S8 → Al2S6 → Al2S4, where Al2S4 conversion governs the overall SRR kinetics and Al2S4 contributes the most to the shuttle effect owing to its fastest generation and slowest consumption. The CoNi-NG raises the Co d-orbital energy level via Ni-to-Co electron transfer to accelerate cleavage of polysulfides, which doubles the exchange current density of rate-determining Al2S4 conversion. Consequently, the sulfur composite (S@CoNi-NG) electrode delivers a specific capacity of ∼1480 mAh gsulfur-1. Such a single-particle methodology for quantitatively deciphering electrocatalytic SRRs offers mechanistic guidance for rationally enhancing battery performance.},
}

@article {pmid42939346,
year = {2026},
author = {Alfaro-Rodríguez, A and Cortes-Altamirano, JL and Reyes-Long, S and Bonilla-Jaime, H and Avila-Camacho, FJ and Moreno-Villalba, LM and Herrera-López, ME and González-Maciel, A and Pérez-Guille, B and Soriano-Rosales, RE and Calderon-Guzman, D and Juaréz-Olguín, H},
title = {Glial Contributions to Pain in Neurodegenerative Disease Models: A Systematic Review of Microglial and Astrocytic Evidence.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939346},
issn = {2076-3425},
abstract = {Background/Objectives: Pain is a common and disabling non-motor manifestation of neurodegenerative disorders, but the contribution of glial cells to nociceptive processing remains incompletely understood. This systematic review evaluated evidence from preclinical models of neurodegenerative diseases linking microglial and astrocytic activity to pain. Methods: The protocol was prospectively registered in PROSPERO (CRD420251084310), and reporting followed PRISMA 2020. We conducted the original electronic search in PubMed/MEDLINE; during major revision, we conducted supplementary searches in Scopus and Web of Science Core Collection. Across the three sources, we identified 2248 records. After hierarchical deduplication by DOI, PMID, and normalized title, 1567 unique records were screened. Eligible in vivo studies assessed microglial and/or astrocytic alterations together with pain- or nociception-related outcomes. Risk of bias was independently evaluated by two investigators using the SYRCLE tool, and findings were synthesized qualitatively. Results: Twenty-six studies met the eligibility criteria: sixteen examined multiple sclerosis/experimental autoimmune encephalomyelitis (61.5%), seven Parkinson's disease (26.9%), two Alzheimer's disease-related models (7.7%), and one Huntington's disease model (3.8%); no eligible amyotrophic lateral sclerosis study was identified. Pain-related alterations involved inflammatory, neuroimmune, synaptic, and astrocyte-associated pathways, but the evidence was strongly model-dependent. Findings based on individual studies, including early astrocytic contributions in experimental autoimmune encephalomyelitis and altered inflammatory allodynia in an Alzheimer's disease model, are interpreted as study-specific observations requiring replication. Conclusions: The available evidence supports context-dependent associations between glial responses and nociceptive processing; however, marker specificity, EAE predominance, sex and age imbalance, and incomplete reporting of bias control procedures limit causal and cross-disease generalization.},
}

@article {pmid42939372,
year = {2026},
author = {Swindell, WR and Ali, A and Iacoangeli, A and Bhai, S},
title = {Meta-Analysis of ALS Post-Mortem Cerebral Cortex Transcriptome Studies Identifies Robust Shifts in Gene Expression Despite Significant Between-Study Heterogeneity.},
journal = {Brain sciences},
volume = {16},
number = {10},
pages = {},
pmid = {42939372},
issn = {2076-3425},
abstract = {Background: ALS is characterized by motor neuron failure with potential neurocognitive comorbidity. Cortical neurons, and their support cells, exhibit pathologic features, some of which have been identified in post-mortem transcriptome studies of the cortex from ALS patients and control subjects. These studies, however, have utilized varying technologies with few attempts to reconcile findings. Methods: This study used meta-analysis to evaluate differential gene expression (ALS vs. control) from 16 prior transcriptome studies utilizing multiple technologies (microarray, bulk RNA-seq or snRNA-seq). Normalization with GC content correction was used to mitigate downstream biases impacting differential expression. Results: Approximately one-third of protein-coding genes (5930 of 16,579) exhibited significant between-study effect size heterogeneity (FDR < 0.05), which was frequently associated with variation in average post-mortem interval. Nonetheless, we identified 269 and 273 differentially expressed genes (DEGs) with relatively consistent increased or decreased expression in the ALS cortex, respectively (FDR < 0.05 with SMD ≥ 0.20 or SMD ≤ -0.20). ALS-increased DEGs were associated with transcription (RNA polymerase), cell signaling (TGF-beta, PI3K), interneurons, microglia, endothelial cells, and deep laminar layers (L5, L6). ALS-decreased DEGs were associated with transcription (RNA polymerase), glial cells (astrocytes, oligodendrocytes) and the L1 layer. There was significant overlap between DEGs from the ALS cortex and those previously identified from ALS spinal cord and blood. Conclusions: These findings highlight signaling pathways, cell types and cortical layers associated with robust changes in ALS cortex gene expression. Our results illustrate the importance of meta-analysis as a tool for understanding between-study heterogeneity and identifying repeatable findings across technologies.},
}

@article {pmid42939724,
year = {2026},
author = {Hutchison, LL and Parkes, MM and Pioro, EP},
title = {Serotonergic Dysfunction and the Interacting Role of TAR DNA-Binding Protein 43 in the Progression of Amyotrophic Lateral Sclerosis: A Scoping Review.},
journal = {Biomolecules},
volume = {16},
number = {10},
pages = {},
pmid = {42939724},
issn = {2218-273X},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology ; *DNA-Binding Proteins/metabolism ; *Serotonin/metabolism ; Animals ; Disease Progression ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons and widespread neural dysfunction. Loss of serotonin (5-HT) signaling and TAR DNA-binding protein 43 (TDP-43) dysfunction have both been identified as contributing factors to disease progression, although their relationship has yet to be fully defined. The objective of this review was to assess whether any mechanistic links exist between serotonergic dysfunction and TDP-43 proteinopathy in ALS. A scoping review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. Databases were queried for the peer-reviewed literature concerning ALS pathophysiology, 5-HT, and TDP-43 (1946 to January 2026). Articles were screened and data independently extracted by two reviewers, which were subsequently synthesized qualitatively (n = 14). The current literature suggests that serotonergic dysfunction can be identified early in ALS pathology, indicated by decreased 5-HT concentration, degeneration of raphe projections, and changes in receptor activity. TDP-43 proteinopathy is a defining characteristic of ALS progression, characterized by cytoplasmic mislocalization and aggregation of TDP-43. Additionally, studies have identified bidirectional links between these dysfunctions: TDP-43 impairs serotonergic transmission, and 5-HT deficiency may drive pathological TDP-43 aggregation. Many mechanisms affected by both serotonergic and TDP-43 dysfunction are associated with disease progression including excitotoxicity, metabolic disturbances, and network hyperexcitability. Despite this, there is a lack of direct experimental evidence elucidating connections between these pathologies. Serotonergic dysfunction and TDP-43 proteinopathy may be linked by shared mechanisms in ALS, though specific causality has not been identified. Further research should aim to clarify the connection between these processes and discover therapeutic targets.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/pathology/physiopathology
*DNA-Binding Proteins/metabolism
*Serotonin/metabolism
Animals
Disease Progression

@article {pmid42939744,
year = {2026},
author = {Mohamed, YK and Yan, LJ},
title = {Edaravone for Potential Mitigation of Oxidative Stress and Inflammation in Kidney Disease.},
journal = {Biomolecules},
volume = {16},
number = {10},
pages = {},
pmid = {42939744},
issn = {2218-273X},
mesh = {Humans ; *Oxidative Stress/drug effects ; *Edaravone/therapeutic use/pharmacology ; Animals ; *Inflammation/drug therapy/metabolism ; *Kidney Diseases/drug therapy/metabolism/pathology ; Anti-Inflammatory Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Free Radical Scavengers/therapeutic use/pharmacology ; },
abstract = {Edaravone (EDA) is a synthetic free-radical scavenger FDA-approved for amyotrophic lateral sclerosis (ALS) treatment in the United States and is used clinically for treatment of acute ischemic stroke in Japan and other countries. While its antioxidant activity has been the primary focus of investigation in the mitigation of oxidative-stress-related injury, EDA exhibits anti-inflammatory, anti-fibrotic, anti-apoptotic, and anti-necrotic effects in animal models. These properties make it a potentially attractive therapeutic agent for kidney disease, where oxidative stress and inflammation contribute to renal cell injury, mitochondrial dysfunction, and progression of disease. In this review, we cover the underlying mechanisms of oxidative stress and inflammation in renal injury, and pharmacological and free-radical-scavenging mechanisms of EDA. Preclinical evidence in several kidney diseases, including ischemic/reperfusion injury, nephrotoxin-induced disease, and diabetic kidney disease, has been used to assess EDA for efficacy. In addition, we explore the modulatory roles of key signaling pathways, such as Nrf2 and NF-κB, in protective effects of EDA against oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, necrosis, and fibrosis. Finally, we highlight the potential of EDA as a therapy in future clinical applications for various kidney diseases such as acute kidney injury (AKI) and chronic kidney disease (CKD). It should also be emphasized that as EDA's renal efficacy evidence described in this review is largely limited to animal studies, robust human clinical data are lacking. Therefore, additional clinical studies are still needed to fully elucidate the efficacy, safety, and benefits of EDA for prevention and treatment of human kidney disease.},
}

Humans
*Oxidative Stress/drug effects
*Edaravone/therapeutic use/pharmacology
Animals
*Inflammation/drug therapy/metabolism
*Kidney Diseases/drug therapy/metabolism/pathology
Anti-Inflammatory Agents/therapeutic use/pharmacology
Signal Transduction/drug effects
Free Radical Scavengers/therapeutic use/pharmacology

@article {pmid42940139,
year = {2026},
author = {Carata, E and Mariano, S and Tenuzzo, BA and Panzarini, E},
title = {Advancing the Translational Pipeline: From In Vivo and In Vitro 2D Models to Next-Generation Cell Culture Models for Amyotrophic Lateral Sclerosis Modelling and Drug Discovery.},
journal = {Biomedicines},
volume = {14},
number = {10},
pages = {},
pmid = {42940139},
issn = {2227-9059},
abstract = {Background: Amyotrophic lateral sclerosis (ALS) is still a global health challenge, as there is no effective treatment due to the inadequacy of conventional experimental platforms for comprehending pathogenic mechanisms and developing therapy. Objectives: This review details the recent progress and clinical utility of next-generation iPSC-derived 3D in vitro systems integrated with microfluidics, CRISPR-Cas9 gene editing, multi-omics readouts, and AI-based machine learning, which are emerging as transformative platforms for recapitulating key ALS pathological hallmarks. Methods: A literature search was performed using PubMed and Web of Science, including only English-language publications. All the published papers collected covered the period from January 2015 to June 2026. Results: Human induced pluripotent stem cell (iPSC) cerebral organoids, assembloids, and organ-on-a-chip technologies are revolutionizing research into ALS by providing a way to model the complex spatial organization, cellular heterogeneity, and neural network dynamics of the human brain. Moreover, recent bioengineering advancements enable the inclusion of functional neurovascular units, the integration of resident immune cells (microglia), and the use of 3D bioprinting to accelerate the functional maturation of age-related phenotypes. CRISPR-Cas9 genome editing, OMICS, and machine learning improve tools for studying ALS and identifying therapeutic targets. Conclusions: Novel cell culture models may bridge the gap between preclinical animal models and human clinical trials and reduce the duration and costs of translation. Future work is likely to integrate bioprinting with organ-on-chip microfluidics, CRISPR-based genetic editing, and multi-omics readouts to build increasingly faithful, patient-specific ALS models for both basic research and precision therapeutics.},
}

@article {pmid42941452,
year = {2026},
author = {Gołąb-Janowska, M and Wełnicka-Wesołowska, A and Baumert, B and Machowska-Sempruch, K and Meller, A and Sobuś, A and Paczkowska, E and Kotlęga, D and Nowacki, P and Machaliński, B},
title = {Functional Status, Quality of Life and Survival After Repeated Intrathecal Administration of Autologous Lineage-Negative Cells in Amyotrophic Lateral Sclerosis.},
journal = {Journal of clinical medicine},
volume = {15},
number = {20},
pages = {},
pmid = {42941452},
issn = {2077-0383},
support = {STRATEGMED1/234261/2/NCBR/2014//National Centre for Research and Development/ ; },
abstract = {Background/Objectives: Adjuvant cell-based strategies are still being explored in amyotrophic lateral sclerosis (ALS). Materials and Methods: In this open-label, single-arm study of intrathecal autologous bone marrow-derived lineage-negative (LIN[-]) cells, we report functional status, quality of life, and survival after three administrations at six-week intervals. A total of 45 patients with sporadic ALS were qualified: 42 received all three administrations and 23 completed the 24-week assessment schedule, while 19 stopped attending because of deterioration. Results: In the 23 completers, Norris scale scores were stable until week 13 and then declined (p = 0.00004), and the Amyotrophic Lateral Sclerosis Assessment Questionnaire 40 (ALSAQ-40) followed the same pattern (p = 0.0019), whereas the ALS Functional Rating Scale-Revised (ALSFRS-R) declined at a constant 0.5 points per month. In all 42 treated patients the Norris score fell during treatment (0.95 points per month; 95% CI 0.52-1.38), so the plateau was confined to completers, who had milder baseline disease. Dose-related differences in quality of life were confounded by baseline imbalance; survival analyses were exploratory. Cell number did not correlate with cerebrospinal fluid brain-derived neurotrophic factor (BDNF) after the third administration in the 39 patients with paired samples (ρ = 0.14). No adverse event was recorded in 126 procedures, but harms were not graded systematically. Conclusions: These exploratory findings do not demonstrate efficacy; a sham-controlled trial with blinded raters is required.},
}

@article {pmid42941856,
year = {2026},
author = {Gómez-Pérez, CA and Ramírez-García, MÁ and Yescas-Gómez, P},
title = {The Role of SOD1 and Oxidative Stress in Amyotrophic Lateral Sclerosis: An Overview.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42941856},
issn = {1422-0067},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology ; *Superoxide Dismutase-1/genetics/metabolism ; *Oxidative Stress ; Animals ; Reactive Oxygen Species/metabolism ; Mutation ; Motor Neurons/metabolism/pathology ; Signal Transduction ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder that selectively affects motor neurons. The median survival time after diagnosis is 2 to 5 years. Oxidative stress (OS), driven mainly by reactive oxygen species (ROS), plays a central role in motor neuron (MN) degeneration. In this narrative review, we analyse the pathogenic role of SOD1 variants and their contribution to OS in ALS. SOD1 mutations alter the Cu/Zn superoxide dismutase enzyme, thereby promoting oxidative damage and triggering neuroinflammatory cascades via the MAPK, NF-κB and Nrf2/ARE signalling pathways. We also discuss emerging proteomic and machine-learning biomarkers, as well as the current therapeutic landscape. Riluzole and edaravone are approved treatments, while AMX0035 was approved in 2022 but withdrawn in 2024. Masitinib and EPI-589 remain investigational. In the realm of genetic therapies, the antisense oligonucleotide tofersen received accelerated FDA approval in 2023 for SOD1-ALS, primarily due to its ability to reduce plasma neurofilament light chain levels. However, the clinical benefit remains modest. RNA interference has reached human trials, while CRISPR/Cas9 remains in the preclinical stage. Both approaches have shown promising results in experimental models. Further research into ALS pathogenesis is needed to develop treatments that integrate antioxidant, anti-inflammatory, and gene-editing strategies.},
}

Humans
*Amyotrophic Lateral Sclerosis/metabolism/genetics/therapy/pathology
*Superoxide Dismutase-1/genetics/metabolism
*Oxidative Stress
Animals
Reactive Oxygen Species/metabolism
Mutation
Motor Neurons/metabolism/pathology
Signal Transduction

@article {pmid42941925,
year = {2026},
author = {Gómez-Pérez, CA and Ramírez-García, MÁ and Ruiz-Sánchez, E and Romero-Hidalgo, S and Ochoa-Morales, A and Jara-Prado, A and Méndez-Armenta, M and Nava-Ruiz, C and Yescas-Gómez, P},
title = {Identification of SOD1 Gene Variants in Mexican Patients with Amyotrophic Lateral Sclerosis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42941925},
issn = {1422-0067},
support = {262111//Secretariat of Science, Humanities, Technology, and Innovation (SECIHTI)/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *Superoxide Dismutase-1/genetics ; Mexico/epidemiology ; Female ; Mutation ; Male ; Middle Aged ; Aged ; Gene Frequency ; Genetic Variation ; Adult ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressing, fatal neurodegenerative disorder that selectively affects motor neurons. Clinical manifestations include progressive muscle weakness, amyotrophy, fasciculations, dysphagia, and fatal respiratory failure. The median survival after symptom onset is typically 2 to 5 years. Despite its severity, the epidemiological profile and genetic landscape of ALS in Latin American populations, particularly in Mexico, remain unclear. In this study, we evaluated the mutational spectrum of the SOD1 gene in a Mexican cohort of 156 ALS patients. Using high-resolution melting (HRM) analysis and Sanger sequencing, we identified 22 SOD1 variants in 42 of 156 patients (overall variant carrier frequency, 26.92%). Pathogenic or likely pathogenic (P/LP) variants were found in 21 patients (13.5%). Notably, 5 of the 22 variants were novel, expanding the spectrum of SOD1 variants. The variant carrier frequency identified in this study is higher than that reported for European populations but similar to frequencies observed in Asian populations. Our results highlight the distinct genetic heterogeneity of ALS in Mexico and demonstrate that HRM is a rapid and effective method for identifying SOD1 gene variants.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/epidemiology
*Superoxide Dismutase-1/genetics
Mexico/epidemiology
Female
Mutation
Male
Middle Aged
Aged
Gene Frequency
Genetic Variation
Adult

@article {pmid42942089,
year = {2026},
author = {Lv, X and Huang, M and Long, W and Li, X and Hu, Z and Feng, Y and Du, J and Long, Q and Chen, Y and Shi, M and Qin, D},
title = {Epigenetic Mechanisms in Neurodegenerative Diseases: From Genetic Regulation to Therapeutic Potential.},
journal = {International journal of molecular sciences},
volume = {27},
number = {20},
pages = {},
pmid = {42942089},
issn = {1422-0067},
support = {YPKLS2025-029//Yunnan Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Dis-ease in Prevention and Treatment/ ; KUST-KH2022017Y//Kunming University of Science and Technology & the First People's Hospital of Yunnan Province Joint Special Project on Medical Research/ ; 202401AY070001-135//Yunnan Provincial Department of Science and Technology-Kunming Medical University Joint Special Project/ ; },
mesh = {Humans ; *Epigenesis, Genetic ; *Neurodegenerative Diseases/genetics/therapy/metabolism ; Animals ; DNA Methylation ; Gene Expression Regulation ; RNA Methylation ; Biomarkers/metabolism ; Histones/metabolism ; Epitranscriptome ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are multifactorial disorders in which genetic susceptibility alone cannot account for sporadic onset, clinical diversity, or age-dependent progression. Epigenetic mechanisms-DNA methylation, histone modifications, non-coding RNAs, and m6A RNA methylation-bridge environmental and intracellular cues to stable gene expression changes. Emerging evidence associates epigenetic dysregulation with amyloid-β/tau pathology in AD, α-synuclein pathology in PD, and TDP-43/C9orf72-associated toxicity in ALS, while functional studies suggest that selected epigenetic alterations may contribute to these processes. In this narrative review, we distinguish associative, functional, and mechanistic evidence using claim-specific criteria based on experimental perturbation, direct molecular assessment, and pathway-dependence or rescue testing, while considering the study system. We further evaluate the translational promise of epigenetic biomarkers in liquid biopsies, while emphasizing the major barriers that separate bench findings from bedside application, including poor target specificity, limited blood-brain barrier penetration, and the absence of biomarker-guided patient stratification. By integrating pathological mechanisms, biomarker development, and therapeutic strategies, this review argues that future epigenetic research in neurodegeneration must prioritize causal validation, CNS-penetrant drug development, and prospective trials integrating epigenetic profiling to achieve meaningful clinical impact.},
}

Humans
*Epigenesis, Genetic
*Neurodegenerative Diseases/genetics/therapy/metabolism
Animals
DNA Methylation
Gene Expression Regulation
RNA Methylation
Biomarkers/metabolism
Histones/metabolism
Epitranscriptome

@article {pmid42927744,
year = {2026},
author = {Mishchenko, TA and Grechukhina, AA and Kulikov, SS and Olajide, OJ and Mitroshina, EV and Krysko, DV and Vedunova, MV},
title = {When the Brain Signals Danger: Roles of Calreticulin and HMGB1 in Cell Death Mechanisms in Neurooncology and Neurodegeneration.},
journal = {Biochemistry. Biokhimiia},
volume = {91},
number = {10},
pages = {1822-1841},
doi = {10.1134/S0006297926601565},
pmid = {42927744},
issn = {1608-3040},
mesh = {Humans ; *HMGB1 Protein/metabolism ; *Calreticulin/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Brain/metabolism/pathology ; Cell Death ; Signal Transduction ; Alarmins/metabolism ; },
abstract = {Contrary to the classical paradigm of brain immune privilege, damage-associated molecular patterns (DAMPs) act as key mediators in the dialogue between CNS cells and the immune system, determining pathways of immune response development. This review examines the role of key DAMPs - calreticulin (CRT) and high-mobility group box 1 protein (HMGB1) - in the functioning of CNS under normal conditions and during the development of neuropathologies, particularly oncological and neurodegenerative processes. Under normal conditions, CRT and HMGB1 ensure functioning of the brain, acting as necessary effectors of neurogenesis and homeostatic plasticity. In neurooncology, exposure of CRT on the surface of dying cells and release of HMGB1 serve as powerful adjuvant signals for antigen-presenting cells, inducing immunogenic cell death (ICD). Particular attention is given to the mechanisms of passive HMGB1 release during various types of regulated cell death (apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis), as well as to the role of redox modifications of the protein, which determine its pro-inflammatory, immunogenic, or tolerogenic properties. In neurodegeneration (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), excessive DAMP release exacerbates the development of chronic neuroinflammation, disrupts integrity of the blood-brain barrier (BBB), and forms a vicious cycle of pathological changes. Detection of CRT and HMGB1 in biological fluids or brain tissues has important prognostic potential, and regulation of their signaling pathways opens promising approaches for overcoming tumor resistance or inhibiting progressive neurodegenerative changes in the brain.},
}

Humans
*HMGB1 Protein/metabolism
*Calreticulin/metabolism
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Brain/metabolism/pathology
Cell Death
Signal Transduction
Alarmins/metabolism

@article {pmid42927931,
year = {2026},
author = {Luan, J and Yun, Y and Jiao, Y and Wang, Y and Ma, M and Shan, D and Wang, H and Ji, X and Tang, Y and Li, J and Zhan, Z and Sun, X and Gao, N and Lin, P and Yan, C and Sun, X and Yu, D and Liu, S and Liu, F},
title = {Cortical Motor Hierarchy Disruption Is Associated With Functional Status in Early Amyotrophic Lateral Sclerosis.},
journal = {Journal of cachexia, sarcopenia and muscle},
volume = {17},
number = {5},
pages = {},
doi = {10.1002/jcsm.70411},
pmid = {42927931},
issn = {2190-6009},
support = {2025CXPT133//the Key R&D Program of Shandong Province/ ; 2022ZLGX03//the Key R&D Program of Shandong Province/ ; ZR2023MH180//the Natural Science Foundation of Shandong Province/ ; 20201125//the Qilu Young Scholarship of Shandong University/ ; ZR2023ZD14//the Shandong Provincial Natural Science Foundation Major Basic Research Project/ ; 2025M782111//the China Postdoctoral Science Foundation/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/pathology ; Female ; Male ; Middle Aged ; Magnetic Resonance Imaging ; *Motor Cortex/physiopathology/pathology ; Aged ; Cross-Sectional Studies ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterised by progressive muscle wasting and functional decline. Although cortical motor network disruption is a hallmark of ALS, the large-scale functional hierarchy alterations and their underlying molecular mechanisms in the early stage of the disease (ALS-ES) remain poorly understood. We aimed to characterise cortical gradient changes in early-stage ALS and to examine their neurochemical and transcriptomic correlates, as well as their cross-sectional associations with clinical functional status.

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

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

CONCLUSIONS: Early-stage ALS is characterised by a collapsed cortical functional hierarchy centred on the motor-somatosensory axis. These alterations were spatially associated with normative neurochemical maps and distinct transcriptomic annotations related to energy metabolism and RNA processing. These findings identify cross-sectional cortical functional-hierarchy alterations associated with functional status in early-stage ALS and provide a multi-scale framework for investigating their neurochemical and transcriptomic correlates.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/pathology
Female
Male
Middle Aged
Magnetic Resonance Imaging
*Motor Cortex/physiopathology/pathology
Aged
Cross-Sectional Studies

@article {pmid42927993,
year = {2026},
author = {Clarysse, M and Korsos, S and Cuypers, C and Raes, E and Vlaminck, L},
title = {Chirurgische behandeling van unilateraal geïmpacteerde maaltanden in de bovenkaak bij een paard.},
journal = {Journal of veterinary dentistry},
volume = {},
number = {},
pages = {8987564261493278},
doi = {10.1177/08987564261493278},
pmid = {42927993},
issn = {2470-4083},
abstract = {Impactie van permanente maaltanden bij het paard wordt voornamelijk gerapporteerd ter hoogte van de mandibula, terwijl betrokkenheid van de maxilla zeldzaam is. Dit rapport beschrijft een ongewone presentatie van congenitale impactie van drie opeenvolgende maxillaire molaren bij een 4-jarige merrie. Computertomografie toonde complexe ruimtelijke verhoudingen tussen de geïmpacteerde elementen, de sinusbodem en de aangrenzende structuren, deze werden op conventionele radiografie niet volledig onderkend en waren essentieel voor de chirurgische planning. Chirurgische extractie via een botflap van de sinus maxillaris liet gecontroleerde sectionering en aansluitende verwijdering van alle aangetaste elementen toe. Histopathologisch onderzoek van botstalen uit de sinusbodem toonde reactieve osteosclerose, wat veroorzaakt kan worden door chronische druk en/of sinusitis. Als postoperatieve complicaties ontstonden een oromaxillaire communicatie en een secundaire sinusitis na verlies van de polysiloxaanplug; deze werden behandeld door herhaardelijk debrideren en sinoscopische lavage. Op lange termijn resulteerde de behandeling in een bevredigend functioneel herstel en behoud van oraal comfort, niettegenstaande het verlies van meerdere maaltanden in de bovenkaak.},
}

@article {pmid42929812,
year = {2026},
author = {Zhang, N and Freeman, DD and Polster, BM},
title = {BAX, VDAC, Gasdermin, and Permeability Transition Pores in Inflammatory Mitochondrial DNA Release: Is This the "Hole" Story?.},
journal = {Cells},
volume = {15},
number = {20},
pages = {},
doi = {10.3390/cells15201839},
pmid = {42929812},
issn = {2073-4409},
support = {R01NS112212/NS/NINDS NIH HHS/United States ; R21NS133527/NS/NINDS NIH HHS/United States ; R21 NS133527 (B.M.P.)./NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; *DNA, Mitochondrial/metabolism ; Animals ; *bcl-2-Associated X Protein/metabolism ; *Mitochondrial Permeability Transition Pore/metabolism ; *Voltage-Dependent Anion Channels/metabolism ; Mitochondria/metabolism ; *Inflammation/metabolism ; },
abstract = {Disease-modifying neuroprotective therapies for traumatic brain injury (TBI), stroke, and age-related neurodegenerative disorders have proven elusive. Interest in mitochondrial outer membrane permeabilization mechanisms as a drug target evolved from the 1990s discovery of BAX/BAK-mediated mitochondrial cytochrome c release as an apoptotic cell death trigger. However, enthusiasm waned as subsequent findings revealed that apoptosis is not the dominant cell death mechanism in the mature brain. The more recent discovery of mitochondrial DNA (mtDNA) as an inflammatory trigger produced renewed interest in mitochondrial permeability pathways. In particular, the DNA-sensing molecule cGAS and its downstream effector STING were implicated in the pathogenesis of several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and TBI. Nevertheless, these findings raised a puzzling question: how does mtDNA, which resides in the mitochondrial matrix surrounded by double membranes, escape to initiate inflammatory responses without triggering cytochrome c-dependent cell death? Here, we review the many proposed mechanisms for mtDNA release, including several that do not require mitochondrial membrane holes, and discuss advances toward pharmacological targeting of these pathways. Identification of the specific mtDNA efflux pathway(s) proximal to maladaptive neuroinflammatory responses may yield new treatment strategies for AD, TBI, and other neurological diseases.},
}

Humans
*DNA, Mitochondrial/metabolism
Animals
*bcl-2-Associated X Protein/metabolism
*Mitochondrial Permeability Transition Pore/metabolism
*Voltage-Dependent Anion Channels/metabolism
Mitochondria/metabolism
*Inflammation/metabolism

@article {pmid42929861,
year = {2026},
author = {Gong, X and Wei, H and Shen, L and Wang, Q and Wu, J and Wang, W and Xu, T},
title = {Single-Dose Intrathecal rAAV2-Retro Delivering Anti-hSOD1 miRNA Confers Robust Neuroprotection in Adult ALS Mice.},
journal = {Cells},
volume = {15},
number = {20},
pages = {},
doi = {10.3390/cells15201890},
pmid = {42929861},
issn = {2073-4409},
support = {22ZR1414500//Natural Science Foundation of Shanghai/ ; 21ZR1407700//Natural Science Foundation of Shanghai/ ; },
mesh = {Animals ; *Amyotrophic Lateral Sclerosis/genetics/therapy/pathology ; *MicroRNAs/genetics/metabolism/administration & dosage ; *Superoxide Dismutase-1/genetics/metabolism ; Injections, Spinal ; *Dependovirus/genetics/metabolism ; Mice ; Humans ; Insulin-Like Growth Factor I/metabolism ; *Neuroprotection ; Disease Models, Animal ; Motor Neurons/metabolism/pathology ; Gene Silencing ; Genetic Vectors ; Spinal Cord/metabolism/pathology ; Mice, Inbred C57BL ; },
abstract = {Amyotrophic lateral sclerosis (ALS) kills within a few years of onset, and the drugs licensed for treatment change that course only marginally. Silencing SOD1 has become a credible treatment route, but two gaps hold this approach back: an efficient vector platform for spinal cord transduction with limited peripheral transduction and evidence on whether adding neurotrophic support to gene silencing has any effect. We built an rAAV2-retro platform for intrathecal delivery. One intrathecal dose of an eGFP-expressing vector transduced all spinal cord segments and several brain regions, with a clear preference for spinal motor neurons and low expression in the liver and heart. Side by side in adult mice, we then used this platform to compare miRNA-mediated silencing of human SOD1, overexpression of IGF1, and the two together in SOD1[G93A] animals. A single injection of rAAV2-retro carrying an anti-hSOD1 miRNA extended median survival by 25 days, improved motor performance, protected neuromuscular junctions, spared α-motor neurons, and damped gliosis and apoptosis. IGF1 on its own also lengthened survival and limited neuronal loss, but it left motor performance unchanged. The benefit of IGF1 over miRNA alone was observed on most endpoints under the conditions tested; a modest, nominally significant improvement in hindlimb clasping was observed, which should be interpreted as exploratory given the number of comparisons performed. Silencing of hSOD1 therefore accounts for most of the benefit, and no statistically detectable additional benefit was observed for IGF1 on top of hSOD1 silencing under the conditions tested. A single intrathecal dose of rAAV2-retro-miRNA is thus an effective gene silencing approach in the SOD1[G93A] mouse model, with limited peripheral transduction in the liver and heart observed in C57BL/6J mice. However, these data also show the difficulty of achieving additional benefit by adding IGF1 under the conditions tested.},
}

Animals
*Amyotrophic Lateral Sclerosis/genetics/therapy/pathology
*MicroRNAs/genetics/metabolism/administration & dosage
*Superoxide Dismutase-1/genetics/metabolism
Injections, Spinal
*Dependovirus/genetics/metabolism
Mice
Humans
Insulin-Like Growth Factor I/metabolism
*Neuroprotection
Disease Models, Animal
Motor Neurons/metabolism/pathology
Gene Silencing
Genetic Vectors
Spinal Cord/metabolism/pathology
Mice, Inbred C57BL

@article {pmid42930312,
year = {2026},
author = {Nguyen, TT and Wang, L and Dao, TK},
title = {Biomimetic Coverage Optimization in WSNs via an Enhanced Spider-Wasp Optimizer with Adaptive Learning and Dual-Median-Point Guidance.},
journal = {Biomimetics (Basel, Switzerland)},
volume = {11},
number = {10},
pages = {},
doi = {10.3390/biomimetics11100760},
pmid = {42930312},
issn = {2313-7673},
support = {FITGR20250//Fuzhou Institute of Technology/ ; },
abstract = {Coverage optimization in wireless sensor networks (WSNs) is a non-convex deployment problem on which population-based optimizers often converge prematurely and lose diversity. This paper proposes the Enhanced Spider-Wasp Optimizer (ESWO), an extension of the Spider-Wasp Optimizer (SWO) conceptually inspired by the foraging and nesting behavior of Pompilidae wasps. ESWO integrates (i) an Adaptive Learning Strategy (ALS) that uses four types of positional gaps among individuals to sustain diversity, (ii) a dual-median-point guidance (DMPG) mechanism that steers exploitation towards the midpoint of two elite solutions, and (iii) a position-update rule with nest-overlap avoidance. Coverage is evaluated on a discretized target grid with a Euclidean binary-disk sensing model and an energy-penalized fitness. In four scenarios (25-65 nodes; 50 × 50 to 165 × 165 m[2]), ESWO was compared with seven algorithms, including SWO. It achieved coverage rates of 81%, 88%, 92% and 85%, the highest in every scenario (tied with MGWO at 81% in the smallest). In the 100 × 100 m[2] scenario it reached 85% coverage after 523 iterations, against 601-698 for the competitors, although final convergence iteration counts were not uniformly the lowest. Over 15 runs, ESWO obtained a mean coverage of 90.2% (SD 1.2), a 95% success rate and the lowest estimated energy consumption (175.3 J).},
}

@article {pmid42931148,
year = {2026},
author = {Giecko, M and Bossowski, F and Bossowska, M and Moniuszko-Malinowska, A and Chorąży, M and Sarnowska, M and Grygorczuk, S},
title = {Amyotrophic Lateral Sclerosis in a Patient Treated for Neurosyphilis: A Case Report.},
journal = {Neurology international},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/neurolint18100193},
pmid = {42931148},
issn = {2035-8385},
abstract = {BACKGROUND/OBJECTIVES: Neurosyphilis is a recognized treatable mimic of amyotrophic lateral sclerosis (ALS); syphilis serology is commonly included in the work-up of suspected motor neuron disease. We describe the converse situation: neurosyphilis that delayed recognition of coexisting ALS.

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

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

CONCLUSIONS: Identifying a treatable mimic does not close the diagnostic process. Combined upper and lower motor neuron signs that continue to progress despite adequate treatment of neurosyphilis should prompt early electrodiagnostic evaluation for ALS, even though the relative contribution of each condition may remain uncertain.},
}

@article {pmid42926632,
year = {2026},
author = {Barbier, M and Ichalalen, M and Amador, MD and De Houwer, JFH and Suh, E and Lejeune, FX and Bieth, T and Reyes, C and Henry, E and Hinks, AE and Martin-Hardy, P and Rinaldi, D and Araktingi, L and Seelaar, H and Roué-Jagot, C and , and Lagarde, J and Sarazin, M and Salachas, F and Bruneteau, G and Teichmann, M and Levy, R and Bernard, E and Kaat, LD and Van Deerlin, V and Haase, G and van Swieten, J and Rapinat, A and Gentien, D and Le Ber, I},
title = {Somatic instability of the C9orf72 repeat expansion in blood differs between patients with amyotrophic lateral sclerosis or frontotemporal dementia.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.10.06.26364580},
pmid = {42926632},
abstract = {Individuals carrying a G4C2 repeat expansion in C9orf72 can develop amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD), at various and unpredictable ages. The contribution of the expansion to this extreme clinical variability remained a matter of debate. In this work, we validated the use of optical genome mapping to efficiently size this expansion from blood and applied this method to a cohort of 54 repeat expansion carriers including patients with FTD (n = 23), ALS (n = 22) and presymptomatic individuals (n = 9). Despite the high variability in expansion profiles, distinct groups can be inferred. Although consensus repeat profiles were similar between FTD and ALS patients, relationships between repeat number, indexes of repeat instability, and the age at sampling differed between clinical conditions. An age at sampling-dependent increase of repeat instability in blood was observed in presymptomatic carriers and FTD patients (p = 0.01 and p = 0.04 respectively), in contrast to patients with ALS (p = 0.9). The proportion of shorter repeats ([500-1500 repeats]) increased with the age at sampling in ALS patients but decreased in presymptomatic and FTD cohorts, while the proportion of larger repeats (>2000 G4C2), in particular those exceeding 4000 repeats, increased along with the age at sampling in presymptomatic carriers and FTD cases (p <1.10 [-e4] and p = 0.006 respectively) conversely to patients with ALS (p = 0.98). In conclusion, this work strongly supports different dynamics of repeat instability of the C9orf72 pathogenic expansion in blood linked to the clinical evolution. These findings provide new insights into the relationship between expansion profiles and clinical variability.},
}

@article {pmid42926777,
year = {2026},
author = {Ding, YN and Bahati, M and Li, MQ and Guan, PP and Wang, P},
title = {A CNS-targeted atovaquone nanotherapy mitigates complement activation and neuromuscular degeneration in ALS.},
journal = {Materials today. Bio},
volume = {41},
number = {},
pages = {103738},
pmid = {42926777},
issn = {2590-0064},
abstract = {Complement-mediated glial inflammation and synaptic injury are increasingly implicated in amyotrophic lateral sclerosis (ALS), but clinically translatable complement-modulating therapies remain limited. Atovaquone (ATQ) is an approved, poorly water-soluble small molecule with reported immunomodulatory activity. We investigated whether ATQ could modulate C1qb or C5aR1-associated pathology and whether lactoferrin (Lf)-derived nanomicelles could improve delivery to the spinal cord. ALS spinal-cord single-cell transcriptomic and pathway-enrichment analyses were combined with screening of an FDA-approved drug library, molecular docking and surface plasmon resonance (SPR). Lf-ATQ nanomicelles were characterised by dynamic light scattering, transmission electron microscopy and fluorescence distribution studies. Complement/inflammasome responses were examined in microglial and motor-neuron-microglia models. Therapeutic effects were evaluated in mice expressing the human superoxide dismutase 1 G93A variant (SOD1[G93A]) by motor testing, compound muscle action potential recording, histology, immunostaining, western blotting and proteomics. Complement genes, particularly C1qb and C5aR1, were enriched in microglia, whereas glutamatergic-synapse and axon-guidance programmes were negatively enriched. In cellular models and SOD1[G93A] spinal cord, Lf-ATQ reduced C1qb, NLRP3 and multiple inflammatory mediators, attenuated glial reactivity and altered autophagy-related proteins. Treatment preserved rotarod performance, grip strength, gait parameters, compound muscle action potential amplitude and gastrocnemius morphology. Proteomic analysis indicated remodelling of complement/coagulation, vesicular-transport and synaptic modules. These findings support Lf-ATQ as a central nervous system (CNS) -oriented, complement-regulating nanotherapy candidate for ALS. Direct functional target-inhibition assays, quantitative ATQ pharmacokinetics, long-term safety assessment and validation in non-SOD1 models remain necessary before translational conclusions can be drawn.},
}

@article {pmid42926935,
year = {2026},
author = {Celier, A and Lanore, A and Hesters, A and Hussein, S and Benchikh, R and Bruneteau, G and Morélot-Panzini, C and Parfait, M and Piljan, M and Le Guennec, L and Weiss, N and Demeret, S and Mayaux, J and Marois, C},
title = {Outcomes of patients with amyotrophic lateral sclerosis admitted to the ICU for acute respiratory failure.},
journal = {Annals of intensive care},
volume = {16},
number = {},
pages = {100183},
pmid = {42926935},
issn = {2110-5820},
abstract = {BACKGROUND: Data on patients with amyotrophic lateral sclerosis (ALS) admitted to the intensive care unit (ICU) for acute respiratory failure are scarce, and early prognostic markers are lacking.

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

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

CONCLUSION: ICU admission for acute respiratory failure in ALS is associated with substantial short-term mortality, consistent with the poor prognosis inherent to the natural history of the disease. Hypoxemia at admission identifies a subgroup at particularly high risk of death and may help inform early prognostic assessment and shared decision-making. However, patients who survive the acute ICU phase frequently achieve favorable short-term outcomes, with most living at home at 3 months.},
}

@article {pmid42927514,
year = {2026},
author = {McHutchison, C and Wuu, J and Cosentino, S and Saldana, R and Vadella, E and Benacerraf, A and McBane, K and Gonzalez, AS and Stark, JH and Li, Y and Abrahams, S and Benatar, M},
title = {Mild cognitive impairment in presymptomatic amyotrophic lateral sclerosis.},
journal = {Journal of neurology},
volume = {273},
number = {11},
pages = {},
pmid = {42927514},
issn = {1432-1459},
support = {4365//Muscular Dystrophy Association/ ; 172123//Muscular Dystrophy Association/ ; 2015//The ALS Association/ ; R01 NS105479/NS/NINDS NIH HHS/United States ; U54 NS090291//CReATe Scholarship funded by the National Institutes of Health/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/complications/physiopathology ; Female ; Male ; *Cognitive Dysfunction/etiology/genetics/physiopathology/diagnosis/epidemiology ; *Prodromal Symptoms ; Middle Aged ; C9orf72 Protein/genetics ; Aged ; Superoxide Dismutase-1/genetics ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are clinically and biologically related, and each may be preceded by a prodromal stage of disease. Mild cognitive and behavioural impairment (MCI/MBI) have also been observed in those with clinically manifest ALS. The primary aim of this study was to characterise MCI in presymptomatic ALS.

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

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

CONCLUSION: The observed frequency and temporal course of MCI-ft in presymptomatic ALS, using criteria based on subthreshold cognitive performance and decline, expands understanding of this phase of disease. These findings help to inform future research examining the risk of phenoconversion to clinically manifest disease and aid the design of disease prevention trials.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/complications/physiopathology
Female
Male
*Cognitive Dysfunction/etiology/genetics/physiopathology/diagnosis/epidemiology
*Prodromal Symptoms
Middle Aged
C9orf72 Protein/genetics
Aged
Superoxide Dismutase-1/genetics
Neuropsychological Tests

@article {pmid42924853,
year = {2026},
author = {Regazzetti, M and Kiper, P and Merico, A and Rossi, S and Bulcão Visco, D and Luque Moreno, C and Baba, A},
title = {Feasibility and apparent safety of functional electrical stimulation-assisted cycling in amyotrophic lateral sclerosis and primary lateral sclerosis: a single-arm longitudinal pilot feasibility study.},
journal = {European journal of translational myology},
volume = {},
number = {},
pages = {},
doi = {10.4081/ejtm.2026.16025},
pmid = {42924853},
issn = {2037-7452},
abstract = {Functional electrical stimulation-assisted cycling may be relevant in motor neuron disease, but its feasibility and safety in amyotrophic lateral sclerosis and primary lateral sclerosis remain unclear. The authors aimed to assess feasibility, apparent safety, and exploratory pre-post clinical changes of a three-week functional electrical stimulation-assisted cycling protocol in ambulatory inpatients with amyotrophic lateral sclerosis or primary lateral sclerosis. Fifteen patients were assessed; 11 were enrolled (5 ALS, 6 PLS) and received 15 supervised 30-minute FES-cycling sessions over three weeks in addition to conventional neuromotor rehabilitation. Bilateral eight-channel stimulation targeted quadriceps, tibialis anterior, hamstrings, and gastrocnemius during active or active-assisted cycling. Feasibility outcomes were enrollment, completion, tolerance, adverse events, and pre-post data availability. Clinical outcomes were analyzed descriptively. Eleven of 15 assessed patients were enrolled (73.3%; 5 ALS, 6 PLS). All enrolled participants completed the protocol, no adverse events were documented, and complete pre-post data were available. Exploratory outcomes showed favorable short-term changes in mobility, walking, strength, and spasticity. This protocol appears feasible and apparently safe in selected ambulatory inpatients. Findings are hypothesis-generating and support a prospective controlled feasibility trial before efficacy is tested.},
}

@article {pmid42925434,
year = {2026},
author = {Shah, A and Godad, A and Bagwe Parab, S},
title = {Unlocking therapeutic potential of Wnt signaling pathway in neurodegenerative diseases.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42925434},
issn = {1573-7365},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Wnt Signaling Pathway/drug effects/physiology ; Animals ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {The Wnt Signaling pathway is a regulatory network that is highly conserved in the central nervous system and is essential for the survival of neurons, synaptic plasticity, and the blood-brain barrier's integrity. The pathophysiology of major neurodegenerative and neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), is highly influenced by canonical and non-canonical Wnt Signaling dysregulation, according to increasingly compelling evidence. In addition to emphasising common molecular events such as GSK-3β overactivation, β-catenin destabilisation, neuroinflammation, synaptic dysfunction, and BBB disruption, this study offers a comparative and mechanistic overview of Wnt pathway changes across various illnesses. This article identifies overlapping treatment targets, such as GSK-3β, DKK1, LRP5/6, and Wnt ligands, by integrating common and disease-specific Wnt-associated pathways, in contrast to traditional disease-specific reviews. Furthermore, new translational approaches involving natural substances, Wnt modulators, and pathway-targeted treatments are critically examined. All things considered, this study presents Wnt Signaling as a potential neuroprotective and regenerative target for upcoming precision-based treatments in neurodegenerative disorders.},
}

Humans
*Neurodegenerative Diseases/metabolism/drug therapy
*Wnt Signaling Pathway/drug effects/physiology
Animals
Blood-Brain Barrier/metabolism/drug effects

@article {pmid42925563,
year = {2026},
author = {Niu, Y and Zhang, D and Gong, T and Guo, G and Zhang, H and Gao, C and Yang, J},
title = {Constructing functional neural circuits to model amyotrophic lateral sclerosis with induced pluripotent stem cell-derived brain organoids.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRRONLINE-D-26-00781},
pmid = {42925563},
issn = {1673-5374},
abstract = {Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons. Recent advances in human-induced pluripotent stem cell-derived brain organoids offer an innovative platform to model amyotrophic lateral sclerosis in a human-specific context. These three-dimensional organoid systems allow for the study of neuronal circuit-level dysfunction, which is central to amyotrophic lateral sclerosis pathogenesis, by incorporating multiple neuronal subtypes and supporting glial populations. In particular, the integration of region-specific brain organoids into assembloid models has enabled the reconstruction of functional long-range projections and cortico-motor circuits, closely resembling human neural connectivity. This review summarizes the generation and application of human induced pluripotent stem cell-derived brain organoids for amyotrophic lateral sclerosis research, with a focus on the reconstruction of neural circuits, multi-omics profiling, and functional assays. We also discuss how organoid systems can be leveraged for drug discovery and personalized medicine in amyotrophic lateral sclerosis, highlighting their potential to unveil human-specific disease mechanisms. Lastly, we address the current challenges and future directions for improving the physiological relevance of organoid models in amyotrophic lateral sclerosis research.},
}

@article {pmid42925619,
year = {2026},
author = {Moreira, JVA and Pinheiro, CVA and de Souza, RF and Chiappa, GR and Ramos, SC and da Silva de Magalhães, MJ and de Aguiar, DR and Dos Santos, DF},
title = {The clinical spectrum of suicide-related outcomes in amyotrophic lateral sclerosis: A systematic review and meta-analysis.},
journal = {General hospital psychiatry},
volume = {103},
number = {},
pages = {204-212},
doi = {10.1016/j.genhosppsych.2026.10.002},
pmid = {42925619},
issn = {1873-7714},
abstract = {OBJECTIVE: To synthesize clinically distinct suicide-related outcomes in amyotrophic lateral sclerosis (ALS) and comparative suicide risk without pooling non-equivalent constructs.

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

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

CONCLUSIONS: Suicide-related experiences in ALS are clinically distinct. Clinicians should clarify meaning, assess intent and immediacy, evaluate decision-making capacity and treatable psychiatric symptoms, and address palliative and psychosocial needs. A death wish or assisted-dying preference should not be assumed to indicate active suicidal intent.},
}

@article {pmid42925692,
year = {2026},
author = {Ocampo, DEM and Martínez, SS},
title = {Dynamic UV-Vis monitoring of ternary pharmaceutical photodegradation using multivariate curve resolution and predictive modeling.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {367},
number = {Pt 2},
pages = {129014},
doi = {10.1016/j.saa.2026.129014},
pmid = {42925692},
issn = {1873-3557},
abstract = {Ultraviolet (UV) photodegradation of multicomponent pharmaceutical systems generates complex spectral signals due to overlapping absorption bands and transient intermediates, limiting conventional quantitative approaches. To address this challenge, an integrated chemometric strategy was developed to predict concentration profiles in dynamic ternary mixtures of paracetamol (PAR), naproxen sodium (NPX), and diclofenac sodium (DIC) in spiked river water using Ultraviolet-visible (UV-Vis) spectroscopy. UV-Vis spectra from individual photolysis experiments were analyzed by Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) to estimate concentration profiles of the parent pharmaceuticals. These profiles were associated with ternary mixture spectra reconstructed by linear combination of the spectral data obtained from the individual photolysis experiments. The combined spectral data, together with experimentally acquired calibration data, served as input to develop a linear Partial Least Squares (PLS) and non-linear Artificial Neural Network (ANN) models, enabling simultaneous prediction of component concentrations. The degree of nonlinearity in the calibration datasets was first assessed using the Non-Linearity Degree (NLD), yielding values of 0.248, 0.398, and 0.214 for PAR, NPX, and DIC, respectively. These results exceeded the 0.05 threshold, indicating significant non-linear behavior in the calibration datasets. Accordingly, the linear PLS model showed limited predictive performance, particularly for DIC. In contrast, the non-linear ANN model achieved higher predictive accuracy, demonstrating its superior suitability for the dynamically evolving multicomponent systems.},
}