RevDate: 2025-12-15
CmpDate: 2025-12-15

Dunlop RA, Cox PA, Mehta P, et al (2025)

miRNA Biomarkers Diagnose Amyotrophic Lateral Sclerosis in Circulating Blood.

Molecular neurobiology, 63(1):298.

A rapid, accurate diagnostic test for amyotrophic lateral sclerosis (ALS) would reduce diagnostic delays and improve patient outcomes. We extracted eight circulating miRNAs from 788 blood plasma samples and analyzed them using qPCR for ALS diagnostic accuracy. The biomarker parameters were established previously using 449 individual blood samples and applied prospectively to an independent cohort for validation of a predictive model. The primary outcome was ALS classification accuracy as measured by diagnostic sensitivity, specificity, positive and negative predictive values (PPV, NPV), and area under the curve (AUC). The secondary outcome was comparative fold-regulation values determined prior to data collection. The diagnostic test had an AUC of 0.98 (95% CI 0.97-0.99), with 97% sensitivity (95% CI 96-98), 93% specificity (95% CI 90-96), 93% PPV (95% CI 91-96), and 97% NPV (95% CI 96-98). The fold-regulation values exceeded or were equal to prior calculated values. Streamlined methods resulted in higher diagnostic accuracy, cut both assay time and cost, reduced technical barriers, and enhances the feasibility for widespread clinical adoption. The high accuracy of this diagnostic biomarker suggests that continued evaluation is warranted.

RevDate: 2025-12-15

Pieper AA, BD Paul (2025)

Hydrogen Sulfide Signaling in Neurodegenerative Movement Disorders.

Handbook of experimental pharmacology [Epub ahead of print].

Hydrogen sulfide (H2S) is a gaseous signaling molecule, also known as a gasotransmitter, present in nearly all mammalian organs. It plays crucial roles in regulating various physiological processes in both the brain and peripheral systems. The body maintains tight control over H2S levels, as both excessive and deficient levels can disrupt normal physiological functions and lead to disease. H2S has a significant impact on cognitive and motor functions, which are often compromised in neurodegenerative disorders. It modulates signaling and metabolism primarily by post-translationally modifying reactive cysteine residues on proteins through sulfhydration, also known as persulfidation. This chapter reviews the signaling mechanisms regulated by H2S in neurodegenerative diseases that significantly affect motor function, specifically focusing on Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), and Leigh syndrome (LS), as well as other mitochondrial disorders. While PD, HD, and SCA are linked to decreased levels of H2S, elevated levels of H2S are associated with ALS, DS, and LS. We also explore potential therapeutic applications of modulating H2S levels in the brain.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Tam SB, Waldeck NJ, Wright M, et al (2026)

A role for the cholinergic neuron circadian clock in RNA metabolism and mediating neurodegeneration.

Life science alliance, 9(3): pii:9/3/e202503508.

Circadian clocks are encoded by a transcription-translation feedback loop that aligns physiological processes with the solar cycle. Previous work linking the circadian clock to the regulation of RNA-binding proteins (RBPs) provides a foundation for the vital examination of their mechanistic connections in the context of amyotrophic lateral sclerosis (ALS)-a fatal neurodegenerative disease commonly marked by disrupted RBP function. Here, we reveal that the spinal cord cholinergic neuron rhythmic transcriptome is enriched for genes associated with ALS and other neurodegenerative diseases. We show that there is time-of-day-dependent expression of ALS-linked RBP transcripts and rhythmic alternative splicing of genes involved in microtubule cytoskeleton organization, intracellular trafficking, and synaptic function. Through in silico analysis of RNA sequencing data from sporadic ALS patients, we find that gene expression profiles altered in disease correspond with rhythmic gene networks. Finally, we report that clock disruption through cholinergic neuron-specific deletion of clock activator BMAL1 increases neurodegeneration and drives time-of-day-dependent alternative splicing of RNA processing genes. Our results establish a role for the cholinergic neuron circadian clock in RNA metabolism and mediating neurodegeneration.

RevDate: 2025-12-15

Esposto J, Stock NL, Huber RJ, et al (2025)

Differential binding of copper and zinc to a TDP-43 RNA recognition motif decapeptide and disulfide formation at residues C173/5 revealed by ESI-MS/MS.

Analytical biochemistry pii:S0003-2697(25)00270-2 [Epub ahead of print].

Copper (Cu) and zinc (Zn) metal ions play important roles in the proper functioning and localization of neurological proteins, such as transactive response DNA-binding protein 43 (TDP-43), which is linked to amyotrophic lateral sclerosis (ALS). Previous experimental and computational studies have identified putative Zn-binding regions within the RNA recognition motif 1 (RRM1) of TDP-43. However, Cu-binding interactions have been less explored despite their redox activity in regulating thiol (C173/175) conversion to disulfide within the RRM1 domain, influencing protein structure and function. Herein, the structural characterization and fragmentation pattern analysis of a TDP-43 decapeptide (166-HMIDGRWCDC-175), within RRM1, coordinated to Cu(II) and Zn(II) ions using electrospray ionization tandem mass spectrometry (ESI-MS/MS) was conducted under non-denaturing conditions. Higher-energy collision dissociation (HCD) fragmentation analysis identified that Cu(II) prefers His/Met residues, while Zn(II) was weakly coordinated to various binding sites in the peptide, specifically His, Met, Glu, Cys, Trp and Asp residues. Computational modeling using a metal ion binding server (MIB2) confirmed the binding sites and coordination sphere of metal-peptide complexes. No significant coordination to C173 and C175 was observed with Cu or Zn, as identified by using a double Cys mutant peptide. A complete thiol-to-disulfide conversion was observed in the presence of Cu(II)/(I) only, which was confirmed by the comparison of a preformed intramolecular disulfide peptide. Overall, unique differential coordination environments were observed for each metal ion with the peptide. The study provides new insights into metal ion interactions with TDP-43 RRM1 peptide, leading to a greater understanding of metal homeostasis in TDP-43 protein biochemistry and neurodegeneration.

RevDate: 2025-12-15

Vijayasimha M (2025)

Toward neonatal analytical stewardship: building on Cadamuro et al.'s minimum-volume framework.

RevDate: 2025-12-15

Haenssler AE, Okada J, Eshghi M, et al (2025)

What can vowel acoustics reveal about the communicative participation of people living with ALS?.

Amyotrophic lateral sclerosis & frontotemporal degeneration [Epub ahead of print].

Objective: Bulbar dysfunction often diminishes the accuracy and speed of the tongue, lip, and jaw movements necessary for speech production. Vowel acoustic features derived from speech recordings can serve as sensitive markers of articulatory accuracy and movement timing. We examined whether degraded speech caused by amyotrophic lateral sclerosis (ALS), assessed through vowel acoustic features, was associated with communicative participation restrictions. As a secondary aim, we assessed the association of two global speech characteristics, rate and intelligibility, with vowel features and communicative participation. Materials & Methods: Thirty-three people with ALS (plwALS) recorded a reading passage and completed surveys using a smartphone application. Speaking rate and acoustic vowel features (duration, vowel articulation index [VAI]) were extracted from the recordings. Three speech-language pathologists rated speech intelligibility. Communicative participation was assessed using the Communicative Participation Item Bank (CPIB) short form. Bivariate correlation, partial correlation, and regression analyses were used to evaluate the associations between vowel features, intelligibility, speaking rate, and CPIB scores. Results: Significant bivariate correlations, ranging from rs = -0.39 to rs = 0.64, were found between speech variables and CPIB scores. A combined regression model including VAI, vowel duration, and sex explained 52% of the variance in CPIB scores. Including speaking rate or intelligibility in the partial correlation analysis attenuated the associations between vowel acoustics and CPIB. Conclusions: Vowel features and global dysarthria characteristics are linked to communicative participation in ALS. Clinical practices designed to target vowel production, speaking rate, and intelligibility may help to maintain daily communication in ALS.

RevDate: 2025-12-15

Drake RE, Bond GR, DR Becker (2025)

Letter to the Editor regarding Schrader et al.'s (2025) "Work and recovery from substance use disorder in Veterans Affairs".

Psychiatric rehabilitation journal pii:2027-05594-001 [Epub ahead of print].

Comments on an article by S. W. Schrader et al. (see record 2026-54463-001). Schrader et al. recently reported on VA programs for veterans in early stages of recovery from substance use disorder (SUD), finding that 78% of 78 veterans elected to receive therapeutic work activity, which has a primary goal of clinical recovery rather than employment, and only 22% selected programs focusing on competitive employment. Three possible interpretations may explain Schrader et al.'s anomalous finding and deserve further research. They are discussed in the current commentary. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

RevDate: 2025-12-15

Šakotić RJ, I Crişan (2025)

Laying the Groundwork for Clinical Neuropsychology in Romania: Beliefs and Practices of Psychologists Regarding Validity Testing in Clinical Assessment.

Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists pii:8380192 [Epub ahead of print].

OBJECTIVE: The present study aimed to explore and document Romanian psychologists' practices and beliefs regarding validity testing in clinical assessment, given the lack of neuropsychology as a practice field in this country.

METHOD: We developed a questionnaire addressing several key aspects, including demographic and professional information, and beliefs and practices related to validity testing in clinical assessment. The questionnaire was distributed to all practitioners licensed in clinical psychology registered on the official website of the Romanian College of Psychologists (RCP). The final sample consisted of 344 practitioners, 312 of whom had been active in assessments during the previous year.

RESULTS: Our findings revealed several cultural particularities, including the preference of 49.4% of the sample for employing the Tree Drawing Test (Koch, K. (1954). Der Baumtest - Der Baumzeichenversuch als psychodiagnostisches Hilfsmittel. Hans Huber. Romanian translation by Mocanu, S. (2002). Testul Arborelui - Diagnosticul psihologic cu ajutorul testului arborelui. Profex. Bucuresti) - a projective drawing technique - as a validity test. Only 16.7% of practitioners reported using empirically supported validity tests in clinical evaluations, and several performance validity tests were reported by 2-12.5% of the sample. Additionally, the prevalence of malingering was estimated to be 5%-20% and most respondents associated it with personality disorders.

CONCLUSIONS: The results indicate a need to bridge the gap between science and practice by adopting evidence-based approaches within the Romanian assessment culture. Our survey offers novel empirical insights into the current state of validity assessment in Romania, thereby contributing foundational knowledge that may support the legitimization and further development of neuropsychology within the national context.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Sabey TB, Shanklin BC, Colquitt JA, et al (2025)

The approach-inhibition theory of power: A meta-analytic test and synthesis.

Psychological bulletin, 151(10):1245-1279.

Keltner et al. (2003) presented an integrative theory of the social implications of possessing power. Their theory-the approach-inhibition theory of power-quickly became the dominant lens for empirical investigations of how power influences a person's cognition, affect, and behavior. Despite the many benefits of Keltner et al.'s theory, the past 20 years of research have surfaced several potential issues with the theory, including empirical dissensus, mediational ambiguity, and questions about cognitive versus affective primacy. The purpose of this study is to resolve these issues by conducting the first meta-analytic synthesis of the literature on the outcomes of power. Specifically, we tested Keltner et al.'s propositions that power is positively related to the approach-oriented outcomes of attention to rewards, automatic cognition, positive affect, and disinhibited behavior and negatively related to the inhibition-oriented outcomes of attention to threats, controlled cognition, negative affect, and inhibited behavior. Our meta-analysis included a final set of 1,712 effect sizes from 813 independent samples of 432 manuscripts with 269,534 participants. Our analysis demonstrates that the theory is well-supported; approach associations are larger than inhibition associations; power influences behavior indirectly through attention, cognition, and affect; and those indirect effects are largely conveyed through affect. Based on these findings, we suggest several future directions that scholars can take as the literature on power continues to evolve. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

RevDate: 2025-12-15

Vandermorris A, Metzger DL, Vyver E, et al (2025)

Correction: Response to Kulatunga Moruzi et al.'s (2025) "The Cass Review and Gender-Related Care for Young People in Canada: A Commentary on the Canadian Paediatric Society Position Statement on Transgender and Gender-Diverse Youth".

RevDate: 2025-12-15

Xu X, Zhou Q, Zhang X, et al (2025)

Untargeted metabolomics based on LC-MS and GC-MS reveal metabolic reprogramming and putative biomarkers in amyotrophic lateral sclerosis.

Chinese medical journal [Epub ahead of print].

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unknown etiology. The absence of reliable biochemical and imaging markers often delays diagnosis and limits treatment effectiveness. As metabolic reprogramming is increasingly recognized as a hallmark of ALS, a comprehensive untargeted metabolomics analysis was employed to identify critical metabolic perturbations in ALS and explore novel candidate biomarkers with potential utility in clinical diagnosis.

METHODS: Plasma from two independent cohorts comprising 399 participants (170 ALS patients, 200 healthy controls, and 29 ALS-unrelated neurological disease controls) was included. Cohort 1 was recruited from Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital (April 2020-September 2022), and cohort 2 from Sichuan Academy of Sciences-Sichuan Provincial Hospital, Ruijin Hospital, Shanghai Jiaotong University Affiliated Sixth People's Hospital, and The First Affiliated Hospital of Dalian Medical University (October 2022-February 2023). Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics approaches were used to identify metabolic alterations and potential diagnostic biomarkers for ALS. Complementary multivariable and univariable statistical approaches were applied to characterize disease-specific metabolic reprogramming in ALS. In addition, the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of differential metabolites, and binary logistic regression analysis was used to construct a multivariate biomarker model.

RESULTS: Metabolic changes of ALS were mainly observed in amino acids, fatty acyls , and purines. Inosine and hypoxanthine were found to be the most significantly and critically dysregulated metabolites in ALS. Aminoacyl-transfer ribonucleic acid (tRNA) biosynthesis and amino acid metabolism were regarded as the most significantly perturbed pathways. Across both cohorts, 26 metabolites were consistently changed. Notably, a biomarker panel comprising hypoxanthine, inosine, and trigonelline was constructed using binary logistic regression, achieving excellent diagnostic performance in distinguishing ALS from controls, with an area under the ROC curve of 0.982 in cohort 1 (sensitivity 0.970, specificity 0.940) and 0.934 in cohort 2 (sensitivity 0.942, specificity 0.791).

CONCLUSION: The disturbed pathways and biomarker candidates identified in this study may provide novel insights into ALS pathogenesis and improve diagnostic strategies.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Li L, Yang W, Hong Y, et al (2025)

Identification of Nanoplastics by Probing the Viscous Nanoenvironment.

Small science, 5(12):e202500430.

With the growing prevalence of global microplastic and nanoplastic pollution, the accumulation of nanoplastics in the human body has increased, heightening the risk of noncommunicable diseases including cancer, cardiovascular disease, and amyotrophic lateral sclerosis. However, the development of fluorescent probes for detecting nanoplastics remains challenging due to the lack of reactive sites on nanoplastics for conventional design of responsive probes. In this work, a novel strategy for the sensitive detection of nanoplastics by probing the viscous nanoenvironment surrounding them is presented. This study synthesizes a cationic fluorescent probe, Purification by silica gel column chromatography (CH2Cl2/MeOH) provided (E)-2-(2-(4-(dimethylamino)nanphthalen-1-yl)vinyl)-1,3,3-trimethyl-3H-indol-1-ium (named HCY due to its structural similarity to hemicyanine dyes) as a tawny solid (HCY), via a simple one-step reaction. HCY demonstrates high sensitivity to nanoplastics, achieving an 8.5-fold fluorescence enhancement in the presence of carboxylated polystyrene nanoplastics, with a detection limit of 0.153 μg mL[-1]. Moreover, HCY exhibits excellent biocompatibility, enabling the monitoring of nanoplastics level in living cells and visualization of nanoplastics distribution in zebrafish. This work offers a new design strategy for responsive fluorescent probes and provides a promising avenue for detecting environmental pollutants.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Roy T, Al-Chalabi A, Iacoangeli A, et al (2025)

Biomarkers in ALS trials: from discovery to clinical utility.

Frontiers in neuroscience, 19:1636303.

INTRODUCTION: Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disorder characterized by motor neuron degeneration, leading to muscle weakness, paralysis, and eventual respiratory failure. Despite advances in understanding its pathology, effective therapies remain limited, underscoring the need for reliable biomarkers to aid early diagnosis, monitor disease progression, and optimize clinical trials. This systematic review explores the role of biomarkers in ALS, focusing on their application in clinical trials to accelerate therapeutic development and enhance patient care.

METHODS: A comprehensive search of PubMed, EMBASE, MedLine, and Google Scholar identified 93 studies investigating various biomarkers, including neurofilament light chain (NFL), inflammatory markers, genetic markers like SOD1 and C9orf72, and imaging modalities.

RESULTS: NFL emerged as a robust biomarker, strongly correlating with disease progression and therapeutic response, and was frequently used in trials like RESCUE-ALS and CENTAUR. Genetic biomarkers, such as C9orf72 and SOD1 mutations, provided insights into ALS mechanisms and informed targeted therapeutic approaches. Emerging biomarkers, such as retroviral elements, show potential but require further validation. Included studies span key trials such as Lighthouse-II, MIROCALS, and MND-SMART.

DISCUSSION: This systematic review evaluates which biomarkers are currently validated for monitoring disease progression and therapeutic response in ALS clinical trials, including protein, genetic, inflammatory, metabolic, and imaging markers. It also highlights the critical role of biomarkers in advancing MND clinical trials by enabling adaptive trial designs, patient stratification, and the use of surrogate endpoints, thereby reducing trial duration and improving efficiency. The review also highlights the translational gap between biomarker discovery and clinical application, emphasizing their potential to optimize trial design and patient stratification. While biomarkers like NFL have transformed trial methodologies, challenges such as disease specificity and inter-patient heterogeneity persist. Future efforts should focus on multimodal biomarker approaches to achieve comprehensive disease assessment and advance personalized therapeutic strategies, ultimately improving outcomes for patients with MND.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Yi X, Zhou W, Cheng C, et al (2025)

Remimazolam-remifentanil general anaesthesia without muscle relaxants for percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: A retrospective analysis.

Indian journal of anaesthesia, 69(12):1413-1416.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Ross D, Lewis O, McLean O, et al (2025)

Thermally activated irreversible homogenization of G-quadruplexes in an ALS/FTD-associated gene.

bioRxiv : the preprint server for biology pii:2025.06.02.657482.

UNLABELLED: A significant proportion of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases exhibit a substantial copy number expansion of the hexanucleotide GGGGCC/GGCCCC sequence in the C9ORF72 gene. The GGGGCC sequence forms a non-canonical DNA structure called a G-quadruplex (G4) which has been associated with the disease states and with nucleic acid condensate formation. G4s can fold into various topologies, which can differentially impact fidelity of DNA synthesis. However, how G4 conformational heterogeneity and its regulation impact hexanucleotide repeat expansion is unclear, and important clues may lie in the thermodynamic properties of different G4 topologies. Here, we use temperature-swept CD spectroscopy to observe configurational homogenization of an initially heterogeneous population of G4s over a small range of temperatures, demonstrating thermally activated behavior. We further show that this reaction is irreversible, since subsequent temperature sweeps do not show CD shifts from non-parallel to parallel G4 topologies. Finally, we provide an analytical theory based on a two-state thermodynamic model which is compatible with experimental evidence, and we discuss alternate mechanisms for the homogenization transition. These findings suggest that kinetic regulation of non-canonical DNA structures may play a role in cellular homeostasis or disease pathogenesis.

SIGNIFICANCE: The GGGGCC repeats in the C9ORF72 gene expand in copy number in certain neurodegenerative diseases, forming non-canonical DNA structures called G-quadruplexes (G4) which are associated with the pathological state. However, why the repeat expansion occurs is not known, and a key may lie in the thermodynamic stability of certain G4 conformations. Here, we use CD spectroscopy to experimentally report thermally activated heat-induced G4 conformation homogenization, from a heterogeneous population to the parallel configuration. We derive an analytical biophysical theory which is compatible with this experimental observation, which is shown to be irreversible. Our in vitro tuning of the free energy landscape that modulates G4 conformational fidelity motivates a search for possible in vivo enzymatic regulators.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Mehta PR, Solomon T, Pickles S, et al (2025)

U7 small nuclear RNA splice-switching therapeutics for STMN2 and UNC13A in Amyotrophic Lateral Sclerosis.

bioRxiv : the preprint server for biology pii:2025.11.26.690143.

TDP-43 nuclear depletion in amyotrophic lateral sclerosis (ALS) causes de-repression of cryptic exons (CEs) in multiple transcripts, including UNC13A and STMN2 , disrupting synaptic transmission and neurite outgrowth. We developed a therapeutic U7 snRNA (tU7) approach that suppresses TDP-43-dependent mis-splicing, restores target gene expression, rescues neuronal functions in human iPSC-derived neurons, and shows target engagement in vivo , positioning tU7-mediated splicing correction as a promising therapeutic strategy for ALS.

RevDate: 2025-12-15
CmpDate: 2025-12-15

O'Connor JT, Loo HQ, Guo C, et al (2025)

TDP-43 suppression of ATP8A2 cryptic splicing implicates phosphatidylserine-driven neuroinflammation in ALS/FTD.

bioRxiv : the preprint server for biology pii:2025.11.21.689833.

Inappropriate externalization of phosphatidylserine (PS) is a candidate mechanism of pathogenic neuroinflammation, a critical driver of neurodegenerative disease. ATP8A2, a flippase that maintains PS on the plasma membrane inner leaflet, is mutated in both Wabbler-lethal mice and patients with the ataxia syndrome CAMRQ4. Here, we identify ATP8A2 as a target of TDP-43 cryptic exon suppression, and demonstrate that ATP8A2 loss leads to immune-mediated neurodegeneration. ATP8A2 splicing is significantly dysregulated following TDP-43 depletion in human neurons and in brains of patients with Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). In mice, Atp8a2 loss increases PS exposure and promotes neuroinflammation. Depletion of peripheral macrophages rescues motor axon degeneration and doubles Atp8a2 knockout mouse lifespan, while depletion of both peripheral macrophages and central microglia quadruples lifespan and improves coordination. Hence, ATP8A2 is a pathologically relevant TDP-43 target and inhibition of phagocytic immune cell attack against neurons is a potential treatment for patients with CAMRQ4 and ALS-FTD.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Tendulkar S, Wu T, Strickland A, et al (2025)

Dysregulated lactate metabolism synergizes with ALS genetic risk factors to accelerate motor decline.

bioRxiv : the preprint server for biology pii:2025.11.24.690227.

Neurons rely on glial lactate shuttling for metabolic support, which declines with aging and in neurodegenerative disease. Full disruption of lactate shuttling in peripheral nerves causes progressive axon degeneration, but we were interested to understand how partial disruption, a scenario more relevant to aging and disease, contributes to neurodegeneration risk. Pyruvate and lactate are interconverted by lactate dehydrogenases (LDHA and LDHB) in both lactate producing and consuming cells. We therefore began by investigating Ldhb knockout mice (loss of LDHA, the dominant LDH in liver and muscle, caused embryonic lethality), and discovered that they develop progressive neuromuscular junction atrophy and functional decline without axon degeneration. Because even Ldhb+/- heterozygosity significantly affects motor behavior, we also wondered about a potential link to congenital disease and pursued this by identifying rare loss-of-function LDHB variants among ALS patients. Next, to better understand how LDHB loss leads to motor decline, we selectively deleted it in defined cell types. SC-specific deletion caused robust motor defects, whereas motor neuron-specific deletion has little effect. Reasoning that neuronal LDHB deficiency could model age-associated decline in lactate metabolism, we asked whether it would interact with ALS genetic risk. Indeed, motor-neuron LDHB deficiency synergizes with relatively mild ALS risk variants, TDP43-Q331K and Sod1-D83G knock-in alleles, to produce early motor neuropathy, indicating that LDHB loss enhances disease risk. These findings establish lactate metabolism as a modifier of motor system vulnerability and highlight it as a therapeutic target in peripheral as well as central neurodegeneration.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Sutter AB, Buksh BF, Mojsilovic-Petrovic J, et al (2025)

The molecular mechanism of uptake and cell-to-cell transmission of arginine-containing dipeptide repeat proteins.

bioRxiv : the preprint server for biology pii:2025.11.25.690484.

UNLABELLED: Micro-satellite repeat expansion of the 5' GGGGCC 3' sequence in the C9orf72 gene is the most common monogenic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) translated from the mutant allele can be detected in postmortem brains of afflicted individuals. The arginine containing peptides, poly-PR and poly-GR, are particularly noxious to cells. Both have been shown to undergo cell-cell transmission, but the underlying mechanisms are not understood. We found rapid internalization and nucleolar localization of bath-applied hemagglutinin (HA) tagged poly-PR with twenty repeats (HA-PR 20) in cell lines and neurons. Small molecule and RNAi approaches implicated a temperature-dependent, fluid phase endocytosis mechanism in HA-PR 20 uptake. We sought to identify DPR-related cell surface uptake factors using a high-resolution proximity labeling technique developed in the MacMillan group, termed µMap. DPR-iridium conjugates identified candidate cell-surface proteins which were interrogated in an RNAi screen. Focusing on our strongest candidate, chondroitin sulfate proteoglycan 4 (CSPG4), we showed that cellular uptake of HA-PR 20 is blocked by inhibition of glycosaminoglycan chain synthesis (using drugs or RNAi) and knockdown or ablation of CSPG4 (using RNAi or CRISPR editing). Reduction of CSPG4 protected PR 20 -induced neuronal toxicity. We used a dual reporter system to interrogate in vitro neuron-to-neuron transmission of PR 50 and found that PR 50 synthesized by one neuron readily spread to neighboring neurons. Transmission was significantly reduced when CSPG4 was knocked down. These results suggest CSPG4 is an important factor in poly-PR internalization and transmission and therefore may be a therapeutic target to slow DPR transmission and disease progression.

SIGNIFICANCE STATEMENT: A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common monogenic form of ALS/FTD. This expansion leads to dipeptide repeat protein (DPR) production through non-canonical translation of repeat-containing RNA. DPRs have been shown to transmit between cells, but how this occurs is not well understood. We identified the cell surface protein chondroitin sulfate proteoglycan 4 (CSPG4) as a mediator of the uptake and intercellular spread of toxic arginine-rich DPRs. Targeting CSPG4 may provide a strategy to block DPR transmission and slow disease progression.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Guedes A, de Camargo OP, Matos EP, et al (2025)

EVALUATION OF A DECADE OF ONCOLOGICAL-ORTHOPEDIC PROCEDURES IN BRAZIL (2015-2024) AND THE IMPACT OF COVID-19.

Acta ortopedica brasileira, 33(spe3):e297250.

OBJECTIVE: To evaluate the regional distribution of hospital admission authorizations (AIH), total and average hospitalization cost (AHC), average length of stay, number of deaths and mortality rate related to oncological-orthopedic procedures funded by the Unified Health System (SUS) between 2015 and 2024, with an emphasis on the impact of the COVID-19 pandemic.

METHODS: Ecological study with time series based on data obtained from the SUS Hospital Information System, analyzed by Brazilian regions in the pre-pandemic, pandemic and post-pandemic periods. Regional differences were calculated using ANOVA or Kruskal-Wallis. The impact of the pandemic was analyzed using T-tests and ARIMA with intervention. Statistical analysis was performed in R.

RESULTS: 9,120 AIHs were recorded, mostly in the Southeast (4,375) and South (2,252) regions. Multiple regional variations were found for all the variables evaluated. Only the AHC was impacted - there was an increase in costs per procedure; The other variables maintained the trend after the beginning of the pandemic.

CONCLUSIONS: Despite the increase in the AHC, we did not observe significant variation in the number of AIH, ALS, and MR when analyzing the pre-pandemic and pandemic periods, suggesting that there was no direct impact on the performance of the analyzed procedure. Level of Evidence III; Retrospective f comparative study e.

RevDate: 2025-12-15
CmpDate: 2025-12-15

Yan K, Deng J, Yong Y, et al (2025)

Proteomic Identification of ALDOA as a Pathogenic TDP-43 Interaction Partner in ALS.

Degenerative neurological and neuromuscular disease, 15:123-132.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons, and its pathogenesis has not been fully elucidated. TAR DNA-binding protein 43 (TDP-43), as one of the key pathogenic genes in ALS, participates in the disease process through interactions with various proteins. This study aims to investigate the interaction mechanism between TDP-43 and aldolase A (ALDOA) in ALS.

METHODS: HEK293T cell models transfected with wild-type and mutant TDP-43 (TDP-43[M337V]) plasmids were constructed. The interaction between TDP-43 and ALDOA was analyzed through proteomic screening of specific peptides and co-immunoprecipitation, and the co-localization of the two in cells was detected by immunofluorescence. Changes in ALDOA expression levels after intervention with mutant TDP-43 were detected by Western blot and quantitative real-time PCR.

RESULTS: Proteomic analysis identified ALDOA as a potential interacting protein of TDP-43. Protein-protein interaction (PPI) analysis, co-immunoprecipitation, and immunofluorescence experiments further confirmed that both wild-type and mutant TDP-43 interact with ALDOA. Western blot and quantitative real-time PCR results showed that, compared with the wild-type TDP-43 group, the ALDOA expression was significantly increased in the TDP-43[M337V] mutant group.

CONCLUSION: TDP-43 interacts with ALDOA in ALS, and the TDP-43[M337V] mutation significantly promotes ALDOA expression, suggesting that ALDOA may be involved in the pathogenesis of TDP-43-mediated ALS. These findings provide new insights into the pathogenesis of ALS and highlight a potential therapeutic target.

RevDate: 2025-12-15

Jung HJ, Cheong EN, So J, et al (2025)

ALS With and Without Upper Motor Neuron Signs: A Comparative Study Supporting the Gold Coast Criteria.

Annals of clinical and translational neurology [Epub ahead of print].

OBJECTIVE: The Gold Coast criteria permit diagnosis of amyotrophic lateral sclerosis (ALS) even without upper motor neuron (UMN) signs. However, whether ALS patients with UMN signs (ALSwUMN) and those without (ALSwoUMN) share similar characteristics and prognoses remains unclear. This study compared clinical features, disease progression, electrophysiological findings, biomarker profiles, imaging parameters, and survival between these groups.

METHODS: ALS patients diagnosed according to the Gold Coast criteria were classified into ALSwUMN (n = 51) and ALSwoUMN (n = 20) groups. We evaluated clinical data, motor evoked potentials (MEP), and serum biomarkers, including cardiac Troponin T, neurofilament light chain, glial fibrillary acidic protein, and brain-derived neurotrophic factor. Imaging parameters, including cortical thickness and white matter volume, were also evaluated. Survival was analyzed using the Kaplan-Meier method.

RESULTS: The groups showed broadly similar clinical features, disease progression, and biomarker profiles. Abnormal MEPs were more frequent in ALSwUMN (94.0%) than in ALSwoUMN (63.2%, p = 0.017). Both groups demonstrated cortical thinning in the precentral and entorhinal regions compared to healthy controls. ALSwUMN exhibited thinning in the lateral orbitofrontal, insular, and temporal pole regions, while ALSwoUMN showed thinning in the pars opercularis. White matter volume was reduced in both groups in the thalamus, cerebellum, and amygdala, with additional brainstem atrophy in ALSwUMN. No significant survival difference was observed.

INTERPRETATION: Despite minor distinctions in electrophysiological and imaging findings, ALSwoUMN had overall comparable clinical profiles and outcomes to ALSwUMN. These findings support recognizing ALSwoUMN within the ALS spectrum under the Gold Coast criteria.

RevDate: 2025-12-15

Maitland S, Birkbeck M, Schofield I, et al (2025)

MRI of Neurogenic Human Motor Units Following Poliomyelitis.

Muscle & nerve [Epub ahead of print].

INTRODUCTION/AIMS: Surviving motor units in neurogenic diseases demonstrate collateral reinnervation. Scanning electromyography (EMG) reveals normal motor unit corridor length, but with "silent regions," suggesting that reinnervation does not result in increased motor unit size but may increase motor unit complexity. Motor unit magnetic resonance imaging (MUMRI) pairs MR imaging with electrical nerve stimulation to visualize individual motor units. This study aimed to assess the motor unit dimensions and complexity in patients with previous poliomyelitis compared to healthy controls.

METHODS: Patients with a history of polio were recruited from the British Polio Fellowship, compared to a retrospective cohort of healthy controls. They underwent medical history and examination of lower limb power, fatigue assessment (fatigue severity score, FSS), and a 3 T MUMRI scan of the less-affected lower limb. The cross-sectional area, maximum, and minimum Feret diameter of the motor unit territories in tibialis anterior were calculated. Motor unit complexity was computed using the Hausdorff box-counting method.

RESULTS: Of 12 polio survivors, n = 8 (6 female) were suitable for analysis and were compared to 19 controls. The mean motor unit maximum Feret diameter was 10.3 ± 3.1 mm compared to 8.4 ± 5.2 mm in controls (p = 0.34). The mean shape complexity was 0.59 ± 0.12 compared to 0.45 ± 0.2 in controls (p = 0.03).

DISCUSSION: Polio survivors demonstrate motor units with normal dimensions but increased shape complexity, indicating nonuniform collateral reinnervation largely limited to existing territories. The size and shape of motor units could help in understanding the physiological processes behind reinnervation, both in polio and other neurogenic diseases such as amyotrophic lateral sclerosis.

RevDate: 2025-12-14
CmpDate: 2025-12-14

Le Friec J, Mourier H, Couly S, et al (2025)

Positive modulation of sigma-1 receptor: a new weapon to mitigate disease progression in amyotrophic lateral sclerosis.

Translational neurodegeneration, 14(1):68.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterised by degeneration of motor neurons, leading to muscle weakness and progressive paralysis. Currently, no treatment is available to halt or reverse the progression of the disease. Oxidative stress, mitochondrial dysfunction, accumulation of unfolded proteins and inflammation are interconnected key actors involved in ALS. A potent therapeutic strategy would be to find molecules that break this vicious circle leading to neuronal dysfunction and death. Targeting sigma-1 receptor (S1R) could meet this objective, as this chaperone protein modulates many cell survival mechanisms. So far, the impact of S1R activation in ALS has been studied using specific agonists and mostly on the SOD1 mutation that represents only 2% of patients. In the present study, the impact of two different S1R activators, the reference agonist PRE-084 and the positive modulator OZP002, was compared on two key ALS genes: TDP43 and C9orf72.

METHODS: The dissociation of S1R from Binding immunoglobulin Protein (BiP) was determined using ELISA. OZP002 toxicity was compared to PRE-084 on zebrafish larvae with increasing concentrations. The efficacy of OZP002 and PRE-084 was evaluated on the locomotor escape response of zebrafish expressing mutant TDP43 or one C9orf72 toxic dipeptide. Their effects on NRF2 target gene expression were studied by qPCR. The beneficial effect was further examined on the locomotor performances of TDP43[A315T] mice using rotarod and beam walking tests. We also performed analysis on motor neuron loss and glial reactivity.

RESULTS: OZP002 is a positive modulator of S1R, that increases the dissociation of the S1R-BiP complex induced by orthosteric agonists. S1R activation by both OZP002 and PRE-084 restored the locomotor response of ALS zebrafish expressing either TDP43 or one C9orf72 toxic dipeptide. The neuroprotection was due at least in part to the NRF2 cascade stimulation but not with a direct interaction. More importantly, OZP002 and PRE-084 prevented locomotor defects and degeneration of spinal motor neurons in TDP43[A315T] transgenic mice. Astroglial and microglial reactivities were also reduced by both activators.

CONCLUSIONS: We here emphasize the therapeutic value of S1R activation in mitigating ALS pathology. Additionally, we show that the positive modulators pave the way for the development of new S1R-activating compounds for ALS treatment.

RevDate: 2025-12-14

Donison N, Hintermayer MA, Palik J, et al (2025)

MAPK family members differentially regulate pThr175 tau-mediated pathogenicity.

Neurobiology of disease pii:S0969-9961(25)00440-1 [Epub ahead of print].

The phosphorylation of tau is a critical determinant of both its physiological function and the induction of pathological misfolding and aggregation. We have previously provided evidence that tau phosphorylation at Thr175 results in the exposure of the N-terminal phosphatase-activating domain (PAD) leading to the subsequent phosphorylation of Thr231, and formation of tau oligomers. A number of tauopathies, including chronic traumatic encephalopathy (CTE), amyotrophic lateral sclerosis with cognitive impairment (ALSci), and experimental traumatic brain injury (TBI) have been proposed to be associated with this cascade of events. However, the cellular mechanism by which Thr175 tau is phosphorylated remains unclear. In this study we identified ERK2, JNK1, and p38 as candidate kinases through molecular and histological analyses in a rodent model of TBI, where increased kinase activity and protein interaction were associated with pThr175 tau. We confirmed that both ERK2 and JNK1 are capable of phosphorylating Thr175 tau in vitro, but only ERK2-mediated phosphorylation of Thr175 tau induced the pathological cascade characterized by PAD exposure and the generation of oligomeric, truncated and neurofibrillary tau. Thr175 phosphorylation was also associated with an altered interaction between tau and the molecular chaperone protein DnaJC7, which regulates tau misfolding. Additionally, we observed that pThr175 and pThr231 tau were increased by oxidative stress, which was associated with the activation of the MAPK signaling pathways. These findings further clarify the mechanisms leading to Thr175 tau phosphorylation and its role in pathological tau formation by identifying ERK1 and JNK2 as important cellular mediators.

RevDate: 2025-12-13

Bhatia S, Mohanty V, Balappanavar AY, et al (2025)

Fostering the concept of "inclusion oral health" through experiential learning: A mixed-methods approach to explaining health inequities to dental students.

Social science & medicine (1982), 390:118859 pii:S0277-9536(25)01190-6 [Epub ahead of print].

BACKGROUND: "Inclusion oral health" (IOH) is an emerging framework focusing on developing innovative solutions to tackle oral health inequities. We intend to provoke reflection, stimulate discussion, and give students practice in responding to the needs of vulnerable population. Newer experiential teaching models have shown substantial potential for affecting values and behaviors of dental students towards underserved population. Hence, it was our aim to teach third-year dental students about IOH while simultaneously comparing the effectiveness of conventional and experiential teaching methods.

METHOD: All third-year dental students (n = 40) enrolled at a teaching dental hospital in New Delhi, India, were allocated into groups A (standard teaching, n = 20) and B (experiential teaching, n = 20). Data were collected from January to March 2023. A questionnaire based on the theme was used for pre-post assessment. A didactic lecture on the topic was delivered to both groups. Group B participants were further shown an educational movie and a field visit to a shelter. Reflections were collected from both groups using Rolfe et al.'s reflective model. Statistical and thematic analysis was performed.

RESULTS: After the intervention, knowledge of group B participants (Δk = 28.9) was higher than A (Δk = 15.8) (p = 0.04). There was a shift in the attitude of students towards community service and social responsibility, especially among the group B participants. Thematic analysis of "Reflections" revealed 6 themes under 3 main domains.

CONCLUSION: Thematic analysis shed light on the learning continuum for creating socially-sensitive and proactive dental workforce. Contemporary concepts like IOH should be woven into the dental curriculum to introduce students to critical thinking and realistic problem-solving. Experiential teaching was effective in educating the concept through engagement and critical reflection.

RevDate: 2025-12-13

Gomez-Almeria M, Martinez-Gonzalez L, Matos AT, et al (2025)

Assessment of the therapeutic effect of IGS2.7, a CK1δ protein kinase inhibitor, in combination with riluzole for the treatment of ALS-associated TDP-43 proteinopathy.

Neuropharmacology pii:S0028-3908(25)00512-X [Epub ahead of print].

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which no effective treatments currently exist. The FDA and EMA have approved only riluzole, a drug that modestly extends patient survival by 3 to 18 months. In our research, we have identified a novel CK1δ inhibitor, IGS2.7, which modulates TDP-43 proteinopathy, the main ALS pathological hallmark, in both patient-derived cellular models and TgTDP-43 mice. To assess the potential of IGS2.7 as a therapeutic candidate and considering riluzole remains the standard care for ALS patients, we evaluated its effects in combination with riluzole. Our results demonstrate that co-administration of IGS2.7 and riluzole at effective doses does not cause adverse effects. However, no additional therapeutic benefit was observed beyond that of IGS2.7 monotherapy, suggesting that IGS2.7 may be viable as either a stand-alone treatment or as an adjunct to riluzole. Notably, when suboptimal doses of both drugs were administered, a combined effect was observed. This suggests that, once IGS2.7 reaches clinical testing, its use together with lower doses of riluzole may enhance therapeutic efficacy while potentially minimizing side effects. Additional in vivo pre-clinical studies will be required to further evaluate this possibility, although only clinical trials will ultimately determine its clinical relevance.

RevDate: 2025-12-13

Alessandrini F, Wright M, Kurosaki T, et al (2025)

TDP-43 dysfunction compromises UPF1-dependent mRNA metabolism in ALS.

Neuron pii:S0896-6273(25)00848-7 [Epub ahead of print].

Up-frameshift protein 1 (UPF1)-mediated mRNA decay maintains transcriptome integrity and cellular homeostasis. However, its role in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by TAR DNA-binding protein 43 (TDP-43) pathology and disrupted mRNA metabolism in motor neurons (MNs), remains unresolved. Here, we integrated RNA sequencing (RNA-seq) after UPF1 knockdown with RNA immunoprecipitation (RIP)-seq of phosphorylated UPF1 to delineate direct UPF1 targets in induced pluripotent stem cell (iPSC)-derived MNs. These transcripts are enriched for autophagy and structurally characterized by GC-rich, long 3' untranslated regions (3' UTRs). UPF1 activity, measured by this transcript signature, is diminished in TDP-43-depleted and ALS patient MNs. Mechanistically, TDP-43 depletion impairs UPF1 phosphorylation; the two proteins interact in an RNA-dependent manner and co-aggregate in pathological inclusions in ALS tissue. Transcriptomic analyses reveal convergent regulation of alternative polyadenylation and 3' UTR length by UPF1 and TDP-43, processes disrupted in ALS models and patient neurons. Our study defines the mRNA surveillance network of UPF1 in MNs and uncovers a link between RNA decay, TDP-43 dysfunction, and ALS neurodegeneration.

RevDate: 2025-12-13

Argo A, Puntarello M, Malta G, et al (2025)

Verification of the persistence of sperm traces under different chain-of-custody conditions. Care pathway and justice for victims of sexual violence and abuse.

Forensic science, medicine, and pathology [Epub ahead of print].

The primary aim of this study was to verify the persistence of seminal traces under varying chain-of-custody conditions, along with determining how different contamination factors, time intervals between collection, and storage methods influence the detectability of semen in the context of sexual assault cases. This study combined laboratory and field analyses to simulate real-case scenarios. Three forensic detection tools-Sperm Tracker Lab, Sperm Tracker Spray, and RSID™ tests-were evaluated on multiple substrates (skin, hair, nylon, cotton, and car interiors) and under various contamination conditions, including the presence of blood, dust, soil, and bodily fluids. Detection techniques included contact-pressure methods (Sperm Tracker Lab), application on uneven surfaces (Sperm Tracker Spray), fluorescence-based searches with ALS (alternative light sources), and immunochromatographic testing (RSID™ kits) for sperm-specific proteins. Positive findings were confirmed via microscopic examination and DNA analysis. All the samples were labelled and stored following strict chain-of-custody protocols. Sperm Tracker Spray demonstrated consistent effectiveness, successfully detecting minimal volumes (1-2 µL) across a wide range of materials. Conversely, ALS showed reduced sensitivity, especially in the presence of diluted or minimal traces and on textured or dark fabrics. RSID™ kits provided reliable confirmation of the presence of semen, even when environmental or biological contamination was present. Accurate and thorough documentation of the chain of custody proved essential for preserving sample authenticity and reducing the risk of error. The findings underscore the importance of a multidisciplinary forensic approach combining specialized reagents, confirmatory immunochromatographic testing, and rigorous adherence to chain-of-custody procedures. This integrated strategy enhances the reliability of seminal trace detection in investigations of sexual assault. Moreover, verifying trace persistence under diverse conditions contributes significantly to the evidentiary value of forensic samples in judicial contexts.

RevDate: 2025-12-13
CmpDate: 2025-12-13

Li Y, Zhou Y, Yu L, et al (2025)

Myeloid Irf5 Deficiency Enhances the Therapeutic Efficacy of IMD-0354 in a TDP-25-Induced Neurodegeneration Model.

Molecular neurobiology, 63(1):290.

Neuroinflammation is recognized as a key contributor to the pathogenesis and progression of amyotrophic lateral sclerosis (ALS), with dysregulated innate immune activation implicated in exacerbating neuronal injury. However, the molecular mechanisms by which macrophages contribute to neurodegeneration in motor neurons harboring TAR DNA-binding protein 43 (TDP-43) mutations are not fully understood. M1 macrophages were generated from the bone marrow of Irf5 knockout or wild-type mice and co-cultured with the NSC34 motor neuron-like cell line overexpressing the C-terminal fragment of TDP-43 (TDP-25) using a Transwell system. Mitochondrial alterations, and apoptosis were evaluated through Western blotting, flow cytometry, and transmission electron microscopy. IMD-0354 mitigated mitochondrial dysfunction and apoptosis induced by TDP-25 exposure. This neuroprotective effect was attenuated in the presence of pro-inflammatory macrophages. Notably, the absence of Irf5 expression in macrophages amplified the protective efficacy of IMD-0354. Irf5 expression in macrophages may modulate the therapeutic efficacy of IMD-0354 in the context of TDP-43-associated proteinopathy, indicating a potential target for enhancing treatment strategies in ALS-related neurodegeneration through inhibiting inflammation.

RevDate: 2025-12-13
CmpDate: 2025-12-13

Schmitt P, Schumann P, Koerbs A, et al (2025)

Motor phenotypes and neurofilament light chain in genetic amyotrophic lateral sclerosis-results from a multicenter screening program.

Journal of neurology, 273(1):22.

OBJECTIVE: In genetic amyotrophic lateral sclerosis (ALS), the clinical phenotypes, disease progression and neurofilament light chain (NfL) levels are incompletely characterized.

METHODS: In a total cohort of 1988 ALS patients, a subcohort of genetic ALS linked to C9orf72 (n = 137), SOD1 (n = 54), TARDBP (n = 27), and FUS (n = 19) was investigated. The phenotypes of onset region, propagation and motor neuron involvement were analyzed according to the OPM classification. Serum NfL (sNfL) was measured and related to ALS progression (ALSPR, monthly change of ALS Functional Rating Scale-Revised). To quantify NfL elevation relative to ALSPR, the logNfL(index), the log-transformed ratio of sNfL to ALSPR was calculated.

RESULTS: C9orf72-associated ALS showed frequent bulbar onset (n = 42.6%), higher ALSPR (0.95, SD 0.84), highest NfL (116.3, SD 72.7 pg/mL) and logNfL(index) (5.02, SD 0.88). SOD1-ALS had mostly limb onset (n = 96.1%), slower ALSPR (0.57, SD 0.60), high NfL (76.1, SD 61.4 pg/mL) and a comparably high logNfL(index) (4.94, SD 1.03). FUS-ALS exhibited mostly limb onset (82.4%), lower motor neuron dysfunction (70.6%), a wide range of faster (22.2%) to slower ALSPR (55.6%), lower NfL (66.2, SD 32.9) and logNfL(4.65, SD 0.9). TARDBP-ALS displayed the lowest ALSPR (0.53, SD 0.52), the lowest NfL (43.3, SD 31.8 pg/mL) and the lowest logNfL(index) (4.40, SD 0.7).

CONCLUSION: In C9orf72-ALS, the phenotype and NfL profile are close to typical ALS. The finding of distinct phenotypes and NfL patterns in SOD1-, FUS- and TARDBP-associated ALS underscores the relevance of genetic ALS for prognostic counseling, clinical trial design, treatment expectations and unraveling of pathogenic mechanisms in ALS.

RevDate: 2025-12-12
CmpDate: 2025-12-12

Eshak D, M Arumugam (2025)

Integrative analysis of transcriptomics and drug-target networks identifies SMN1 as a novel biomarker and therapeutic target for amyotrophic lateral sclerosis.

Journal, genetic engineering & biotechnology, 23(4):100615.

Amyotrophic lateral sclerosis (ALS) is a prevalent and debilitating neurodegenerative disorder characterized by the selective degeneration of motor neurons. This study aims to unravel the molecular mechanisms underlying ALS through an integrated analysis of drug-target networks and gene expression data. Gene expression datasets related to ALS, including GSE115130 and GSE76220, were retrieved from the GEO database and systematically analyzed. Differential gene expression (DEG) analysis identified key upregulated and downregulated genes, while weighted gene co-expression network analysis (WGCNA) uncovered gene modules associated with ALS pathology. DEG analysis revealed genetic insights into ALS by pinpointing genes potentially involved in disease development and progression. WGCNA provided a systems-level understanding of ALS mechanisms, identifying highly correlated gene clusters and their relationship with clinical ALS characteristics. In the GSE115130 dataset, 6,105 genes were upregulated and 6,069 were downregulated. Conversely, the GSE76220 dataset showed 4,850 upregulated genes and 7,691 downregulated genes. Using the STRING database, a protein-protein interaction (PPI) network was constructed to investigate the functional relationships among ALS-associated genes. The findings highlighted the significant role of the survival motor neuron 1 (SMN1) gene in ALS, particularly in sporadic cases. Additionally, drug-target network mapping identified potential therapeutic targets and candidate drugs, offering valuable insights into the molecular mechanisms of ALS and possible interventions. This integrative approach underscored SMN1 as a novel diagnostic biomarker and potential therapeutic target for ALS, emphasizing its critical role in disease pathogenesis. These findings pave the way for further mechanistic studies and clinical validation, aiming to enhance therapeutic strategies for ALS.

RevDate: 2025-12-12

Andersen CA, Jenssen C, Poppleton A, et al (2025)

Point-of-care ultrasound in primary care - EFSUMB core curriculum and training recommendations, a position paper.

Ultraschall in der Medizin (Stuttgart, Germany : 1980) [Epub ahead of print].

English abstract: Frontline physicians working in primary care increasingly use diagnostic ultrasound examinations and simple ultrasound-guided procedures as part of their daily practice. Primary care is organized in many ways across Europe and as a result, primary care physicians have different qualifications in terms of using and integrating point-of-care ultrasound in patient care. To ensure high quality and standardized practice across Europe, this position paper of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) describes training recommendations and a generic core curriculum for frontline physicians working in primary care. The core curriculum was developed through a Delphi process and includes basic ultrasound examinations corresponding to the EFSUMB competence level 1 for medical ultrasound practice. The training recommendations are intended to build a common foundation while national adjustments must be made to ensure relevance in the clinical setting and patient population. German abstract: In der Primärversorgung tätige Ärzte setzen zunehmend diagnostische Ultraschalluntersuchungen und einfache ultraschallgesteuerte Verfahren als Teil ihrer täglichen Routine ein. Die Primärversorgung ist in Europa sehr unterschiedlich organisiert, sodass die Qualifikationen der Ärzte, die Point-of-Care-Ultraschall in der primären Patientenversorgung einsetzen und integrieren, sehr unterschiedlich sind. Mit dem Ziel, eine hohe Qualität und standardisierte Ausübungspraxis in ganz Europa zu gewährleisten, stellt dieses Positionspapier der European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) Ausbildungsempfehlungen und ein PoCUS Basis-Curriculum für in der Primärversorgung tätige Ärzte vor. Das Basis-Curriculum wurde im Rahmen eines Delphi-Verfahrens entwickelt und umfasst grundlegende Ultraschalluntersuchungen, die dem EFSUMB-Kompetenzniveau 1 für die medizinische Ultraschallpraxis entsprechen. Die Ausbildungsempfehlungen sollen eine gemeinsame Grundlage schaffen, wobei durch nationale Anpassungen die Relevanz für das konkrete klinische Umfeld und die betreuten Patientengruppen sichergestellt werden muss.

RevDate: 2025-12-12

Savasan-Sogut M, Campos-Melo D, MJ Strong (2025)

3'UTR variants of ALS-linked RNAs modify subcellular and cellular phenotypes.

The FEBS journal [Epub ahead of print].

While most human genes express mRNA 3'untranslated region (3'UTR) variants of different lengths, their impact on cell physiology and disease remains largely unknown. Here, we studied 3'UTR length heterogeneity in amyotrophic lateral sclerosis (ALS) and determined that three ALS-linked transcripts exhibit lengthening of their 3'UTRs in patient samples. We investigated phenotypical effects in a neuronal cell line expressing these 3'UTRs and observed that expression of these unique 3'UTRs induces morphological changes at different levels. Among the most expressed 3'UTR variants in ALS, NEFH 3'UTR-Long induces the formation of nuclear RNA clusters, and Superoxide Dismutase 1 3'UTR-Long diminishes filopodia in the plasma membrane. Sequestosome 1 3'UTR-Long did not show major changes in nuclear RNA clusters or filopodia. Our findings provide the first evidence that 3'UTRs can modulate cellular phenotype independent of the coding region, further expanding the impact of alterations in mRNA biogenesis in ALS.

RevDate: 2025-12-12

Myers AK, Sakheim M, Rivell C, et al (2025)

Anxiety-associated behaviors following ablation of Miro1 from cortical excitatory neurons.

eNeuro pii:ENEURO.0436-25.2025 [Epub ahead of print].

Autism spectrum disorder, schizophrenia, and bipolar disorder are neuropsychiatric conditions that manifest early in life with a wide range of phenotypes, including repetitive behavior, agitation, and anxiety (American Psychological Association, 2013). While the etiology of these disorders is incompletely understood, recent data implicate a role for mitochondrial dysfunction (Norkett et al., 2017; Khaliulin et al., 2025). Mitochondria dynamically translocate to intracellular compartments to support energetics and free-radical buffering; failure to achieve this localization results in cellular dysfunction (Picard et al., 2016). Mitochondrial Rho-GTPase 1 (Miro1) resides on the outer mitochondrial membrane and facilitates microtubule-mediated mitochondrial motility and homeostasis (Fransson et al., 2003). The loss of MIRO1 is reported to contribute to the onset/progression of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease (Kay et al., 2018). We have hypothesized that MIRO1 also has a role in nervous system development and function (Lin-Hendel et al., 2016). To test this, we ablated Miro1 from cortical excitatory progenitors by crossing floxed Miro1 mice with Emx1-Cre mice and used mice of either sex for experiments. We found that mitochondrial mis-localization in migrating excitatory neurons was associated with reduced brain weight, decreased cortical volume, and subtle cortical disorganization. Adult Miro1 conditional mutants exhibit agitative-like behaviors, including decreased nesting behavior and abnormal home cage activity. The mice exhibited anxiety-like behavior and avoided confined spaces, features that have been linked to several human behavioral disorders. Our data link MIRO1 function with mitochondrial dynamics in the pathogenesis of several neuropsychiatric disorders and implicate intracellular mitochondrial dynamics to some anxiety-like behaviors.Significance Statement Neuropsychological disorders such as autism spectrum disorder, schizophrenia, and bipolar disorder have overlapping endophenotypes. While the mechanisms underlying these disorders are poorly understood, recent evidence implicates mitochondrial dysfunction and cellular mis-localization playing a role. Mitochondria support energy requirements and other physiological functions in cells. Previous research from our lab has shown distinct dynamic localization patterns within migrating excitatory and inhibitory neurons during development. To further examine the importance of mitochondrial localization, we ablated MIRO1, a protein important for coupling mitochondria to motor proteins, in excitatory neurons. The mis-localization of mitochondria in migrating excitatory neurons is associated with diminished motor skills and anxiety-like behavior in post-natal mice.

RevDate: 2025-12-12

eBioMedicine (2025)

The accelerating pace of amyotrophic lateral sclerosis research.

EBioMedicine, 122:106079.

RevDate: 2025-12-12

Ealy A, Serapiglia AM, N Panicker (2025)

Sterile Innate Immune Mechanisms in Neurodegenerative diseases.

The Journal of biological chemistry pii:S0021-9258(25)02891-1 [Epub ahead of print].

Neurodegenerative diseases are characterized by the dysfunction and death of susceptible neuronal populations. Increasing evidence has demonstrated that sustained neuroinflammation and activation of innate immune complexes underlie neurodegeneration, worsening disease progression and outcomes. Sterile inflammation (which occurs in the absence of infection) can be triggered by neurodegenerative disease-associated misfolded proteins. These studies highlight the need to decipher the complexities of innate immune signaling mechanisms and their contribution to neuropathology. In this review, we focus on major neurodegenerative diseases that have a well-documented neuroinflammatory component: Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS) and Frontotemporal Dementia (FTD). In the context of these diseases, we discuss recent advances in innate-immune mechanisms that have been demonstrated to partake in disease progression and neurodegeneration. These include evolutionarily conserved innate-immune signaling complexes whose uncontrolled activation amplifies neurodegeneration, damaging lipid droplets that accumulate within myeloid cells and prevent their ability to clear toxic protein aggregates, as well as genome-wide studies implicated genes/proteins. The individual and/or concerted actions of these pathways could be leveraged to rationally target the pathogenesis or progression of neurodegenerative diseases.

RevDate: 2025-12-12

Mitsiadou D, Xirodimas DP, J Polanowska (2025)

NEDD8, stress granules, and amyotrophic lateral sclerosis: unveiling the therapeutic potential of the NEDP1 protease.

Essays in biochemistry pii:236896 [Epub ahead of print].

Protein quality control (PQC) systems are crucial for maintaining cellular proteostasis, particularly under stress that promotes misfolded protein accumulation. A central component of this response is the assembly of stress granules (SGs), cytoplasmic condensates of RNA and proteins that temporarily stall translation. Aberrant SG dynamics, often linked to mutations in SG proteins, contribute to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), where persistent protein aggregates are hallmarks. This review examines the emerging role of the ubiquitin-like modifier NEDD8 and its deconjugating enzyme NEDP1 in regulating SG homeostasis. Recent studies identify NEDP1 as a critical factor controlling SG clearance. Inhibition of NEDP1 enhances SG turnover, prevents pathological solidification, and promotes the disassembly of toxic aggregates through hyper-NEDDylation of PARP1, a DNA repair enzyme that also governs SG dynamics. Unlike broad-spectrum PARP1 inhibitors, which can impair DNA repair and cause cytotoxicity, NEDP1 inhibition offers a stress-specific approach that preserves normal cellular functions. Encouragingly, NEDP1 inhibition effectively causes aggregate elimination in ALS patient-derived fibroblasts and restores motility in Caenorhabditis elegans disease models. Altogether, these findings highlight NEDP1 as a key regulator of SG regulation and a promising therapeutic target for ALS and related neurodegenerative disorders.

RevDate: 2025-12-12
CmpDate: 2025-12-12

Kara NS, Ozisik O, Baudot A, et al (2025)

Investigating the Potential Roles of Environmental Exposures on the Pathology of Amyotrophic Lateral Sclerosis by Overlap Analysis.

Neurotoxicity research, 43(6):51.

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease causing motor neuron loss. 90-95% of ALS cases are sporadic, and the interplay of genetic predispositions and environmental exposures is essential in ALS pathology. Several neurotoxic exposures, such as smoking, pesticides, and organic solvents, have been implicated as affecting the risk of ALS. However, it is unclear how these exposures impact specific cellular mechanisms and influence ALS risk. We investigated the potential mechanisms of toxicity of diesel exhaust, toluene, pesticides, and smoking on ALS pathology through a bioinformatics approach. We retrieved the gene sets targeted by these environmental exposures, and the gene sets involved in ALS-associated biological processes. We performed overlap analysis to assess the statistical significance of the overlap between the gene sets associated with environmental exposures and those linked to ALS. Response to oxidative stress, synaptic signaling, lipid metabolic process, cellular oxidant detoxification, and regulation of gliogenesis significantly overlapped with the gene sets targeted by each of the four environmental exposures. Contrarily, chaperone-mediated autophagy, DNA repair, and regulation of action potential, significantly overlapped only with the gene sets targeted by diesel exhaust, pesticides, and toluene, respectively. Finally, transport across the blood-brain barrier, vesicle-mediated transport, actin filament-based transport, autophagy, transport to the Golgi and subsequent modification of proteins, metabolism of lipids, regulation of neurotransmitter receptor levels, and axon guidance significantly overlapped only with the gene set targeted by tobacco smoke pollution. This study aims to investigate the molecular relationships between neurotoxic exposures and ALS by overlap analysis, providing a framework that can be applied to investigate other exposure-disease interactions.

RevDate: 2025-12-12

Yu H, Zhang X, Liu Z, et al (2025)

Explaining Isoform Selectivity of c-Jun N-Terminal Kinase 3 (JNK3) Inhibitors through Its Development and Structural Insights.

Journal of medicinal chemistry [Epub ahead of print].

c-Jun N-terminal kinase 3 (JNK3), a member of the mitogen-activated protein kinase (MAPK) family, is selectively enriched in the brain. It plays a significant role in the pathogenesis of neurodegenerative disorders, glaucoma, amyotrophic lateral sclerosis, and cancer, which makes it a promising drug target. However, the advancement of JNK3 inhibitors has been challenged by limited isoform selectivity. This article explains the pathway regulated by JNK3 and the unique functions of JNK3. A detailed structural analysis of JNK3 complexes with ligands is presented to uncover the molecular basis of binding interactions. The inhibitors are systematically classified according to their chemical scaffolds, and the reason for their isoform selectivity was discussed, providing a structural rationale for the evolution of JNK3 inhibitor design. The perspective concludes with an exploration of the challenges in the discovery of selective JNK3 inhibitors and proposes innovative strategies to surmount these obstacles.

RevDate: 2025-12-12
CmpDate: 2025-12-12

Gutral J, Cypryańska M, JB Nezlek (2025)

A Polish language version of Wood et al.'s multidimensional Authenticity Scale.

Current issues in personality psychology, 13(4):254-260.

BACKGROUND: There is considerable interest among personality psychologists in authenticity. To provide researchers with a tool to study dispositional authenticity among speakers of Polish, we created a Polish language version of Wood et al.'s multidimensional measure of authenticity. Wood et al.'s measure has 12 items and measures three constructs: four items for selfalienation; authentic living; and accepting external influence.

PARTICIPANTS AND PROCEDURE: Participants were 825 Polish adults (M age = 42.7, SD = 15.4; 50% women) who were recruited by a professional survey company. Participants completed the newly developed measure of authenticity, and for validation purposes, they completed measures of Ryff's model of well-being, self-esteem, satisfaction with life, and stress, the same measures used by Wood et al.

RESULTS: A confirmatory factor analysis found that the Polish version of the scale had the same three factors as the original measure developed by Wood et al., and the loadings of the items on the factors were consistent with those presented by Wood et al. The three scales of the new measure were reliable. Moreover, relationships between the authenticity scales and the validation measures were similar to those reported by Wood et al.

CONCLUSIONS: The present results suggest that our proposed Polish language version of Wood et al.'s multidimensional authenticity scale measures a similar set of constructs to those measured by the original English language scale. Therefore, we believe our new measure should be useful for researchers interested in studying dispositional authenticity among Polish language speakers.

RevDate: 2025-12-12

Hor JH, Ow JR, Ng W, et al (2025)

Depletion of BLOC1S1 with splice-switching oligonucleotides in ALS motor neurons improves mitochondrial respiration and rescues disease phenotypes.

Molecular therapy : the journal of the American Society of Gene Therapy pii:S1525-0016(25)01049-4 [Epub ahead of print].

Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressing and debilitating neurodegenerative disease, yet the mechanisms underlying disease onset and progression remain poorly understood, particularly in sporadic ALS. Emerging evidence suggests that mitochondrial dysfunction and metabolic dysregulation are central to ALS pathophysiology. A key feature of ALS motor neurons (MNs) is hyper-acetylation of mitochondrial proteins, which disrupt mitochondrial respiration and energy homeostasis. In this study, we identify BLOC1S1 (also known as GCN5L1) as a novel regulator of mitochondrial acetylation in ALS. We demonstrate that BLOC1S1 is significantly upregulated in ALS patient-derived MNs, post-mortem motor cortices, and spinal cords of ALS mouse models. Functional studies in induced pluripotent stem cell (iPSC)-derived MNs reveal that BLOC1S1 depletion rescues key disease phenotypes. Therefore, we develop an efficacious splice-switching antisense oligonucleotide (SSO) that induces nonsense-mediated decay of BLOC1S1 transcripts as a potential therapeutic candidate. Besides mitigating ALS-relevant cellular deficits in MN cultures from diverse genetic backgrounds, it was validated to extend disease-free and overall survival that is associated with improved rotarod performance in an ALS mouse model. These findings establish BLOC1S1 as a critical modifier of disease progression in ALS and highlight its potential as a novel therapeutic target.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Soares ÁM, de Paula Cruz ECO, da Silva LG, et al (2025)

Anatomical references for the transopercular approach to the insula: a 1.5 Tesla magnetic resonance study.

Neurosurgical review, 49(1):63.

OBJECTIVE: This study aimed to establish the topographic relation of the limiting sulci of the insula with structures on the brain surface, in addition to determining a new anatomical point to objectively identify the Berger-Sanai quadrants.

METHODS: 1.5 Tesla MRI was used to analyze 100 insulas and their relation to the brain surface. The projection of the anterior (ALS), superior (SLS), and inferior (ILS) limiting sulci of the insula onto the brain surface was determined, together with the relations between these sulci and the anterior Sylvian point (ASP), the inferior frontal sulcus (IFS), and the superior temporal sulcus (STS). The central point of the Berger-Sanai quadrants was identified based on the inferior Rolandic point (IRP). The projection of this central point onto the insula and the brain surface were also identified.

RESULTS: The following measurements were calculated: the mean anteroposterior distance between the ASP and ALS, 3.2 mm ± 0.7 mm; the mean craniocaudal distance from the ASP to the SLS, 10.5 mm ± 1.8 mm; the mean craniocaudal distance between the IFS and SLS, 15.5 mm ± 2.5 mm; the mean craniocaudal distance from the end of the IFS to the SLS, 13.5 mm ± 2.9 mm; the mean craniocaudal distance between the STS and ILS, 4.0 mm ± 1.9 mm; the mean craniocaudal distance from the end of the STS to the ILS, 6.1 mm ± 2.4 mm; and the mean laterolateral distance from the STS to the ILS, 22.7 mm ± 3.5 mm. The central point of the Berger Sanai quadrants was determined to be over the Sylvian fissure, at a mean distance of 7.3 mm ± 1.2 mm anterior to the IRP. This point projected over the precentral gyrus in 79% of cases and the posterior short gyrus of the insula in 68%.

CONCLUSIONS: The data obtained in this study demonstrate a close topographic relationship between easily identifiable structures on the brain surface (ASP, IFS and STS) and the limiting sulci of the insula. We propose a simple, novel way to find the central point of the Berger Sanai quadrants based on their relation with the IRP. The findings determined here can assist neurosurgeons in locating the insula, especially in transopercular approaches.

RevDate: 2025-12-11

Riley S, Nguyen V, Bhattacharjee R, et al (2025)

TMT-based quantitative proteomic assessment of Vicia sativa induced neurotoxicity by β-cyano-L-alanine and γ-glutamyl-β-cyano-L-alanine in SH-SY5Y cells.

Scientific reports pii:10.1038/s41598-025-30121-2 [Epub ahead of print].

β-cyano-L-alanine (BCA) and γ-glutamyl-β-cyano-L-alanine (GBCA) are the primary antinutritional compounds in Vicia sativa, a high-protein, drought-tolerant legume. While their neurotoxicity in monogastric animals has been reported, the molecular basis remains largely unknown. In this study, we optimised a rapid in vitro assay using retinoic acid-differentiated SH-SY5Y human neuroblastoma cells to assess BCA and GBCA toxicity, and then applied Tandem mass tags (TMT)-mass spectrometry (MS)-based quantitative proteomics to identify dysregulated proteins. BCA treatment dysregulated the proteins involved in DNA damage, translation, and oxidative stress, many of which are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease, as well as various cancers. In contrast, GBCA impacted the proteins linked to mitosis, cell cycle regulation, and apoptosis pathways. Interestingly, the absence of overlapping dysregulated proteins between BCA- and GBCA-treated cells suggested that the two toxins likely induce neurotoxicity via distinct mechanisms. These findings offer new insights into the molecular and cellular alterations caused by V. sativa toxins and their implications for animal feed safety.

RevDate: 2025-12-11

Maas D, Spindler A, Zappi I, et al (2025)

Response to Olsen et al's ''Summation and recommendations for the safe and effective use of topical and oral minoxidil".

RevDate: 2025-12-11
CmpDate: 2025-12-11

Fujioka Y, S Ishigaki (2025)

Decoding ALS from the tail end of RNA.

Cell genomics, 5(12):101102.

In this issue of Cell Genomics, McKeever et al.[1] generate a single-nucleus transcriptomic atlas of ALS/FTLD brain and reveal widespread alternative polyadenylation changes. Their findings highlight 3' end RNA processing as a central integrator of stress responses, cell-type specificity, and disease susceptibility, offering new mechanistic insight and potential therapeutic directions.

RevDate: 2025-12-11

Gu Y, Chen Y, Tang X, et al (2025)

Multi-omics analyses identify potential epigenetic loci associated with survival in amyotrophic lateral sclerosis across diverse populations.

EBioMedicine, 123:106071 pii:S2352-3964(25)00521-3 [Epub ahead of print].

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with highly diverse survival time. However, genetic and epigenetic factors influencing ALS survival across diverse populations remain unclear.

METHODS: We performed whole-genome sequencing (WGS) and DNA methylome array in blood DNA of patients with ALS. For survival analysis, we used Cox proportional hazards model for genetic variants, DNA methylation (DNAm) of CpG sites or CpG-SNPs in Chinese and Canadian cohorts, followed by meta-analysis. We performed pathway enrichment analysis for candidate genes inferred from DNAm events associated with survival. In paired genome and methylome data, we analysed the effect of the candidate CpG-SNP genotypes on DNAm status.

FINDINGS: Genome-wide cross-population meta-analysis of common variants in 511 patients with ALS showed a suggestive association of CAV1/CAV2 rs117002347 genotypes with survival. Epigenome-wide cross-population meta-analysis in 459 patients revealed that ALS survival was significantly linked to DNAm of 88 CpGs on 40 genes, and highlighted the AMPK and cytoskeleton pathways. Epigenome-wide cross-population meta-analysis of CpG-SNPs in 459 patients identified 8 loci on 4 genes, including BAG6 (cg27014438/rs28732154), which was further validated in another 204 patients with ALS. Moreover, analysis of paired genome/epigenome data (n = 454) indicated that BAG6 rs28732154 genotypes may modulate cg27014438 methylation, which is also a cis-eQTM of BAG6 expression in blood.

INTERPRETATION: Our study identified BAG6 cg27014438 methylation as a potential epigenetic modifier of ALS survival. BAG6 cg27014438 methylation is modulated by rs28732154 genotypes, and linked to BAG6 expression. Our findings extended our understanding of epigenetic modifiers in ALS survival.

FUNDING: This work was supported by the National Natural Science Foundation of China (82071430, 82371878) (MZ), Shanghai Municipal Natural Science Foundation General Program (22ZR1466400) (MZ), the Fundamental Research Funds for the Central Universities (MZ), the G. Harry Sheppard Memorial Research Fund, and Canadian Consortium on Neurodegeneration in Aging (ER).

RevDate: 2025-12-11

Dashnaw CM, Gonzalez M, Abdolvahabi A, et al (2025)

Heteroaggregation of Wild-Type and ALS Mutant SOD1.

ACS chemical neuroscience [Epub ahead of print].

The presence of wild-type (WT) Cu, Zn superoxide dismutase-1 (SOD1) can increase the toxicity of mutant SOD1 proteins linked to amyotrophic lateral sclerosis (ALS). The mechanism of synergy is unclear but might involve interactions between WT and mutant SOD1 in native or non-native states. One unanswered question is will the diverse rates of mutant SOD1 homofibrillization converge in the presence of WT SOD1? To answer this question, we assessed the coaggregation of mutant and WT SOD1 in vitro, including (i) how WT SOD1 affected the formation rate and stability of mutant fibrils and (ii) the proximity of WT and mutant SOD1 in heterofibrils. For most mutations studied, the presence of WT SOD1 slowed nucleation and propagation of mutant fibrils while increasing fibril thermostability. The D90A SOD1 protein was one exception: WT SOD1 had a nearly negligible effect on its rate of nucleation. The cross-seeding of soluble mutant SOD1 with WT fibrils (and of soluble WT SOD1 with mutant fibrils) suggests that both proteins can occupy the same fibril. Mass spectrometry of heterofibrils treated with an NHS-ester cross-linker (∼8 Å) suggested that WT and E100G mutant SOD1 are colocalized in heterofibrils, possibly stacked in an alternating configuration.

RevDate: 2025-12-11

Canosa A, Callegaro S, Manera U, et al (2025)

Brain metabolic connectivity in ALS due to C9ORF72 hexanucleotide expansion: a [[18]F]FDG-PET study.

European journal of nuclear medicine and molecular imaging [Epub ahead of print].

PURPOSE: Our aim was to investigate brain metabolic connectivity, as assessed via [[18]F]FDG-PET, in ALS patients carrying the C9ORF72 expansion (C9-ALS).

METHODS: We compared brain metabolism of C9-ALS and patients without mutations of the main ALS-related genes (ctrl-ALS) through the two-sample t-test model of SPM12. Metabolic clusters showing a significant difference between the two groups were used as seed regions for an interregional correlation analysis (IRCA) in each group to evaluate metabolic connectivity.

RESULTS: As compared to ctrl-ALS, C9-ALS showed a relative hypometabolism in bilateral thalamus and left precentral and postcentral gyri, and a relative hypermetabolism in bilateral cerebellum and brainstem. In the IRCA, a positive correlation was found between the thalamic seed region and the cingulate cortex, including its anterior part. This correlation was broader in C9-ALS than in Ctrl-ALS. A negative correlation between the thalamic seed region and the sensorimotor cortex was only found in C9-ALS. In the IRCA, based on the cerebellar/brainstem cluster, positive correlations with the seed region substantially represented autocorrelation in both groups. Negative correlation, which mainly included frontal cortices, was more extensive in C9-ALS than in Ctrl-ALS.

CONCLUSION: In the comparison with ctrl-ALS, C9-ALS showed a relatively lower metabolism in the thalami and a relatively higher metabolism in the brainstem and the cerebellum. As compared to ctrl-ALS, C9-ALS showed a predominant involvement of the salience network, which is related to cognitive and behavioural control. The cerebellum might be recruited to cope with cognitive impairment to a greater extent in C9-ALS than in ctrl-ALS.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Zhang R, Gao B, Li R, et al (2025)

Meta-analysis of the effects of dance- and movement-based kinesthetic games on cognitive function in older adults with cognitive impairment (CI) under different intervention periods.

Aging clinical and experimental research, 37(1):343.

OBJECTIVE: To evaluate the effects of different types and durations of exergame interventions on cognition in elderly individuals with cognitive impairment (CI) through a meta-analysis.

METHODS: A computerized search was conducted in databases including Cochrane Library, PubMed, Web of Science, Embase, and CNKI from database inception to September 2025. Quality assessment and data extraction were performed on the included studies. Results measures included the MoCA , MMSE, etc. The study designs were randomized controlled trials or qua-si-experimental studies. The Cochrane Handbook's risk of bias tool was used for quality assessment, and Rev Man 5.0 software was employed to conduct meta-analyses on the ef-fects of dance-based and movement-based exergames on cognitive function in elderly CI patients.

RESULTS: A total of 13 studies involving 433 CI patients were included. Analysis of the 13 studies showed that dance-based exergaming was significantly superior to exercise-based exergaming in cognitive ability (SMD = 0.73, P < 0.01); interventions lasting ≥8 weeks were more effective than those lasting <8 weeks (SMD = 1.01, P = 0.02).

CONCLUSION: Dance-based exergames significantly improve cognition in elderly individu-als with CI, with better effects observed in long-term interventions. However, more high-quality studies are needed to verify these findings and to supplement analyses on ex-ercise dose effects.

RevDate: 2025-12-11

González-Velasco Ó, Parlato R, Yilmaz R, et al (2025)

Somatic gene mutations in the motor cortex of patients with sporadic amyotrophic lateral sclerosis.

Brain : a journal of neurology pii:8377145 [Epub ahead of print].

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of cortical and spinal motor neurons. Mendelian germline mutations often cause familial ALS (fALS) but only approximately ten percent of sporadic ALS cases (sALS). We leveraged DNA and single cell RNA-sequencing data from autopsy tissue to explore the presence of somatic mosaic variants in sALS cases. Deep targeted panel sequencing of known ALS disease genes in motor cortex tissue revealed an enrichment of low allele frequency variants in sALS, but not in fALS with an identified monogenic cause. In silico analysis predicted increased pathogenicity of mosaic mutations in various known ALS mutational hot spots. In particular, we identified the somatic FUS variant p.E516X, located in an established hotspot for germline ALS mutations, which leads to nucleo-cytoplasmic mislocalization and aggregation typical for ALS FUS pathology. Additionally, we performed somatic variant calling on single cell RNA-sequencing data from sALS tissue and revealed a specific accumulation of somatic variants in excitatory neurons, reinforcing a neuron-autonomous disease initiation. Collectively, this study indicates that somatic mutations within the motor cortex, especially in excitatory neurons, may contribute to sALS development.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Khalid YA, Saad MB, ME Nasreddin (2025)

Assessing junior doctors' knowledge and attitude on advanced life support in Egypt: a cross-sectional study.

African journal of emergency medicine : Revue africaine de la medecine d'urgence, 15(4):100927.

INTRODUCTION: Cardiovascular diseases are a leading cause of mortality worldwide, with cardiac arrest survival heavily dependent on timely and effective resuscitation efforts. Junior doctors often serve as first responders in hospitals, yet their advanced life support (ALS) knowledge and training adequacy remain underinvestigated in Egypt. This study assessed the knowledge and attitudes of junior doctors in Egypt regarding basic life support (BLS) and ALS, identified knowledge gaps, and suggests improvements in resuscitation training programs.

METHODS: A cross-sectional survey was conducted among 184 junior doctors, including house officers, general practitioners, and residents, across multiple healthcare centres in Egypt. Data was collected via an online questionnaire based on European Resuscitation Council guidelines, evaluating demographic factors, BLS/ALS knowledge, and attitudes toward cardiac arrest management. Statistical analysis explored associations between knowledge scores and participant characteristics.

RESULTS: Participants demonstrated inadequate knowledge with mean BLS and ALS scores of 59 % and 61.8 %, respectively. Significant deficiencies were noted in pediatric resuscitation, cardiac arrest diagnosis, IV access, and capnography interpretation. Residents and those attending ALS workshops scored significantly higher (p < 0.05), while prior clinical exposure did not correlate with higher knowledge scores. Most participants (91.3%) expressed a need for further ALS training.

DISCUSSION: Junior doctors in Egypt show deficient ALS knowledge with critical gaps that may impact patient outcomes. Structured ALS training and curriculum reforms are urgently needed to enhance emergency preparedness and improve cardiac arrest survival.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Imtiaz E, Mahato RK, Soomro S, et al (2025)

Nanomedicine-enhanced delivery of CRISPR-Cas13 for RNA editing in C9orf72-associated ALS.

Annals of medicine and surgery (2012), 87(12):9167-9168.

RevDate: 2025-12-11

Shi Y, Zhao T, Peng L, et al (2025)

Investigating the shared genetic architecture between post-traumatic stress disorder and neurodegenerative diseases: a large-scale genomewide cross-trait analysis.

International journal of surgery (London, England) pii:01279778-990000000-04086 [Epub ahead of print].

BACKGROUND: Post-traumatic stress disorder (PTSD), the most prevalent psychopathological consequence following traumatic events, profoundly impacts human life amidst global societal pressures. Emerging twin and family studies suggest that individuals with stress-related disorders face an elevated risk of neurodegenerative diseases, yet the genetic underpinnings of this association remain poorly understood.

METHODS: Here, we present a comprehensive framework elucidating this genetic basis. Using bivariate causal mixture models (MiXeR), we quantified polygenic overlap between PTSD (N = 1,280,933) and four neurodegenerative phenotypes (N = 115,803- 487,511), leveraging summary statistics from the largest PTSD genome-wide association study to date. Conditional/conjunction false discovery rate (FDR) analysis identified shared genomic loci.

RESULTS: MiXeR revealed considerable genetic variant sharing between neurodegenerative diseases and PTSD. Subsequent conjunction FDR analysis pinpointed 15 distinct shared loci. ρ-HESS local genetic correlation analysis identified seven significant local genetic correlations, with Chr6: 61,880,512-63,552,888 emerging as the most significant shared locus between PTSD and Alzheimer's disease. Cross-trait analyses using MTAG and CPASSOC identified 174 PTSD risk loci associated with at least one psychiatric disorder. Protein-coding genes mapped to known and novel shared loci exhibited specific spatial developmental trajectories. Through a framework incorporating five fundamental TWAS algorithm models, we identified 27 novel susceptibility genes that passed rigorous screening. Polygenic risk score (PRS) stratification in the UK Biobank cohort revealed dose-dependent relationships between PRS and risks of Alzheimer's disease, multiple sclerosis, and Parkinson's disease, with limited support for ALS and PTSD.

CONCLUSIONS: These findings illuminate the shared genetic architecture between PTSD and neurodegenerative phenotypes, advancing our understanding of their neurobiological interconnections. And enhance statistical power for detecting shared loci, thereby refining the characterization of common genetic mechanisms underlying PTSD and neurodegenerative pathologies.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Ali YY, Fares NV, Ayad MF, et al (2025)

Toward Practical and Sensitive Fluorescence Analysis: Factorial Design-Optimized o-Phthalaldehyde Derivatization for Synchronous Spectrofluorimetric Determination of Modafinil in Plasma and Dosage Form.

Luminescence : the journal of biological and chemical luminescence, 40(12):e70383.

The current research discusses a simple, sensitive, and practical spectrofluorimetric method for Modafinil (MDF) analysis. MDF can improve the fatigue symptoms associated with amyotrophic lateral sclerosis. MDF's aliphatic primary amide moiety can undergo base-catalyzed condensation with o-phthalaldehyde to give a highly fluorescent isoindoline derivative measured at 445 nm using synchronous spectrofluorimetry with Δλ of 110 nm. Different factors were studied using a two-level factorial design to reach the optimum conditions for the analysis. The method validation was carried out following the International Conference on Harmonization guidelines. The calibration curve was established to illustrate how relative fluorescence intensity varies with MDF concentration, and linearity was attained over the range of 10-7000 ng mL[-1], with an average recovery of 100.51% ± 0.91%. The limit of detection (LOD) was determined to be 3.21 ng mL[-1] while the quantitation limit (LOQ) was found to be 9.74 ng mL[-1]. The developed method demonstrated its effectiveness in determining MDF in tablets and spiked human plasma with recoveries of 100.43% ± 0.16 and 96.07% ± 1.55, respectively. MoGAPI, AGREE, and BAGI assessments yielded scores of 72, 0.62, and 70, respectively. The results show that the method is user-friendly and can be used in routine applications.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Sancho J, Ferrer S, J Signes-Costa (2025)

Noninvasive Ventilation Effectiveness in Amyotrophic Lateral Sclerosis.

Journal of clinical medicine, 14(23): pii:jcm14238609.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons; respiratory problems are the leading cause of death and hospital admissions and are secondary to progressive weakness of the respiratory muscles and upper airway. Noninvasive ventilation (NIV) can increase survival, alleviate symptoms, reduce hospital admissions, and improve the quality of life of these patients. The key factor in respiratory management of patients with ALS is achieving effective NIV; ineffective NIV has a negative impact on survival, with a reduction of up to 50% compared to patients with an effective technique. The most common cause of ineffective NIV is air leaks; other causes include upper airway obstruction events, residual hypoventilation, hyperventilation, and upper airway obstruction secondary to an oronasal mask. Regular monitoring of the effectiveness of NIV is essential given its impact on survival; the key tools that detect the main problems are the presence of hypoventilation symptoms, arterial blood gases, nocturnal oximetry and capnography, and built-in ventilator software. Different measures have been proposed to address the ineffectiveness of NIV, such as fitting the mask to reduce air leaks, increasing ventilatory support for residual hypoventilation, decreasing ventilatory support for hyperventilation, or a trial with a nasal mask to address oronasal interface effects. In the case of obstruction, the most common measure is to increase positive expiratory pressure during NIV. These measures enable NIV to be effective in 58% of cases, achieving a survival rate similar to that of patients who have effective NIV from the outset.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Gratzer A, Gdynia N, Sasse N, et al (2025)

Rehabilitation in Amyotrophic Lateral Sclerosis: Recommendations for Clinical Practice and Further Research.

Journal of clinical medicine, 14(23): pii:jcm14238590.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition characterized by the degeneration of upper and lower motor neurons. This degeneration leads to a gradual muscle weakness, dysarthria, dysphagia, respiratory insufficiency, and, in some patients, alterations in cognitive and behavioral performance. Regardless of advancements made in pharmacological and gene-targeted interventions, a definitive curative treatment remains elusive. Consequently, rehabilitation plays a pivotal role in preserving autonomy, participation, and overall quality of life. This review outlines the current evidence and clinical approaches related to multidisciplinary rehabilitation in ALS. It covers physical and occupational therapy, respiratory, speech and language, psychological, and palliative care domains. Evidence supports moderate tailored exercise programs, early respiratory therapy, and structured management of mobility deficits, spasticity, pain, dysphagia, and communication impairments as key elements of symptomatic treatment. Psychological and social support, which includes the involvement of caregivers and relatives, enhances emotional well-being and coping resilience. Even with progressive development of gene-targeted and disease-modifying therapies, rehabilitation will stay relevant for maintaining long-term motor function. This review highlights the need for standardized, evidence-based rehabilitation protocols and intensified neurorehabilitation research to strengthen clinical outcomes and quality of life as key therapeutic goals in ALS management.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Krysiak D, Ćwiertnia M, Wójcik M, et al (2025)

Analysis of Medical Response Team Interventions and the Impact of Certified Training on the Treatment of Patients with Hypoglycaemia-A Simulation Study.

Journal of clinical medicine, 14(23): pii:jcm14238318.

Background/objectives: The effectiveness of emergency medical procedures administered to a patient in a life-threatening condition depends, to a large degree, on the knowledge and skills of medical response team personnel. Their competencies can be developed through participation in training and then verified during emergency medicine championships. Methods: The research was conducted on the basis of one of the tasks carried out during the '16th International Winter Championships in Emergency Medicine'. The task was completed by 28 Polish emergency response teams from ambulance stations across the country. The teams carried out a simulated scenario related to procedures with a patient with hypoglycaemia. The teams' interventions were assessed in accordance with European Resuscitation Council (ERC) guidelines by judges selected from among academic lecturers and ERC instructors. Results: The research showed that 86% of the teams obtained the maximum number of points for adhering to safety procedures. Further, 61% of the teams obtained the maximum of 6 points for the initial assessment, with the average number of points obtained by the teams being 5.54. The average number of points for the physical examination was 21.04, with only one team obtaining the maximum result of 26 points. Additionally, 57% of the teams obtained the maximum number of 6 points for the medical consultation, with the average obtained by the teams being 5.43. The teams obtained, on average, 8.18 points for the correct treatment of hypoglycaemia, with 68% of the teams obtaining the maximum of 9 points. The research demonstrated a positive correlation between the quality of patient examination and the collection of medical data, and the effectiveness of hypoglycaemia treatment. It was also shown that if the team leader had completed an ALS course, they obtained higher scores for the treatment of hypoglycaemia, although this finding is specific to this scenario. Conclusions: The teams demonstrated generally high performance in a simulated hypoglycaemia scenario. More complete assessment and history-taking were associated with higher treatment scores. Correct treatment was achieved in 79% of ALS-led teams versus 44% of non-ALS teams, although this observation is specific to this simulation and should not be generalised.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Basavarajappa BS, S Subbanna (2025)

From Synaptic Plasticity to Neurotoxicity: Endocannabinoid Influence on Addiction and Neurodegeneration.

International journal of molecular sciences, 26(23): pii:ijms262311632.

The endocannabinoid system (eCBS) is a versatile neuromodulatory network that orchestrates synaptic plasticity, reward processing, and neuronal homeostasis. Increasing evidence implicates eCBS dysregulation in both addiction and neurodegenerative (ND) disorders, suggesting overlapping molecular and cellular mechanisms underlying these conditions. This review synthesizes recent advances in understanding how eCBS components-cannabinoid receptors (CB1 and CB2), endogenous ligands (anandamide and 2-arachidonoylglycerol), and their metabolic enzymes-modulate dopaminergic and glutamatergic signaling within reward and reinforcement circuits. Chronic exposure to drugs of abuse, including alcohol, opioids, cocaine, and methamphetamine, perturbs eCBS homeostasis, promoting oxidative stress, neuroinflammation, excitotoxicity, mitochondrial dysfunction, and protein aggregation-pathological features common to Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. These overlapping mechanisms disrupt neuronal integrity and contribute to progressive neurotoxicity, highlighting shared pathogenic pathways between addiction and neurodegeneration. Despite these advances, critical gaps remain in delineating how substance-induced eCBS alterations precipitate neurodegenerative cascades. Addressing these gaps will be essential for harnessing the eCBS as a therapeutic target to mitigate addiction-driven neurotoxicity and age-related cognitive decline.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Mukhija S, Hering L, Schreiner SJ, et al (2025)

Multimodal Biomarker Characterization of the ALS/FTD Spectrum: A Real-World Clinical Dataset Analysis.

International journal of molecular sciences, 26(23): pii:ijms262311496.

Diagnosis and prognosis of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) spectrum remain largely dependent on clinical assessments due to a lack of established fluid biomarkers. While neurofilaments and the cerebrospinal fluid (CSF) phosphorylated-tau/total-tau ratio (pTau:tTau) have been studied, their limitations, including their lack of clinical implementation and low specificity, necessitate multimodal approaches. This study aimed to characterize the biological features of the ALS/FTD spectrum through integration of clinically available parameters. We conducted a retrospective, single-center, cross-sectional study analyzing routinely collected clinical, neuroimaging, CSF, and serum data from 229 samples, including 45 from patients with ALS, 26 from patients with FTD, 158 from patients with other neurodegenerative diseases, and 29 from cognitively healthy controls. We implemented propensity score-weighted comparisons, an F1 score-based optimal cut-point determination for the pTau:tTau ratio, and a regularized XGBoost-based multimodal feature modeling approach. The biomarker and model performance was evaluated by the area under the precision-recall curve (AUC-PR). Feature importance analysis identified characteristic indicators of the ALS/FTD spectrum. Consistent with the prior literature, the pTau:tTau ratio was significantly reduced in ALS/FTD, but the classification performance was modest (AUC-PR 0.32). A multimodal model integrating clinical, biofluid, and neuroimaging features achieved a notably better performance (AUC-PR 0.75). Feature importance analysis revealed an ALS/FTD signature beyond the pTau:tTau ratio characterized by higher global cognition, younger age, an altered Aβ42/pTau ratio, and immunoglobulin changes (CSF IgG:IgA, serum IgG). Integration of clinical routine data centered on tau, amyloid, and immunological pathophysiology as well as temporal disease dynamics provide a contextualized biological characterization of the ALS/FTD spectrum. This approach offers a foundation for hypothesis generation regarding ALS/FTD pathophysiology and biomarker-supported diagnosis.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Salvany S, Hernández S, Casanovas A, et al (2025)

Chronic Overexpression of Neuronal NRG1-III in Mice Causes Long-Term Detrimental Changes in Lower Motor Neurons, Neuromuscular Synapses and Motor Behaviour.

International journal of molecular sciences, 26(23): pii:ijms262311421.

Neuregulins (NRGs) are ligands of tyrosine kinase receptors from the ErbB family and play multiple developmental roles. NRG1-ErbB signaling regulates myelination and has been associated with amyotrophic lateral sclerosis (ALS) pathology. Given the potential therapeutic relevance of this pathway for motor neuron (MN) diseases, we employed a transgenic (TG) mouse with persistent neuronal overexpression of neuregulin type III (NRG1-III) to investigate its impact on the neuromuscular system. We performed an analysis of phenotypic changes in this TG model, including motor behavior, neuropathological evaluation by immunocytochemistry and ultrastructural examination of the spinal cord, peripheral nerves, and neuromuscular junctions (NMJs). Calcium dynamics in cultured MNs were also examined. We found that cholinergic C-boutons on TG MNs, where NRG1-III typically accumulates, exhibited upregulation of C-bouton-associated proteins and expansion of the subsynaptic cistern (SSC)-associated endoplasmic reticulum. Calcium imaging revealed altered homeostasis in TG MNs, accompanied by the upregulation of molecules linked to axonal plasticity. At NMJs, regressive changes involving autophagic dysregulation were observed. These alterations were accompanied by increased motor activity in behavioral tests. Overall, our findings indicate that persistently elevated NRG1-III signaling compromises MN connectivity and long-term health, a factor to consider when developing therapeutic strategies for neurodegenerative diseases such as ALS.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Apolloni S, Tortoriello S, Milani M, et al (2025)

Extracellular Matrix Remodeling in Motor Neuron Diseases.

International journal of molecular sciences, 26(23): pii:ijms262311376.

The extracellular matrix (ECM) constitutes a dynamic scaffold composed of both cellular and non-cellular elements that not only ensure tissue integrity but also regulate signaling events crucial for development and homeostasis. While its dysregulation has long been investigated in cancer, fibrosis, and autoimmunity, increasing evidence implicates ECM remodeling in neurodegenerative diseases, including motor neuron diseases (MNDs). Amyotrophic lateral sclerosis and spinal muscular atrophy, the most studied MNDs, both exhibit profound ECM alterations that influence synaptic connectivity, glial reactivity, and neuroinflammation. This review outlines recent data on ECM dynamics in MNDs, highlighting shared and disease-specific mechanisms, their potential as biomarkers, and therapeutic opportunities targeting the ECM environment to preserve neuronal function and slow disease progression.

RevDate: 2025-12-11
CmpDate: 2025-12-11

Butcher EL, S Arthur (2025)

Emerging Roles of Bile Acids in Neuroinflammation.

International journal of molecular sciences, 26(23): pii:ijms262311301.

Bile acids, once considered mere digestive detergents, have emerged as multifaceted signaling molecules with systemic influence extending far beyond the gastrointestinal tract. Recent discoveries reveal their capacity to modulate immune responses, cross the blood-brain barrier, and interact with central nervous system (CNS) cells through their receptors. Neuroinflammation, a key driver of neurodegenerative and neuroimmune disorders, is increasingly linked to bile acid signaling pathways that regulate glial activation, cytokine production, and neuronal survival. This review compiles the current evidence connecting bile acids to CNS inflammation, highlighting mechanistic insights, disease-specific alterations, and the gut-microbiome-bile acid-brain axis. It also explores the therapeutic potential of bile acid derivatives and receptor modulators, as well as their emerging role as biomarkers in conditions such as Alzheimer's disease, multiple sclerosis, and hepatic encephalopathy. Despite promising advances, critical gaps remain, including the need for bile receptor mapping in human CNS cells, standardized CNS bile acid profiling, and longitudinal metabolomic studies. Bridging these gaps may unlock new strategies for targeting neuroinflammation through bile acid-immune crosstalk.

RevDate: 2025-12-10

Dalton C, Mojsilovic-Petrovic J, Safren N, et al (2025)

Ubiquitin Proteasome System Components, RAD23A and USP13, Modulate TDP-43 Solubility and Neuronal Toxicity.

The Journal of neuroscience : the official journal of the Society for Neuroscience pii:JNEUROSCI.0906-25.2025 [Epub ahead of print].

At autopsy, >95% of ALS cases display a redistribution of the essential RNA binding protein TDP-43 from the nucleus into cytoplasmic aggregates. The mislocalization and aggregation of TDP-43 is believed to be a key pathological driver in ALS. Due to its vital role in basic cellular mechanisms, direct depletion of TDP-43 is unlikely to lead to a promising therapy. Therefore, we have explored the utility of identifying genes that modify its mislocalization or aggregation. We have previously shown that loss of rad-23 improves locomotor deficits in TDP-43 C. elegans models of disease and increases the degradation rate of TDP-43 in cellular models. To understand the mechanism through which these protective effects occur, we generated an inducible mutant TDP-43 HEK293 cell line. We find that knockdown of RAD23A reduces insoluble TDP-43 levels in this model and primary rat cortical neurons expressing human TDP-43[A315T] Utilizing a discovery-based proteomics approach, we then explored how loss of RAD23A remodels the proteome. Through this proteomic screen, we identified USP13, a deubiquitinase, as a new potent modifier of TDP-43 induced aggregation and cytotoxicity. We find that knockdown of USP13 reduces the abundance of sarkosyl insoluble mTDP-43 in both our HEK293 model and primary rat neurons, reduces cell death in primary rat motor neurons, and improves locomotor deficits in C. elegans ALS models.Significance Statement Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease (NDD) with no effective therapies. The mislocalization and aggregation of TAR DNA binding protein 43 (TDP-43) is a key pathological marker of ALS and other NDDs. Due to its vital functions, targeted therapeutic reduction of TDP-43 could be problematic. Here, we have explored the utility of targeting modifier genes. We find that knockdown of two members of the ubiquitin proteasome system, RAD23A and USP13, enhance TDP-43 solubility and decrease TDP-43 induced neurotoxicity.

RevDate: 2025-12-10

Spindler A, Maas D, Zappi I, et al (2025)

Response to Huang et al's ''Real-world efficacy of ritlecitinib in treating alopecia areata across various anatomical sites: Potential rapid response predictors".

RevDate: 2025-12-10

Ding W, Guo J, Lu Y, et al (2025)

Nocturnal hypoxemia mediates age-related sleep fragmentation in amyotrophic lateral sclerosis: a polysomnographic case-control study.

Acta neurologica Belgica [Epub ahead of print].

OBJECTIVE: To evaluate sleep architecture disruptions in amyotrophic lateral sclerosis (ALS) using polysomnography (PSG) and identify clinical/demographic correlates for targeted interventions.

METHODS: Forty definite/probable ALS patients (revised El Escorial criteria) without primary sleep disorders and 40 age/sex/BMI-matched controls underwent full polysomnography (PSG). Sleep parameters (total sleep time [TST], sleep efficiency [SE], wake after sleep onset [WASO], N1-N3, rapid eye movement [REM] sleep), respiratory indices (AHI, minimum peripheral oxygen saturation (min SpO₂), SpO₂ range/coefficient of variation [CV]), and clinical metrics (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R], Hospital Anxiety and Depression Scale [HADS]) were compared. Multivariate regression identified independent sleep predictors, and mediation analysis quantified min SpO₂'s role in age-sleep fragmentation relationships.

RESULTS: ALS patients showed significantly reduced TST (371.54 ± 67.62 vs. 495.13 ± 45.69 min, p = 0.004), SE (69.95 ± 13.79 vs. 85.10 ± 7.03%, p = 0.009), N2 sleep (127.33 ± 56.75 vs. 204.28 ± 67.16 min, p = 0.013), N3 sleep (61.70 ± 33.67 vs. 91.90 ± 44.06 min, p = 0.021), and REM sleep (66.09 ± 35.85 vs. 84.66 ± 37.65 min, p = 0.012) alongside elevated WASO (131.70 ± 78.82 vs. 64.26 ± 44.18 min, p = 0.015). Nocturnal oxygenation was impaired (min SpO₂: 89.3 ± 3.1% vs. 93.7 ± 2.4%, p < 0.001; SpO₂ CV: 3.7 ± 1.5% vs. 1.8 ± 0.9%, p < 0.001), though AHI and REM AHI were comparable (AHI: p = 0.087; REM AHI: p = 0.134). Age (β = -0.28, p = 0.02) and min SpO₂ (β = 0.31, p = 0.01) independently predicted TST. Mediation analysis confirmed min SpO₂ partially explains age-related TST reduction (indirect effect: -0.14, 95% CI: -0.28 to - 0.03; accounting for 43.8% of the total effect).

CONCLUSION: Our data confirm profound sleep architecture disruption and nocturnal hypoxemia in ALS independent of primary sleep disorders. Critically, we establish min SpO₂ as a partial mediator of age-related sleep fragmentation, suggesting that early management of hypoxemia may improve sleep quality. Larger prospective studies validating these mechanisms and their impact on disease progression are warranted.

RevDate: 2025-12-10

Correa-Arrieta C, Castellar-Leones S, Ruiz-Ospina E, et al (2025)

Amyotrophic lateral sclerosis in Colombia: a population-based study of incidence and socioeconomic determinants.

Amyotrophic lateral sclerosis & frontotemporal degeneration [Epub ahead of print].

Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with variable global incidence. In Latin America, limited population-level data hinder accurate burden estimation and public health planning. This study estimated ALS incidence in Colombia from 1984 to 2024, analyzing regional distribution patterns and the demographic and socioeconomic profiles of affected individuals. Methods: This cross-sectional, population-based study analyzed 2185 clinically confirmed ALS cases reported to the Colombian National Institute of Health. Diagnoses were established using El Escorial or Gold Coast criteria. Annual and cumulative incidence rates were estimated using national population data. Demographic, geographic, and socioeconomic variables were classified under international standards, and all statistical analyses were performed using Python (version 3.12). Results: A total of 2185 ALS cases diagnosed between 1984 and 2024 were included. For the most recent decade (2015-2024), the national cumulative incidence was 41.46 per million inhabitants, with a steady increase in annual incidence. Bogotá and Caldas showed the highest cumulative incidence, whereas Chocó and Casanare reported the lowest. The mean age at diagnosis was 59.9 years, with a slight male predominance (male-to-female ratio 1.11:1). Socioeconomic disparities were evident: 18.0% of patients had no formal education, and over 40% were economically inactive at diagnosis. Conclusions: ALS incidence in Colombia is lower than that reported in high-income regions, but shows pronounced geographic and socioeconomic heterogeneity. These findings underscore the need to strengthen diagnostic capacity, improve equitable access to neurology services, and advance research on environmental and genetic determinants of ALS in Latin America.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Shamsi A, Alrouji M, AlOmeir O, et al (2025)

Correction: CRISPR-Cas9: bridging the gap between aging mechanisms and therapeutic advances in neurodegenerative disorders.

Frontiers in cellular neuroscience, 19:1739705.

[This corrects the article DOI: 10.3389/fncel.2025.1681891.].

RevDate: 2025-12-10
CmpDate: 2025-12-10

Yu L, Yang Z, Ming Z, et al (2025)

Evaluation of ascending aorta and radial artery elasticity in patients with type 2 diabetes mellitus via velocity vector imaging.

Quantitative imaging in medicine and surgery, 15(12):12044-12054.

BACKGROUND: A decrease in arterial elasticity may contribute to accelerated atherosclerosis, the sequelae of which are the most common causes of death in type 2 diabetes mellitus (T2DM) patients. The aim of this study was to assess ascending aorta (AA) and radial artery (RA) elasticity in T2DM patients via velocity vector imaging (VVI).

METHODS: We enrolled 50 patients with T2DM and 52 age- and sex-matched nondiabetic individuals as controls. All the participants underwent echocardiography and RA ultrasound examinations. AA elasticity parameters, i.e., ascending aortic mean longitudinal strain (ALS), ascending aortic global circumferential strain (ACS), ascending aortic fractional area change (FAC), and RA elasticity parameters, i.e., radial arterial mean longitudinal strain (RLS) and radial arterial global circumferential strain (RCS), were evaluated with VVI. The differences in arterial elasticity parameters between diabetic and non-diabetic patients were evaluated by a paired t-test. Spearman correlation coefficients were calculated to demonstrate the relationship between arterial elasticity parameters and clinical risk factors and cardiovascular biometrics in T2DM patients.

RESULTS: We found that the T2DM group presented significantly lower ALS, ACS, FAC, RLS and RCS values than the control group did (all P<0.05). There were significant associations between all arterial elasticity parameters and glycosylated hemoglobin (HbA1c) and diabetes duration (ALS and HbA1c: r=-0.36, ALS and diabetes duration: r=-0.52, ACS and HbA1c: r=-0.32, ACS and diabetes duration: r=-0.38, FAC and HbA1c: r=-0.36, FAC and diabetes duration: r=-0.32, RLS and HbA1c: r=-0.39, RLS and diabetes duration: r=-0.46, RCS and HbA1c: r=-0.31, RCS and diabetes duration: r=-0.39, respectively; P<0.01). Additionally, the ALS was significantly negatively correlated with fasting plasma glucose (FPG) (r=-0.30, P<0.05).

CONCLUSIONS: The elasticity of the AA and RA in T2DM patients was impaired. Decreased arterial elasticity was associated with poor blood glucose control and a longer duration of diabetes. Further studies are needed to assess the clinical value of VVI findings for predicting future cardiac events.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Barahona-López C, Plans-Beriso E, Diez-Echave P, et al (2025)

Personalized prevention of neurodegenerative diseases: scoping review and evidence gap map.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(12):e70980.

Neurodegenerative diseases represent a major public health challenge due to their high prevalence and poor prognosis. Identifying biomarkers to stratify individuals by their risk of developing these diseases may help to define new personalized prevention interventions. The objective of this study was to conduct a scoping review of biomarkers for primary and secondary personalized prevention of neurodegenerative diseases. The search targeted biomarkers in adults or high-risk subpopulations in clinical or public health settings for Alzheimer's disease, vascular dementia, Lewy body disease, frontotemporal dementia, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Ultimately, 286 papers were included in the review and the interactive gap map. There is a strong focus on Alzheimer's disease, and most papers included -omics-based biomarkers and/or used artificial intelligence. Genetics/genomics are at the forefront of current scientific research, although there is a notable gap in studying gene-environment interactions, and studies in clinical settings are still scarce. HIGHLIGHTS: Research indicates a strong focus on Alzheimer´s disease and limited research in other diseases. Genetics and genomics are at the forefront of current scientific research. We found biomarkers for predicting progression in mild cognitive decline. There is a notable gap in studying gene-environment interactions. Studies investigating biomarkers in a clinical context are still scarce.

RevDate: 2025-12-10
CmpDate: 2025-12-10

Saracino D, Cipriano L, Houot M, et al (2025)

Quantifying multimodal longitudinal brain changes in presymptomatic C9orf72 disease.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(12):e70902.

INTRODUCTION: The presymptomatic phase of frontotemporal dementia and amyotrophic lateral sclerosis associated with C9orf72 repeat expansion features widespread structural brain changes. We aimed at fulfilling the unmet need of quantitative magnetic resonance imaging (MRI)-derived measures suitable for disease tracking.

METHODS: We compared the profile of longitudinal gray (GM) and white matter (WM) changes in 66 presymptomatic carriers and 52 controls over 3-year follow-up and appraised their annualized rate of change (ARC).

RESULTS: Both putamen (p < 0.01) and left insula (p = 0.005) volumes declined the most in carriers over 40, with an ARC up to four-fold higher than in controls. Increases in mean diffusivity occurred first in the left uncinate fasciculus, followed by thalamo-cortical bundles (p < 0.05), associated with higher neurofilament levels.

DISCUSSION: Our study highlighted the GM and WM structures showing the greatest longitudinal decline during the preclinical stage, whose ARC may serve as an MRI-derived biomarker for longitudinal surveillance and therapeutic outcome.

CLINICAL TRIAL REGISTRATION: NCT02590276 and NCT05358431.

HIGHLIGHTS: We studied longitudinal multimodal MRI changes in presymptomatic C9orf72 disease. Carriers displayed faster atrophy in putamen, insula and cerebellar regions. Mean diffusivity increased mainly in uncinate and thalamo-cortical tracts. These differences were even more significant in older (> 40) participants. We proposed targeted annualized rate of change as a quantitative biomarker.

RevDate: 2025-12-10

Huang J, Liu Y, Li M, et al (2025)

Safety and efficacy of botulinum toxin injection for sialorrhea in amyotrophic lateral sclerosis: a systematic review and meta-analysis.

BMC neurology, 25(1):496.

RevDate: 2025-12-09

Kulappu Arachchige SN, Abeykoon AMH, Stevenson MA, et al (2025)

Assessment of tracheal mucosal thicknesses is a preferable method for evaluation of the immunogenicity of Mycoplasma gallisepticum vaccines in poultry.

Vaccine, 72:128063 pii:S0264-410X(25)01361-1 [Epub ahead of print].

Live-attenuated vaccines are commonly used to control chronic respiratory disease (CRD) caused by Mycoplasma gallisepticum in poultry. A previous review found that measures of tracheal lesions are better indicators of the validity of a vaccine efficacy test than air sac lesions. Here we extend those observations by comparing the raw tracheal mucosal thickness (TMT) and gross air sac lesion score (ALS) data from published vaccine efficacy studies to provide insights into standardising methods for evaluation of M. gallisepticum vaccine efficacy by identifying the most discriminative and reproducible parameter to demonstrate the efficacy of vaccines and the validity of immunogenicity tests. Our analyses revealed that a higher proportion of trials detected a ≥ 80 % effectiveness of challenge based on TMT, with a significantly lower number of biological replicates, than ALS. Furthermore, a significantly higher proportion of vaccinated-and-challenged groups had a proportion protected of ≥80 %, a reduction in lesions of ≥30 % and a mitigated fraction of ≥0.80, with a significantly lower number of biological replicates, compared to the positive-control group when analyses were based on TMT rather than ALSs. These findings indicate that TMT is a more discriminative and reproducible parameter to assess the efficacy of a vaccine and the validity of an efficacy test, and hence that this should be the primary outcome variable used to evaluate M. gallisepticum vaccine efficacy studies. Furthermore, the ability of TMT to discriminate these groups with fewer biological replicates enhances animal welfare by reducing the number of animals needed for efficacy studies.

RevDate: 2025-12-09

Svendsen O, Stevens MWR, Hamamura T, et al (2025)

Reporting quality standards in gaming disorder treatment evidence: A systematic review.

Acta psychologica, 262:106063 pii:S0001-6918(25)01377-0 [Epub ahead of print].

BACKGROUND: The treatment evidence base for gaming disorder (GD) has grown steadily over the past two decades. A systematic review by King et al. (2017) of 30 studies reported that GD treatment studies tended to favor psychotherapy approaches, but the research was limited by poor reporting standards as assessed by the Consolidated Standards of Reporting Trials (CONSORT) framework. This systematic review aimed to conduct a follow up evaluation of the reporting quality of subsequent GD treatment studies.

METHODS: A literature search of six databases yielded 51,056 records, which resulted in 31 eligible studies after screening. Each study's reporting quality was assessed using the CONSORT statement, and then these assessments were compared to King et al.'s (2017) review.

RESULTS: This review identified several methodological improvements since 2017: 61 % of studies were randomized controlled trials (vs. 40 % in 2017), 90 % included control groups (vs. 63 %), and follow-up duration increased to 6.1 months (vs. 3.5 months; p = .032). Reporting improved for participant flow (87.1 % vs. 43.3 %; p = .001) and group-level statistics (74.2 % vs. 36.7 %; p = .003), but some areas showed no improvement.

DISCUSSION: There have been several improvements in GD treatment study design and reporting, including controls, randomization and follow up, reflecting an increasing number of higher quality trials for the condition. Most of the studies with higher reporting quality (i.e., scoring ≥30/46 on the CONSORT framework) were psychotherapy-based. Future research should employ designs with longer follow-ups, broader assessment of outcomes, and standardized ICD-11-aligned tools. Pharmacological treatments, including novel pharmacotherapies for other addictions (e.g., Naltrexone), are underexplored and lack high quality evidence.

RevDate: 2025-12-09

Hamzeloo M, Bogenschütz L, Hackländer RPM, et al (2025)

Evaluating the generalizability of the normative odor rating across cultures: Evidence from a German-speaking sample.

Acta psychologica, 262:106056 pii:S0001-6918(25)01370-8 [Epub ahead of print].

Olfactory perception varies across cultures, yet the cross-cultural generalizability of normative odor ratings remains underexplored. This study investigates the generalizability of normative odor ratings to a German-speaking sample by assessing 24 odors across eight dimensions-familiarity, frequency, pleasantness, irritability, context availability, discriminability, age of acquisition, and verbalizability-in 124 German-speaking participants (Mage = 22.36, SD = 3.24). Building on Moss et al.'s (2016) methodology with English-speaking participants, we examined the consistency of these dimensions, the influence of odor familiarity, and the role of odor-specific properties versus individual differences. Results revealed significant intercorrelations among the dimensions, except for age of acquisition, which negatively correlated with others, confirming the importance of early exposure in olfactory perceptual saliency and linguistic accessibility. For high-familiar odors, strong correlations with Moss et al.'s ratings were found for familiarity (r = 0.805), frequency (r = 0.799), pleasantness (r = 0.792), context availability (r = 0.794), discriminability (r = 0.967), and verbalizability (r = 0.844), and age of acquisition (r = 0.750), but not for irritability (r = 0.495). Low-familiar odors showed only a moderate correlation for verbalizability (r = 0.530), highlighting the role of exposure in cross-cultural consistency. Variance across odors significantly exceeded variance across participants, indicating reliable differentiation by odor properties. These findings suggest that normative odor ratings show strong cross-sample consistency across the two samples, particularly for familiar odors. This study supports the utility of normative ratings in olfactory research while highlighting the role of familiarity and context in cross-cultural perception.

RevDate: 2025-12-09

Matur Z, Deveci Ş, Y Erdal (2025)

Correlations of cerebrospinal fluid neurofilament light chain levels with clinical and electromyography findings in amyotrophic lateral sclerosis.

Irish journal of medical science [Epub ahead of print].

BACKGROUND: This study aimed to examine correlations between cerebrospinal fluid neurofilament light chain (CSF NfL) levels, and clinical and electrophysiological findings in amyotrophic lateral sclerosis (ALS). Compare CSF NfL and total protein levels between ALS and other central nervous system (CNS) neurodegenerative disorders.

METHODS: This retrospective study analyzed 46 ALS patients (Gold Coast criteria) and 33 non-ALS neurodegenerative controls. We documented time from symptom onset to diagnosis, revised ALS Functional Rating Scale (ALSFRS-R) scores at CSF sampling, initial involvement regions (bulbar/cervical/lumbosacral), and extent of lower motor neuron (LMN) involvement.

RESULTS: ALS patients had significantly higher CSF NfL levels than non-ALS controls (4221 ± 2585 vs. 3004 ± 2788 pg/mL, p = 0.025). In the ALS group, CSF NfL levels showed significant inverse correlation with ALSFRS-R scores (r = -0.332, p = 0.024), and patients demonstrating involvement in all four-region on needle electromyography exhibited the highest CSF NfL levels. Among the ALS cohort 18 patients (39%) had died by the last follow-up, and patients who died during the study exhibited significantly higher baseline CSF NfL levels (median: 5115 pg/mL) compared to surviving patients (median: 3276 pg/mL; p = 0.007).

CONCLUSIONS: Our study demonstrated that CSF NFL levels were significantly elevated in ALS compared to other neurodegenerative disorders. Higher CSF NFL concentrations correlated with more rapid functional decline, more extensive LMN degeneration, and poorer survival outcomes.

RevDate: 2025-12-09

Levine AA, Rucker JA, Cockerham A, et al (2025)

U.S. health plan coverage of Neuromuscular Disease Therapies: An assessment of policy availability and restrictions.

Journal of neuromuscular diseases [Epub ahead of print].

BACKGROUND: Health plan policies managing neuromuscular disease (NMD) therapies may impose burdensome requirements on patients and providers. While prior research has explored payer restrictions for rare NMD treatments, limited evidence exists on policies specifically governing therapy initiation and reauthorization.

OBJECTIVES: To examine initial and reauthorization coverage policies for therapies targeting five NMDs-Duchenne muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, generalized myasthenia gravis, and Lambert-Eaton myasthenic syndrome-across all U.S. state Medicaid programs and leading commercial health plans.

METHODS: We constructed a database of coverage decisions issued by 50 states and DC Medicaid programs and 35 major commercial insurers, including both fee-for-service and managed care organizations. We analyzed (1) policy availability and coverage frequency, (2) initial coverage requirements (e.g., subgroup restrictions, step therapy, prescriber type), (3) reauthorization criteria, and (4) approval durations.

RESULTS: Of 1204 potential decisions, 908 (75%) had publicly available policies. Of these, 558 (46%) included reauthorization criteria. Among covered therapies, 96% imposed restrictions beyond FDA label indications. Requirements varied by payer type, NMD, and therapy. Average approval durations were 6 months for initial coverage and 10 months for reauthorization.

CONCLUSIONS: Many plans lacked publicly accessible policies, and most covered therapies were subject to restrictive requirements. These barriers-such as step therapy, narrow prescriber criteria, and short approval periods-may delay treatment and disrupt care continuity. Findings underscore the need for greater transparency and reform in prior authorization and pharmacy benefit design to support timely access to NMD therapies.

RevDate: 2025-12-09

Ma T, Zhu H, Zhu J, et al (2025)

Evaluation of pathogenicity, host resistance, biological properties and chemical control of Xanthomonas fragariae Strain JD1 causing angular leaf spot on strawberry.

Plant disease [Epub ahead of print].

Angular leaf spot (ALS), caused by the quarantine pathogen Xanthomonas fragariae, is a major bacterial disease threatening global strawberry production. In China, its continued spread across multiple regions poses a significant and persistent epidemiological threat to the strawberry industry. Recently, ALS has emerged as a great threat to strawberry industry in the Jiande, Zhejiang province (located at 29°N, 119°E). This study reports the first isolation and characterization of X. fragariae strain JD1 from symptomatic strawberry leaves in Jiande, Zhejiang Province. The identification of strain JD1 was confirmed through species-specific PCR, analysis of colony characteristics, and phylogenetic clustering based on 16S rRNA and HrpB gene sequences. Pathogenicity assays revealed strain JD1 resulted in water-soaked lesions progressing to necrotic patches on leaves, along with systemic colonization of crown tissues showing water-soaked, reddish-brown lesions without cavity formation. Additionally, resistance evaluation across six strawberry cultivars revealed that 'Yue Xiu' was the most susceptible, followed closely by 'Jiande Hong', 'Hong Yu', 'Li Fen', and 'Hong Yan', while 'Fen Yu' exhibited the highest resistance. Biological characterization showed that strain JD1 grows optimally at 25°C and pH 7.0, with significant inhibition observed at 35°C and under acidic (pH 4) or alkaline (pH 9) conditions. In bactericide screening, tetramycin and benziothiazolinone were identified as highly effective against JD, followed by sintracin acetate aqueous with minor efficacy, whereas kasugamycin and quinoline copper showed limited or no efficacy. Collectively, these findings not only emphasize the threat posed by X. fragariae strain JD1 to strawberry production but also provide critical insights that inform integrated management strategies, including the use of resistant cultivars, environmental controls, and targeted bactericides, for controlling ALS.

RevDate: 2025-12-09

Rosenfeld J, Abrahams S, McHutchinson C, et al (2025)

Utility of patient subgrouping in ALS clinical trials: a World Federation of Neurology white paper.

Amyotrophic lateral sclerosis & frontotemporal degeneration [Epub ahead of print].

The heterogeneity among the amyotrophic lateral sclerosis (ALS)/MND patient population is well recognized but not well understood. Such heterogeneity may represent a significant confound in our current and prior clinical trials as certain subgroups of patients might have a selective response (or resistance) to a novel therapeutic. The basis on which to segregate the patient population is, however, unclear. The ALS/MND Committee of the World Federation of Neurology (WFN) convened a symposium to discuss various strategies that might be considered for separating (stratifying) the population to further study. The results of that conference are presented here as a white paper, reflecting current understanding of several of the various criteria that could be implemented to divide the patient population as presented and discussed at that meeting. Consideration of grouping patients based on phenotype, cognitive involvement, imaging, or electrophysiology is presented here.

RevDate: 2025-12-09

Anonymous (2025)

Erratum.

Neuro-degenerative diseases, 25(4):227.