bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–05–31
53 papers selected by
Luca Bolliger, lxBio
  1. SOD1 amyotrophic lateral sclerosis associated with Neurosarcoidosis: a case report and review of the literature.
  2. From Mutation to Manifestation: Penetrance in Amyotrophic Lateral Sclerosis.
  3. Motor neuron disease in Africa: a critical appraisal of the literature.
  4. Diagnostic Revision From Primary Lateral Sclerosis to Amyotrophic Lateral Sclerosis: A Cohort Study.
  5. Expanding the phenotypic spectrum of SOD1‑related ALS: upper motor neuron predominance in a p.D91A case.
  6. Oxidative-Nitrosative Stress and Routine Biochemical Parameters in Amyotrophic Lateral Sclerosis: Associations with Clinical Status and Disease Duration-A Pilot Study.
  7. RNA-centric approaches in amyotrophic lateral sclerosis: prospects for future therapeutics.
  8. APOE ε4 Allele is Associated with Cognitive Impairment in Chinese Sporadic ALS: A Retrospective Cohort Study.
  9. Emerging Therapeutic Strategies for Neurodegenerative Diseases: A Comprehensive Review of Recent Advances and Future Directions.
  10. Anchoring ALS Prognosis: Neurofilament Light Chain Outperforms Inflammatory, Metabolic, and CNS Barrier Biomarkers in the METABALS Cohort.
  11. Targeting the type-I interferon response in amyotrophic lateral sclerosis.
  12. Evaluation of triumeq treatment on a TDP-43 mouse model of amyotrophic Lateral sclerosis.
  13. The Molecular Basis of Partial Reversal or Significant Slowing of ALS, Parkinson's Disease, and Lewy Body Dementia by Mesenchymal Exosomes/Secretome.
  14. Diagnostic differences between military veterans and non-veterans: data from the United States National ALS Registry.
  15. 5-Hydroxytryptamine Distribution Alteration in Both Neuron and Synapse of Tg(SOD1*G93A)1gur Mice: A Potential Intervention Candidate Strategy for Amyotrophic Lateral Sclerosis.
  16. Exosome-mediated gut-brain axis signaling in neurodegenerative diseases: Mechanisms, experimental evidence, and therapeutic perspectives-A narrative review.
  17. Association between creatinine-to-cystatin C ratio and ALSFRS-R across clinical phenotypes.
  18. Feasibility and Tolerability of Ketogenic Interventions in Amyotrophic Lateral Sclerosis-A Dose-Finding Case Series.
  19. Ketogenic diet as a therapeutic strategy for neurodegenerative diseases: from mechanisms to translational challenges.
  20. VAPB confers selective neuroprotection by driving autophagic degradation of pathogenic aggregates in ALS.
  21. From Axonal Growth to Neurodegeneration: The Dual Role of Neurofilament Dynamics in Health and Disease.
  22. Air pollutants and amyotrophic lateral sclerosis in a population-based registry: investigating disease susceptibility, progression and survival.
  23. An integrated single-nucleus ribonucleic acid sequencing and spatial transcriptomic atlas reveals stage-specific neuronal and glial trajectories in a mouse model of amyotrophic lateral sclerosis.
  24. Protein Disulfide Isomerase Disassembles TDP-43/G3BP1 Condensates and Antagonizes TDP-43 Pathological Aggregates.
  25. Reevaluating the role of beta2-microglobulin: new insights on selective vulnerability in ALS pathology.
  26. The role of adiponectin and cytokines in Amyotrophic lateral sclerosis: assessment of disease progression and survival status.
  27. ERVK activity in CD8+ T cell immune cell compartment in patients with ALS.
  28. Proteomic Analysis of Corpora Amylacea Extracted From Post-mortem Brain of MAiD-end-of-life Sporadic ALS Patients.
  29. The Bright and Dark Sides of Nitric Oxide in Neurodegenerative Diseases.
  30. Discovering Hidden Vocal Subtypes: An Unsupervised Acoustic-Biomechanical Exploration of Voice Profiles.
  31. L-α-GPC in Cognitive Decline: Mechanisms and Clinical Evidence in Neurodegenerative Disorders.
  32. Understanding psychological adjustment in patients with amyotrophic lateral sclerosis and their caregivers: a scoping review.
  33. Physiological levels of 3-hydroxykynurenine alter mitochondrial function and morphology in neuronal cells.
  34. RNA-Binding Protein TAF15 Suppresses Toxicity in a Yeast Model of FUS Proteinopathy.
  35. Targeting mitochondrial dysfunction to quell neuroinflammation in central nervous system (CNS): a new strategy for treating CNS disease with nanomedicines.
  36. Cholesterol metabolism in neurodegenerative diseases: mechanisms and therapeutic advances.
  37. Beyond outcomes: patients' lived experience of exoskeleton-assisted gait training in amyotrophic lateral sclerosis.
  38. Sleep disturbances and respiratory dysfunction in amyotrophic lateral sclerosis.
  39. Neuroprotective role of cyanidin in Alzheimer's and Parkinson's disease: current insights and the road ahead.
  40. Neurodegeneration at the crossroads: the gut-brain axis and blood-brain barrier in Parkinson's disease - a review.
  41. Caspase-4 transgenic mice exhibit cytoplasmic TDP-43 accumulation and age-dependent neuropathology.
  42. Brain-First vs. Body-First Models in Neurodegenerative Disease: A Perspective Review.
  43. Somatic variation in multiple sclerosis: from blood to brain.
  44. Longitudinal CSF and Serum Biomarker Dynamics in Tofersen-Treated SOD1-ALS: A Real-World Multicentre Cohort Study.
  45. AI-driven insights into protein misfolding and innate immunity in neurodegenerative diseases.
  46. Putative glymphatic dysfunction links extracellular fluid dysregulation to white matter degeneration and clinical impairment in amyotrophic lateral sclerosis.
  47. Nucleoside-Analog Reverse-Transcriptase Inhibitors (NRTIs) Against Multiple Sclerosis: Comprehensive Review on a Possible Novel Therapeutic Approach.
  48. Integrated pharmacological and Omega-3 therapy modulates immunometabolic pathways and neuro-ophthalmological outcomes in relapsing-remitting multiple sclerosis.
  49. Hydrogels-based nasal sprays for nose-to-brain delivery: Formulation strategies, composite systems, and performance optimization.
  50. Extracellular matrix-derived matrikines as emerging modulators of neuroinflammation and central nervous system signaling.
  51. Application of a Blood-Brain Barrier Organ-on-a-Chip Model for Assessment of Countermeasure Efficiency Against Eastern Equine Encephalitis Virus.
  52. Ultrasound-Enhanced Drug Delivery in Pediatric Neuro-Oncology: A New Therapeutic Strategy.
  53. Sexually dimorphic roles of toll-like receptors in the central nervous system.
  1. Oxf Med Case Reports. 2026 May;2026(5): omag078
    SOD1 amyotrophic lateral sclerosis associated with Neurosarcoidosis: a case report and review of the literature.
    Al-Alya AlSabah, Haatem Reda.
      We describe a 37-year-old man with coexisting amyotrophic lateral sclerosis (ALS) caused by a mutation in superoxide dismutase 1 (SOD1) and probable neurosarcoid myeloradiculitis. The concurrence of the two rare conditions posed significant diagnostic and therapeutic challenges. We discuss the diagnostic timeline, therapeutic interventions, outcomes over half a decade of care, and a review of relevant literature.
    Keywords:  Neurosarcoidosis; SOD1; amyotrophic lateral sclerosis; motor neuron disease; neuroinflammation
    DOI:  https://doi.org/10.1093/omcr/omag078
  2. Genes (Basel). 2026 May 18. pii: 576. [Epub ahead of print]17(5):
    From Mutation to Manifestation: Penetrance in Amyotrophic Lateral Sclerosis.
    Elodie Richard, Sally Al-Hajj Vourc'h, Sylviane Marouillat, Stéphane Beltran, Hélène Blasco, Philippe Corcia, Patrick Vourc'h.
      Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord. While most cases are sporadic, around 10% are familial. Recent genetic studies show that many apparently isolated cases carry pathogenic mutations, highlighting the importance of penetrance, the probability that a causal mutation manifests clinically. This review focuses on mutation penetrance in ALS (C9orf72, SOD1, TARDBP, FUS genes), its variability across genes, age, and environmental or genetic modifiers, and its implications for genetic counseling. Identification of pathogenic mutations informs the monitoring of relatives and, in some cases, gives access to targeted therapies or clinical trials. Counseling of asymptomatic relatives must consider incomplete penetrance, which can lead to delayed or absent disease manifestation. ALS exists on a clinical and genetic continuum including related disorders, such as frontotemporal dementia, further influencing risk interpretation. Advances in panel, whole-exome and whole-genome sequencing refine our understanding of penetrance and enable precise diagnostics, and potential tailored therapies. Understanding penetrance is therefore essential to translate mutation discovery into informed clinical decisions and genetic counseling in ALS.
    Keywords:  ALS; genetic counseling; genetics; variable expressivity
    DOI:  https://doi.org/10.3390/genes17050576
  3. Nat Rev Neurol. 2026 May 26.
    Motor neuron disease in Africa: a critical appraisal of the literature.
    Jeannine M Heckmann, Niki Floudiotis, Akintomiwa Makanjuola, Adesola Ogunniyi, Andre Mochan, Rhanda R Mongwe, Dilraj S Sokhi, Melissa Nel.
      Motor neuron disease (MND) refers to a group of neurodegenerative diseases that cause motor neuron degeneration and death. The most common subtype, amyotrophic lateral sclerosis (ALS), is characterized by both upper and lower motor neuron impairment, which can manifest clinically in the bulbar region or asymmetrically in a limb. Typically, the disease progresses over several months, and death from respiratory failure occurs within 2-5 years of onset. As we highlight in this Review, data on MND in Africa are sparse, although common observations in this region - and in other populations with relatively low life expectancy - include apparent earlier disease onset and lower disease incidence compared with the rest of the world. In view of the HIV epidemic in Africa, we critically examine the evidence for an association between ALS and HIV infection. We briefly discuss conditions that might be regarded as ALS mimics and summarize the limited data on MND genetics in this region. Other issues pertinent to people living with MND in Africa include the absence of cognitive and behavioural data and the limited access to multidisciplinary clinics, therapies and palliative care. We share our perspective on how the ALS Africa Network is coordinating a shift in the African MND landscape to improve patient care.
    DOI:  https://doi.org/10.1038/s41582-026-01221-y
  4. Neurology. 2026 Jun 23. 106(12): e218055
    Diagnostic Revision From Primary Lateral Sclerosis to Amyotrophic Lateral Sclerosis: A Cohort Study.
    Eva M J de Boer, Sean W Willemse, Jan H Veldink, H Stephan Goedee, Alexander F J E Vrancken, Wouter van Rheenen, Henk-Jan Westeneng, Leonard H van den Berg, Michael A van Es.
       BACKGROUND AND OBJECTIVES: Primary lateral sclerosis (PLS) is defined as a pure upper motor neuron syndrome and is a diagnosis of exclusion, amyotrophic lateral sclerosis (ALS) being the most likely alternative diagnostic consideration. A minimum disease duration of 2 years is required for the diagnosis of PLS, after which patients are classified as probable PLS (P-PLS) and subsequently as definite PLS (D-PLS) after 4 years. Our aim is to apply the current diagnostic criteria to a population-based cohort and investigate which clinical characteristics are associated with a diagnostic revision to ALS.
    METHODS: This cohort study included patients meeting the current diagnostic criteria for PLS retrospectively from the Dutch Motor Neuron Disease Registry. Diagnostic revision to ALS was based on clinical assessment, EMG findings according to the revised El Escorial Criteria, or if patients had died from disease progression within 4 years of disease onset. Clinical characteristics were compared for patients who underwent diagnostic revision with ALS vs true PLS. Subdistribution hazard ratios (SHRs) for characteristics associated with diagnostic revision were determined using Fine-Gray regression.
    RESULTS: We included 478 patients (median age of onset 59.3 years, interquartile range 50.8-67.0, 47.9% female), of whom 311 (65.1%) met criteria for P-PLS and 167 (34.9%) for D-PLS at diagnosis. Eighty-eight patients (18%) underwent diagnostic revision to ALS, 76 cases (86%) before 4 years of disease duration. Patients whose diagnosis was revised to ALS had higher median age at onset (63.4 vs 58.0 years, p = 5.20 × 10-4), more often had bulbar onset (38.6% vs 19.7%, p = 6.19 × 10-4), and faster progression (median ALS Functional Rating Scale-revised slope 0.43 vs 0.18, p = 6.05 × 10-11). The risk of diagnostic revision increased if progression rate was faster (SHR 3.08 95% CI 1.69-5.60, p = 2.35 × 10-4) and if diagnosis was P-PLS compared with D-PLS (SHR 3.08, 95% CI 1.65-5.74, p = 3.96 × 10-4).
    DISCUSSION: In our cohort, most diagnostic revisions from PLS to ALS were in patients with a disease duration of less than 4 years. Besides disease duration, a faster progression rate was associated with diagnostic revision from PLS to ALS. Adding progression rate to the current diagnostic criteria could increase accuracy and help identify patients at higher risk of developing ALS.
    DOI:  https://doi.org/10.1212/WNL.0000000000218055
  5. Neurodegener Dis Manag. 2026 May 25. 1-5
    Expanding the phenotypic spectrum of SOD1‑related ALS: upper motor neuron predominance in a p.D91A case.
    Laura Tavaglione, Niccolò Madonia, Lucia Corrado, Cristoforo Comi, Sandra D'Alfonso, Letizia Mazzini, Fabiola De Marchi.
      Mutations in superoxide dismutase 1 SOD1 are the second most common genetic cause of ALS, usually associated with prevalent lower motor neuron phenotypes. We describe a 66-year-old woman with slowly progressive spastic paraparesis, initially diagnosed as primary lateral sclerosis, who carried a heterozygous p.D91A mutation. Clinical and neurophysiological findings indicated predominant upper motor neuron involvement, an unusual presentation for this mutation. This case broadens the SOD1 phenotypic spectrum and highlights the importance of early genetic testing in atypical motor syndromes, given the availability of targeted therapies where diagnostic delay may limit benefit.
    Keywords:  Amyotrophic lateral sclerosis; SOD1; gene mutation; motor neuron disease; tofersen
    DOI:  https://doi.org/10.1080/17582024.2026.2676822
  6. Biomolecules. 2026 May 13. pii: 721. [Epub ahead of print]16(5):
    Oxidative-Nitrosative Stress and Routine Biochemical Parameters in Amyotrophic Lateral Sclerosis: Associations with Clinical Status and Disease Duration-A Pilot Study.
    Pavlína Malá, Nela Váňová, Ondřej Malý, Oldřich Vyšata.
       BACKGROUND: This pilot study examined whether oxidative-nitrosative stress is associated with clinical status in amyotrophic lateral sclerosis (ALS). We analyzed associations between plasma markers of oxidative-nitrosative imbalance and ALSFRS-R, disease duration, survival, and routine biochemical parameters.
    METHODS: Twenty-nine ALS patients fulfilling the Gold Coast diagnostic criteria were enrolled. Plasma levels of 3-nitrotyrosine (3-NT), 8-oxo-2'-deoxyguanosine (8-oxodG), malondialdehyde (MDA), glutathione (GSH), non-protein thiols (NP-SH), and non-protein disulfides (NP-SS-NP), as well as creatinine, urea, uric acid and BMI, were measured. Associations with ALSFRS-R and disease duration were evaluated using non-parametric correlation analyses and second-order polynomial regression (adjusted R2), while survival was explored using Kaplan-Meier analysis and multivariable Cox regression. Given the modest sample, we considered statistical power and applied Benjamini-Hochberg false discovery rate (FDR) correction within marker families.
    RESULTS: At the uncorrected significance level, 3-NT showed a positive correlation with ALSFRS-R and a negative correlation with disease duration, and NP-SH correlated negatively with disease duration; however, these associations did not remain significant after FDR correction (FDR-adjusted p ≥ 0.099). Other oxidative-nitrosative markers and biochemical parameters showed no robust relationships with clinical measures. In Cox models, 3-NT was not significantly associated with survival (HR 3.44 per 1 nM, 95% CI 0.25-47.97, p = 0.358), whereas older age predicted higher mortality (HR 1.05 per year, 95% CI 1.00-1.10, p = 0.036).
    CONCLUSIONS: 3-NT and NP-SH exhibited the strongest trends among the investigated markers, but their clinical associations in this small cross-sectional cohort remain exploratory and require confirmation in larger longitudinal studies.
    Keywords:  3–nitrotyrosine; amyotrophic lateral sclerosis; disease duration; motor neuron disease; neurodegeneration; non-protein thiols; oxidative–nitrosative stress; oxidative–nitrosative stress biomarkers; plasma biomarkers
    DOI:  https://doi.org/10.3390/biom16050721
  7. Expert Opin Ther Targets. 2026 May 29.
    RNA-centric approaches in amyotrophic lateral sclerosis: prospects for future therapeutics.
    Valentina La Cognata, Giulia Gentile, Giovanna Morello, Maria Guarnaccia, Sebastiano Cavallaro.
       INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by profound clinical and molecular heterogeneity, which has substantially hindered the development of effective therapies. Significant advances in ALS research have been driven by the study of RNA biology, together with the implementation of advanced transcriptomic technologies and artificial intelligence - based algorithms, which are assuming a transformative role in reshaping the field.
    AREAS COVERED: We discuss how genome-wide expression profiling enables the identification of molecular signatures for drug discovery and repurposing, facilitates the stratification of patients into biologically distinct subtypes for more refined clinical trials, and guides the development of novel nucleic acid-based therapies. Furthermore, we explore the potential of transcriptomics to identify molecular vulnerabilities during pre-symptomatic stages, paving the way for early intervention.
    EXPERT OPINION: The convergence of transcriptomics and artificial intelligence is poised to fundamentally redefine ALS, transforming it from a single clinical entity into a spectrum of molecularly defined disorders, each potentially amenable to targeted therapeutic intervention. While challenges in translating high-dimensional data into clinical practice remain, the integration of transcriptomics with advanced computational tools promises to accelerate the transition toward a new era of personalized medicine in ALS.
    Keywords:  AI; ASO; Amyotrophic lateral sclerosis; RNA; drug discovery; drug repurposing; early intervention; patient stratification; transcriptomics
    DOI:  https://doi.org/10.1080/14728222.2026.2682782
  8. Biomed Environ Sci. 2026 May 20. 39(5): 564-571
    APOE ε4 Allele is Associated with Cognitive Impairment in Chinese Sporadic ALS: A Retrospective Cohort Study.
    Qiong Hua Sun, Xuan Xuan, Yu Guo Du, Yu Cui Zhai, Tie Ma, Feng Duan, Cui Qiao Xia, Xu Sheng Huang, Yong Hua Huang, Hong Fen Wang.
       Objective: To evaluate the effects of apolipoprotein E (APOE) genotype and serum APOE levels on cognitive and motor phenotypes in Chinese patients with sporadic amyotrophic lateral sclerosis (ALS).
    Methods: APOE genotypes were determined in 289 patients with sporadic ALS, and serum APOE levels were measured in a subset of 222 patients. Cognitive function was assessed using the Edinburgh Cognitive and Behavioural ALS Screen. We examined the association of APOE genotype and serum levels with age at onset, site of onset, disease progression rate (DPR), time to generalization of symptoms (TTG), and cognitive performance.
    Results: No significant differences were observed in sex, age at onset, site of onset, DPR, or TTG among patients with different APOE genotypes. Similarly, serum APOE levels did not correlate with these clinical variables. However, the APOE-ε4 allele was associated with lower ALS-specific cognitive scores, particularly in the domain of verbal fluency.
    Conclusion: Our study provides preliminary evidence linking the APOE-ε4 allele to cognitive impairment, particularly in language fluency, among Chinese patients with ALS. These findings support the hypothesis that APOE genotype contributes to ALS etiology and suggest its role in shaping distinct cognitive phenotypes in the disease.
    Keywords:  APOE genotypes; APOE serum levels; APOE ε4 allele; Amyotrophic lateral sclerosis; Cognition
    DOI:  https://doi.org/10.3967/bes2026.038
  9. Cells. 2026 May 18. pii: 928. [Epub ahead of print]15(10):
    Emerging Therapeutic Strategies for Neurodegenerative Diseases: A Comprehensive Review of Recent Advances and Future Directions.
    Masood Sepehrimanesh, Sarah Victoria Melen, Fatima Yeasmin, Victor Adeleke Ojo, Francisca Walden, Humaira Urmee, Jenna Etheridge, Aruna Kumari Nasu.
      Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the urgent need for innovative therapeutic strategies. This review highlights recent advances in the understanding of disease etiology and emerging treatment approaches, with a particular focus on modalities with translational potential. We discussed novel disease-modifying interventions, including gene and cell therapies, RNA-targeting strategies, and immunotherapies aimed at clearing misfolded proteins such as amyloid-β, tau, and α-synuclein. In parallel, we examined the evolving recognition of neuroinflammation and mitochondrial dysfunction as actionable therapeutic targets, alongside progress in precision medicine and biomarker-guided approaches that enable early diagnosis and individualized treatment. Additionally, we summarized developments in repurposed pharmacological agents, neuroprotective compounds, and lifestyle interventions, emphasizing the importance of integrative, multimodal strategies. Across AD, PD, and ALS, convergent molecular mechanisms, including protein misfolding, oxidative stress, and disrupted proteostasis, present opportunities for cross-disease therapeutic targeting. Finally, we addressed key challenges and future directions, including translating preclinical efficacy into clinical success, optimizing CNS-targeted delivery systems, and navigating ethical considerations surrounding gene editing and stem cell therapies.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; neuroinflammation; protein aggregation
    DOI:  https://doi.org/10.3390/cells15100928
  10. Mol Neurobiol. 2026 May 28. pii: 657. [Epub ahead of print]63(1):
    Anchoring ALS Prognosis: Neurofilament Light Chain Outperforms Inflammatory, Metabolic, and CNS Barrier Biomarkers in the METABALS Cohort.
    Hugo Alarcan, Charlotte Veyrat-Durebex, Pierre-François Pradat, Julien Cassereau, Alain Destee, Philippe Couratier, William Camu, Jean-Philippe Neau, Marie-Céline Fleury-Lesaunier, Patrick Emond, Diane Dufour, Yara Al Ojaimi, Antoine Lefèvre, Patrick Vourc'h, Philippe Corcia, Christian R Andres, Hélène Blasco.
      Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder with marked biological heterogeneity. Despite extensive research, reliable prognostic biomarkers remain limited, with neurofilament light chain (NfL) being the only marker increasingly implemented in clinical practice. The objective of this study is to assess and compare the prognostic value of NfL, circulating markers of central nervous system (CNS) barrier dysfunction, inflammatory mediators, kynurenine pathway metabolites, and global metabolomic profiles in patients with ALS. Seventy-two patients with ALS from the prospective multicenter METABALS cohort were included. Serum, cerebrospinal fluid (CSF), and urine samples were collected at diagnosis. NfL concentrations, markers of blood-brain and blood-spinal cord barrier permeability (albumin quotient, S100B, neuron-specific enolase [NSE]), 48 inflammatory mediators, kynurenine pathway metabolites, and untargeted metabolomic profiles were measured. Associations with clinical features, disease progression, and survival were investigated using univariate analyses and multivariate models. Serum and CSF NfL concentrations were strongly associated with ALS Functional Rating Scale-Revised scores, respiratory function, diagnostic delay, and survival. Higher serum NfL concentrations at diagnosis predicted shorter survival (ROC AUC = 0.86). In all multivariate and multi-block models, serum NfL was the only biomarker independently associated with survival. Markers of CNS barrier integrity, inflammatory mediators, and metabolomic signatures showed limited prognostic value but provided insights into metabolic remodeling and barrier dysfunction. In this integrated multi-omics study, serum NfL clearly outperformed inflammatory, metabolic, and CNS barrier markers as a prognostic biomarker in ALS, supporting its central role in clinical stratification while complementary biological markers highlighted several relevant pathophysiological mechanisms.
    Keywords:  Amyotrophic lateral sclerosis; Biomarkers; Central nervous system; Metabolomic; Neurofilament light chain
    DOI:  https://doi.org/10.1007/s12035-026-05949-y
  11. Neural Regen Res. 2026 May 14.
    Targeting the type-I interferon response in amyotrophic lateral sclerosis.
    Valeria Gerbino.
      
    DOI:  https://doi.org/10.4103/NRR.NRR-D-26-00133
  12. Sci Rep. 2026 May 27.
    Evaluation of triumeq treatment on a TDP-43 mouse model of amyotrophic Lateral sclerosis.
    Megan Fowler, Jillian M Carr, Julian Gold, Adam Walker, Mary-Louise Rogers.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the accumulation of TAR DNA Binding Protein (43 kDa; TDP-43) within the cytoplasm of neurons. Endogenous retroviruses (ERVs) have been implicated in ALS pathology and the application of antiretroviral therapy, specifically Triumeq, has been proposed for treatment of ALS. However, evidence to support the actions of Triumeq in ALS is lacking. This study investigates the effects of the antiretroviral treatment Triumeq on ALS disease that occurs through TDP-43 pathology by utilising the doxycycline (Dox)-suppressible rNLS8 TDP-43 expression mouse model. In this model, TDP-43 accumulation in the cytoplasm is induced after removal of Dox. Disease was assessed through measures of body weight, neurological score, motor function, urinary p75ECD and inflammatory marker expression. Mice were treated with Triumeq and TDP-43 pathology and inflammatory marker expression examined. Triumeq treatment significantly improved motor function early on in the disease course but did not impact other disease progression markers or disease endpoint. In this TDP-43 ALS mouse model, there was a positive association of TDP-43 mRNA levels with transcription factor ATF4, and inflammatory markers CXCL10 and IRF-1, and Triumeq treatment negated this association. Triumeq treatment transiently and modestly improved motor function and influenced TDP-43 associated inflammatory gene expression in an ALS mouse model. These findings support the potential use of Triumeq in treating TDP-43-associated ALS and supports further investigation to better understand if the beneficial actions of Triumeq are via disruption of TDP-43-driven inflammation in ALS.
    Keywords:  Amyotrophic Lateral Sclerosis; Antiretroviral Therapy; Endogenous Retrovirus; Inflammation; Neurodegeneration; TDP-43; Triumeq
    DOI:  https://doi.org/10.1038/s41598-026-55433-9
  13. Int J Mol Sci. 2026 May 16. pii: 4483. [Epub ahead of print]27(10):
    The Molecular Basis of Partial Reversal or Significant Slowing of ALS, Parkinson's Disease, and Lewy Body Dementia by Mesenchymal Exosomes/Secretome.
    Chadwick C Prodromos, Ruby Del Villar, Andrew Striegel, Gerard Pena, Rohan Dixit.
      Neuromuscular and neurodegenerative (NMND) disorders are diseases that cause progressive damage to the central nervous system leaving patients with symptoms that negatively affect everyday living with death almost inevitable. These include amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), and Parkinson's disease (PD) with cases expected to increase in the future. Intranasally administered stem cell-derived exosomes/secretome have been seen as potential therapeutic options for these disorders in preclinical animal models. This study sought to observe the efficacy of mesenchymal stem cell-derived exosomes/secretome in patients with ALS, LBD, and PD. Based off these preclinical studies, we conducted a case-controlled series experiment with 86 patients with ALS, LBD, or PD, with the independent variable being the treatment and the dependent variable being the clinical response. These patients were recruited and given intranasal instillations of various MSC-derived exosome/secretome products. Subsequent treatments were given to patients who did not have a response to one product. Patients were followed up at one week, one, two, three, and six months post-treatment. Historical external controls were used for comparison to clinical outcomes. There were no serious adverse events in any patient. A total of 67 of 86 (77%) patients showed a positive clinical response to at least one product. Outcomes were strongly associated with greater treatment frequency for ALS and LBD. Intranasal administration of MSC-derived exosome/secretome products were safe, and most patients showed overall improvement with at least one product. Some patients also saw a substantial decrease in the rate of decline compared to historical controls. These results also give rise to the hypothesis: do MSC-derived exosomes/secretome treatments show efficacy in other NMND disorders? The primary limitation of this study is the 6-month follow-up.
    Keywords:  ALS; LBD; PD; exosome; secretome
    DOI:  https://doi.org/10.3390/ijms27104483
  14. Amyotroph Lateral Scler Frontotemporal Degener. 2026 May 29. 1-10
    Diagnostic differences between military veterans and non-veterans: data from the United States National ALS Registry.
    Jaime Raymond, Theodore Larson, Suraya Mohidul, Drake Martin-Greene, Kirt Love, Vincent Mehta, James Wymer, Ileana Howard, D Kevin Horton, Paul Mehta.
      Background and Aim: Veterans in the U.S. have been reported to have a higher risk of developing amyotrophic lateral sclerosis (ALS) than the general population. However, it is unclear whether veterans experience differences in symptom recognition, diagnostic timing or access to care. This study examined differences reported in clinical characteristics and diagnostic trajectories between male veteran (MV) and non-veteran male (NVM) ALS patients enrolled in the U.S. National ALS Registry. Methods: We conducted a propensity score-matched analysis using self-administered military and clinical surveys from 2014 to 2024. Among 2,891 male ALS patients, MV were matched 1:1 with NVM on smoking history, birth year, head injury history, and region of residence at diagnosis. Outcomes included reported symptoms, time from symptom onset to diagnosis, and time to selected interventions. Results: Overall, 802 MV were matched to 802 NVM. Veterans were older at and reported longer intervals from symptom onset to ALS diagnosis (20.8 vs 16.7 months, p = 0.0004). MV were more likely to report difficulty swallowing and falls. Veterans were also more likely to use noninvasive breathing equipment (p = 0.0322). Findings from time-to-event analyses showed MV received wheelchairs or scooters statically earlier than NMV (log-rank p = 0.0028). Conclusions: Among participants in the Registry, MV reported differences in diagnostic timing, symptoms, and the use of supportive interventions compared to NVM. These findings may reflect differences in healthcare access, care pathways, and disease recognition over intrinsic differences in ALS biology. Because Registry participation is voluntary and data are self-reported, the result may not be generalizable to the broader ALS population.
    Keywords:  ALS; MND; National ALS Registry; amyotrophic lateral sclerosis; military; mortality; motor neuron disease; veteran
    DOI:  https://doi.org/10.1080/21678421.2026.2677528
  15. CNS Neurosci Ther. 2026 Jun;32(6): e70946
    5-Hydroxytryptamine Distribution Alteration in Both Neuron and Synapse of Tg(SOD1*G93A)1gur Mice: A Potential Intervention Candidate Strategy for Amyotrophic Lateral Sclerosis.
    Lijun Zhou, Menghua Li, Qi Dai, Xiwang Liu, Cheng Li, Huifeng Jiao, Haili Pan, Renshi Xu.
       AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; the precise pathogenesis of sporadic ALS (sALS) has not yet been elucidated up to now. Previous studies revealed that the abnormal alterations of some non-motor neurons (non-MN) were a potential pathogenesis of sALS. Therefore, this study aims to search the potential evidences of non-MN in the pathogenesis of ALS via exploring potential relationships between 5-hydroxytryptamine (5-HT) neurons and the development of ALS.
    METHODS: We employed fluorescent immunohistochemistry to investigate the altered distribution patterns of 5-HT and tryptophan hydroxylase 2 in the spinal cord and brainstem of Tg(SOD1*G93A)1Gur (TG) and wild-type (WT) mice. Additionally, we used western blot to analyze the expression levels of 5-hydroxytryptamine receptor 1A (5-HTR1A) and 5-HTR2A.
    RESULTS: Our findings revealed that 5-HT synapses were primarily distributed in the funiculus lateralis, anterior horn, posterior horn, central lateral column, and the area around the central canal of cervical, thoracic, and lumbar segments, and raphe nucleus as well as lateral paragigantocellular nucleus, and gradually reduced following age increase in WT mice. However, 5-HT synapses in the spinal cord and 5-HT neurons in the brainstem gradually increased following the progression of disease and presented a significantly negative correlation between the increased distribution of 5-HT synapses and neurons and the reduction of neural cell number (positively correlated with the increase in neural cell death) at the onset and/or progression stage of TG mice. 5-HTR1A significantly increased, while 5-HTR2A significantly decreased at the onset stage of TG mice.
    CONCLUSION: Our study speculated that the distribution changes of 5-HT synapses in the spinal cord and 5-HT neurons in the brainstem play a potential protective role in the pathogenesis of sALS through a compensatory 5-HT increase.
    Keywords:  5‐hydroxytryptamine; amyotrophic lateral sclerosis; brainstem; pathogenesis; spinal cord
    DOI:  https://doi.org/10.1002/cns.70946
  16. Animal Model Exp Med. 2026 May 26.
    Exosome-mediated gut-brain axis signaling in neurodegenerative diseases: Mechanisms, experimental evidence, and therapeutic perspectives-A narrative review.
    Waheeb Sami Aggad, Rakesh Ghosh, Hailah M Almohaimeed, Zuhair M Mohammedsaleh, Fayez M Saleh, Amany I Almars, S Renuka Jyothi, Rajashree Panigrahi, Ajoy Kumer, Bikram Dhara.
      The stomach and the brain are connected by a sophisticated two-way communication mechanism called the gut-brain axis. Extracellular vesicles, particularly exosomes, that move bioactive substances between the stomach and the brain, such as proteins, lipids, metabolites, and microRNAs, may improve the gut-brain axis. In the past years, the role of exosome-mediated communication has been recognized as significant in relation to the etiology, continued progression, and potential treatment of neurodegenerative disorders. The authors of this review article present a summary of the current understanding of the relationship of gut microbiome, exosome biogenesis, and the pathophysiological development of neurodegenerative diseases. Evidence from laboratory studies, animal studies, and newly emerging human studies suggests that microbiome-based metabolites and inflammatory mediators may modulate how exosomes are produced, what they carry, and how they interact with the blood-brain barrier. These exosomal signals may impact neuroinflammation, neuronal signaling, and the spread of pathological proteins of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. In addition, they examine some possible ways to target the gut-brain axis from a therapeutic perspective, including manipulating the gut microbiome, providing probiotics and/or prebiotics, performing fecal microbiota transplantation, and/or using engineered extracellular vesicles as vehicles for drug delivery. The authors also outline some of the methodological differences that make it difficult to assess the effects of exosomes.
    Keywords:  Alzheimer's disease; Parkinson's disease; blood–brain barrier; exosomes; extracellular vesicles; gut–brain axis; microRNA; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.1002/ame2.70226
  17. BMC Neurol. 2026 May 25.
    Association between creatinine-to-cystatin C ratio and ALSFRS-R across clinical phenotypes.
    Yoshihisa Fujiwara, Akihiro Hashiguchi, Shiori Yamashiro, Hiroshi Seno, Yuichiro Ohya, Daigo Yasutomi, Natsumi Fujisaki, Miwako Kido, Shugo Suwazono, Takashi Tokashiki.
       BACKGROUND: Reliable and accessible biomarkers for amyotrophic lateral sclerosis (ALS) are scarce. Creatinine (Cre) reflects muscle mass, whereas cystatin C (CysC) may reflect neurodegeneration without being directly influenced by muscle mass; however, both have limitations. We aimed to investigate whether the creatinine-to-cystatin C ratio (Cre/CysC) was cross-sectionally associated with functional status in patients with ALS.
    METHODS: We retrospectively analyzed 30 patients diagnosed with ALS at the National Organization Hospital Okinawa Hospital between 2021 and 2024. Baseline ALS Functional Rating Scale-Revised (ALSFRS-R) scores and serum Cre and CysC levels were recorded. Associations with the ALSFRS-R were assessed using Spearman's correlation, with subgroup analyses by sex, site of onset, age at diagnosis, body mass index (BMI), and diagnostic delay. Multivariable analyses were performed to examine the independent association between Cre/CysC and ALSFRS-R while accounting for relevant clinical covariates.
    RESULTS: Cre/CysC showed a stronger cross-sectional correlation with ALSFRS-R (rs=0.648, p = 0.0001) than Cre alone (rs =0.427) or CysC (rs =-0.119). Exploratory subgroup analyses showed generally positive associations in several subgroups, although no statistically significant association was observed in the small bulbar-onset subgroup. In multivariable analysis adjusted for age at onset and diagnostic delay, Cre/CysC remained independently associated with ALSFRS-R (β = 20.1, 95% CI 6.41-33.9, p = 0.006). Given the small sample size and cross-sectional design, these findings should be interpreted as exploratory.
    CONCLUSIONS: Cre/CysC showed a stronger cross-sectional association with functional status than either marker alone. Because it is derived from routine laboratory tests, Cre/CysC may represent a simple exploratory measure associated with functional status in ALS. However, the present findings do not establish prognostic utility or fully account for disease stage and biological heterogeneity. Prospective longitudinal studies incorporating disease progression measures and broader clinical and genetic characterization are warranted.
    Keywords:  Amyotrophic lateral sclerosis; Creatinine-to-cystatin C ratio; Muscle mass reduction; Neurodegeneration; Retrospective study
    DOI:  https://doi.org/10.1186/s12883-026-04983-6
  18. Nutrients. 2026 May 21. pii: 1628. [Epub ahead of print]18(10):
    Feasibility and Tolerability of Ketogenic Interventions in Amyotrophic Lateral Sclerosis-A Dose-Finding Case Series.
    Christine Herrmann, Samantha Satari, Andrea Weber, Tanja Ruschitzka, Luisa Jagodzinski, Zeynep Elmas, Felicitas Becker, Lars Richter, Maximilian Wiesenfarth, Sebastian Michels, Jochen H Weishaupt, Joachim Schuster, Johannes Dorst.
      Background/Objectives: Weight loss and hypermetabolism are negative prognostic factors in amyotrophic lateral sclerosis (ALS). Ketone bodies (β-hydroxybutyrate, βHB) as high-energy substrates may compensate for this energy deficit, since a ketogenic diet (KD) has been shown to increase survival and stabilize body weight in the SOD1 mouse model. In this case series, we tested exogenous ketone salts (KS), ketone esters (KE), and a KD, in patients with ALS and in healthy subjects to identify novel therapeutic interventions for subsequent clinical studies. Methods: KS (KetoForce® (KetoSports, Frisco, TX, USA)) were tested in healthy subjects (11.7 g and 15.6 g βHB) and patients (15.6 g βHB 3×/day over 3 days). KE (KE4® (KetoneAid, Falls Church, VA, USA)) containing 10.0 g βHB were applied in healthy subjects (once) and in patients (3×/day over 2 days). For the KD, KetoCal® 2.5:1 LQ MCT MF Vanilla (Nutricia, Frankfurt, Germany) was applied via percutaneous endoscopic gastrostomy over four weeks. Regular capillary βHB measurements were conducted, and adverse events were recorded. Results: Between January 2021 and March 2025, we treated nine patients with ALS and two healthy subjects at the Department of Neurology of Ulm University, Germany. KE and KS increased βHB temporarily. However, the elevation was more pronounced following KE (maximum 2.2-2.7 mmol/L vs. 0.8-1.2 mmol/L). The KD increased βHB levels continuously with nighttime fluctuations. No adverse events occurred under KE. KS caused diarrhea in 3/5 patients and 1/2 healthy subjects. The KD was well tolerated, with mild gastrointestinal symptoms occurring in all patients. Conclusions: All ketogenic approaches increased βHB blood levels. While the KD and KE provided good tolerability, KS caused significant gastrointestinal side effects. KD seems to be an interesting candidate for future clinical studies, as it prompted a long-term increase in βHB while providing satisfying tolerability. Since maintaining a KD long-term is difficult for oral-feeding patients, KE may constitute a feasible alternative.
    Keywords:  amyotrophic lateral sclerosis; ketogenic diet; ketone esters; ketone salts; β-hydroxybutyrate
    DOI:  https://doi.org/10.3390/nu18101628
  19. Transl Neurodegener. 2026 May 25. pii: 24. [Epub ahead of print]15(1):
    Ketogenic diet as a therapeutic strategy for neurodegenerative diseases: from mechanisms to translational challenges.
    Ana Margarida Salgueiro, Marisa Ferreira-Marques, Rodrigo F N Ribeiro, Sara M Lopes, Dina Pereira, Daniela G Costa, Magda M Santana, Luís Pereira de Almeida, Cláudia Cavadas.
      The ketogenic diet (KD) is increasingly recognized as a promising therapeutic strategy for neurodegenerative disorders because of its multifaceted impacts on key pathophysiological mechanisms. This review explores the molecular pathways through which KD may protect against neurodegeneration, including the use of ketone bodies as alternative energy substrates, reduction of oxidative stress and inflammation, modulation of autophagy and protein aggregation, and impact on the gut microbiome. The potential benefits of KD are explored across neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, based on both preclinical and clinical evidence that supports its feasibility. However, challenges in long-term safety, patient adherence, and clinical practicality limit its widespread adoption. This review underscores the potential of KD for treating neurodegeneration on the basis of current scientific evidence while highlighting the need for further research to optimize its application and address existing gaps.
    Keywords:  Ketogenic diet; Neurodegenerative diseases; Neuroinflammation; Therapeutic strategy
    DOI:  https://doi.org/10.1186/s40035-026-00557-1
  20. Acta Neuropathol Commun. 2026 May 29.
    VAPB confers selective neuroprotection by driving autophagic degradation of pathogenic aggregates in ALS.
    Priyanka Tripathi, Haihong Guo, Alfred Yamoah, Ramkumar Mathur, Panagiotis Doukas, Alice Dreser, Christopher Marvin Jesse, Eleonora Aronica, Andreas Hermann, Harry Steinbusch, Gary Anthony Brook, Joachim Weis, Anand Goswami.
      During the progression of amyotrophic lateral sclerosis (ALS), only specific motor neurons (MNs) preferentially deteriorate, while others are spared until the disease reaches its end stage. Resilient MNs possess several protective factors, yet the precise molecular mechanism(s) underlying selective neuronal vulnerability remains poorly understood. Vesicle-associated membrane protein (VAMP)-binding protein B (VAPB) is an endoplasmic reticulum (ER) protein involved in protein quality control (PQC) mechanisms, including unfolded protein response (UPR) as well as autophagy. A dominantly inherited P56S mutation in the VAPB gene has been linked to ALS8, atypical ALS, and late-onset spinal muscular atrophy (SMA). The P56S VAPB mutation causes ER-associated inclusions, disorganization, and ER stress, contributing to MN degeneration through toxic gain and loss of function. Over-expression of VAPB protein confers neuroprotection in a mouse model of ALS, and increased levels of neuronal VAPB inversely correlate with the absence of pathological aggregates. We hypothesize that VAPB is crucial for motor neuron survival by promoting autophagic degradation of ALS-associated aggregates, while lack of VAPB confers neuronal vulnerability. We analyzed the brain and spinal cord from sporadic (s) and familial (f) ALS patients, comparing patterns of VAPB immunoreactivity using immunohistochemistry, complemented by Western and dot blot analysis. Pathophysiological insights from these studies were further explored using cell culture models, including MNs derived from induced pluripotent stem cells (iPSCs). Consistent with our hypothesis we observed that MNs/neurons resistant to ALS exhibited elevated levels of VAPB and were devoid of pathogenic aggregates. Similarly, ALS-resistant oculomotor neurons showed increased VAPB immunoreactivity compared to normal controls. VAPB was often found to be sequestered within toxic aggregates alongside autophagy-related proteins in the lumbar spinal cord MNs. Notably, a compensatory increase in VAPB immunoreactivity was observed at the C-bouton synapse, suggesting a potential alternative mechanism of neuroprotection. Supporting these findings, in vitro experiments indicated that VAPB overexpression promoted autophagy and assisted in clearing ALS-associated RNA-binding protein aggregates. In summary, VAPB promotes selective neuronal survival by facilitating the autophagic clearance of toxic aggregates. Abnormal VAPB accumulations likely disrupt these neuroprotective processes.
    Keywords:  ALS8; Autophagy; RBPs; Selective MN vulnerability; VAPB
    DOI:  https://doi.org/10.1186/s40478-026-02298-8
  21. NeuroSci. 2026 May 09. pii: 58. [Epub ahead of print]7(3):
    From Axonal Growth to Neurodegeneration: The Dual Role of Neurofilament Dynamics in Health and Disease.
    Yikang An, Hongying Lan, Jialong Xiong, Ruoyan Jing, Dongjin Gu, Haoyang Zhang, Xinping Liu, Qi Zhao, Feng Wang.
      Neurofilaments (NFs) are the predominant type IV intermediate filaments in differentiated neurons, functioning not just as static scaffolds, but as active drivers of radial axonal growth and nerve conduction velocity. While their physical properties are well characterized, a critical gap remains in synthesizing how their dynamic assembly and developmental subunit switching directly dictate neurodegenerative outcomes. This review breaks down the molecular architecture and stepwise kinetic assembly of NFs, detailing their role in polarized transport and the formation of a protective viscoelastic gel network within axons. We specifically highlight the physiological expression switching of early subunits, such as alpha-internexin and peripherin, during neuronal maturation, a process often overlooked in traditional structural reviews. By examining how specific gene mutations and aberrant hyperphosphorylation trigger axonal transport jams and protein aggregation, we map the direct pathways leading to amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth (CMT) disease. Finally, we emphasize that a precise mechanistic decoding of NF structural dynamics and their pathological disruption is essential for understanding the fundamental etiology of these neurodegenerative conditions.
    Keywords:  Charcot–Marie–Tooth disease; aberrant phosphorylation; amyotrophic lateral sclerosis; assembly mechanisms; axonal growth; expression switching; intermediate filaments; neurodegenerative diseases; neurofilaments; protein aggregation
    DOI:  https://doi.org/10.3390/neurosci7030058
  22. Amyotroph Lateral Scler Frontotemporal Degener. 2026 May 28. 1-9
    Air pollutants and amyotrophic lateral sclerosis in a population-based registry: investigating disease susceptibility, progression and survival.
    LOMBARD AIR POLLUTANTS STUDY GROUP
      Objective: to investigate the association between long-term exposure to fine particulate matter (PM2.5) and nitrogen oxides (NOx) with ALS risk, progression, and survival. Methods: We conducted a population-based study in Lombardy, Italy. A case-control analysis included 161 incident ALS cases (2011-2014) and 161 age-, sex-, and province-matched controls. Average residential exposures to PM2.5 and NOx over the 20 years before diagnosis were estimated using European Monitoring and Evaluation Programme data and analysed with conditional logistic regression. A retrospective cohort of 135 ALS cases was used to assess associations with disease progression (ΔFS) and mortality using logistic and Cox regression models, adjusting for demographic and lifestyle factors. Results: Higher PM2.5 exposure in the 20 years preceding diagnosis was associated with increased ALS risk (adjusted OR per 5 µg/m³ increase 1.19; 95% CI 1.01-1.40), with consistent findings across sensitivity analyses. NOx was not associated with ALS incidence. In contrast, NOx exposure in the 5 years before diagnosis was marginally associated with increased mortality (adjusted HR 1.12; 95% CI 1.00-1.26), whereas PM2.5 was not. Neither pollutant was significantly associated with disease progression rate. Conclusions: Long-term PM2.5 exposure was associated with higher ALS risk, while NOx showed a modest association with mortality. These findings support a role of air pollution in ALS susceptibility and highlight the need for integrated environmental prevention strategies to mitigate the burden of neurodegenerative diseases.
    Keywords:  PM2.5; amyotrophic lateral sclerosis; epidemiology; pollutant; risk factors
    DOI:  https://doi.org/10.1080/21678421.2026.2677537
  23. Neural Regen Res. 2026 May 14.
    An integrated single-nucleus ribonucleic acid sequencing and spatial transcriptomic atlas reveals stage-specific neuronal and glial trajectories in a mouse model of amyotrophic lateral sclerosis.
    Qi Zhou, Tian Gong, Jiahao Liu, Junpeng Ma, Minxiu Zheng, Ziwei Zhong, Haitao Deng, Haiyan Lin, Nan Feng, Xiao Lei, Chengsheng Zhang.
      Amyotrophic lateral sclerosis is a progressive multifocal neurodegenerative condition involving motor neurons and other cell types. To analyze spatiotemporal cellular dynamics in amyotrophic lateral sclerosis, we performed single-nucleus ribonucleic acid sequencing and spatial transcriptomics analysis of cervical spinal cords from wild-type control mice and SOD1-G93A transgenic mice in the pre-symptomatic (d50), early symptomatic (d90), and late-stage (d130) phases of disease. Single-nucleus ribonucleic acid sequencing identified 17 cell clusters and showed that progressive neuronal loss occurred over time, paralleled by glial expansion. Spatial transcriptomics mapped these clusters anatomically onto oligodendrocytes in white matter, neurons in horns, and diffuse astrocytes/microglia. Subcluster analysis demonstrated neuronal heterogeneity, with early mitochondrial stress in ventral motor neurons evolving into synaptic dysfunction, transient maturation peaks in interneurons, and amplified age-related decline in amyotrophic lateral sclerosis. Astrocyte and oligodendrocyte subclusters, which were originally misclustered due to spot-level contamination, were reinterpreted to highlight A1-reactive states and progenitor expansions, validated by immunohistochemistry detection of serum/glucocorticoid regulated kinase 1. Temporal profiles tracked the transition from compensatory to inflammatory gliosis, while gene signatures were linked to human amyotrophic lateral sclerosis cohorts, including complement activation and mitochondrial dysfunction. This study provides a high-resolution spatiotemporal cellular map of amyotrophic lateral sclerosis pathogenesis through the integration of single-nucleus and spatial transcriptomics, uncovering early mitochondrial impairment in neurons, delineating the trajectory of neurotoxic glial states, and identifying compensatory progenitor responses, to highlight the highly intricate interaction between glial reactivity and neuronal susceptibility that drives the pathogenesis of ALS.
    Keywords:  amyotrophic lateral sclerosis; astrocytes; cellular atlas; motor neurons; oligodendrocytes; single-nucleus RNA sequencing; spatial transcriptomics; spinal cord; temporal trajectories; therapeutic targets
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00859
  24. Adv Sci (Weinh). 2026 May 25. e16846
    Protein Disulfide Isomerase Disassembles TDP-43/G3BP1 Condensates and Antagonizes TDP-43 Pathological Aggregates.
    Jia-Qi Liu, Hao Liu, Yu-Xuan Sun, Yuying Li, Xiangyi Liu, Li-Qiang Wang, Zhaofei Yang, Qi Fu, Xiaojiao Xu, Jie Chen, Yingshuang Zhang, Jun Zhou, Weidong Le, Mengchao Cui, Yi Liang.
      Cytoplasmic mislocalization and aggregation of transactive response DNA-binding protein-43 (TDP-43) is a common pathological feature of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer's disease with TDP-43 pathology (AD-TDP); the exact role of protein disulfide isomerase (PDI), an enzyme with chaperone activity, in modulating the pathological behavior of TDP-43 is unknown. In this study, we report that wild-type PDI, through its specific interaction with TDP-43, markedly attenuates phase separation of TDP-43, competitively displaces G3BP1 to disassemble TDP-43/G3BP1 condensates, and further counteracts the pathological mislocalization, abnormal phosphorylation, and pathological aggregation of TDP-43 through the b' domain of the enzyme. Ultimately, this alleviates mitochondrial damage and neuronal toxicity caused by TDP-43 aggregation and suppresses UNC13A cryptic splicing in stressed cells. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP-43 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS and AD-TDP patients. These findings not only provide new insights into the pathogenic mechanisms of TDP-43 in neurodegenerative diseases such as ALS and AD-TDP, but also propose PDI as a potential therapeutic target.
    Keywords:  TDP‐43; amyotrophic lateral sclerosis; mitochondrial impairment; protein aggregation; protein disulfide isomerase; protein phase separation
    DOI:  https://doi.org/10.1002/advs.202516846
  25. Acta Neuropathol. 2026 May 29. pii: 63. [Epub ahead of print]151(1):
    Reevaluating the role of beta2-microglobulin: new insights on selective vulnerability in ALS pathology.
    Melanie Leboeuf, Jik Nijssen, Laura Helen Comley, Julio Cesar Aguila Benitez, Irene Mei, Silvia Gómez Alcalde, Ramón A Muñoz de Bustillo-Alfaro, Vlad Radoi, Susanne Nichterwitz, Christoph Schweingruber, Abraham Acevedo Arozena, Eva Hedlund, Staffan Cullheim.
      Amyotrophic lateral sclerosis (ALS) is characterized by the selective loss of motor neurons (MNs). Why these neurons are particularly vulnerable in ALS remains unclear, as does why certain MN groups remain resistant throughout the disease course. We investigated the role of the human leukocyte antigens (HLAs) and beta2-microglobulin (β2m) in MN susceptibility to ALS, given their reported involvement in both prolonging and shortening disease progression. Loss of HLAs in ALS has also been shown to increase MNs vulnerability to toxicity exerted by activated astrocytes. RNA sequencing of control tissues demonstrated that disease-resistant oculomotor neurons (OMNs) and Onuf's MNs exhibited β2m and HLA mRNA levels comparable to those of vulnerable spinal MNs, suggesting that baseline differences in these transcripts do not explain the differential vulnerabilities of these MN groups. However, HLA protein levels showed an inverse correlation with spinal MN size, with the large MNs, those lost early in ALS, displaying the lowest HLA expression. HLA protein levels were also reduced in spinal MNs from end-stage ALS patient tissues, while remaining relatively unchanged in OMNs. In contrast, spinal MNs uniquely exhibited significant upregulation of β2m and HLA-C transcripts during disease, likely reflecting a protective compensatory response. Together, these findings suggest that β2m and HLAs may contribute to spinal MN vulnerability in ALS. To assess their functional role, β2m knockout mice were crossbred with SOD1G93A ALS mice. Loss of β2m did not alter life span of the ALS mice, but led to partial preservation of lumbrical muscle innervation that was insufficient to maintain motor function. Analysis of GFAP immunoreactivity revealed marked neuroinflammation activation in the spinal cords of β2m knockout mice. As these mice retain normal MN numbers and life-span, this indicates that loss of functional MHC-I, even in the presence of astrocyte activation, is insufficient to cause MN disease. Furthermore, β2m knockout significantly increased GFAP activation in SOD1G93A mice, but did not further exacerbate disease progression, suggesting that loss of functional MHC-I does not necessarily render MNs more vulnerable to astrocyte toxicity. Overall, these findings indicate that β2m and HLAs are dynamically regulated in ALS, and may influence MN vulnerability, but they are not major disease modifiers in ALS.
    Keywords:  Amyotrophic lateral sclerosis; Beta2-microglobulin; MHC-I; Motor neuron; Selective vulnerability
    DOI:  https://doi.org/10.1007/s00401-026-03024-3
  26. Sci Rep. 2026 May 27.
    The role of adiponectin and cytokines in Amyotrophic lateral sclerosis: assessment of disease progression and survival status.
    Jing Zhang, Mei Tian, Tongyang Niu, Rui Li, Qi Liu, Man Liu, Xiaomeng Zhou, Hui Dong, Yaling Liu.
      Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disorder. ALS typically progresses rapidly, leading to respiratory failure within 3 to 5 years of symptom onset. Identifying risk factors that influence disease progression and survival is critical for enhancing management strategies. The present study therefore investigated the roles of inflammatory factors and adipokines (especially adiponectin) in the progression and prognosis of ALS. The study included 80 ALS patients, with a follow-up period of 1.5 years. Survival analysis was performed using a Cox regression, with hazard ratios (HR) and 95% confidence intervals (CI) presented via forest plots. Our results indicated that ALS patients in the fast-progressing group exhibited lower levels of adiponectin (p < 0.001) and IL-10 (p < 0.001). The Cox regression and forest plot results suggest the potential of adiponectin (HR = 0.905, 95%CI: 0.866-0.946, p < 0.001), IL-10 (HR = 0.968, 95%CI: 0.951-0.986, p < 0.001), δFS (HR = 1.234, 95%CI: 1.065-1.430, p = 0.005) and ALSFRS-R (HR = 0.820, 95%CI: 0.765-0.878, p < 0.001) as potential risk factors. In addition, these risk factors are significantly associated with poor survival prognosis in high-risk populations (all p < 0.001). This study identifies adiponectin, IL-10, ALSFRS-R, and δFS as key risk factors influencing ALS progression and prognosis.
    Keywords:  Adiponectin; Amyotrophic lateral sclerosis; Inflammatory factors; Prognosis; Progression
    DOI:  https://doi.org/10.1038/s41598-026-54291-9
  27. J Neuroinflammation. 2026 May 23.
    ERVK activity in CD8+ T cell immune cell compartment in patients with ALS.
    Snigdda Sharma, Claudia Cortés-Pérez, Sasha Bird, Domenico Di Curzio, Alex Vandenakker, Kerri Schellenberg, Renée N Douville.
      Endogenous retrovirus-K (ERVK) expression has been associated with Amyotrophic Lateral Sclerosis (ALS), and its viral proteins can be detected in affected brain and spinal cord tissues. Despite confirmation of ERVK load in the blood of patients with ALS, few studies have examined ERVK protein expression in immune cells. ERVK produces an enzyme called integrase (IN), which can cause DNA damage during the integration of viral DNA into the host genome. Given that genomic instability is a hallmark of ALS, we hypothesized that the ERVK IN enzyme may also be expressed in lymphoid and myeloid-derived immune cells of patients. Peripheral blood mononuclear cells (PBMC) were isolated from blood specimens using Ficoll isolation, and either flash-frozen for western blot analyses or affixed onto slides using the cytospin technique for subsequent confocal microscopy analysis. Image analysis of confocal micrographs revealed that ERVK IN expression was significantly elevated in CD3+CD8+ T cells from a subset of patients with ALS as compared to controls. CD3+CD8+ T cells in ALS exhibit enhanced number and size of ERVK IN puncta within the nucleus and at the plasma membrane. The DNA damage load, as measured by marker γH2AX, was strongly associated with ERVK IN levels in both controls and patients with ALS. Stratification of molecular data based on clinical parameters showed an association of elevated ERVK IN load in CD8+ T cells from patients with ALS with lower ALSFRS-R and higher King's scores, as well as a significant decline in lung function metrics. In bulk PBMC from patients with ALS, ERVK IN was associated with expression of immune checkpoint marker PD-1, but not T cell exhaustion marker TOX. ERVK IN in CD14+CD11b+ myeloid cells was also elevated, with ERVK+ cells exhibiting notable membrane ruffling typical of immune cell activation and increased expression of HLA-DR. However, ERVK IN expression in monocytes was not correlated with clinical metrics in patients with ALS. This work points to the use of ERVK IN in CD8+ cytotoxic T cells as a blood biomarker for ALS clinical trials, especially those focused on testing the efficacy of antivirals as a therapeutic strategy for ALS.
    Keywords:  Amyotrophic Lateral Sclerosis (ALS); DNA damage; Endogenous retrovirus-K (ERVK/HERV-K); Inflammation; Integrase (IN); Monocytes; Peripheral blood mononuclear cells (PBMC); T cells
    DOI:  https://doi.org/10.1186/s12974-026-03871-7
  28. Brain Behav. 2026 May;16(5): e71486
    Proteomic Analysis of Corpora Amylacea Extracted From Post-mortem Brain of MAiD-end-of-life Sporadic ALS Patients.
    Alexandre Paquet, Lydia Touzel-Deschênes, Vincent Roy, Stephan Saikali, Nicolas Dupré, François Gros-Louis.
       PURPOSE: Corpora amylacea (CA) are starch-like inclusions that accumulate in the central nervous system (CNS) with aging and are enriched in neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS). Although often regarded as waste reservoirs, their cellular origins, molecular composition, and pathological significance remain poorly understood.
    METHODS: Here, we performed an unbiased proteomic analysis of purified CAs isolated from post-mortem brains of sporadic ALS patients and controls.
    FINDINGS: In-depth mass spectrometry identified 4,470 proteins, of which 658 were quantified, revealing distinct ALS-specific proteomic signatures. Enriched proteins included markers of cytoskeletal remodeling, mitochondrial dysfunction, and proteostasis disruption, as well as known ALS-associated proteins such as TDP-43 and neurofilament proteins. These findings demonstrate that CAs serve as reservoirs of dysfunctional, disease-relevant proteins and capture key pathological processes in ALS.
    CONCLUSION: By applying an unbiased proteomic approach to purified CAs, this study provides the first comprehensive map of their protein content in ALS, supporting their potential as biomarker sources and as a source of mechanistic insights into neurodegeneration.
    SIGNIFICANCE: Unbiased analyses of CAs in the context of ALS have yet to be undertaken. This study provides the first proteomic profiling of purified CAs, isolated from ALS patient brains using biochemical methods, revealing that CAs harbor disease-relevant proteins implicated in sporadic ALS. By demonstrating that CAs act as reservoirs of dysfunctional proteins related to metabolism, cytoskeletal organization, and proteostasis, our findings highlight their potential as a novel source of ALS-specific mechanistic insight into disease pathology.
    Keywords:  ALS; Corpora amylacea; biomarkers; mass spectrometry; neurodegeneration
    DOI:  https://doi.org/10.1002/brb3.71486
  29. J Pers Med. 2026 May 01. pii: 246. [Epub ahead of print]16(5):
    The Bright and Dark Sides of Nitric Oxide in Neurodegenerative Diseases.
    Lucia Buccarello, Costanza Montagna, Sabina Di Matteo, Renata Mangione, Giuseppe Carota, Jay Sibbitts, Romana Jarosova, Susan M Lunte, Giacomo Lazzarino, Giuseppe Caruso.
      Nitric oxide (NO) plays an important role in neuronal communication, synaptic plasticity and vascular regulation. Due to its important function in neuronal homeostasis, NO imbalance is associated with neurodegeneration. Specifically, in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and frontotemporal lobar degeneration (FTLD), an excessive amount of NO, mostly produced by inducible NO synthase (iNOS), reacts with superoxide to form peroxynitrite, driving oxidative/nitrosative stress, mitochondrial dysfunction, and aberrant protein modifications. In AD, NO dysregulation promotes amyloid-β (Aβ) accumulation, tau hyperphosphorylation and synaptic loss, creating a self-perpetuating cycle of neuronal damage. NO's dual role, protective at physiological levels but harmful if overproduced, underscores the therapeutic potential of antioxidant compounds that restore the balance of NO/NOS (especially iNOS) while preserving physiological functions. However, despite the emerging role of antioxidant-based therapeutic approaches, clinical translation is limited by the complexity of NO signaling and the absence of safe, specific NOS inhibitors. By targeting the molecular switch from protective to toxic, NO activity may offer new personalized treatment avenues for neurodegenerative diseases.
    Keywords:  carnosine; neurodegeneration; neuroprotection; neurotoxicity; nitric oxide; oxidative stress
    DOI:  https://doi.org/10.3390/jpm16050246
  30. J Voice. 2026 May 26. pii: S0892-1997(26)00225-0. [Epub ahead of print]
    Discovering Hidden Vocal Subtypes: An Unsupervised Acoustic-Biomechanical Exploration of Voice Profiles.
    Margarita Pérez-Bonilla, Paola Díaz-Borrego, Marina Mora-Ortiz, Fernando J Mayordomo-Riera, Eloy Girela-López.
       OBJECTIVE: This study aims to explore latent acoustic-biomechanical patterns of voice production using an unsupervised multivariate approach, and to identify data-driven vocal profiles across individuals with amyotrophic lateral sclerosis (ALS) and nonneurological dysphonia.
    METHODS: A cross-sectional sample of 100 individuals, including patients with ALS and individuals with nonneurological dysphonia, was analyzed. Sustained vowel phonation was recorded and characterized using 26 variables, including standard acoustic measures (fundamental frequency -fo-, jitter, shimmer, and harmonics-to-noise ratio (HNR)) and 22 biomechanical parameters. Principal component analysis was applied to investigate relationships among variables and reduce dimensionality. Unsupervised clustering was performed at both the variable level to identify functional groupings and the participant level to derive data-driven voice profiles. Cluster validity was assessed using internal indices. Post hoc statistical comparisons and chi-square tests were used descriptively to characterize between-cluster differences and their relationship with clinical categories.
    RESULTS: The first five principal components explained 70.7% of the total variance, revealing structured relationships between acoustic and biomechanical features. Participant level clustering consistently supported a two-profile solution. Fifteen voice parameters differed significantly between profiles after false discovery rate correction, with the largest effects observed for shimmer, HNR, and the biomechanical parameter Pr11, reflecting differences in vocal stability and noise-related characteristics. The identified profiles were not significantly associated with clinical diagnostic categories.
    CONCLUSIONS: An unsupervised multimodal analysis of sustained phonation revealed two coherent vocal profiles that transcend traditional diagnostic labels. These data-driven voice phenotypes may capture functional patterns of voice production and support future efforts toward more refined and personalized characterization of voice disorders.
    Keywords:  Acoustics; Amyotrophic lateral sclerosis; Biomechanical parameters; Unsupervised clustering; Vocal phenotypes; Voice analysis
    DOI:  https://doi.org/10.1016/j.jvoice.2026.05.002
  31. Neuropsychiatr Dis Treat. 2026 ;22 579603
    L-α-GPC in Cognitive Decline: Mechanisms and Clinical Evidence in Neurodegenerative Disorders.
    Vannisa Artasya Putri, Raira Salsabila Hapsari, Riezki Amalia.
      Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and vascular dementia are characterized by progressive neuronal loss, synaptic dysfunction, and cognitive decline. Despite the widespread use of symptomatic treatments, including acetylcholinesterase inhibitors and dopaminergic agents, these disorders remain incurable and lack disease-modifying therapies. L-α-Glycerylphosphorylcholine (L-α-GPC), a naturally occurring choline-containing phospholipid, has attracted interest for its dual roles as a precursor to acetylcholine biosynthesis and a modulator of neuroprotective signaling pathways. This narrative review summarizes current preclinical and clinical evidence regarding the mechanistic and clinical relevance of L-α-GPC in neurodegenerative disorders associated with cognitive impairment. Preclinical studies suggest that L-α-GPC can cross the blood-brain barrier, enhance cholinergic neurotransmission, upregulate neurotrophic factors such as brain-derived neurotrophic factor (BDNF), and modulate inflammatory responses, including those involving the α7 nicotinic acetylcholine receptor pathway. In animal models, L-α-GPC has been associated with improved cognitive performance, reduced neuroinflammation, and attenuation of amyloid-β and tau-related pathological features. Clinical studies have reported potential benefits of L-α-GPC, either as monotherapy or in combination with agents such as donepezil, in patients with AD, vascular dementia, mild cognitive impairment (MCI), and PD-related cognitive decline. However, the interpretation of these findings should be cautious because the available evidence remains heterogeneous, with notable variability in study design, dosage regimens, treatment duration, and outcome measures. Further well-designed, large-scale randomized controlled trials, together with biomarker-based assessments, are needed to clarify the therapeutic relevance and optimal clinical application of L-α-GPC in cognitive decline and neurodegenerative disorders. Overall, current evidence indicates that L-α-GPC may represent a promising adjunctive approach, although more robust validation is still required.
    Keywords:  Alzheimer’s disease; L-α-GPC; acetylcholine; cognitive decline; mild cognitive impairment; neurodegeneration; neuroprotection
    DOI:  https://doi.org/10.2147/NDT.S579603
  32. Amyotroph Lateral Scler Frontotemporal Degener. 2026 May 29. 1-14
    Understanding psychological adjustment in patients with amyotrophic lateral sclerosis and their caregivers: a scoping review.
    Marion Sommers-Spijkerman, Fabiola Müller, Esther Kruitwagen-Van Reenen, Johanna M A Visser-Meily, Rien Uitslag, Anita Beelen.
       OBJECTIVE: Psychological adjustment is a major focus in the care of people with amyotrophic lateral sclerosis (ALS) and their caregivers, given its critical role in maintaining quality of life (QoL). This scoping review aimed to gain a better understanding of ALS patients' and caregivers' psychological adjustment, to inform future care and research.
    METHODS: PubMed, Web of Science, PsycINFO, Embase and CINAHL were searched for peer-reviewed studies reporting associations of psychological factors with patient/caregiver QoL. Psychological factors were categorized by type (cognitive, emotional or behavioral responses), and by strength (weak, moderate, strong) and direction (positive, negative) of their association with patient/caregiver QoL.
    RESULTS: Twenty-nine studies were included, identifying twelve cognitive responses (hope, positive thinking/reframing, psychological flexibility, resilience, coping/pain self-efficacy, helplessness, hopelessness, pain catastrophizing, rumination, self-perceived burden, self-stigma), two emotional responses (emotional support, venting) and three behavioral responses (independence, positive action, substance use) associated with patient QoL. Five cognitive responses (resilience, mindfulness, hopelessness, passive reaction coping, psychological inflexibility) and one behavioral response (positive action) were found associated with caregiver QoL.
    CONCLUSIONS: A range of cognitive, emotional and behavioral responses, most notably cognitive responses, were found to shape patient and/or caregiver psychological adjustment, hence may serve as potential targets in ALS clinical practice. Nonetheless, empirical evidence is limited by heterogeneity in outcomes and measures and a lack of longitudinal, multivariable, and caregiver-oriented research. More systematic, standardized and longitudinal data collection is needed to clarify how psychological adjustment processes evolve throughout the disease trajectory and to identify modifiable targets for psychological supportive care.
    Keywords:  Amyotrophic lateral sclerosis; psychological adjustment; quality of life; scoping review
    DOI:  https://doi.org/10.1080/21678421.2026.2671166
  33. bioRxiv. 2026 May 13. pii: 2026.05.13.724856. [Epub ahead of print]
    Physiological levels of 3-hydroxykynurenine alter mitochondrial function and morphology in neuronal cells.
    Jordan Cassidy, Mary E W Collier, Flaviano Giorgini.
      Mitochondrial morphology and function are critical determinants of neuronal function and survival, with disruptions in mitochondrial dynamics often preceding the overt neuronal dysfunction seen in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease. The kynurenine pathway accounts for 95% of dietary tryptophan catabolism and many of the metabolites are neuroactive, including redox-active 3-hydroxykynurenine (3-HK). 3-HK is present under normal physiological conditions in the central nervous system (CNS) and is elevated during inflammation. While supraphysiological levels of 3-HK have been associated with neurotoxicity, the effects of physiological concentrations on neuronal cells, and specifically their mitochondria, remain poorly understood. Here we assessed viability, ATP levels and redox status to determine cellular health and function in neuronal cells exposed to physiological levels of 3-HK, alongside confocal imaging and transcriptomic profiling, finding significant alterations in mitochondrial function and morphology. Interestingly, a biphasic influence of 3-HK on mitochondrial morphology was observed, with an elongated network as well as decreased surface area and volume being observed only at the lowest concentration of 3-HK, reflecting normal physiological levels. At the highest 3-HK concentration tested, reflecting an inflammatory situation, an increased number of mitochondria were present, accompanied by increased activation of caspase-3/7 and enhanced production of mitochondrial superoxide. These results highlight a previously unknown role for 3-HK in regulating mitochondrial function and structure, possibly through altered fission and fusion events, suggesting that subtle changes in kynurenine pathway metabolism may contribute to early mitochondrial dysfunction in neurological disease.
    DOI:  https://doi.org/10.64898/2026.05.13.724856
  34. J Fungi (Basel). 2026 May 06. pii: 341. [Epub ahead of print]12(5):
    RNA-Binding Protein TAF15 Suppresses Toxicity in a Yeast Model of FUS Proteinopathy.
    Elliott Hayden, Aicha Kebe, Shuzhen Chen, Abagail Chumley, Chenyi Xia, Widad El-Zein, Quan Zhong, Shulin Ju.
      Mutations in an RNA-binding protein FUS are known to cause familial amyotrophic lateral sclerosis (ALS). Since this discovery, mutations in several other RNA-binding proteins (RBPs) have also been linked to ALS. Some of these ALS-associated RBPs have been shown to colocalize with ribonucleoprotein (RNP) granules such as stress granules and processing bodies (p-bodies). Increasing evidence has emerged supporting a hypothesis that the impaired clearance, inappropriate assembly, and dysregulation of RNP granules play a role in ALS. Through the genome-scale overexpression screening of a yeast model of FUS toxicity, we found that TAF15, a human RBP with a similar protein domain structure and belonging to the same FET protein family as FUS, suppresses FUS toxicity in yeast. The suppression by TAF15 is specific to FUS and not found in other yeast models of neurodegenerative disease-associated proteins. We showed that the RNA recognition motif (RRM) of TAF15 is required for its suppression of FUS toxicity. Furthermore, FUS and TAF15 physically interact, and the C-terminus of TAF15 is required for both the physical protein-protein interaction and its protection against FUS toxicity. Finally, while FUS induces and colocalizes with both stress granules and p-bodies, TAF15 only induces and colocalizes with p-bodies. Importantly, the co-expression of FUS and TAF15 induces more p-bodies than individually expressing each gene alone, and FUS toxicity is exacerbated in yeast that is deficient in p-body formation. Overall, our findings suggest a role of increased p-body formation in the suppression of FUS toxicity by TAF15.
    Keywords:  ALS; FET proteins; genetic screen; p-bodies; stress granules
    DOI:  https://doi.org/10.3390/jof12050341
  35. Sci Bull (Beijing). 2026 May 19. pii: S2095-9273(26)00519-0. [Epub ahead of print]
    Targeting mitochondrial dysfunction to quell neuroinflammation in central nervous system (CNS): a new strategy for treating CNS disease with nanomedicines.
    Shuya Wang, Min Liu, Xiaojing Shi, Tingli Xiong, Ruishi Li, Wenxuan Zheng, Qiong Huang, Yayun Nan, Kelong Ai.
      Neuroinflammation has emerged as an important pathogenic factor in central nervous system (CNS) disease, including various neurodegenerative diseases, brain injuries, and autoimmune conditions, affecting approximately 3 billion people worldwide. Mitochondrial dysfunction within neurovascular unit (NVU) cells not only initiates neuronal damage and blood-brain barrier (BBB) disruption but also critically reprograms immunometabolism, shifting microglia and infiltrating immune cells toward a pro-inflammatory, glycolysis-dominant state while impairing anti-inflammatory, oxidative phosphorylation-dependent functions. This metabolic rewiring fuels a vicious, self-amplifying cycle between mitochondrial impairment and sustained neuroinflammation. Consequently, targeting mitochondrial dysfunction has therefore emerged as a promising therapeutic strategy for controlling neuroinflammation. However, the double-membrane structure of mitochondria, coupled with the restrictive BBB, imposes formidable barriers to therapeutic delivery. Nanomedicine offers unprecedented opportunities. Advanced nanodrugs, engineered with mitochondrial-targeting ligands, stimuli-responsive materials, or biomimetic coatings, enable precise delivery of therapeutics directly to impaired mitochondria within the CNS. This review summarizes recent advances in mitochondrial dysfunction-induced neuroinflammation, highlights emerging nanotechnology-based mitochondrial targeting strategies in various CNS diseases, and discusses the existing challenges and future perspectives for translating these approaches into effective CNS therapies.
    Keywords:  Blood-brain barrier; Central nervous system; Mitochondria; Nanomedicines; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.scib.2026.05.020
  36. Mol Neurodegener. 2026 May 28.
    Cholesterol metabolism in neurodegenerative diseases: mechanisms and therapeutic advances.
    Dezhen Tu, Yuxiao Zheng, Pingping Ding, Miao Shen, Wangyang Tang, Bin Wei, Hongyan Wang.
      Cholesterol metabolites are abundant in the central nervous system (CNS) that regulate cell membrane fluidity, signal transduction, and inter- and intracellular vesicular transport, as well as cell proliferation/cell death or migration. Brain cholesterol synthesis and metabolism are tightly coupled to the functional homeostasis of neurons, glial cells or microglia, and dysregulation of these processes has been strongly implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This review provides a comprehensive overview of how cholesterol synthesis, esterification, efflux, uptake, and oxidation affect the CNS function, highlighting the function of key enzymes or metabolites in distinct brain cell types during neurodegeneration. Based on single-cell/nucleus RNA sequencing data from the brains of AD, PD, and HD patients, we summarize cell-type-specific genes in cholesterol metabolism pathways, shedding new light to understand cellular heterogeneity. The role of cholesterol-derived neurosteroids in neurodegenerative diseases is also discussed. Furthermore, how cholesterol metabolites modulate the formation, aggregation, and degradation of amyloid-β (Aβ), α-synuclein and huntingtin, as well as Tau protein phosphorylation are outlined. Finally, future research directions are proposed that aim to understand neurodegenerative diseases with new angle.
    Keywords:  Astrocyte; Cholesterol metabolism; Microglia; Neurodegeneration; Neuron; Oligodendrocyte
    DOI:  https://doi.org/10.1186/s13024-026-00951-3
  37. Amyotroph Lateral Scler Frontotemporal Degener. 2026 May 25. 1-9
    Beyond outcomes: patients' lived experience of exoskeleton-assisted gait training in amyotrophic lateral sclerosis.
    Ghida Trad, Timothée Lenglet, Giorgia Querin, Sophie Blancho, Véronique Marchand-Pauvert, Jean-Yves Hogrel, Pierre-François Pradat.
       OBJECTIVES: To explore patients' expectations and lived experience of Atalante exoskeleton-assisted gait training in amyotrophic lateral sclerosis (ALS).
    METHODS: In the EXALS study (NCT06199284), 10 ambulatory ALS participants completed 18 sessions of Atalante exoskeleton-assisted gait training. After completion of the intervention phase, post-training semi-structured interviews were audio-recorded, transcribed verbatim, and analyzed using inductive qualitative content analysis approach. Structured interview items were summarized descriptively.
    RESULTS: Ten participants reported positive expectations and experiences. Initial expectations most often included contributing to research (5/10), maintaining walking ability (4/10), and improving gait quality/balance (3/10). Expectation fulfillment was high (very satisfied: 7/10). The rehabilitative aspect was most frequently ranked as most reflective of the experience (rank 1: 4/10), followed by motivational/recreational (rank 2: 4/10), psychological/emotional was most often ranked last (rank 5: 5/10). Participants described perceived benefits including improved upright posture, stability, reduced stiffness, smoother gait, and reduced fear of falling, though some effects were described as short-lived. Three-word summaries were predominantly positive (8/10), commonly "interesting" and "motivating," with occasional negatives (tiring/heavy/repetitive/disappointing; 2/10). Compared with conventional physiotherapy, sessions were perceived as more dynamic and walking-focused, with a structured, innovative, closely supervised set-up. Suggested improvements centered on increasing access/dose, expanding walking space and training content, and enhancing safety/user control. Most participants would continue training if available (8/10), most commonly preferring two sessions per week (4/8).
    CONCLUSIONS: Exoskeleton-assisted gait training was experienced as acceptable and meaningful. Translating this into practice will require aligning future protocols with patient priorities, autonomy/safety, access and delivery logistics, and broader functional content alongside quantitative evaluation.
    Keywords:  Amyotrophic lateral sclerosis; Atalante exoskeleton; gait training; qualitative research; semi-structured interview
    DOI:  https://doi.org/10.1080/21678421.2026.2674021
  38. Amyotroph Lateral Scler Frontotemporal Degener. 2026 May 29. 1-7
    Sleep disturbances and respiratory dysfunction in amyotrophic lateral sclerosis.
    Kato Bracaval, Joke De Vocht, Fouke Ombelet, Laura Van Den Bulcke, Anne-Marie Peeters, Boris Deleu, Bart Vrijsen, Alexandros Kalkanis, Bertien Buyse, Dries Testelmans, Maarten Van Den Bossche, Philip Van Damme.
       OBJECTIVE: To investigate how respiratory dysfunction and site of onset influences changes in sleep architecture in people with ALS (pwALS).
    METHODS: We conducted a retrospective observational study, analyzing demographic data, lung function tests, and polysomnography (PSG) measures. Descriptive statistics, correlation analyses, and survival analyses were performed.
    RESULTS: Our cohort had 240 pwALS, 63% male, median age at onset 59.3 (IQR 16.5) years. Median time from onset to PSG was 27.5 (IQR 25) months. Most pwALS had spinal onset (79%). Spirometry at time of PSG showed a reduced Forced Vital Capacity (FVC) (58; (IQR 26) %). We saw a significant FVC decline (3.9; (IQR 4) % per month) in the months before PSG. The sleep quality assessment in pwALS revealed a reduced total sleep time (339; (IQR 144.7) minutes), diminished sleep efficiency (62.8; (IQR 26.5)%) and increased wake after sleep onset (172; (IQR 130.2) minutes) when compared to normal values of healthy age-matched adults. The spinal onset group had a higher number of arousals. In the multivariate linear regression model adjusted for age and sex, FVC is a significant predictor for sleep efficiency (β = 3.359, p = 0.0059). Spinal onset, a slower rate of FVC decline in the months preceding PSG and a preserved FVC (≥ 70%) at the time of PSG were associated with improved survival.
    CONCLUSION: We observed substantial sleep disturbances in our cohort overall with substantially increased arousals in the spinal group. FVC is a significant predictor for sleep efficiency and the decline in FVC is linked to survival.
    Keywords:  Amyotrophic lateral sclerosis; forced vital capacity; respiratory dysfunction; sleep disturbances; sleep efficiency
    DOI:  https://doi.org/10.1080/21678421.2026.2671162
  39. Inflammopharmacology. 2026 May 23.
    Neuroprotective role of cyanidin in Alzheimer's and Parkinson's disease: current insights and the road ahead.
    Bushra Bashir, Nandani Andotra, Prince Sharma, Tripti Sharma, Smriti Chauhan, Ankit Awasthi, Shareen Singh, Thakur Gurjeet Singh, Sachin Kumar Singh, Sukriti Vishwas.
      Neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by progressive neuronal loss within the central nervous system, affecting more than 64 million individuals worldwide. Degeneration of cholinergic and dopaminergic neurons leads to cognitive impairment, motor dysfunction, and neuropsychiatric disturbances. Currently available pharmacotherapies provide only symptomatic relief, largely targeting single mechanistic pathways without halting disease progression. Increasing evidence supports the therapeutic potential of plant-derived bioactive compounds owing to their multitargeted pharmacological properties. Among these, cyanidin (CN), a naturally occurring flavonoid, exhibits potent antioxidant, anti-inflammatory, anti-apoptotic, and senolytic activities. CN has been shown to mitigate mitochondrial dysfunction and protect cholinergic and dopaminergic neurons, thereby addressing key pathological features of AD and PD. However, its clinical translation is limited by poor aqueous solubility (log P 2.41), reduced systemic bioavailability, and inadequate brain penetration. Nanotechnology-based novel drug delivery systems (NDDS), including lipid-based, polymeric, and inorganic nanoparticles, offer promising strategies to enhance CN solubility, stability, bioavailability, and blood-brain barrier permeability. This review discusses the pathophysiological mechanisms of AD and PD, the neuroprotective potential of CN, limitations associated with its conventional delivery, and the emerging role of nanoformulations in optimizing brain-targeted therapy.
    Keywords:  Alzheimer’s disease; Anti-inflammatory; Antioxidant; Cyanidin; Nanoformulations; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s10787-026-02271-w
  40. Front Pharmacol. 2026 ;17 1813134
    Neurodegeneration at the crossroads: the gut-brain axis and blood-brain barrier in Parkinson's disease - a review.
    Nada K Gamal, Rafik Fakhry, Youmna Hatem, Engy Rashed, Reem Marzouk, Ahmed K M Bukr, Nadia Akawi, Mina Y George.
      Parkinson's disease (PD), which is one of the most common neurodegenerative illnesses, involves abnormal deposition of α-Synuclein and loss of dopaminergic neurons in the substantia nigra. Beyond this, there is increasing evidence that the gut-brain axis (GBA) and blood-brain barrier (BBB) interfere in disease initiation and progression. Dysbiosis of the gut microbiota affects the intestine and the BBB, allowing microbial metabolites and proinflammatory mediators to enter the CNS, causing neuroinflammation and neurodegeneration. Studies show that α-Synuclein pathology can originate in the gut and reach the brain via the vagus nerve. This review summarizes the connections among GBA, BBB, and PD, focusing on oxidative damage, inflammatory cascades, decreased expression of tight junction proteins, and signaling pathways such as TLR4/MyD88/NF-κB. In addition, we discuss therapeutic strategies that target the microbiota-BBB axis, such as probiotics, fecal microbiota transplantation, natural compounds (e.g., piperine, anethole, polymannuronic acid, Paeonia lactiflora), and stem cell therapy, which have demonstrated neuroprotective potential in animal models. Overall, the literature emphasizes the importance of restoring gut homeostasis and BBB integrity, and suggests that getting this axis right may offer novel opportunities for PD treatment. Future research is crucial to validate the efficacy of this approach clinically and to develop tailored therapies to prevent or delay PD progression.
    Keywords:  Parkinson’s disease; blood-brain barrier; gut microbiota; gut-brain axis; inflammation; neuroprotection
    DOI:  https://doi.org/10.3389/fphar.2026.1813134
  41. Nat Commun. 2026 May 27.
    Caspase-4 transgenic mice exhibit cytoplasmic TDP-43 accumulation and age-dependent neuropathology.
    Qingqing Jia, Longhong Zhu, Dandan Li, Zhenchun Nan, Junqi Hou, Yue Zhao, Gaolu Zhu, Kaili Ou, Mingwei Guo, Huajie Dui, Xiangyi Liu, Xiao-Xin Yan, Su Yang, Li'an Huang, Dongsheng Fan, Shihua Li, Xiao-Jiang Li, Peng Yin.
      TAR DNA-binding protein (TDP-43) is a multifunctional protein that binds DNA and RNA within the nucleus. In neurodegenerative diseases like Amyotrophic Lateral Sclerosis (ALS), TDP-43 is mislocalized to the cytoplasm, forming inclusions. Current TDP-43 transgenic mouse models generally fail to exhibit significant cytoplasmic accumulation and loss of nuclear TDP-43, which hampers the investigation of cytoplasmic TDP-43 pathology. We previously discovered that primate-specific caspase-4 (CASP4) can cleave TDP-43, producing truncated fragments that are mislocalized to the cytoplasm. Here we show that a transgenic mouse model that expresses human CASP4 and recapitulates the cytoplasmic mislocalization of endogenous TDP-43 and motor dysfunction in an age-dependent manner. Moreover, CASP4 mice exhibited gene expression changes and neuropathology similar to patients with sporadic ALS. Inhibition of CASP4 by its antisense oligonucleotide ameliorated TDP-43 pathology and subsequent neurotoxicity in CASP4 mice. Thus, CASP4 mice present a valuable animal model for exploring endogenous TDP-43-mediated pathogenesis and therapeutics.
    DOI:  https://doi.org/10.1038/s41467-026-73724-7
  42. NeuroSci. 2026 May 08. pii: 57. [Epub ahead of print]7(3):
    Brain-First vs. Body-First Models in Neurodegenerative Disease: A Perspective Review.
    Giuseppe Forte, Maria Casagrande.
      Recent advances in neurodegenerative disease research increasingly support the existence of multiple trajectory signatures underlying the heterogeneity of cognitive decline syndromes. Originally proposed in Parkinson's disease, the brain-first and body-first models have emerged as conceptual frameworks to explain variability in disease onset, prodromal features, and progression across dementia-related disorders. Brain-first phenotypes are defined by the early emergence of central nervous system pathology and cognitive symptoms, whereas body-first phenotypes are characterized by prominent peripheral or autonomic dysfunctions that precede central involvement. Within this perspective, neurodegeneration is not viewed as a uniform, brain-restricted process, but a dynamic interaction between central, peripheral, and network-level mechanisms. Integrating central and peripheral biomarkers, autonomic physiology, and alterations in functional connectivity provides a coherent framework for interpreting phenotypic heterogeneity and prodromal dysregulation across dementia syndromes. Current evidence supporting brain-first and body-first trajectories is largely associative, and their clinical translation requires rigorous validation. Accordingly, this narrative perspective review aims to provide a critical and integrative conceptual framework that synthesizes existing evidence, identifies unresolved questions, and outlines research priorities for trajectory-based stratification, rather than offering a definitive diagnostic classification or pharmacological evaluation. The present work adopts a conceptual and mechanistic perspective rather than a clinically prescriptive or trial-oriented one. Its aim is to articulate a generative framework capable of producing testable hypotheses about disease trajectories and biomarker constellations across neurodegenerative syndromes.
    Keywords:  autonomic dysfunction; biomarkers; body-first; brain-first; dementia; disease trajectories; narrative review; neurodegenerative diseases; phenotypic heterogeneity
    DOI:  https://doi.org/10.3390/neurosci7030057
  43. Curr Opin Genet Dev. 2026 May 26. pii: S0959-437X(26)00055-9. [Epub ahead of print]99 102488
    Somatic variation in multiple sclerosis: from blood to brain.
    Justin P Rubio.
      Multiple sclerosis (MS) is a progressive autoimmune disease of the central nervous system (CNS) that affects nearly 3 million people worldwide. Pathologically, MS is characterised by inflammation, demyelination and neurodegeneration, leading to declining neurological function and increasing disability. To date, investigations of somatic variation in MS have focused primarily on peripheral immune cells and, more recently, neurons. Deep targeted and exome sequencing of blood‑derived T cells have not demonstrated enrichment of somatic driver mutations in individuals with MS compared with controls. In contrast, whole‑genome sequencing of single neurons from chronic MS lesions has revealed a markedly elevated, age-adjusted somatic mutation burden, suggesting a mechanistic link between inflammation and neurodegeneration. Together, these findings provide support for further investigation of somatic mosaicism across both peripheral and CNS‑resident cell types in MS. Future studies will benefit from advances in genome sequencing that enable more accurate detection of ultra-rare somatic variants, combined with single-cell and complementary genomic technologies, to more definitively assess the role of somatic variation in MS pathogenesis. Ultimately, it is anticipated that insights from this work will translate into novel therapeutic targets and interventions to alleviate MS progression.
    DOI:  https://doi.org/10.1016/j.gde.2026.102488
  44. Int J Mol Sci. 2026 May 09. pii: 4208. [Epub ahead of print]27(10):
    Longitudinal CSF and Serum Biomarker Dynamics in Tofersen-Treated SOD1-ALS: A Real-World Multicentre Cohort Study.
    Andrea Giordano, Jessica Mandrioli, Federica Cerri, Christian Lunetta, Hamidreza Saebfar, Marcella Catania, Claudia Battipaglia, Laura Leone, Francesca Trojsi, Maria Vizziello, Francesca Gerardi, Matteo Farè, Aida Zulueta, Rachele Piras, Matteo Giacchino, Giulia Gianferrari, Eleonora Dalla Bella, Teuta Domi, Dario Bonanomi, Giuseppe Ganci, Raffaella Lombardi, Giuseppe Lauria, Nilo Riva.
      Tofersen is a gene-targeted therapy for superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS), but neurofilament light chain (NfL) may not fully capture the biological response to treatment. We performed a multicentre retrospective longitudinal study including 24 patients with SOD1-ALS treated with intrathecal tofersen at four Italian referral centres between 2022 and 2025. Cerebrospinal fluid (CSF) and serum biomarkers were assessed at baseline, month 3, month 6, and last available administration using single-molecule array assays to quantify NfL, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL-1), and total Tau. NfL decreased after treatment initiation in both CSF and serum, providing the clearest pharmacodynamic signal. In contrast, CSF GFAP increased progressively over follow-up, while CSF total Tau and UCHL-1 rose mainly at later timepoints; serum GFAP, total Tau, and UCHL-1 also showed increases during follow-up. ALS Functional Rating Scale-Revised trajectories were broadly stable, whereas disease progression rate was lower at last follow-up than at baseline. Greater reductions in CSF NfL were observed in pathogenic versus uncertain SOD1 variants, and early serum NfL and UCHL-1 changes were associated with longer-term changes in disease progression. These findings suggest that longitudinal multi-analyte profiling may refine biological response stratification beyond NfL alone in tofersen-treated SOD1-ALS.
    Keywords:  GFAP; SOD1-ALS; UCHL–1; cerebrospinal fluid; longitudinal study; neurofilament light chain; precision medicine; serum biomarkers; tofersen; total Tau
    DOI:  https://doi.org/10.3390/ijms27104208
  45. Front Immunol. 2026 ;17 1814357
    AI-driven insights into protein misfolding and innate immunity in neurodegenerative diseases.
    Hui Xin Deng, Jing Ling Cao, Yao Wu, Si Jin Jiang, Qian Qian Fang, Bi Yue Zhu, Yong Jian Jiang.
      Neurodegenerative diseases encompass a diverse group of disorders ranging from adult-onset conditions such as Alzheimer's and Parkinson's disease to pediatric forms including neuronal ceroid lipofuscinoses (NCLs), Niemann-Pick type C (NPC), and infantile neuroaxonal dystrophy (INAD), all of which are characterized by protein misfolding and chronic neuroinflammation. During their occurrence and development, the innate immune system, especially the immune responses mediated by microglia in the central nervous system, plays a crucial regulatory role. Increasing evidence indicates that misfolded and abnormally aggregated proteins, such as β-amyloid (Aβ), Tau, α-synuclein, and TDP-43, are not only neurotoxic factors but can also act as damage-associated molecular patterns (DAMPs) recognized by innate immune receptors, thereby triggering persistent neuroinflammatory responses. However, traditional experimental and computational methods still have significant limitations in systematically analyzing the "protein misfolding-innate immune activation" mechanism. In recent years, artificial intelligence has made breakthrough progress in protein structure prediction, multi-conformation modeling, and integration of multi-omics data, providing a new research paradigm for revealing the intrinsic relationship between protein misfolding and innate immunity across the spectrum of neurodegenerative diseases. This article systematically reviews the latest applications of artificial intelligence in predicting the conformational characteristics of misfolded proteins, simulating the protein aggregation process, revealing the mechanism of innate immune perception, and reconstructing the regulatory network of neuroinflammation. It focuses on discussing the significance of deep learning models such as AlphaFold, I-TASSER, RoseTTAFold, Phyre2, and ESMFold in the field of protein structure prediction, as well as the related research on multi-modal AI technology in revealing the complex molecular mechanisms behind neurodegenerative diseases, such as combining AI with mathematical models to simulate the spread of misfolded proteins and further exploring the association with disease progression. The review also highlights the potential of AI to address the diagnostic challenges unique to pediatric neurodegenerative disorders, which, despite their rarity, collectively impose devastating lifelong burdens. In summary, AI tools not only deepen our understanding of the molecular mechanisms underlying both adult and childhood neurodegenerative diseases but also open up new avenues for developing innovative diagnostic tools and treatment methods.
    Keywords:  artificial intelligence; innate immune; misfolded proteins; neurodegenerative disease; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1814357
  46. BMC Med. 2026 May 27.
    Putative glymphatic dysfunction links extracellular fluid dysregulation to white matter degeneration and clinical impairment in amyotrophic lateral sclerosis.
    Xin Jin, Yan Fu, Ting Qiu, Jianyu Li, Huixiong Zhang, Yifan Chen, Kewei Chen, Yuanchao Zhang, Junling Wang, Xiaoping Yi, Lena Palaniyappan, B Blair Braden.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and prominent extra-motor involvement. Impaired clearance of neurotoxic proteins has led to increasing interest in the brain glymphatic system; however, its in vivo associations with brain microstructure and clinical heterogeneity remain incompletely understood.
    METHODS: One hundred forty-six patients with ALS and 149 demographically matched healthy controls (HCs) underwent multimodal MRI and comprehensive clinical assessments. Putative glymphatic function was quantified using diffusion tensor imaging along perivascular space (DTI-ALPS). Extracellular free water fraction (FWF) and free-water-corrected fractional anisotropy (fwcFA) were derived to characterize extracellular fluid and white matter microstructure. Group differences were assessed using vertex-wise and voxel-wise analyses with correction for multiple comparisons. Associations among imaging metrics and clinical measures were evaluated using correlation and serial mediation analyses.
    RESULTS: Compared with HCs, patients with ALS exhibited significantly reduced DTI-ALPS index, widespread increases in cortical FWF, bidirectional alterations in white matter FWF, and extensive reductions in fwcFA across major white matter tracts. Reduced DTI-ALPS was associated with changes in extracellular free water and white matter microstructural integrity, whereas FWF and fwcFA measures were associated with functional, cognitive, and emotional outcomes. Mediation analyses identified significant indirect associations between DTI-ALPS and both functional and cognitive measures through a pathway involving cortical FWF, white matter FWF, and fwcFA, although direct associations were not observed.
    CONCLUSIONS: These findings provide in vivo evidence that putative glymphatic dysfunction co-occurs with extracellular fluid alterations, white matter microstructural changes, and clinical impairment in ALS. Multi-compartment diffusion imaging may offer complementary markers for characterizing brain microstructure and its clinical relevance in ALS.
    Keywords:  ALS; DTI-ALPS; Free-water fraction; Glymphatic system; White matter integrity
    DOI:  https://doi.org/10.1186/s12916-026-04948-z
  47. Neurol Int. 2026 May 12. pii: 89. [Epub ahead of print]18(5):
    Nucleoside-Analog Reverse-Transcriptase Inhibitors (NRTIs) Against Multiple Sclerosis: Comprehensive Review on a Possible Novel Therapeutic Approach.
    Alfonso Martinisi, Paolo Paganetti.
      To this day, the etiology of multiple sclerosis has yet to be fully comprehended by the scientific community. However, the knowledge on mechanisms leading to the development of this neurodegenerative autoimmune disorder increases daily, along with the development of new disease-modifying treatments. A correlation between Epstein-Barr Virus infection and the disease incidence has recently shed light on possible innovative antiviral therapies. Here, we review the literature on Human Endogenous Retroviral sequences as emerging actors for the impairment of remyelination as a major challenge in disease progression. Our primary focus is the HERV-W envelope protein, which has been found at elevated levels in individuals affected by this condition and is suggested here as a potential therapeutic target. We then continue analyzing the clinical cases where antiretroviral drugs have been tested to treat multiple sclerosis patients and, from successes and failures, we finally narrow down our therapeutic hypothesis to the administration of Nucleoside-analog Reverse Transcriptase Inhibitors to target the HERV-W envelope protein, possibly leading to remyelination and significantly improving the condition of those affected by the disease. The main purpose of this review is to present a rationale for the therapeutic potential of this drug class and offer a new perspective for therapeutic options against multiple sclerosis.
    Keywords:  HERV; NRTI; antiretrovirals; multiple sclerosis; remyelination
    DOI:  https://doi.org/10.3390/neurolint18050089
  48. Immunotherapy. 2026 May 27. 1-11
    Integrated pharmacological and Omega-3 therapy modulates immunometabolic pathways and neuro-ophthalmological outcomes in relapsing-remitting multiple sclerosis.
    Tablo Ahmed Merza Mohammed, Teshk Nouri Shawis, Talar Ahmad Merza Mohammad, Maysoon Al-Haideri.
       AIMS: To investigate the immunometabolic and neuro-ophthalmological effects of combined Fingolimod, Metformin, Fluoxetine, and Omega-3 therapy in patients with relapsing-remitting multiple sclerosis (RRMS).
    MATERIALS AND METHODS: A total of 80 RRMS patients were analyzed. Peripheral blood mononuclear cells and serum samples were assessed for gene expression of apoptosis- and oxidative stress-related markers (BCL2, BAX, CASP3, NRF2, SOD2, AMPK2), cytokine levels (IL-6, TNF-α, IL-10, IFN-γ), and Th1/Th17 ratio. Optical coherence tomography (OCT) and visual evoked potentials (VEP) were used to evaluate neuro-ophthalmological outcomes.
    RESULTS: Omega-3 supplementation was associated with reduced pro-inflammatory cytokines (IL-6, TNF-α) and increased IL-10 levels. It was also linked to higher expression of antioxidant-related genes (NRF2, SOD2, AMPK2) and modulation of T-cell balance, reflected by a reduced Th1/Th17 ratio. Integrated analysis showed distinct clustering of treatment groups, with Omega-3-associated profiles linked to anti-inflammatory and antioxidant signatures. These changes were correlated with improved RNFL thickness and VEP parameters.
    CONCLUSIONS: Omega-3 supplementation was associated with coordinated immunometabolic changes and improved neuro-ophthalmological indicators in RRMS patients, suggesting its potential as an adjunct to standard therapies.
    Keywords:  Omega-3; Relapsing-remitting multiple sclerosis; central nervous system; immune system; immunomodulation; inflammation; metabolic changes
    DOI:  https://doi.org/10.1080/1750743X.2026.2676451
  49. Eur J Pharm Biopharm. 2026 May 22. pii: S0939-6411(26)00141-4. [Epub ahead of print] 115120
    Hydrogels-based nasal sprays for nose-to-brain delivery: Formulation strategies, composite systems, and performance optimization.
    Xinshuang Wang, Wenna Huang, Yanyan Zhou, Kewu Zhu.
      Nose-to-brain drug delivery has been extensively investigated for central nervous system therapy due to its ability to bypass the blood-brain barrier and reduce systemic exposure. Among available intranasal dosage forms, hydrogels-based nasal sprays have emerged as a promising platform due to their ability to prolong nasal residence and enable controlled drug release. This review, from the perspective of formulation-oriented design of hydrogel nasal sprays, focuses on composite systems, spray performance, and drug specific strategies in addition to material selection. Recent advances highlight the integration of nanocarriers within hydrogel matrices to achieve coordinated control of drug protection, release behavior, and mucosal retention, effectively addressing key challenges in nasal drug delivery. Meanwhile, key spray-related critical quality attributes, including viscosity, droplet size, and spray dynamics, are extensively reviewed with respect to their effects on nasal cavity deposition and nose-to-brain delivery efficiency. Finally drug specific formulation design is discussed as a central factor guiding strategies for small molecules, macromolecules, and oligonucleotide drugs. Overall, this review proposes a formulation-oriented and systems-level framework to guide the rational development and clinical translation of hydrogels-based nasal spray dosage forms for nose-to-brain drug delivery.
    Keywords:  Brain targeting; Composite delivery systems; Hydrogels; Nasalspray; Nose-to-brain delivery
    DOI:  https://doi.org/10.1016/j.ejpb.2026.115120
  50. Rev Neurosci. 2026 May 26.
    Extracellular matrix-derived matrikines as emerging modulators of neuroinflammation and central nervous system signaling.
    Emma C Creed, Mitchell Beckedorf, Samantha C Y Yudin, Fern L Deyholos, Andis Klegeris.
      Neuroinflammation underlies many neurodegenerative disorders and is orchestrated by interactions between microglia, astrocytes, and neurons. While cytokines, chemokines, and damage-associated molecular patterns (DAMPs) are established neuroimmune mediators, extracellular matrix (ECM)-derived protein fragments, collectively termed matrikines, have received little attention in the central nervous system (CNS). Emerging evidence suggests that matrikines constitute a distinct and functionally important class of neuroimmune modulators. This review focuses on six CNS-relevant matrikines: type I collagen-derived acetylated Pro-Gly-Pro (Ac-PGP) and Gly-His-Lys (GHK); laminin-derived Ile-Lys-Val-Ala-Val (IKVAV) and Tyr-Ile-Gly-Ser-Arg (YIGSR); elastin-derived Val-Gly-Val-Ala-Pro-Gly (VGVAPG); and endorepellin, corresponding to domain V of perlecan. We describe their generation, receptor interactions, and signaling properties, and summarize their established effects in peripheral tissues and the limited evidence for CNS-specific roles. Current findings indicate that CNS matrikines may arise by peripheral entry through a compromised blood-brain barrier (BBB), proteolysis of the BBB basement membrane, or local degradation of CNS interstitial matrix and perineuronal nets during injury or disease. Their CNS effects are highly context- and cell-specific, ranging from neuroprotection and enhanced neuronal survival to modulation of microglial and astrocytic functions, cell migration, autophagy, and direct neurotoxicity. Collectively, evidence supports matrikines as CNS signaling molecules that complement classical immune mediators. Of note, studies using human CNS cells and tissues remain largely absent and should be prioritized to assess translational relevance. Systematic profiling of CNS matrikines, combined with mechanistic studies of their cell-specific signaling, especially in human cells, may reveal novel biomarkers and therapeutic targets, offering new avenues for intervention in neurodegenerative and other neurological disorders.
    Keywords:  astrocytes; brain matrikines; extracellular matrix; microglia; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.1515/revneuro-2026-0014
  51. Viruses. 2026 May 09. pii: 548. [Epub ahead of print]18(5):
    Application of a Blood-Brain Barrier Organ-on-a-Chip Model for Assessment of Countermeasure Efficiency Against Eastern Equine Encephalitis Virus.
    Niloufar A Boghdeh-Olson, Michael D Barrera, Clayton M Britt, David K Schaffer, Jacquelyn A Brown, John P Wikswo, Aarthi Narayanan.
      Infection by neurotropic alphaviruses such as the Eastern equine encephalitis virus (EEEV) causes extensive inflammation in the central nervous system and tissue damage, including disruption of the blood-brain barrier (BBB). Neuroinflammation and BBB disruption following infection are critical pathological considerations for the development of robust countermeasure strategies. Encephalitic disease resulting from EEEV infection currently lacks FDA-approved therapeutic intervention strategies, thus exposing a major capability gap in the ability to address the global health burden that could result from alphavirus infections. In this manuscript, we present a gravity-flow Neurovascular Unit (gNVU) model of the human BBB that may be used for modeling EEEV-induced neuropathology and evaluating countermeasures. The data generated using this model show that EEEV infection causes a time-dependent disruption of BBB integrity and increases the inflammatory load in a manner that correlates with an increase in the viral load. The data also show that the route of introduction of the pathogen has an impact on the pathology measured, with infection through the brain side eliciting a greater inflammatory outcome than infection through the vascular route. Overall, the included data support the utility of this organ-on-a-chip (OOC) platform of the human BBB in understanding encephalitic disease caused by neurotropic viruses and evaluation of therapeutic intervention strategies.
    Keywords:  alphavirus; barrier disruption; blood–brain barrier; eastern equine encephalitis virus; inflammation; neurovascular unit; omaveloxolone; organ-on-a-chip
    DOI:  https://doi.org/10.3390/v18050548
  52. Pharmaceutics. 2026 May 07. pii: 576. [Epub ahead of print]18(5):
    Ultrasound-Enhanced Drug Delivery in Pediatric Neuro-Oncology: A New Therapeutic Strategy.
    Elora Weber, Christian A Smith, Cynthia Hawkins, Uri Tabori, Peter B Dirks, James T Rutka.
      Pediatric brain tumors are highly prevalent and remain one of the leading causes of cancer-related deaths in children. There are numerous different brain tumor types that are now well characterized by magnetic resonance imaging (MRI), patient clinical course, and neuropathological and molecular genetic alterations. One of the challenges with treating pediatric brain tumors with systemic chemotherapy is the inability of several chemotherapeutic agents to cross the blood-brain barrier (BBB), which serves as a protective mechanism for neuronal homeostasis. The BBB primarily comprises microvascular endothelial tight junctions. Controlling BBB permeability to allow for therapeutics to cross and combat brain tumors is now possible using MR-guided focused ultrasound (MRgFUS). In this approach, microbubbles are administered intravenously prior to MRgFUS BBB disruption at the targeted tumor site in the brain. In the presence of MRgFUS, the microbubbles in the brain capillaries oscillate and temporarily disrupt the BBB, enabling systemically administered chemotherapy drugs to cross at the targeted site. In this review, we provide evidence supporting the use of MRgFUS BBB disruption to treat brain tumors in animal models and in ongoing human clinical drug trials. We conclude with efforts to harness the potency of the immune system using MRgFUS against pediatric brain tumors.
    Keywords:  blood-brain barrier; focused ultrasound; glioma; magnetic resonance imaging; medulloblastoma; tumor immune microenvironment
    DOI:  https://doi.org/10.3390/pharmaceutics18050576
  53. Brain Behav Immun. 2026 May 23. pii: S0889-1591(26)00578-7. [Epub ahead of print]137 106830
    Sexually dimorphic roles of toll-like receptors in the central nervous system.
    Stella Elkabes.
      Many neurological and psychiatric diseases and disorders show sex differences in prevalence, incidence, disease manifestation and response to treatment. Yet, historically, most clinical and pre-clinical studies have been conducted disproportionately or exclusively in male subjects. In recent years, this research bias has been increasingly addressed through human and animal studies where both sexes are appropriately represented. These investigations have identified sex-specific disease mechanisms driven by a combination of distinct genetic, anatomical, physiological, hormonal and neural factors in males and females. Sexual dimorphism in immune function has long been recognized. Toll-like receptors (TLRs), important mediators of the innate immune response to pathogens and endogenous danger signals, play sex-biased roles in peripheral immunity. Toll-like receptors are also expressed in cells intrinsic to the central nervous system (CNS). They initiate, not only neuroinflammation in CNS infections and disease and injuries, but also influence neurodevelopment and normal aging. Emerging evidence indicates that TLRs expressed in CNS cells contribute to neural pathology in a sex-specific manner, a research area that warrants further investigations. The aim of the present review is to highlight the sex-specific contribution of TLRs expressed in the CNS to chronic pain, neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's Disease and psychiatric disorders including major depressive disorder (MDD). Major findings are highlighted, essential concepts, controversies and knowledge gaps are discussed, and potential future directions are proposed. Attention is drawn to the importance of advancing this research area given that neuroinflammation is a key player in many CNS pathologies and TLRs are the essential drivers of neuroinflammation.
    Keywords:  Alzheimer’s Disease; Cognitive function; Depression; Innate immunity; Memory; Neurogenesis; Pain; Parkinson’s Disease; Pattern recognition receptors; Toll-like receptor
    DOI:  https://doi.org/10.1016/j.bbi.2026.106830
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