bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–09–20
seventy papers selected by
Luca Bolliger, lxBio
  1. Recent Advancements in Drug Delivery Across the Blood-Brain Barrier in Amyotrophic Lateral Sclerosis (ALS).
  2. Peripheral TDP-43 pathology in amyotrophic lateral sclerosis: toward a systemic proteinopathy.
  3. Chitinases in Tear Fluid of Patients With Amyotrophic Lateral Sclerosis.
  4. Causal relationship between metabolites, cerebral volume, and amyotrophic lateral sclerosis: A 2-step Mendelian randomization analysis.
  5. Lactate Metabolism and Signaling in Amyotrophic Lateral Sclerosis.
  6. Presymptomatic Amyotrophic Lateral Sclerosis: From Early Biomarker Detection to Phenoconversion Prediction.
  7. Hyperactive KIF5A in Neurodegeneration.
  8. Noninvasive ventilation in patients with amyotrophic lateral sclerosis: Is home sleep apnea testing a useful tool for initiating noninvasive ventilation?
  9. Microglia deploy TAM receptors to kill motor neurons in a mouse model of amyotrophic lateral sclerosis.
  10. The hnRNPA1 D262V amyotrophic lateral sclerosis (ALS) mutation is linked to mitochondrial dysfunction.
  11. From Vision to Validation: The Journey of Tofersen in Superoxide Dismutase 1 Gene-Associated Amyotrophic Lateral Sclerosis.
  12. Beneficial Effects of Putative Hydrogen Sulfide (H2S) Donor POM16 in a Genetic Model of Amyotrophic Lateral Sclerosis, FUS [1-359]-Transgenic Mice.
  13. Serum Na-Cl value from routine blood tests reflects CO2 retention in amyotrophic lateral sclerosis.
  14. New approach methodologies in neurotherapeutics development.
  15. Neural Stem Cell-Derived Extracellular Vesicles Improve CNS Delivery and Therapeutic Efficacy of Antisense Oligonucleotide in Amyotrophic Lateral Sclerosis.
  16. Cognitive and Behavioural Profile of SOD1-ALS Across the ALS-FTD Spectrum: A Systematic Review.
  17. Prevalence of and associated factors for sleep disorders in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.
  18. N-of-1 investigational study of a novel antisense oligonucleotide drug in CHCHD10-related ALS shows early signs of efficacy.
  19. ABCD1-Related Disease Presenting as an Upper Motor Neuron-Predominant Amyotrophic Lateral Sclerosis Mimic in a Colombian Female Heterozygote: A Case Report.
  20. Time-dependent adherence to non-invasive ventilation in amyotrophic lateral sclerosis: an observational cohort study.
  21. Metabolic alterations in the absence of a neuromuscular phenotype in humanized SOD1A5V mice.
  22. UA-30 ameliorates motor deficits through RalA-mediated mitophagy in ALS mice.
  23. Radiation Therapy for Sialorrhea in Patients With Amyotrophic Lateral Sclerosis: A Case Series and Critical Review.
  24. Application of Mesenchymal Stromal Cells and Their Exosomes in Neurodegenerative Diseases and Lysosomal Storage Diseases.
  25. Cellular senescence is an early feature and therapeutic target in amyotrophic lateral sclerosis TDP-43Q331K mice.
  26. Unraveling the regulatory nexus of aggrephagy in ALS: identification of novel candidate biomarkers and molecular triggers.
  27. Neuro-glial lipid imbalance in a Drosophila model of amyotrophic lateral sclerosis 8.
  28. Efficacy of Low Dose of Dihydroquercetin (DHQ) in Two Genetic Models of Neurodegeneration: Insights from FUS[1-359]-Tg and APPswe/PS1dE9 Paradigms.
  29. Characterising the motif composition and allele length distribution of ZFHX3 GGC repeat expansions in amyotrophic lateral sclerosis.
  30. The thymus gland is a target and maintainer of amyotrophic lateral sclerosis pathophysiology.
  31. The Paradox of Tau and RNA-Binding Proteins: How Adaptive Stress Granule Regulation Becomes Pathological with Aging.
  32. Atherosclerotic Cardiovascular Diseases Increase ALS Risk by 82% While Optimal Cardiovascular Health Halves It: A 0.5-Million Prospective Cohort Study.
  33. Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?
  34. Astrocytes in Neurodegeneration: Spatial States, Crosstalk, and Emerging Therapies.
  35. From systems to cells: Metabolic mechanisms underlying risk divergence in Alzheimer's disease and amyotrophic lateral sclerosis.
  36. Quantitative Analysis of Axonal Degeneration and TDP-43 Aggregation in Compartmentalized Human iPSC-Derived Motor Neuron-Myotube Co-cultures.
  37. The diagnostic biomarker problem in amyotrophic lateral sclerosis.
  38. Machine Learning for Noninvasive Diagnosis of Neurodegenerative Diseases Using Retinal and Optic Nerve Imaging: A Comprehensive Review.
  39. Thioperamide, a histamine H3 receptor antagonist, attenuates neuroimmune activation and inflammation in the SOD1G93A mouse model of amyotrophic lateral sclerosis.
  40. Optimization and characterization of lipid-based nanocarriers for intranasal delivery in amyotrophic lateral sclerosis.
  41. A‑iMPO: A Design-Time Prediction Toolbox for Blood Brain Barrier Permeation Using an Integrated and Interpretable Multiparameter Optimization Framework.
  42. Multivariate Survival Analysis of a Comprehensive Clinical Trial of Rapamycin in Amyotrophic Lateral Sclerosis Explores Prognostic Factors and Survival Patterns in C9orf72 Carriers.
  43. A human iPSC-based perfusable and membrane-free neurovascular unit-on-chip connecting brain organoids to the blood-brain barrier.
  44. [A New Understanding of the Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex in the Kii Peninsula, Japan, 2026].
  45. Neurological and neuroimaging sequelae of lightning injury: a retrospective study and literature review.
  46. Associations of per- and polyfluoroalkyl substances (PFAS) exposures and firefighting experience with microRNA signatures previously linked to Amyotrophic Lateral Sclerosis (ALS): a cross-sectional analysis of active-duty municipal and airport firefighters.
  47. Hydroxytyrosol as a Multitarget Neuroprotective Agent: Molecular Mechanisms, Pharmacokinetics and Therapeutic Potential in Neurodegenerative Diseases.
  48. Selegiline induces neuroprotection via PGC-1α/Nrf2 gene upregulation in H2O2 -treated hippocampal-derived neural stem/progenitor cells.
  49. EBV-associated autoimmune glial fibrillary acidic protein astrocytopathy with lumbosacral leptomeningeal enhancement: a case report and literature review.
  50. What do ALS motor phenotypes measure? A population-based decomposition of their prognostic dimensions.
  51. Cholesterol Quantification in Brain and Spinal Cord During Development, Demyelination, and Remyelination.
  52. Nigrostriatal imaging in patients with clinically uncertain Parkinsonian syndromes: a head-to-head comparison between SPECT, PET, and MRI.
  53. Serum Biomarkers for Nutritional Monitoring in Motor Neuron Disease: A Longitudinal Cohort Study.
  54. Integrating retinal and brain imaging biomarkers for diagnosis of parkinson's disease: findings from a time-lagged cross-sectional persian cohort study.
  55. Parkinson's disease diagnosis using machine learning and multimodal biomarkers: A systematic review.
  56. Platelet-activating factor in multiple sclerosis: From peripheral inflammation to central neurodegeneration.
  57. Pharmacological modulation of cGAS-STING-NLRP3 signaling by nano-immunomodulators in Alzheimer and Parkinson disease.
  58. Repurposing antimicrobial agents for neuroprotection: Mechanisms, clinical potential, and challenges.
  59. Development and Chemical Stability Assessment of a Methyl-β-Cyclodextrin-Containing Dextromethorphan/ Quinidine Oral Solution for Extemporaneous Compounding.
  60. Comparison of iron and myelin changes in U‑fiber regions of relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorders.
  61. Cannabidiol Ameliorates Blood-Brain Barrier Dysfunction and Inhibits Memory Astrocytes Activation in Mice With Sickness-Like Behaviors.
  62. Caspase-3 dependent, induction of barrier dysfunction and hyperpermeability in blood-brain barrier endothelial cells.
  63. Beyond the field of view: Radiomics and artificial intelligence for organ-specific and systemic disease prediction from localized medical imaging.
  64. Autoimmune processes and production of catalytically active antibodies-abzymes in prone to amyotrophic lateral sclerosis FUS(1-359) mice.
  65. The Oral-Brain Axis: A Unified Framework Linking Trigeminal Sensorimotor Dysfunction, Chronic Stress, Neuroinflammation, and Neurodegeneration.
  66. Smoldering neuroinflammation in progressive multiple sclerosis: mechanisms, imaging biomarkers, and therapeutic opportunities.
  67. Base editing rescues a hereditary motor neuron disease in mouse and patient-derived iPSC organoid models.
  68. Intrathecal Plasma Cell Activity as Measured by the Kappa Free Light Chain Index Is Associated With Retinal Layer Atrophy in Early Multiple Sclerosis.
  69. Data-driven subtyping of Parkinson's disease using MRI: current insights, challenges, and future directions.
  70. The spectrum of C9orf72 repeat lengths in Portuguese frontotemporal dementia and amyotrophic lateral sclerosis patients: from pathogenic expansions to intermediate alleles.
  1. CNS Neurosci Ther. 2026 Sep;32(9): e71078
    Recent Advancements in Drug Delivery Across the Blood-Brain Barrier in Amyotrophic Lateral Sclerosis (ALS).
    Nitesh Sanghai, Kaitlyn Pierce, Nidhi Sharma, Sasha Leggett, Tara Chand Yadav, Pegah Masrori, Devi Atukorallaya, Senthilnathan Palaniyandi, Paul C Marcogliese, Geoffrey K Tranmer.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neurodegenerative disease with limited therapeutic options. The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) present major obstacles to central nervous system (CNS) drug delivery, restricting the effectiveness of many potential therapies. Increasing evidence suggests that BBB and BSCB dysfunction are not only barriers to treatment but also important contributors to ALS pathophysiology.
    OBJECTIVE: To examine current evidence regarding BBB and BSCB dysfunction in ALS and evaluate the implications of stage-dependent barrier alterations for CNS drug delivery and therapeutic outcomes.
    METHODS: Recent mechanistic, pathological, preclinical, and clinical studies examining BBB and BSCB alterations in ALS were reviewed. Evidence on tight junction disorganization, endothelial dysfunction, vascular leakage, altered transporter activity, and emerging therapeutic and drug delivery strategies was analyzed.
    RESULTS: Converging evidence indicates that BBB and BSCB dysfunction are intrinsic and progressive features of ALS pathophysiology rather than passive consequences of neurodegeneration. Barrier impairment emerges early in the disease course and evolves across clinical stages. Disruption of barrier integrity may increase motor neuron vulnerability while modulating CNS drug exposure. Emerging strategies that bypass, exploit, or restore barrier function hold promise for enhancing CNS bioavailability and improving therapeutic outcomes.
    CONCLUSIONS: Improved understanding of barrier alterations may facilitate development of more effective CNS-targeted therapies and improve therapeutic outcomes in ALS patients.
    DOI:  https://doi.org/10.1002/cns.71078
  2. Acta Neuropathol. 2026 Sep 15. pii: 34. [Epub ahead of print]152(1):
    Peripheral TDP-43 pathology in amyotrophic lateral sclerosis: toward a systemic proteinopathy.
    Philippe Codron, Marion Miranda, Maelle Garnier, Shiyang He, Julien Gouju, Julien Cassereau, Pascal Leblanc, Franck Letournel.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Cytoplasmic accumulation of phosphorylated TAR DNA-binding protein 43 (pTDP-43) is the pathological hallmark of most ALS cases. While ALS has traditionally been viewed as a disease confined to the brain, spinal cord and motor nerves, recent studies have reported pTDP-43 pathology in multiple other tissues (skeletal and cardiac muscle, skin, minor salivary glands, gastrointestinal tract and lymph nodes), referred to as peripheral pathology. The detection of pTDP-43 beyond the nervous system suggests that ALS-associated TDP-43 proteinopathy may be more widespread than previously recognized and raises fundamental questions regarding the spatial and temporal landscape of ALS pathology. Peripheral pTDP-43 accumulation may reflect a systemic biological susceptibility affecting multiple tissues, propagation of pathological TDP-43 species between anatomical compartments, or a combination of both mechanisms. While its biological significance is yet to be determined, the presence of pTDP-43 in peripheral tissues broadens the current conceptual framework of ALS. It may also provide new opportunities for pathology-based biomarkers, therapeutic monitoring, and mechanistic studies aimed at understanding disease initiation and progression. However, current evidence is derived from small and methodologically heterogeneous cohorts, and peripheral pTDP-43 pathology is not restricted to ALS, emphasizing the need for larger standardized studies.
    Keywords:  Amyotrophic lateral sclerosis; Biomarkers; Peripheral pathology; Phosphorylated TDP-43; Proteinopathy; Skeletal muscle; TDP-43
    DOI:  https://doi.org/10.1007/s00401-026-03086-3
  3. Eur J Neurol. 2026 Sep;33(9): e70757
    Chitinases in Tear Fluid of Patients With Amyotrophic Lateral Sclerosis.
    Lara Wenz, Lena-Sophie Scholl, Nya Reinhardt, Ricarda von Heynitz, Vincent Gmeiner, Petra Rau, Philipp Jie Müller, Andreas W Wolff, Emily Feneberg, Antonia F Demleitner, Paul Lingor.
       BACKGROUND: Chitinases, including chitotriosidase (CHIT1) and chitinase-3-like protein 1 (CHI3L1), are markers of neuroinflammation, a key process in amyotrophic lateral sclerosis (ALS). Tear fluid (TF) can be collected non-invasively and may represent a promising alternative to CSF or blood to study chitinases.
    METHODS: TF was collected from 50 ALS patients and 50 control subjects using Schirmer strips. CHIT1 and CHI3L1 levels in TF, serum, and CSF were quantified using ELISA. Serum NfL was measured using SIMOA. The frequency of a 24 bp-duplication polymorphism in the CHIT1 gene influencing CHIT1 expression was assessed by PCR.
    RESULTS: No group differences in the distribution of the CHIT1 polymorphism were detected. Carriers of the polymorphism in both ALS and controls showed lower CHIT1 levels in serum and TF. CHI3L1 levels in TF were higher in ALS patients compared to controls (p = 0.007), consistent with changes in CSF but not serum. In ALS, males showed higher TF CHIT1 values compared to females (p = 0.009). Combining TF chitinase values with serum NfL values improved discrimination between ALS and controls.
    CONCLUSIONS: Chitinases are detectable in TF, and CHI3L1 levels recapitulate changes observed in CSF, highlighting its potential for non-invasive longitudinal assessment. Furthermore, chitinase values in TF, together with serum NfL, may act complementarily by capturing distinct aspects of the disease, neuroinflammation and axonal damage. These results suggest TF chitinases and serum NfL could complementarily contribute to the diagnosis and monitoring of the disease, and call for further evaluation of TF as a biomarker source in ALS.
    Keywords:  amyotrophic lateral sclerosis; biomarker; chitinase; neuroinflammation; tear fluid
    DOI:  https://doi.org/10.1111/ene.70757
  4. Medicine (Baltimore). 2026 Sep 18. 105(38): e50769
    Causal relationship between metabolites, cerebral volume, and amyotrophic lateral sclerosis: A 2-step Mendelian randomization analysis.
    Youjia Liu, Sihui Chen, Yanyun Wu, Wenting Zhou, Huifang Shang, Ruwei Ou.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron degeneration. Although metabolic abnormalities have been implicated in ALS, the causal relationships between circulating metabolites and ALS remain unclear. This study aimed to investigate the potential causal associations between plasma metabolites and ALS risk and to explore the mediating role of cerebral volume. A 2-sample Mendelian randomization (MR) study was conducted using publicly available genome-wide association study summary statistics. Genetic instruments for plasma metabolites were obtained from metabolomic GWAS datasets, and ALS-associated genetic data were used as the outcome. The inverse-variance weighted method was used as the primary analysis, with sensitivity analyses performed using MR-Egger regression, weighted median analysis, MR-PRESSO, heterogeneity testing, and leave-one-out analysis. A 2-step MR analysis was further conducted to evaluate whether cerebral volume mediated the associations between metabolites and ALS. Six metabolites showed significant associations with ALS risk. Genetically predicted higher levels of N,N-dimethylalanine, Behenylcarnitine (C22), and deoxycarnitine were associated with increased ALS risk, whereas higher levels of (N(1) + N(8))-acetylspermidine, Betaine, and tetradecadienedioate (C14:2-DC) were associated with decreased ALS risk. Sensitivity analyses supported the robustness of the findings. Two-step MR analysis suggested that cerebral volume did not significantly mediate the associations between these metabolites and ALS risk. This study identified 6 circulating metabolites genetically associated with ALS risk. These findings provide insights into the potential metabolic pathways involved in ALS and suggest that the observed associations are unlikely to be mediated through cerebral volume changes.
    Keywords:  Mendelian randomization; amyotrophic lateral sclerosis; causal inference; cerebral volume; genome-wide association study; metabolomics; neurodegeneration; plasma metabolites
    DOI:  https://doi.org/10.1097/MD.0000000000050769
  5. Cells. 2026 Aug 29. pii: 1571. [Epub ahead of print]15(17):
    Lactate Metabolism and Signaling in Amyotrophic Lateral Sclerosis.
    Xiaonan Ma, Jinmeng Liu, Yingjun Guan, Chunjie Xu, Mu Li, Xue Zhang, Zongze Li, Lanli Zhang, Xuemei Wang, Haoyun Zhang, Yanchun Chen.
      Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons (MNs). Although the specific pathogenesis of ALS is not yet fully understood, there is increasing evidence that abnormal energy metabolism plays a key role in the onset and progression of the disease. Lactate has traditionally been considered a metabolic by-product of glycolysis and has received increasing attention in recent years. Research has shown that lactate is not only an important energy substrate but also a signaling molecule that regulates a variety of physiological processes, including neuron-glia metabolic coupling, neuroprotection and inflammatory responses. In ALS, abnormalities in lactate metabolism, dysfunction of the lactate shuttle, and dysregulation of lactate-related signaling pathways may jointly lead to neuronal energy deficits and increased neuroinflammation, thereby promoting MN degeneration. This review summarizes the latest advances in lactate metabolism and lactate-mediated signaling in ALS, with particular emphasis on their roles in neuronal energy regulation, neuroprotection and inflammatory regulation. In addition, we also discuss potential therapeutic strategies for lactate metabolism and its related pathways, aiming to provide new insights into the pathogenesis of ALS and the development of treatment methods for lactate-related metabolism.
    Keywords:  amyotrophic lateral sclerosis; lactate metabolism; lactate signaling; lactylation; therapy
    DOI:  https://doi.org/10.3390/cells15171571
  6. Diagnostics (Basel). 2026 Sep 05. pii: 2857. [Epub ahead of print]16(17):
    Presymptomatic Amyotrophic Lateral Sclerosis: From Early Biomarker Detection to Phenoconversion Prediction.
    Min Chen, Hexian Li, Qingwen Jin.
      Amyotrophic lateral sclerosis (ALS) usually enters diagnostic pathways after motor symptoms emerge, by which time neural injury has been ongoing. Long-term hereditary ALS cohorts show that some pathogenic-variant carriers may show elevated neurofilament light chain (NfL), mild motor impairment (MMI), electromyographic abnormalities, or imaging changes before clinical manifestation. Since 2022, research has shifted from detecting presymptomatic abnormalities to identifying observable prodromal phenotypes and predicting phenoconversion timing. Operational MMI criteria, longitudinal imaging in chromosome 9 open reading frame 72 (C9orf72) expansion carriers, TAR DNA-binding protein 43 (TDP-43)-related fluid biomarkers, and plasma proteomic models spanning prediction horizons have broadened early identification. The ATLAS study, a trial of tofersen initiated in clinically presymptomatic carriers of superoxide dismutase 1 (SOD1) variants, incorporated specific SOD1 variants and within-person NfL increases into risk monitoring and used these criteria to select participants for the randomized treatment phase. Evidence remains concentrated in a few genetic subtypes, and no single marker accurately predicts individual phenoconversion. Identification requires genotype-specific natural history, serial clinical examinations and biomarker testing, with clinical utility validated in independent longitudinal cohorts and prevention trials.
    Keywords:  amyotrophic lateral sclerosis; genetic ALS; longitudinal monitoring; mild motor impairment; neurofilament light chain; phenoconversion; predictive biomarkers; presymptomatic ALS
    DOI:  https://doi.org/10.3390/diagnostics16172857
  7. Cytoskeleton (Hoboken). 2026 Sep 14. e70204
    Hyperactive KIF5A in Neurodegeneration.
    David Villarroel-Campos, James N Sleigh.
      The highly polarised morphology of neurons and the sheer length of their axons make transport of cargoes throughout the cell a formidable task. Decades of evidence obtained from genetic studies on patients and animal models highlight deficits in axonal transport as a recurrent cause, or early contributing factor, in a plethora of neurodegenerative diseases. Axonal transport abnormalities usually manifest as a slowing of cargo trafficked by molecular motors along microtubules; however, hyperactivation of motors can also lead to disease. That is the case for the kinesin-1 protein KIF5A, in which hyperactive mutations are linked to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus (NEIMY). In this Perspective, we summarise the latest insights into the impact of KIF5A hyperactivity, such as loss of autoinhibition, aggregation, altered cargo binding and microtubule damage. We conclude by discussing possible strategies to counteract these disruptions, with an emphasis on the necessity of restoring axonal transport to physiological levels, a key requirement to maintain neuronal homeostasis.
    Keywords:  amyotrophic lateral sclerosis (ALS); axonal transport; kinesin; microtubules; motor neuron; motor protein
    DOI:  https://doi.org/10.1002/cm.70204
  8. Multidiscip Respir Med. 2026 Sep 16. 21 1088
    Noninvasive ventilation in patients with amyotrophic lateral sclerosis: Is home sleep apnea testing a useful tool for initiating noninvasive ventilation?
    Chiara Sanna, Mauro Sanna, Giuseppe Borghero, Stefania Redolfi.
       INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration and eventual respiratory failure, often first manifesting during sleep. Timely detection of nocturnal respiratory impairment is critical for initiating noninvasive ventilation (NIV), one of the few therapies proven to improve survival. Although polysomnography (PSG) is the reference standard, it is not always readily available in clinical practice.
    CASE PRESENTATION: We describe a 62-year-old man with spinal-onset ALS who underwent home sleep apnea testing (HSAT) for respiratory assessment. Although standard metrics were within normal limits, careful manual analysis of respiratory signals revealed diaphragmatic dysfunction through position-dependent desaturation and paradoxical breathing. NIV was initiated, resulting in improvements in sleep quality and daytime functioning.
    CONCLUSIONS: This case illustrates the value of HSAT as a pragmatic and accessible tool for early detection of respiratory involvement in ALS, particularly when combined with detailed waveform inspection in setting where PSG is unavailable. Additionally, it emphasizes the importance of individualized NIV titration and interface optimization to ensure adherence and therapeutic benefit.
    Keywords:  Noninvasive Ventilation; Amyotrophic Lateral Sclerosis; Home Sleep Apnea Test; initiating NIV
    DOI:  https://doi.org/10.5826/mrm.2026.1088
  9. Nat Commun. 2026 08 15. pii: 9837. [Epub ahead of print]17(1):
    Microglia deploy TAM receptors to kill motor neurons in a mouse model of amyotrophic lateral sclerosis.
    Youtong Huang, Ananya Mavinkurve, Bristy Sabikunnahar, Beth Stevens, Greg Lemke.
      Activation of microglia is a prominent feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that leads to the death of motor neurons. A key component of this activation is elevated expression of the TAM receptor tyrosine kinases Axl and Mer (gene name Mertk). Here we show that germline and microglial-restricted inactivation of the Axl and Mertk genes in the SOD1G93A mouse model of ALS leads to an extension of lifespan, which is tied to the preservation of cholinergic motor neurons and neuromuscular synapses. Also elevated on SOD1G93A neuronal surfaces is the essential TAM co-ligand phosphatidylserine, a potent 'eat-me' signal through which apoptotic cells are engulfed by microglia. Correspondingly, we find that microglial lysosomes are filled with the remains of cholinergic neurons in the SOD1G93A spinal cord, whereas this accumulation is markedly reduced in the SOD1G93AAxl-/-Mertk-/- cord. Together, these results suggest that microglia phagocytically kill living neurons, and thereby hasten death in ALS.
    DOI:  https://doi.org/10.1038/s41467-026-76728-5
  10. Genes Dev. 2026 Sep 15.
    The hnRNPA1 D262V amyotrophic lateral sclerosis (ALS) mutation is linked to mitochondrial dysfunction.
    Yeon J Lee, Koning Shen, Andrew Dillin, Donald C Rio.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by motor neuron loss and has been genetically linked to mutations in RNA-binding proteins. A mutation D262V in the RNA-binding protein hnRNPA1, found in a subset of ALS patients, causes widespread splicing pattern changes. Cells expressing this hnRNPA1 mutation exhibit aggregation, reduced proliferation, altered stress granules and abnormal neuronal growth. To further elucidate how a single amino acid substitution in a splicing factor might impact cell growth, we employed ribosome profiling to study translational dynamics across the transcriptome in hnRNPA1 mutant cells. Differential ribosome occupancy was observed for a small number of transcripts linked to synaptic organization and GTPase functions, as well as disrupted codon usage and a global stalling of translation. This downregulation of translation coincided with suppression of the mTOR/AKT signaling pathway. RNA splicing changes in transcripts from genes linked to cilia/cell projections, GTPase cycles and glutamate signaling were also observed. Importantly, major mitochondrial dysfunction and mitochondrial fragmentation were found in hnRNPA1 D262V mutant cells. Overall, this study demonstrates how a single amino acid change in an RNA binding protein can contribute to disrupting cell growth and mitochondrial function related to defects linked to neuronal death in ALS.
    Keywords:  amyotrophic lateral sclerosis (ALS); hnRNPA1; mitochondria
    DOI:  https://doi.org/10.1101/gad.353720.126
  11. Mayo Clin Proc Innov Qual Outcomes. 2026 Oct;10(5): 100755
    From Vision to Validation: The Journey of Tofersen in Superoxide Dismutase 1 Gene-Associated Amyotrophic Lateral Sclerosis.
    Björn Oskarsson, Michael G Heckman.
      
    DOI:  https://doi.org/10.1016/j.mayocpiqo.2026.100755
  12. Molecules. 2026 Aug 28. pii: 3021. [Epub ahead of print]31(17):
    Beneficial Effects of Putative Hydrogen Sulfide (H2S) Donor POM16 in a Genetic Model of Amyotrophic Lateral Sclerosis, FUS [1-359]-Transgenic Mice.
    Tatyana Strekalova, Anna Gorlova, Johannes P M de Munter, Maya Chervinskaya, Alexey Deykin, Zhanna Aladysheva, Elisaveta Grigorieva, Alexei Lyundup, Sholpan Askarova, Andrey Kostin, Igor Pomytkin.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by rapid motoneuron degeneration. Hydrogen sulfide (H2S), a signaling molecule that regulates post-translational modification, has recently been implicated in the pathophysiology of ALS. Our study aimed to design, synthesize, and investigate the potential effects of (2S)-2-aminopentanethioic S-acid (POM16), an isomer of the slow-releasing H2S donor thiovaline, in a genetic ALS model. FUS [1-359]-tg mice, which recapitulate ALS syndrome, and their wild-type (WT) littermates received POM16 (at a dose of 50/mg/kg) or standard ALS therapy riluzole (at a dose of 8 mg/kg/day) dissolved in drinking water, or vehicle, for six weeks starting at nine weeks of age. The onset of paralysis, physiological and motor functions, muscle atrophy, density of spinal cord motoneurons, gene expression of proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF), and concentration of oxidative stress marker malondialdehyde (MDA) in the spinal cord were studied. POM16-treated mutants displayed significant improvements in body weight, water and diet intake, as well as behavior in the rotarod, wire, and pole tests. The percentage of mice with paralysis on the 6th week of dosing was reduced from 48% in vehicle-treated mutants to 16% in POM16-treated FUS [1-359]-tg mice, while in the riluzole-treated group, it was 38%, not reaching significance. Notably, muscle weight was not significantly improved by the latter treatment, unlike the dosing with POM16. In comparison with vehicle-treated FUS [1-359]-tg mice, POM16-treated mutants had significantly higher motor neuron density in the spinal cord, lower MDA levels, and reduced muscle atrophy ranking. Thus, new compound POM16 has a therapeutic potential to counteract ALS pathology that is likely mediated via anti-oxidative stress mechanisms. Given that any effective treatment of this devastating disease is currently lacking, it is hoped that POM16 can be a promising therapy for ALS.
    Keywords:  (2S)-2-aminopentanethioic S-acid; FUS [1-359]-transgenic mice; amyotrophic lateral sclerosis (ALS); hydrogen sulfide (H2S); neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.3390/molecules31173021
  13. PLoS One. 2026 ;21(9): e0358772
    Serum Na-Cl value from routine blood tests reflects CO2 retention in amyotrophic lateral sclerosis.
    Isamu Yamakawa, Ryota Tamura, Hiroyuki Yabata, Takahito Tsukamoto, Shuhei Kobashi, Yoshitaka Tamaki, Nobuhiro Ogawa, Akihiro Kitamura, Makoto Urushitani.
       BACKGROUND: Respiratory failure is the leading cause of death in amyotrophic lateral sclerosis (ALS). Early detection of CO2 retention is crucial for assessing respiratory failure severity and guiding noninvasive positive pressure ventilation (NPPV) management. However, arterial blood gas analysis is invasive and uncomfortable for routine monitoring.
    OBJECTIVE: We investigated whether the serum sodium-chloride difference (Na-Cl value), calculated from routine blood tests, could serve as a screening marker for CO2 retention in ALS patients.
    METHODS: This retrospective study included 88 ALS patients with 116 paired samples of arterial blood gas and serum electrolyte data. We analyzed correlations between Na-Cl value and blood gas parameters (HCO3-, PCO2), performed receiver operating characteristic (ROC) analysis for detecting CO2 retention (PCO2 ≥ 45 mmHg), and examined relationships with respiratory function (%FVC).
    RESULTS: Na-Cl value showed strong correlation with HCO3- (r = 0.78, p < 0.001) and PCO2 (r = 0.71, p < 0.001). Na-Cl ≥ 37 mEq/L demonstrated sensitivity of 85.11% and specificity of 69.57% for detecting PCO2 ≥ 45 mmHg, with negative predictive value of 87.27% (AUC = 0.842). Na-Cl ≥ 39 mEq/L achieved specificity of 92.75%. Patients with %FVC < 50% had significantly higher Na-Cl, PCO2, and HCO3- values.
    CONCLUSIONS: Serum Na-Cl value serves as a simple, noninvasive screening marker for CO2 retention in ALS. Na-Cl ≥ 37 mEq/L warrants blood gas analysis, while Na-Cl ≥ 39 mEq/L provides specificity >90%. This marker can be calculated from routine blood tests without additional cost, making it suitable for frequent monitoring and reducing the risk of missing intervention timing.
    DOI:  https://doi.org/10.1371/journal.pone.0358772
  14. Neurotherapeutics. 2026 Sep 17. pii: S1878-7479(26)00226-6. [Epub ahead of print]23(6): e01056
    New approach methodologies in neurotherapeutics development.
    Amir P Tamiz, Szczepan W Baran, Thomas Hartung, Wendy W Wu.
      New Approach Methodologies (NAMs) offer substantial opportunities to transform neurotherapeutics discovery, optimization, and development, reducing the timeline to translate central nervous system (CNS) innovations to patients. Strategically deployed, NAMs enhance the predictive value of preclinical studies for human outcomes while reducing reliance on animal models. Current scientific community interest focuses particularly on human-based and -derived systems, in silico and AI-driven models, and advanced microphysiological platforms, reflecting a shift toward human-centric drug development paradigms. Despite this momentum, significant challenges remain, including NAM reproducibility and validation, the establishment of standardized performance criteria, data sharing, and the evolution of regulatory frameworks needed to enable consistent adoption across the neurotherapeutics continuum. Nevertheless, there is a rich history of developing and adopting methodologies, particularly for improving the prediction of neurotherapeutic safety profiles while reducing animal use, and for advancing understanding of drug delivery across the blood-brain barrier, and the assessment of adverse neurological effects. These advances have begun to influence regulatory decision-making and are increasingly reflected in guidance and review practices. Furthermore, NAMs are showing concrete impact in neurological disorders, including Epilepsy, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease, where human-relevant models and computational approaches support more precise characterization of disease mechanisms and therapeutic responses. In this paper, we examine the current and emerging roles of NAMs in neurotherapeutics development from government, academia, and industry perspectives, highlight key opportunities and limitations, and discuss the scientific, technical, and regulatory steps required to fully realize their potential in accelerating safe and effective CNS therapies.
    Keywords:  Neurotherapeutics development; Neurotherapeutics discovery; New approach methodologies; Regulatory; Reproducibility and validation
    DOI:  https://doi.org/10.1016/j.neurot.2026.e01056
  15. J Extracell Vesicles. 2026 Sep;15(9): e70370
    Neural Stem Cell-Derived Extracellular Vesicles Improve CNS Delivery and Therapeutic Efficacy of Antisense Oligonucleotide in Amyotrophic Lateral Sclerosis.
    Yaochao Zheng, Taylor Jade Ellison, Robert Garrard, Jinghui Gao, Xinning Lai, Lin Lan, Jin Xie, Jie Jiang, Yao Yao.
      Antisense oligonucleotides (ASOs) hold clinical promise for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Yet, their efficacy is constrained by the need for invasive delivery, poor central nervous system (CNS) penetration, inefficient cellular uptake and rapid clearance. Here, we developed neural stem cell-derived extracellular vesicles (NSC-EVs) as natural carriers to enhance CNS targeting and therapeutic efficacy of ASO-based treatments for ALS. Using a passive loading method, therapeutic ASOs were efficiently associated with NSC-EVs (NSC-EV-ASO). Compared with free ASOs, NSC-EVs- ASOs exhibited markedly enhanced neuronal uptake in vitro and increased CNS accumulation and neuronal localization in vivo following intracerebroventricular, intranasal, or intravenous administration. Functionally, NSC-EV-ASOs reduced the mutant SOD1 protein expression and the pathogenic hexanucleotide repeats in the C9orf72 loci in ALS cellular models. In the ALS mouse model, intranasal administration of NSC-EV-ASOs more efficiently delayed disease onset, improved motor performance, preserved motor neurons and attenuated astrocyte activation during the study period compared with free ASOs. These findings provide proof-of-concept evidence supporting the potential of NSC-EV as a promising platform that not only enhances CNS delivery of ASOs but also contributes to overall therapeutic activity, offering a synergistic strategy to advance nucleic acid therapeutics for ALS and potentially other neurological diseases.
    Keywords:  amyotrophic lateral sclerosis; antisense oligonucleotide; drug delivery; extracellular vesicles; neural stem cell
    DOI:  https://doi.org/10.1002/jev2.70370
  16. Int J Mol Sci. 2026 Sep 07. pii: 7958. [Epub ahead of print]27(17):
    Cognitive and Behavioural Profile of SOD1-ALS Across the ALS-FTD Spectrum: A Systematic Review.
    Francesco Ginanni, Francesco Nicoletti, Caterina Meoni, Lucrezia Becattini, Michelangelo Mancuso, Cecilia Carlesi, Francesca Bianchi.
      Amyotrophic Lateral Sclerosis (ALS) is increasingly recognized as a multisystem disorder. However, SOD1-associated ALS has traditionally been regarded as an exclusively motor phenotype. This systematic review challenges that paradigm by characterizing the cognitive and behavioural profiles of SOD1 mutation-related ALS. Following PRISMA guidelines, a systematic PubMed search identified 17 eligible studies. Across the included studies, encompassing 222 patients with SOD1 variants, three of the analyzed subjects fulfilled the diagnostic criteria for frontotemporal dementia (FTD), and a larger proportion exhibited multidomain cognitive deficits, including executive dysfunction, language impairment, and working memory decline. Behavioural disturbances, such as apathy, emotional lability, and mental rigidity, were also prominent. The historical assumption that SOD1 mutations completely spare cognitive networks likely reflects an under-recognition of subtle manifestations, compounded by the limited sensitivity of earlier screening tools. These findings indicate that cognitive and behavioural involvement can occur in SOD1-ALS, highlighting a highly heterogeneous phenotype. Encompassing varying degrees of severity-from subtle differences in neuropsychological test scores to formal FTD diagnoses-the current evidence points towards possible variant-specific phenotypes rather than a uniform cognitive syndrome. Routine multidomain cognitive screening is crucial in this population. Properly characterizing these non-motor features allows for more accurate disease staging, better monitoring of clinical progression, and the implementation of truly personalized care strategies.
    Keywords:  SOD1; amyotrophic lateral sclerosis (ALS); behavioural impairment; cognitive impairment; frontotemporal dementia (FTD); neuropsychology; systematic review
    DOI:  https://doi.org/10.3390/ijms27177958
  17. Front Neurol. 2026 ;17 1889217
    Prevalence of and associated factors for sleep disorders in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.
    Genping Xie, Yupeng Guo, Zhuo Wang.
       Background: Sleep disorders stand as prevalent non-motor symptoms in individuals with amyotrophic lateral sclerosis (ALS) and may be linked to respiratory muscle weakness, neurodegenerative changes, and disruption of sleep architecture. Existing studies have reported considerable variability in the prevalence of sleep disorders in ALS patients, and findings regarding associated factors remain inconsistent. Therefore, this study intended to integrate the existing evidence through a meta-analysis to further clarify the prevalence of sleep disorders and their clinical relevant factors.
    Methods: PubMed, Embase, Web of Science, and the Cochrane Library were searched from database inception to January 10, 2026. Cross-sectional, cohort, and case-control studies involving clinically diagnosed adult patients with ALS were included. A random-effects model was used to estimate the pooled prevalence of sleep disorders. Subgroup analyses were performed according to sex, site of onset, age, disease duration, body mass index (BMI), sleep disorder category based on the International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR), sleep-related treatment status, and assessment method (polysomnography [PSG] versus questionnaire-based assessment).
    Results: A total of 31 studies involving 2,762 patients with ALS were included. The pooled prevalence of sleep disorders was 50% (95% confidence interval [CI], 45-56%). Patients with sleep disorders were significantly older than those without sleep disorders (mean difference [MD] = 3.72 years, 95% CI, 2.39-5.05), whereas no significant associations were observed for sex, body mass index (BMI), disease duration, or site of onset. The prevalence did not differ significantly across the ICSD-3-TR categories (p = 0.7367), whereas questionnaire-based studies yielded a significantly higher pooled prevalence than PSG-based studies (p = 0.0367). Sensitivity analyses confirmed the robustness of the findings.
    Conclusion: Approximately half of ALS patients have sleep disorders. Age may be related to the occurrence of sleep disorders, whereas no substantial relations were identified for sex, BMI, disease duration, or site of onset. Routine screening and early intervention for sleep issues should be strengthened in clinical management. Large-scale, multicenter prospective studies are still needed to further clarify the underlying mechanisms and clinical implications.
    Systematic review registration: The publicly accessible registration URL is: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261287352. The systematic review was registered with PROSPERO (registration number: CRD420261287352).
    Keywords:  amyotrophic lateral sclerosis; associated factors; meta-analysis; prevalence; sleep disorders
    DOI:  https://doi.org/10.3389/fneur.2026.1889217
  18. Med. 2026 Sep 14. pii: S2666-6340(26)00298-9. [Epub ahead of print] 101295
    N-of-1 investigational study of a novel antisense oligonucleotide drug in CHCHD10-related ALS shows early signs of efficacy.
    Margot A Cousin, Aditi I Dagli, Laurence Mignon, Jaimin S Shah, Mercedes Prudencio, Tania F Gendron, Angita Jain, Evan Udine, Marka van Blitterswijk, Erik H Middlebrooks, Megan H Donahue, Jany E Dagher, Jens O Watzlawik, Wolfdieter Springer, Tejal Parekh, Zachary T McEachin, Leonard Petrucelli, Björn Oskarsson.
       BACKGROUND: Pathogenic CHCHD10 variants cause a rare, dominantly inherited form of amyotrophic lateral sclerosis (ALS). Non-allele-selective CHCHD10 knockdown may mitigate a toxic gain-of-function mechanism. We evaluated nL-CHCHD-001 in one participant with the p.Arg15Leu variant.
    METHODS: In this open-label N-of-1 study, 320-gapmer antisense oligonucleotides (ASOs) were screened, and a lead candidate was selected according to specificity and non-clinical safety criteria. Six intrathecal doses were administered over 12 months (three 50-mg doses followed by three 75-mg doses). Prespecified primary outcomes were 12-month changes in functional, cognitive, quality-of-life, respiratory, neurofilament light (NfL), and survival measures; secondary outcomes assessed were safety and tolerability. Analyses were descriptive.
    FINDINGS: No serious adverse events occurred. Post-dose headache and fatigue were mild to moderate, and cerebrospinal fluid safety results were unremarkable. Plasma NfL decreased by approximately 50% from a mildly elevated pretreatment baseline and entered the laboratory reference range. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score increased from 33 to 36, vital capacity increased from 48% to 55% (as predicted), cognitive and quality-of-life scores remained stable, and the participant was alive at 12 months.
    CONCLUSIONS: Individualized CHCHD10-directed treatment was feasible and well tolerated and was temporally associated with biomarker and clinical stability or improvement. This N-of-1 study demonstrates the feasibility of developing individualized ASO therapy for CHCHD10-related ALS and provides preliminary evidence of biomarker and clinical benefit. These findings support further evaluation of nL-CHCHD-001 and highlight NfL as a practical treatment-response biomarker for personalized therapeutics in ALS.
    CLINICALTRIALS: gov: NCT06392126.
    FUNDING: This study was supported by the n-Lorem Foundation, National Institutes of Health grants U01NS134684 and KL2 TR002379, and the Kevin Merszei Career Development Award.
    Keywords:  CHCHD10; amyotrophic lateral sclerosis; antisense oligonucleotide; individualized therapy; neurofilament light; translation to patients
    DOI:  https://doi.org/10.1016/j.medj.2026.101295
  19. Cureus. 2026 Aug;18(8): e114605
    ABCD1-Related Disease Presenting as an Upper Motor Neuron-Predominant Amyotrophic Lateral Sclerosis Mimic in a Colombian Female Heterozygote: A Case Report.
    Cristian Correa-Arrieta, Sandra Milena Castellar Leones, Mariana Bernal-Vergara, Mariana Saiz-Briceño, Jorge Diaz-Ruiz, Fernando Ortiz-Corredor.
      We report the case of a 47-year-old Colombian woman with a persistent gait disorder beginning at 46 years of age. Neurological examination showed preserved strength, lower-limb spasticity, diffuse hyperreflexia, brisk jaw jerk, and a unilateral Hoffmann sign, without definite bulbar, respiratory, cognitive, sensory, or cerebellar involvement. Brain MRI showed nonspecific occipital/subcortical T2/FLAIR (fluid-attenuated inversion recovery) white matter hyperintensities, and spinal MRI showed mild degenerative changes without compressive myelopathy or spinal cord signal abnormality. Laboratory evaluation did not identify an inflammatory, infectious, nutritional, metabolic, or endocrine cause of myelopathy. Two electrodiagnostic studies showed preserved motor and sensory nerve conduction, normal late responses, normal motor unit action potentials on needle electromyography, and no evidence of active denervation. Neuromuscular ultrasound was also normal, without nerve enlargement, abnormal muscle echogenicity, atrophy, or fasciculations. Overall, there was no diffuse, progressive, multiregional lower motor neuron pattern, and Gold Coast criteria for amyotrophic lateral sclerosis were not fulfilled. A motor neuron disease gene panel identified a heterozygous pathogenic ABCD1 variant, c.1415_1416delAG, p.Gln472Argfs*83. Repeat expansion testing for C9ORF72, ATXN1, and ATXN2 was normal. Classical plasma very-long-chain and branched-chain fatty acid testing showed elevated C26:0 and increased C24:0/C22:0 and C26:0/C22:0 ratios, with normal phytanic and pristanic acids. The clinical, imaging, electrodiagnostic, biochemical, and molecular findings supported ABCD1-related disease with an adrenomyeloneuropathy-predominant phenotype as the most likely explanation for this upper motor neuron-predominant amyotrophic lateral sclerosis (ALS) mimic. This case highlights the importance of considering ABCD1-related disease in adult women with unexplained noncompressive upper motor neuron syndromes when electrodiagnostic studies do not support ALS.
    Keywords:  abcd1-related disease; adrenomyeloneuropathy; amyotrophic lateral sclerosis mimic; female heterozygote; upper motor neuron syndrome
    DOI:  https://doi.org/10.7759/cureus.114605
  20. Heart Lung. 2026 Sep 13. pii: S0147-9563(26)00236-0. [Epub ahead of print]80 102952
    Time-dependent adherence to non-invasive ventilation in amyotrophic lateral sclerosis: an observational cohort study.
    Federica Riva-Rovedda, Andrea Calvo, Marco Clari, Maria Vittoria Picciaiola, Alessandro Godono, Umberto Manera, Antonio Canosa, Francesca Palumbo, Cristina Moglia, Adriano Chiò, Rocco Francesco Rinaldo, Giuseppe Tabbia, Paolo Solidoro, Valerio Dimonte.
       BACKGROUND: Non-invasive ventilation (NIV) improves survival and quality of life in amyotrophic lateral sclerosis (ALS). However, adherence is frequently suboptimal and longitudinal outpatient data are limited.
    OBJECTIVE: We assessed NIV adherence during the first year of outpatient adaptation, factors associated with time-dependent adherence, and the relationship between adherence and survival.
    METHODS: We conducted a retrospective cohort study including individuals with ALS prescribed with NIV between January 2022 and June 2024 at the outpatient clinic of an Italian referral centre. Functional status, adherence, and device-related complications were recorded at 1, 3, 6, and 12 months. Data about deaths and tracheostomy events were collected.
    RESULTS: Complete adherence data were available for 73 patients. Mean NIV use increased; nevertheless, approximately 30% of patients were non-adherent at 6 and 12 months. NIV-related complications ranged between 30-44%, though they were not significantly associated with adherence. Higher ALSFRS-R respiratory subscore (OR=0.78, 95% CI 0.64-0.95) and having a male caregiver (OR=0.19, 95% CI 0.04-0.96) were associated with reduced adherence. Time-dependent adherence was not significantly associated with survival, whereas older age at diagnosis and PEG placement were associated with a 5% and more than threefold higher risk of death/tracheostomy, respectively (HR 1.05, 95% CI 1.01-1.09; HR 3.42, 95% CI 1.54-7.59).
    CONCLUSION: NIV adherence and NIV-related complications showed dynamic patterns over time. One-third of patients were non-adherent at 6 and 12 months, highlighting the need for tailored interventions throughout follow-up. Although time-dependent adherence was not independently associated with survival, period-averaged adherence appeared to produce a more favourable survival estimate than time-dependent adherence.
    Keywords:  Amyotrophic lateral sclerosis; Non-invasive ventilation; Non-invasive ventilation complications; Survival; Time-dependent adherence
    DOI:  https://doi.org/10.1016/j.hrtlng.2026.102952
  21. Brain Commun. 2026 ;8(5): fcag302
    Metabolic alterations in the absence of a neuromuscular phenotype in humanized SOD1A5V mice.
    David Thompson, Chloe Williams, Georgia Price, Andrew P Tosolini, Clemens Falker-Gieske, Jonathan D Gilthorpe, Giampietro Schiavo, Elizabeth M C Fisher, Thomas J Cunningham.
      Amyotrophic lateral sclerosis caused by mutations in superoxide dismutase 1 (SOD1) accounts for 15-30% of familial cases and is typically autosomal dominant. How single amino acid changes in this small protein cause neurodegeneration is unknown. In North America, SOD1A5V is the most common familial SOD1 mutation and results in an aggressive form of amyotrophic lateral sclerosis. Here, we present a novel genomically humanized mouse model of SOD1A5V , in which the mouse Sod1 locus has been replaced by the human SOD1 gene, with intact genomic architecture of exons and introns, but bearing an A5 V mutation. In agreement with previously reported human genomic knock-in mice, the phenotype is mild; however, transcriptomic and metabolomic profiling reveal significant dysregulation of glycolysis, the tricarboxylic acid cycle, and lipid metabolism. These changes suggest an early bioenergetic imbalance that precedes neuromuscular impairment. Our findings support metabolic dysfunction as an early event in amyotrophic lateral sclerosis pathogenesis. This freely available SOD1A5V model provides a valuable tool for studying amyotrophic lateral sclerosis progression and identifying therapeutic targets for pre-symptomatic treatment.
    Keywords:  ALS; SOD1; gene targeting; mouse models
    DOI:  https://doi.org/10.1093/braincomms/fcag302
  22. J Clin Invest. 2026 Sep 15. pii: e202787. [Epub ahead of print]136(18):
    UA-30 ameliorates motor deficits through RalA-mediated mitophagy in ALS mice.
    Bingge Zhang, Ye He, Ting Su, Xiaomei Li, Xiufen Zhang, Ruijuan Liu, Xiao Han, Ruiming Zhang, Chao Yang, Xinlei Liu, Qinghua Hou, Zaijun Zhang, Yongmei Xie, Gongping Liu, Xifei Yang.
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, skeletal muscle atrophy, paralysis, and eventually death. Mitochondrial dysfunction plays a pivotal role in ALS pathogenesis, although the precise pathogenic mechanisms remain elusive, and effective therapeutic strategies are extremely limited. In this study, we developed a small-molecule inhibitor, UA-30, which directly targets RalA, and explored its potential for the treatment of ALS. We found that when administered via oral gavage for 6 weeks following the onset of motor deficit, UA-30 extended lifespan and improved motor function of SOD1G93A mice, a model of ALS. UA-30 ameliorated motor neuron loss, neuroinflammation, fibrosis, and mitochondrial dysfunction, as evidenced by energy recovery, decreased oxidative stress, and enhanced mitophagy. Mechanistically, UA-30 inhibited RalA activity and thereby modulated ERK/FOXO3a signaling, which inhibited FOXO3a degradation via the ubiquitin-proteasome pathway; enhanced FOXO3a stability; and upregulated the expression of mitophagy-related genes in this ALS mouse model. The beneficial effects of UA-30 in ALS were abolished by overexpression of the constitutively active form of RalA (RalAG23V) or Mdivi-1 treatment. These findings support RalA inhibition as a therapeutic strategy for enhancing mitophagy and mitigating ALS-like pathology and support UA-30 as an orally active candidate for further preclinical development.
    Keywords:  ALS; Cell biology; Mitochondria; Neuroscience
    DOI:  https://doi.org/10.1172/JCI202787
  23. Adv Radiat Oncol. 2026 Sep;11(9): 102135
    Radiation Therapy for Sialorrhea in Patients With Amyotrophic Lateral Sclerosis: A Case Series and Critical Review.
    Ella Zhang, Patrick Oh, Tracy Shamas, Huned S Patwa, Kimberly L Johung.
       Purpose: Radiation therapy (RT) for sialorrhea has historically used 3-dimensional techniques that broadly irradiate both major and minor salivary glands. However, some reports indicate that treatment of minor salivary glands may contribute to excessive xerostomia. In this retrospective case series, we assessed the efficacy and tolerability of oral-cavity-sparing volumetric modulated arc therapy (VMAT) and bilateral electron field radiation for sialorrhea in patients with amyotrophic lateral sclerosis (ALS) and reviewed the relevant literature.
    Methods and Materials: From 2014 to 2025, 6 patients with bulbar-onset ALS and medically refractory sialorrhea were treated with RT to the parotid and submandibular glands (20 Gy in 5 fractions) at a single institution. Five patients received VMAT with 6 MV photons, and one received bilateral 16 MeV electrons. Clinical response, medication use, toxicity, and dosimetry were assessed. A PubMed search using "sialorrhea," "RT," and "amyotrophic lateral sclerosis" was performed for the literature review.
    Results: At a median follow-up of 15.05 months (range, 3.0-61.7 months), 5 of 6 patients (83.3%) achieved symptomatic improvement, with an average 60% patient-reported reduction in salivation and ≥2 point improvement in ALS Functional Rating Scale saliva subscore. Two discontinued anticholinergics, and 1 achieved complete resolution for 3 years. Acute toxicities with VMAT were mild and self-limiting, most commonly parotitis and thickened secretions. The patient treated with electrons developed grade 2 mucositis, not observed with VMAT. Late toxicities, including xerostomia, were minimal and transient. Dosimetry showed higher larynx and oral cavity doses with electrons, whereas VMAT delivered slightly higher spinal cord doses. Critical literature review supported RT as an effective and well-tolerated intervention.
    Conclusions: RT provides durable relief of refractory sialorrhea in ALS with manageable toxicity. VMAT response is comparable with historical outcomes and may offer dosimetric advantages that correlate with reduced acute toxicities, although its clinical benefit and cost-effectiveness warrant further validation.
    DOI:  https://doi.org/10.1016/j.adro.2026.102135
  24. Cells. 2026 Aug 26. pii: 1540. [Epub ahead of print]15(17):
    Application of Mesenchymal Stromal Cells and Their Exosomes in Neurodegenerative Diseases and Lysosomal Storage Diseases.
    Aisylu I Ayupova, Angelina S Sidorova, Ekaterina A Luzina, Albert A Sufianov, Galina Z Sufianova, Azat M Zaynutdinov, Albert A Rizvanov, Valeriya V Solovyeva.
      Mesenchymal stromal cells (MSCs) have emerged as a promising therapeutic platform for central nervous system disorders, including neurodegenerative diseases and lysosomal storage disorders (LSDs). This review examines MSC mechanisms of action-paracrine activity, immunomodulation, antioxidant effects, TFEB-mediated autophagy regulation, and enzymatic cross-correction in LSDs-while critically assessing translational challenges. We provide a comparative analysis of MSC sources, administration routes, dosing regimens, and safety profiles, with emphasis on hemocompatibility and thrombotic risks. The evidence base for MSC efficacy in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and LSDs is systematically reviewed, highlighting both promising signals and limitations. MSC-derived extracellular vesicles are discussed as a cell-free alternative with improved safety and potential blood-brain barrier interaction. We propose an individualized monitoring framework integrating clinical scales, biomarkers, and neuroimaging. Despite preclinical promise, the field faces major hurdles: product standardization, optimal dosing, and the need for large, randomized controlled trials. The most rational path forward lies in combination strategies-MSCs as adjuncts to gene or enzyme replacement therapy-and engineered platforms for sustained delivery. This review provides a roadmap for translational decision-making and identifies critical gaps that must be addressed before MSC-based therapies can be integrated into routine neurological practice.
    Keywords:  cell therapy; cross-correction; exosomes; extracellular vesicles; hemocompatibility; immunomodulation; lysosomal storage disorders; mesenchymal stromal cells; neurodegenerative diseases; neuroinflammation; tissue factor
    DOI:  https://doi.org/10.3390/cells15171540
  25. Neurobiol Dis. 2026 Sep 18. pii: S0969-9961(26)00355-4. [Epub ahead of print] 107610
    Cellular senescence is an early feature and therapeutic target in amyotrophic lateral sclerosis TDP-43Q331K mice.
    Jose A Viteri, Nathan R Kerr, Charles D Brennan, Grace R Kick, Meifang Wang, Arsh Ketabforoush, Harper J Snyder, Peter J Moore, Fereshteh B Darvishi, Anna R Dashtmian, Sindhuja N Ayyagari, Kelly Rich, Yi Zhu, Hiroshi Nishimune, W David Arnold.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration in the motor cortex and spinal cord. Aging is a key risk factor for ALS, and cellular senescence - a hallmark of aging marked by irreversible cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype - has been implicated in neurodegeneration, yet its role in ALS progression remains incompletely understood. Here, we show that molecular markers of cellular senescence emerge in the motor cortex and spinal cord alongside declines in neural and neuromuscular function in TDP-43Q331K ALS mice, supporting senescence as an early feature of ALS pathology. To test whether reduced senescence ameliorates ALS pathology, we evaluated longitudinal senolytic treatment with dasatinib and quercetin (D&Q) in TDP-43Q331K mice. D&Q treatment improved motor behavior, neuromuscular function, and reduced axonal damage as measured by plasma neurofilament light chain, accompanied by robust improvements in motor cortex excitability and preservation of layer V neuron counts. At the cellular level, cortical microglia were implicated as a potential mediator of senolytic benefits based on reduced microglial TDP-43 burden and senescence markers. Together, these findings identify cellular senescence as an early, disease-relevant, and modifiable feature of ALS pathology.
    Keywords:  ALS; Aging; Motor cortex; Neuromuscular; Senescence; Senolytics
    DOI:  https://doi.org/10.1016/j.nbd.2026.107610
  26. Metab Brain Dis. 2026 Sep 16. pii: 221. [Epub ahead of print]41(1):
    Unraveling the regulatory nexus of aggrephagy in ALS: identification of novel candidate biomarkers and molecular triggers.
    Yingzhen Zhang, Kenhui Wei, Hanxiao Lin, Ziming Guo, Yingtong Lu, Tao Ma.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disorder involving multiple systems, with motor neuron degeneration as its primary feature. This disease can be classified into sporadic and familial types. Genes such as SOD1, C9orf72, FUS, and TDP-43 have been identified as the main causative genes for familial ALS. Multiple bioinformatics tools combined with an experimental verification strategy have helped in understanding the association of a selective autophagy pathway called aggrephagy with the disease.
    RESULTS: The transcriptome data of spinal cord tissue from SOD1-G93A mice was obtained from the Gene Expression Omnibus (GEO) database. Based on the GSE281064 dataset, we investigated aggrephagy-related transcriptional alterations in the SOD1-G93A mouse model of ALS. After comparison with the aggrephagy-related genes (AGGRGs) set included in the GeneCards database, 49 candidate genes closely related to the autophagy process were obtained. Functional enrichment analysis showed these genes participate in extracellular matrix remodeling, hyaluronic acid and glycosaminoglycan metabolism, tumor necrosis factor regulation, and lysosomal function, indicating central roles in inflammation, apoptosis, and metabolic disorders. Based on feature selection algorithms, this study employed machine learning methods such as random forest (RF), extreme gradient boosting (XGBoost), and Boruta to conduct multi-angle screening of candidate genes. The intersection of the results ultimately identified three key genes: Ctsb, Kif11, and S100a6.
    CONCLUSIONS: In both the training data and external validation data, Ctsb and S100a6 showed significant upregulation and demonstrated excellent discriminatory capabilities. The nomogram constructed based on Ctsb and S100a6 expression showed potential for distinguishing SOD1-G93A model samples from nontransgenic controls. The predicted probability demonstrated the potential of these two as candidate biomarkers. Meanwhile, further validation is needed in larger independent population cohorts in the future. The SOD1-G93A mouse model and SOD1-G93A-expressing NSC34 cell model showed expression patterns of Ctsb and S100a6 consistent with the bioinformatics findings. Through S100a6 overexpression and knockdown experiments in an NSC34 motor neuron-like ALS model, we found that S100a6 impaired autophagy and promoted SOD1 aggregation. These findings further validate its potential as a biomarker and provide new insights into the pathogenesis of ALS.
    Keywords:  Aggrephagy; Amyotrophic lateral sclerosis; Ctsb; Metal ion homeostasis; S100a6; SOD1; Transcriptome
    DOI:  https://doi.org/10.1007/s11011-026-01987-6
  27. Acta Neuropathol Commun. 2026 Jul 27. pii: 189. [Epub ahead of print]14(1):
    Neuro-glial lipid imbalance in a Drosophila model of amyotrophic lateral sclerosis 8.
    Lovleen Garg, Kriti Chaplot, Gowhith Kuppili, Shweta Tendulkar, Jomon Joseph, Siddhesh Kamat, Girish Ratnaparkhi.
      Membrane Contact sites (MCS) have emerged as physiologically relevant zones that coordinate inter-organelle communication and cellular function. VAPB, an ER-resident MCS tethering protein, plays a central role in regulating MCSs through its numerous protein interactors, thereby influencing cellular homeostasis. A pathogenic missense VAPBP56S mutation causes familial Amyotrophic Lateral Sclerosis 8 (ALS8) in humans, with progressive degeneration of motor neurons. The precise mechanisms underlying the motor neurodegeneration remain poorly understood. In this study, we examine lipid imbalance in the brain of a Drosophila model of ALS8 (VAPBP58S). Specifically, we find that lipid homeostasis is disrupted in an age-dependent manner. Strikingly, cholesterol esters and sphingolipids show an age-dependent increase, while cholesterol shows a decrease. Intriguingly, from a cellular perspective, despite the accumulation of triacylglycerols (TAGs) in the brains of VAPBP58S animals, the increased neutral lipid species do not correlate with lipid droplets (LDs), which are fewer in density and smaller in size. Lipid imbalance and progressive motor dysfunction in VAPBP58S animals can be reversed by expressing VAPBWT, suggesting a relationship between VAPB activity and lipid flux. To uncover VAPB's role in lipid homeostasis, we modulate VAPB activity in neurons and glia to dissect out tissue-specific roles. We find that both cell types contribute to lipid homeostasis in differential ways. In glia, LD flux is strongly dependent on VAPB activity, a dependence further recapitulated in cultured human cell lines, suggesting evolutionary conservation of the regulatory mechanism. Thus, we hypothesize that lipid dysregulation constitutes a critical pathogenic feature of ALS8, with the VAPBP56S allele disrupting lipid homeostasis in the neuro-glial axis.
    Keywords:  Cholesterol; Climbing; Glia; Lipid droplets; Neurodegeneration; VAP33A
    DOI:  https://doi.org/10.1186/s40478-026-02391-y
  28. Cells. 2026 Sep 02. pii: 1598. [Epub ahead of print]15(17):
    Efficacy of Low Dose of Dihydroquercetin (DHQ) in Two Genetic Models of Neurodegeneration: Insights from FUS[1-359]-Tg and APPswe/PS1dE9 Paradigms.
    Ekaterina Lysikova, Kseniia Sitdikova, Aigerim Makhambetova, Kirill Chaprov, Anna Gorlova, Andrey Kostin, Polina Novikova, Alexei Lyundup, Sholpan Askarova, Michail S Kukharsky, Alexey Deykin, Tatyana Strekalova.
      Dihydroquercetin (DHQ), a powerful antioxidant and regulator of cellular metabolism, was proposed for therapy of neurodegenerative disorders. Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) are serious neurodegenerative disorders with oxidative stress as an overlapping feature and unmet therapeutic needs. To date, few studies have explored the efficacy of DHQ in animal models of genetically driven neurodegeneration. Here, APPswe/PS1dE9 (APP/PS1) mice and their wild-type (WT) littermates were orally administered DHQ (0.6 mg/kg/day) for four months, starting at eight months of age. At the age of 12 months, behavioral evaluation was performed, followed by brain staining with Congo red for amyloid plaque scoring and immunohistochemical analysis of GFAP-positive cells for the assessment of astrogliosis. Malondialdehyde (MDA) levels in the prefrontal cortex were studied as a marker of oxidative stress. Second, two-month-old FUS[1-359]-Tg mice, which recapitulate the hallmarks of ALS, received DHQ for 1.5 months and were investigated for general physiological parameters, the onset of paralysis, motor functions, and density of motor neurons in the spinal cord. DHQ-treated APPswe/PS1dE9 mutants displayed a decrease in amyloid plaque density of small size (≤100 μm) in the cortex and thalamus, had normalized MDA levels, improved conditioned taste aversion and Y-maze learning, and ameliorated anxiety measures, whereas their hippocampus-dependent step-down and pellet displacement performance remained impaired. In the second study, DHQ-treated FUS[1-359]-Tg mice showed rescued density of spinal cord neurons, normalized liquid and diet intake, and improved coat state, while the onset of paralysis and motor scores were not significantly ameliorated. Thus, chronic administration of low doses of DHQ exerted neuroprotective effects in both AD and ALS genetic models, which partially translated to reduced manifestations of these diseases.
    Keywords:  APPswe/PS1dE9 mice; Alzheimer’s disease (AD); FUS[1-359]-Tg mice; amyotrophic lateral sclerosis (ALS); antioxidants; dihydroquercetin
    DOI:  https://doi.org/10.3390/cells15171598
  29. J Hum Genet. 2026 Sep 15.
    Characterising the motif composition and allele length distribution of ZFHX3 GGC repeat expansions in amyotrophic lateral sclerosis.
    Project MinE ALS sequencing consortium
      A pathogenic GGC repeat expansion in zinc finger homeobox 3 (ZFHX3), encoding a pure polyglycine (polyG) tract, causes spinocerebellar ataxia type 4 (SCA4). Intermediate expansions of other SCA loci have been implicated in amyotrophic lateral sclerosis (ALS), while repeat motif composition is recognised to influence pathogenicity in neurodegenerative diseases. Given the genetic pleiotropy between ALS and SCA, we evaluated whether ZFHX3 GGC expansions are associated with ALS and characterised repeat motif composition. ZFHX3 GGC repeat sizes were genotyped using ExpansionHunter in short-read whole-genome sequencing data from ALS cases and healthy controls of European ancestry. Repeat sizes were visually inspected using REViewer, and motif configurations were manually derived from a subset. Receiver operating characteristic analysis and Youden's J statistic identified a candidate repeat size threshold. Logistic regression tested associations of repeat length and motif composition with ALS, while regression models assessed clinical phenotypes. Across 5785 ALS cases and 7982 controls, no association was observed between ZFHX3 expansions and ALS risk. Longer alleles showed a nominal association with later disease onset, however this did not remain significant after Bonferroni correction. Among 802 ALS cases and 800 controls, 50 distinct motif compositions were identified, including 11 encoding pure polyG tracts characteristic of pathogenic SCA4 expansions; none were associated with ALS. Although no association with ALS was observed, this study established the dynamic nature of ZFHX3 repeat motif composition and configuration. Variation within and between repeat sizes, including pure polyG repeats, supports consideration of motif composition alongside allele length when evaluating neurodegenerative disease risk.
    DOI:  https://doi.org/10.1038/s10038-026-01513-7
  30. Brain Behav Immun Health. 2026 Nov;57 101323
    The thymus gland is a target and maintainer of amyotrophic lateral sclerosis pathophysiology.
    Julia Pereira Lemos, Daniel Stockholm, Brenda Dinatale, Amanda Silva Chaves, Sonia Pezet, Vinicius Frias Carvalho, Ana Rosa Pérez, Daniella Arêas Mendes-da-Cruz, Wilson Savino, Piera Smeriglio.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons in the brain and spinal cord with evidence of local neuroinflammation. Regulatory T cells (Treg) exert neuroprotective effects and correlate with disease progression, but central mechanisms governing Treg development during ALS remain unclear. We investigated the thymic architecture and T cell differentiation in SOD1-G93A (mSOD1) ALS mice at multiple disease stages. Thymocyte and thymic epithelial cells (TEC) subpopulations, as well as stages of Treg differentiation and suppressive capacity, were analyzed by flow cytometry, in situ immunofluorescence, and functional assays. At late disease stage (120 days-old), mSOD1 mice displayed thymic atrophy, reduced thymocyte numbers, and decreased double-positive (DP), CD4 single-positive (SP), and Treg populations. Foxp3 expression per cell was preserved, but Treg progenitors and mature Treg numbers declined, paralleled by reduced suppressive function in vitro. TEC analysis revealed reduced total and mature medullary TEC (CD80highMHCIIhigh), despite preserved Aire expression. Foxp3+ cells were abnormally localized at cortical sites, away from mTEC, associated with migratory abnormalities and increased apoptosis. TREC evaluation revealed reduced intrathymic sjTREC, consistent with impaired proliferation and differentiation between DN and DP stages, although peripheral sj/βTREC ratios remained stable. Reduced Treg numbers were also observed in lymph nodes draining affected hindlimbs. Our findings identify the thymus as a target organ in ALS, where thymic involution, TEC loss, and Treg dysfunction may compromise immune tolerance. These alterations likely reinforce the role of the thymus in peripheral immune dysregulation and neuroinflammation observed in ALS.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Immune homeostasis; Regulatory T cells (Treg); SOD1-G93A mouse model; Thymocyte development; Thymus
    DOI:  https://doi.org/10.1016/j.bbih.2026.101323
  31. Cells. 2026 Sep 02. pii: 1596. [Epub ahead of print]15(17):
    The Paradox of Tau and RNA-Binding Proteins: How Adaptive Stress Granule Regulation Becomes Pathological with Aging.
    Benjamin Wolozin, Merci Best, Madhav Ellini, Yuran Ma, Sojung Bok, Dylan Hwang, Carolina Filipponi.
      RNA-binding proteins (RBPs) are a large class of proteins that form biological condensates to facilitate their functions. Chronic stress, such as occurs in neurodegenerative diseases, stimulates persistent accumulation of particular RBP condensates as part of the translational stress response, termed stress granules (SGs). These persistent SGs serve as a nidus for aggregation of RBPs to form pathologies that appear in neurodegenerative diseases, such as the occurrence of Tar DNA Binding Protein (TDP-43) in Amyotrophic Lateral Sclerosis. Many of the RBPs that accumulate in SGs are also associated with mutations that are linked to neurodegenerative diseases. The microtubule-associated protein tau is the major intracellular pathology that occurs in Alzheimer's disease. Tau is phosphorylated with stress, whereupon it functions to regulate SG biology; conversely, SGs serve as a crucible for the accumulation of toxic oligomeric tau. The regulation of stress by tau is an inherent part of biology that normally occurs during development and hibernation; however, with aging it becomes pathological, possibly because of the reduced proteostasis associated with aging.
    Keywords:  MAPT; RNA metabolism; TDP-43; biological condensate; liquid–liquid phase separation; membraneless organelle; oligomeric tau; protein aggregation; stress granule; translational stress response
    DOI:  https://doi.org/10.3390/cells15171596
  32. Ann Neurol. 2026 Sep 12.
    Atherosclerotic Cardiovascular Diseases Increase ALS Risk by 82% While Optimal Cardiovascular Health Halves It: A 0.5-Million Prospective Cohort Study.
    Jiali Xie, Haobo Xie, Yaojia Li, Wenhua Jiang, Xinglin Wang, Qingjian Xie, Xueqin Song, Dongsheng Fan, Hong-Fu Li, Binbin Deng.
       OBJECTIVE: The objective of this study was to determine whether prevalent atherosclerotic cardiovascular diseases (ASCVDs) increase the risk of amyotrophic lateral sclerosis (ALS) and whether high cardiovascular health (CVH) can offset this risk.
    METHODS: We prospectively analyzed 502,279 UK Biobank participants (37-73 years) with linked electronic health records. Prevalent ASCVD (coronary artery disease [CAD], ischemic stroke [IS], and peripheral artery disease [PAD]) was ascertained at baseline. CVH was quantified using Life's Essential 8 and categorized as low, moderate, or high. Cox models, joint analyses, and Mendelian randomization were applied.
    RESULTS: Over a median follow-up of 13.74 years, 675 incident ALS cases were documented. A history of ASCVD was associated with a 43% higher risk of ALS (hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.16-1.78, p = 0.001), primarily driven by CAD and IS. Conversely, high CVH was associated with a lower risk of ALS compared with low CVH (HR = 0.52, 95% CI = 0.33-0.81, p = 0.004). Joint analysis revealed that individuals with low CVH and pre-existing ASCVD exhibited the highest ALS risk. Mendelian randomization analyses provided supportive evidence consistent with the observational associations among CAD, IS, and ALS. The inverse association between CVH and ALS risk was most pronounced among participants aged ≤65 years.
    INTERPRETATION: Prevalent ASCVD was associated with a higher risk of ALS, whereas high CVH was associated with a lower risk of ALS. These findings support a potential link between CVH and ALS susceptibility, particularly among individuals aged ≤65 years. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78321
  33. Mol Neurodegener Adv. 2026 ;2(1): 38
    Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?
    Silas A Buck, Sidharth S Madhavan, Laurie H Sanders.
      Many neurodegenerative diseases are characterized by pathological protein aggregation in the brain. Alzheimer's disease displays amyloid-β and tau inclusions in the form of amyloid-β plaques and tau neurofibrillary tangles. Synucleinopathies comprise Parkinson's disease and Dementia with Lewy bodies, which are classified by α-synuclein depositions in the form of Lewy bodies, as well as multiple system atrophy, which displays glial cytoplasmic α-synuclein inclusions. Tar DNA binding protein 43 (TDP-43) inclusions are observed in amyotrophic lateral sclerosis and frontotemporal lobar dementia with TDP-43 inclusions. A separate subgroup of frontotemporal lobar dementias, including Pick's disease, progressive supranuclear palsy and corticobasal degeneration, are characterized by disease-specific patterns of tau pathology and are termed primary tauopathies. Despite these classifications, it is not often appreciated that neurodegenerative diseases commonly display amyloid-β, tau, α-synuclein, and/or TDP-43 co-pathologies not typically associated with that specific disease's pathophysiology. Additionally, in vitro and in vivo proteinopathy models show interactions between pathological forms of these proteins that increase protein aggregation and neurotoxicity, suggesting distinct mechanisms underlying co-pathologies that play a significant role in neurodegeneration. In this review, we describe the frequency of protein co-pathologies across neurodegenerative diseases and preclinical work demonstrating pathological protein synergies that exacerbate protein aggregation and toxicity. We also discuss granulovacuolar degeneration bodies, proteolytically active lysosomal structures that are induced by either pathological tau or α-synuclein accumulation, as an example of a shared cellular response to, and link between, distinct protein pathologies. Finally, we highlight interventional clinical trials which target multiple pathologies and/or specifically target co-pathologies in neurodegenerative diseases, noting that current preclinical and clinical research is limited and this line of investigation should be pursued more vigorously. In all, we find that protein co-pathologies are frequently observed in the brains of common neurodegenerative diseases and serve as important future therapeutic targets for combatting neurodegeneration across clinically distinct diseases.
    Graphical abstract:
    Keywords:  Alzheimer’s disease; Amyloid; Amyotrophic lateral sclerosis; Co-pathology; Granulovacuolar degeneration bodies; Lewy body disease; Synuclein; TDP-43; Tau; Tauopathy
    DOI:  https://doi.org/10.1186/s44477-026-00047-8
  34. Mol Neurobiol. 2026 Sep 14. pii: 893. [Epub ahead of print]63(1):
    Astrocytes in Neurodegeneration: Spatial States, Crosstalk, and Emerging Therapies.
    Lisa Steger, Veit Rothhammer, Friederike Zunke.
      Astrocytes are increasingly recognized as active drivers of neurodegeneration rather than passive responders. Single-cell and spatial transcriptomic analyses reveal that astrocytes occupy heterogeneous, regionally patterned states that align closely with selective neuronal vulnerability. Across Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, and rare primary astrocytopathies, astrocytes consistently converge on dysfunction across four mechanistic axes: breakdown of glutamate homeostasis, impaired ion and water buffering, lysosomal, and autophagic insufficiency, as well as maladaptive inflammatory-stress signaling. Spatial multi-omics demonstrates that these disruptions are not uniformly distributed but instead map to discrete niches, including plaque-adjacent astrocytes in Alzheimer's disease, CD44-high fibrotic-like astrocytes in the substantia nigra in Parkinson's disease, and EAAT2-low ventral horn astrocytes in ALS, consistent with patterns of selective neuronal vulnerability. Primary astrocytopathies including Alexander disease, vanishing white matter disease, and megalencephalic leukoencephalopathy illuminate the causal power of perturbing individual astrocytic modules, revealing how isolated disruptions in proteostasis, translation control, or ion-water coupling can initiate widespread neurodegeneration. By integrating neuropathological, imaging, and transcriptomic evidence across studies, we derive a consensus-based regional framework of astrocytic vulnerability across neurodegenerative diseases. Together, these findings define a unifying framework in which astrocytes transition from homeostatic regulators to pathological amplifiers, highlighting astrocyte states as tractable, region-specific therapeutic targets and illustrating how integration of spatial atlases with mechanistic insights might help develop a framework for targeted astrocyte therapies.
    Keywords:  Astrocyte heterogeneity; Astrocytes; Neurodegeneration; Spatial transcriptomics
    DOI:  https://doi.org/10.1007/s12035-026-06142-x
  35. Neurosci Biobehav Rev. 2026 Sep 16. pii: S0149-7634(26)00439-2. [Epub ahead of print]191 106982
    From systems to cells: Metabolic mechanisms underlying risk divergence in Alzheimer's disease and amyotrophic lateral sclerosis.
    Ana Knezovic, Antonia Krsnik, Jan Homolak, Ana Babic Perhoc, Ana Deskin, Davor Virag, Melita Salkovic-Petrisic, Jelena Osmanovic Barilar.
      Epidemiological studies show an inverse relationship between metabolic disorders and two major neurodegenerative diseases, Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Obesity, type 2 diabetes (T2DM), and reduced physical activity increase AD risk, whereas in ALS cardiometabolic factors, particularly T2DM, show inverse, age-dependent associations with disease risk. This review integrates epidemiological, clinical, and experimental evidence to suggest that cell-type-specific energy metabolism underlies these contrasting risk profiles. Neurons and skeletal muscle differ in metabolic organization, substrate use, and redox capacity. Neurons rely mainly on glucose and lactate and have limited fatty acid oxidation, making them vulnerable to lipid overload, insulin resistance, and oxidative stress, hallmarks of AD. In contrast, skeletal muscle is metabolically flexible, efficiently oxidizes fatty acids, and has strong antioxidant defenses, which may protect against ALS. These cell-type-specific metabolic profiles are proposed to causally shape disease susceptibility: neuronal lipid overload and impaired redox homeostasis promote amyloid and tau pathology in AD, whereas preserved muscle fatty acid oxidation and antioxidant capacity support neuromuscular junction stability and delay motor neuron degeneration in ALS. Hypermetabolism, hypothalamic dysfunction, glial-neuronal coupling and lactate shuttling may further shape disease susceptibility. Overall, these patterns likely reflect distinct cellular responses to metabolic stress.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Diabetes; Fatty acids; Lactate; Muscle cells; Neuronal cells; Obesity
    DOI:  https://doi.org/10.1016/j.neubiorev.2026.106982
  36. Bio Protoc. 2026 Sep 05. 16(17): e5801
    Quantitative Analysis of Axonal Degeneration and TDP-43 Aggregation in Compartmentalized Human iPSC-Derived Motor Neuron-Myotube Co-cultures.
    Anand Ganapathy Subramaniam, Lucas Keniger de Andrade Gensas, Tal Gradus-Pery, Eran Perlson.
      Amyotrophic lateral sclerosis (ALS) is characterized by early and spatially restricted pathology in motor axons, including distal degeneration and accumulation of aggregation-prone proteins such as TDP-43. However, a major limitation in the field has been the lack of approaches that enable robust, quantitative, and compartment-specific analysis of these early axonal events, particularly in human-relevant systems. Here, we describe an integrated experimental and analytical framework that enables quantitative dissection of axonal degeneration and protein aggregation, specifically within distal motor axons. By combining compartmentalized human co-cultures with a dedicated image analysis strategy, this approach enables selective and quantitative analysis of pathological processes specifically within axons, independent of surrounding tissues such as muscle and other cellular compartments. This framework captures both structural degeneration and protein aggregation dynamics at subcellular resolution, enabling spatially resolved quantitative analysis of disease-relevant changes along axons. Importantly, the analytical framework is not limited to TDP-43 but is broadly applicable to diverse aggregation-prone proteins, thereby providing a generalizable platform to study axonal pathology across neurodegenerative diseases. Together, this work provides a scalable approach for investigating axonal pathology as an early and measurable feature of neurodegeneration, with potential applications in mechanistic studies and therapeutic targeting in ALS and related disorders. Key features • Compartmentalized human induced pluripotent stem cell (iPSC)-derived motor neuron-myotube co-cultures for modeling distal axonal pathology. • Microfluidic separation of somatic and distal axonal compartments enabling spatial perturbation and analysis. • Quantitative imaging of neurofilament heavy chain (NFH)-associated axonal degeneration and pTDP-43 accumulation. • Semi-automated workflow for a reproducible, scalable, and modular pipeline for image quantification.
    Keywords:  Amyotrophic lateral sclerosis; Automated image analysis; Axonal degeneration; Human iPSC-derived motor neuron–myotube co-culture; Microfluidic co-culture; TDP-43 aggregation
    DOI:  https://doi.org/10.21769/BioProtoc.5801
  37. Brain. 2026 Sep 15. pii: awag313. [Epub ahead of print]
    The diagnostic biomarker problem in amyotrophic lateral sclerosis.
    Michael Benatar, Joanne Wuu, Martin R Turner, Eric A Macklin.
      In the effort to reduce the long diagnostic delay in amyotrophic lateral sclerosis, an often overlooked problem derives from confusion around the concept of diagnostic biomarkers and the type of data required to develop such tools. A useful diagnostic biomarker is one that can correctly differentiate individuals with, from those without, the disease of interest - and importantly, at a point in time when the diagnosis is otherwise uncertain. This requires a test with a high positive predictive value (the proportion of positive test results that are true positives), a high negative predictive value (the proportion of negative test results that are true negatives), or ideally both. Critically, positive and negative predictive values depend on the context of use for the diagnostic, which determines the prevalence of disease in the population in which the diagnostic test will be used. Almost all diagnostic biomarker studies in amyotrophic lateral sclerosis get this wrong - focusing on data and samples from patients for whom there is no diagnostic uncertainty. This Update distinguishes disease state biomarkers from diagnostic biomarkers; highlights the data required to clinically validate a diagnostic biomarker; underscores the critical importance of understanding the clinical context in which the diagnostic biomarker will be used; and outlines potential strategies for developing diagnostic biomarkers that might be clinically useful.
    Keywords:  clinical context; positive predictive value; prevalence; sensitivity; specificity
    DOI:  https://doi.org/10.1093/brain/awag313
  38. Annu Rev Vis Sci. 2026 Sep;12(1): 155-186
    Machine Learning for Noninvasive Diagnosis of Neurodegenerative Diseases Using Retinal and Optic Nerve Imaging: A Comprehensive Review.
    Ali Aghababaei, Masoud Etemadifar, Amir Atapour-Abarghouei, William Innes, Masoud Aghsaei Fard, Friedemann Paul, Hossein Rabbani, Raheleh Kafieh.
      Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis, encompass a wide range of chronic conditions with irreversible damage to the central nervous system. Current diagnostic workups of these disorders rely on invasive, time-consuming, and costly tests, such as magnetic resonance imaging and cerebrospinal fluid analysis, preventing accurate decision-making and timely therapeutic interventions. The retina is an extension of the central nervous system; thus, retinal imaging, which is a noninvasive and easily accessible tool, provides a unique window to study brain pathologies. There is a great body of evidence suggesting that neurodegenerative disorders are associated with various structural and vascular problems within the retina. Notably, training machine learning models with retinal images has yielded high levels of accuracy in classifying neurodegenerative diseases, encouraging a new era for early and automated diagnosis of these disorders. This article reviews studies that use such models for classifying these disorders.
    Keywords:  machine learning; multiple sclerosis; neurodegenerative disorders; optic nerve; optical coherence tomography; retina
    DOI:  https://doi.org/10.1146/annurev-vision-110423-025837
  39. Immunopharmacol Immunotoxicol. 2026 Sep 18. 1-12
    Thioperamide, a histamine H3 receptor antagonist, attenuates neuroimmune activation and inflammation in the SOD1G93A mouse model of amyotrophic lateral sclerosis.
    Abdullah A Aldossari, Abdulaziz M S Alsaad, Ahmed Nadeem, Mushtaq A Ansari, Sabry M Attia, Saleh A Bakheet, Haneen A Al-Mazroua, Mohammed M Almutairi, Hussain N Alhamami, Wedad S Sarawi, Hatun A Alomar, Majed Ali Algonaiah, Ali A Alshamrani, Alaa A Alanteet, Marwa H Hussein, Mohamed A Mahmoud, Sheikh F Ahmad.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of unknown cause that gradually affects upper and lower motor neurons in the motor cortex, brainstem, and spinal cord. The histamine H3 receptor (H3R), a presynaptic autoreceptor, regulates histamine release through feedback mechanisms. H3R is highly expressed in neurons and microglia, where it influences inflammatory responses.
    METHODS: This study examined the effects of thioperamide, an H3R antagonist, on T cell-mediated immune responses in the SOD1G93A transgenic mouse model of ALS. Mice received daily thioperamide injections (5 mg/kg) for four weeks, beginning at the onset of illness (week 15). Flow cytometry analyzed splenic CD3+ T cells for cytokine and marker expression, including IL-1α, IL-6, IFN-γ, TNF-α, IL-17A, RORγt, iNOS, GM-CSF, TGF-β1, and Foxp3. RT-PCR measured mRNA levels in brain tissue.
    RESULTS: Results showed that thioperamide significantly decreased CD3+IL-1α+, CD3+IL-6+, CD3+IFN-γ+, CD3+TNF-α+, CD3+IL-17A+, CD3+RORγt+, CD3+iNOS+, and CD3+GM-CSF+ cells in the spleen, while increasing regulatory CD3+TGF-β1+ and CD3+Foxp3+ cells. Similarly, brain tissue showed decreased mRNA levels of IL-1α, IL-6, IFN-γ, TNF-α, IL-17A, RORγt, iNOS, and GM-CSF, with higher TGF-β1 and Foxp3 expression.
    CONCLUSIONS: These findings suggest that thioperamide helps reestablish immune balance in SOD1G93A mice by influencing both inflammatory and regulatory T cell pathways.
    Keywords:  Histamine H3 receptor; SOD1G93A transgenic mouse; T cells; amyotrophic lateral sclerosis; thioperamide
    DOI:  https://doi.org/10.1080/08923973.2026.2733883
  40. Naunyn Schmiedebergs Arch Pharmacol. 2026 Sep 14.
    Optimization and characterization of lipid-based nanocarriers for intranasal delivery in amyotrophic lateral sclerosis.
    Dhvani P Padhiyar, Shital Butani, Ravish J Patel.
      Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder for which effective brain delivery of therapeutics remains challenging. Riluzole, a Biopharmaceutics Classification System class II drug used in the management of amyotrophic lateral sclerosis, exhibits low aqueous solubility and undergoes first-pass metabolism, which may limit its bioavailability. The present study aimed to develop and optimize riluzole-loaded nanostructured lipid carriers for intranasal delivery. Riluzole-loaded nanostructured lipid carriers were prepared by the melt-emulsification method and optimized using a four-factor, three-level Box-Behnken design. The effects of lipid composition ratio, surfactant concentration, sonication time, and stirring time on particle size, polydispersity index, and encapsulation efficiency were evaluated. The optimized formulation showed a particle size of 98.43 nm, a polydispersity index of 0.3, a zeta potential of -6.22 mV, an encapsulation efficiency of 89.4%, and a drug loading of 8.94%. Transmission electron microscopy demonstrated spherical nanoparticles, while differential scanning calorimetry and X-ray diffraction findings suggested reduced crystallinity and amorphization of riluzole within the lipid matrix. Fourier transform infrared spectroscopy indicated no significant drug-excipient incompatibility. The optimized formulation exhibited sustained drug release, with approximately 84% drug release over 24 h, and remained stable for 60 days at room temperature. These findings suggest that riluzole-loaded nanostructured lipid carriers are a promising lipid-based nanocarrier system for intranasal delivery and further biological evaluation for nose-to-brain drug delivery in amyotrophic lateral sclerosis.
    Keywords:  Amyotrophic lateral sclerosis; Nanostructured lipid carriers; Nose-to-brain; Riluzole
    DOI:  https://doi.org/10.1007/s00210-026-05866-w
  41. ACS Med Chem Lett. 2026 Sep 10. 17(9): 2055-2065
    A‑iMPO: A Design-Time Prediction Toolbox for Blood Brain Barrier Permeation Using an Integrated and Interpretable Multiparameter Optimization Framework.
    Samiron Phukan, Ashis Nandy, Manjunath Ramarao.
      Design time prioritization of central nervous system (CNS) drug candidates remains a challenge due to the restrictive nature of the blood-brain barrier (BBB) governing brain exposure. Although various multiparameter optimization (MPO) strategies have guided CNS medicinal chemistry for over a decade, existing frameworks rely heavily on heuristic cutoffs and offer limited interpretability across chemically diverse scaffolds. Here, we introduce a next generation CNS-MPO frameworkAragen-iMPO, (A-iMPO)which was developed using 5,129 curated compounds through an integrated workflow combining explainable machine learning, rigorous descriptor selection, and low-dimensional discriminant mapping. This yielded six chemically intuitive features capturing polarity, ionization, size, rigidity, and electronic distribution. The resulting score provides a transparent discriminant function enabling direct compound prioritization through a simple threshold rule. Across internal and external validation sets, A-iMPO outperformed established CNS-focused scoring methods while maintaining mechanistic interpretability, providing a practical and design ready tool for CNS drug discovery.
    Keywords:  BBB permeability; chemical space generalization; design-time prioritization; explainable machine learning; interpretable CNS MPO; medicinal chemistry; molecular descriptors
    DOI:  https://doi.org/10.1021/acsmedchemlett.6c00347
  42. Eur J Neurol. 2026 Sep;33(9): e70756
    Multivariate Survival Analysis of a Comprehensive Clinical Trial of Rapamycin in Amyotrophic Lateral Sclerosis Explores Prognostic Factors and Survival Patterns in C9orf72 Carriers.
    Alex De Nardi, Alessio Paris, Mario Lauria, Ilaria Martinelli, Elisabetta Zucchi, Cecilia Simonini, Jessica Mandrioli, Luca Marchetti.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by considerable variability in survival times. This retrospective study aims to evaluate the prognostic value of a broad range of variables by conducting a comprehensive survival analysis on longitudinal data from RAP-ALS, a clinical trial investigating the effects of rapamycin in ALS patients (n = 63).
    METHODS: Covariates were classified as risk or protective factors according to their hazard ratios. Regularized Cox regression was utilized to select the best-performing multivariate models in cross-validation. Longitudinal measures were incorporated by modeling covariates as time-dependent. Survival times of treated C9orf72 mutation carriers (n = 6) were further investigated through log-rank tests and restricted mean survival time analysis.
    RESULTS: Univariate analyses confirmed several previously established prognostic factors. Multivariate regularized Cox models incorporated neurofilaments, creatinine, clinical scores, and markers of immune activation. Moreover, the inclusion of time-varying covariates allowed us to investigate late-stage risk factors, such as the neutrophil-to-lymphocyte ratio. Additionally, the analysis indicated a protective effect in treated C9orf72 mutation carriers (log-rank test, p = 0.026), which was confirmed after comparing this treatment subgroup with an independent C9orf72+ cohort (n = 40; RMST test, p = 0.04).
    CONCLUSIONS: The survival analysis confirmed the role of previously identified prognostic factors, while suggesting that high-performing multivariate models should integrate multiple ALS pathological hallmarks. Moreover, the observed longer survival among C9orf72 mutation carriers contrasts with prior reports. Due to the small sample size and potential confounding factors, the observed benefits in treated C9orf72 patients should be considered exploratory, supporting evaluation in a larger, genetically stratified trial.
    Keywords:  C9orf72; amyotrophic lateral sclerosis; biomarkers; rapamycin; survival analysis
    DOI:  https://doi.org/10.1111/ene.70756
  43. Lab Chip. 2026 Sep 18.
    A human iPSC-based perfusable and membrane-free neurovascular unit-on-chip connecting brain organoids to the blood-brain barrier.
    Henrique Nogueira Pinto, Lois Kistemaker, Mikhail Ponomarenko, Arthur A Ermakov, Manon Karsten-van Diepen, Susanne M A van der Pol, R Jeroen Pasterkamp, Stephanie D Beekhuis-Hoekstra, Nienke M de Wit, Emma J van Bodegraven, Helga E de Vries, Elly M Hol.
      The blood-brain barrier (BBB) protects the central nervous system by restricting entry of harmful blood-borne factors, but this selectivity actively limits delivery of therapeutics to the brain. Because BBB function is shaped by dynamic interactions within the neurovascular unit (NVU), particularly between brain endothelial cells, pericytes, and astrocytes, there is a need for human-relevant models that capture both barrier properties and neurovascular crosstalk in a controlled setting. Here, we present a novel human induced pluripotent stem cell (iPSC)-based NVU-on-chip that couples a perfusable, vessel-like BBB compartment to an adjacent open-top chamber housing a human brain organoid (hBO) via a membrane-free, hydrogel-based interface. This design enables co-culture of BBB and parenchymal components in close proximity while allowing direct cell-cell interactions at the barrier-tissue boundary without an artificial porous membrane. Using this platform, we demonstrate stable on-chip co-culture and show that hBO-derived astrocytes can sprout, migrate toward the BBB compartment and establish direct contact with endothelial cells, recapitulating the NVU structure. This system offers a human-specific framework for modeling NVU biology in health and disease and for evaluating BBB penetration together with downstream effects of candidate therapeutics on hBO.
    DOI:  https://doi.org/10.1039/d6lc00157b
  44. Brain Nerve. 2026 Sep;78(9): 1023-1029
    [A New Understanding of the Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex in the Kii Peninsula, Japan, 2026].
    Yasumasa Kokubo.
      The distribution of amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) in the Kii Peninsula of Japan exhibits regional variations, with ALS/PDC in the Hohara focus closely resembling that in Guam and ALS in the Kozagawa focus. Recent structural analysis using cryo-electron microscopy revealed that the tau filaments in patients with ALS/PDC in Kii have a chronic traumatic encephalopathy (CTE) fold, confirming the disease's distinct pathological identity and commonality with the Guam focus. While the exact causal genes remain unidentified, research utilizing patient-derived induced pluripotent stem cells and proteomic analysis has uncovered endogenous mitochondrial dysfunction, specifically involving decreased expression of CHCHD2 and SSBP1. The presence of migrant cases further suggests that ALS/PDC is a multifactorial disorder triggered by environmental factors that influence genetic vulnerability. Although the incidence of ALS in Kozagawa and Hohara districtst has declined, new cases with PDC continue to emerge in Hohara. Identifying these modifiable environmental triggers is crucial for preventing and eradicating neurological disorders.
    DOI:  https://doi.org/10.11477/mf.188160960780091023
  45. Neurol Res Pract. 2026 Sep 14. pii: 77. [Epub ahead of print]8(1):
    Neurological and neuroimaging sequelae of lightning injury: a retrospective study and literature review.
    Tim Steinberg, Carsten Lukas, Berthold Schalke, Christina Wendl, Ralf Linker, Bernhard Neumann, Ingo Kleiter.
       BACKGROUND: Lightning injuries (LI) can affect multiple organs, including the peripheral and central nervous system (CNS). Neuroimaging studies in LI are scarce, and it is unknown whether off-target changes in the CNS occur.
    METHODS: Retrospective review of patients who were treated in two neurology tertiary referral centers for sequelae of LI between 2004-2024 and had magnetic resonance imaging (MRI) or computed tomography (CT) of the CNS. A narrative literature search was performed to identify other studies on neuroimaging after LI.
    RESULTS: Of 31 patients (39% female, median age 38 years), 30 had cranial neuroimaging (28 had cranial MRI, five cranial CT), and 14 spinal MRI. The median delay between LI and first neuroimaging was 67 days. Cranial MRI or CT showed two cases of brain edema, one accompanied by subarachnoid bleeding, one case of laminar cortical necrosis after resuscitation, and one case with hyperintensities in the hippocampi. 14 patients with cranial MRI had unspecific white matter lesions. In six of 14 patients who received a spinal MRI, intramedullary spinal cord lesions were found. A review of 54 published patients revealed pathological neuroimaging in 24 (44%) cases. Main findings were hypoxic encephalopathy after cardiac arrest, intracerebral bleeding, cerebral ischemia, brain edema and subarachnoid bleeding.
    INTERPRETATION: Typical neuroimaging findings after LI include brain edema, intracerebral or subarachnoid bleeding, ischemia, hypoxic encephalopathy, and intramedullary spinal cord lesions. Moreover, brain white matter lesions are common, which are of unknown significance, since clinical correlates are rare and pre-existing pathologies often cannot be ruled out.
    Keywords:  Climate change; Intracerebral bleeding; Lightning injury; Myelopathy
    DOI:  https://doi.org/10.1186/s42466-026-00523-2
  46. Neurotoxicology. 2026 Sep 17. pii: S0161-813X(26)00198-1. [Epub ahead of print] 103577
    Associations of per- and polyfluoroalkyl substances (PFAS) exposures and firefighting experience with microRNA signatures previously linked to Amyotrophic Lateral Sclerosis (ALS): a cross-sectional analysis of active-duty municipal and airport firefighters.
    Brooke A Hawkes, Jaclyn M Goodrich, Shawn C Beitel, Cynthia Porter, Jefferey L Burgess, Alesia M Jung, Melissa A Furlong.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unclear etiology in sporadic cases. Blood microRNA (miRNA) expression varies between individuals with and without ALS. Firefighters may face elevated ALS risks due to occupational exposures, including elevated serum per- and polyfluoroalkyl substances (PFAS) concentrations.
    METHODS: This study investigates the association between occupational firefighter characteristics (years of experience, incumbent status (binary; 1=incumbent, 0=recruit), serum PFAS) and ALS-relevant miRNA expression in U.S. firefighters across 10 states. MiRNA expression was quantified from blood collected from 608 firefighters. Serum PFAS concentrations were available for a subset of 302 participants. We identified 19 ALS-related miRNAs using miRWalk's Disease Ontology. Adjusted linear regression models estimated associations between exposures and miRNA expression, controlling for demographic and occupational factors.
    RESULTS: In analyses of firefighter occupational characteristics (n=608), incumbent firefighters had significantly altered expression in ten ALS-related miRNAs compared to new recruits (p<0.05) and all remained significant after false discovery rate (FDR) adjustment for multiple testing (q<0.20). Years of firefighting was associated with lower expression of multiple miRNAs, including hsa-miR-23a-3p (β = -11.276, 95% CI: -18.870, -3.682), and this association remained significant after FDR correction. In PFAS analyses (n=302), higher serum PFAS concentrations were associated with 13 significant PFAS-miRNA associations (p<0.05) involving ALS-related miRNAs, including Sm-PFOS and hsa-let-7i-5p (β = -0.169, 95% CI: -0.287, -0.052), hsa-let-7c-5p (β = -0.128, 95% CI: -0.218, -0.037), and hsa-let-7e-5p (β = -0.113, 95% CI: -0.210, -0.017); PFNA and hsa-let-7c-5p (β = -0.126, 95% CI: -0.214, -0.037); and PFHxS and hsa-let-7i-5p (β = -0.126, 95% CI: -0.223, -0.029). Six remained significant after FDR adjustment (q < 0.20). Hsa-let-7e-5p was significantly lower in firefighters with higher Sm-PFOS, n-PFOS, and in incumbent firefighters.
    CONCLUSIONS: Significant associations between PFAS exposure, firefighting status, and ALS-related miRNAs suggest that PFAS exposure and firefighting characteristics are associated with miRNA expression patterns previously linked to ALS, warranting further investigation into potential biological pathways.
    Keywords:  PFAS; disease biomarkers; epigenetics; firefighter health; neurodegenerative disease; occupational exposure; occupational health
    DOI:  https://doi.org/10.1016/j.neuro.2026.103577
  47. Molecules. 2026 Sep 05. pii: 3113. [Epub ahead of print]31(17):
    Hydroxytyrosol as a Multitarget Neuroprotective Agent: Molecular Mechanisms, Pharmacokinetics and Therapeutic Potential in Neurodegenerative Diseases.
    Pura Ballester-Navarro, Ana María García-Muñoz, Desirée Victoria-Montesinos, Pilar Zafrilla.
      Neurodegenerative diseases arise from interacting oxidative, inflammatory, mitochondrial, and proteostatic disturbances. Hydroxytyrosol (HT), an olive phenol, has been proposed as a multitarget neuroprotective compound. This narrative review integrates HT chemistry, parent/metabolite pharmacokinetics, blood-brain barrier (BBB) evidence, mechanisms, disorder-specific models, and human studies. Direct HT evidence is strongest for nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) activation and experimental modulation of α-synuclein; support for AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial protection, nuclear factor-kappa B (NF-κB)-related inflammation, and amyloid-β (Aβ) is predominantly preclinical, whereas tau, autophagic flux, and ubiquitin-proteasome effects remain preliminary. Oral HT is rapidly absorbed but extensively conjugated, and no study has quantified parent HT or its major metabolites in the human brain or cerebrospinal fluid after oral supplementation. Isolated-HT trials show systemic antioxidant or anti-inflammatory biomarker effects, while cognitive findings derive mainly from phenolic-rich olive matrices and cannot be assigned to HT alone. No disease-modifying efficacy has been established for isolated HT in Alzheimer's disease (AD), Parkinson's disease (PD), or related disorders. HT is therefore a mechanistically plausible candidate, but human brain exposure, dose-response, and efficacy require adequately powered disease-specific trials.
    Keywords:  hydroxytyrosol; mitochondrial dysfunction; neurodegenerative diseases; nutraceuticals; oxidative stress
    DOI:  https://doi.org/10.3390/molecules31173113
  48. Cell Mol Biol (Noisy-le-grand). 2026 May 31. 72(5): 47-53
    Selegiline induces neuroprotection via PGC-1α/Nrf2 gene upregulation in H2O2 -treated hippocampal-derived neural stem/progenitor cells.
    Alireza Abdanipour, Ali Nikfar, Hadi Feizi.
      Oxidative stress mediated by reactive oxygen species (ROS) is a major contributor to the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, multiple sclerosis, and amyotrophic lateral sclerosis. Selegiline, a monoamine oxidase B inhibitor, has been reported to exert neuroprotective effects, although its precise cytoprotective mechanisms remain unclear. In this study, we investigated the effects of selegiline on apoptosis, necrosis, and cell survival in hydrogen peroxide (H₂O₂)-treated hippocampal-derived neural stem/progenitor cells (HD-NSPCs) in vitro. Passage 3 HD-NSPCs were treated with varying concentrations of selegiline (10⁻³ to 10⁻⁹ M) prior to exposure to 125 μM H₂O₂. Cell viability was assessed using the MTT assay, while apoptosis and necrosis were evaluated using TUNEL and acridine orange/ethidium bromide staining, respectively. Real-time RT-PCR was performed to quantify mRNA levels of PGC-1α, Nrf2, and Bcl-2. Treatment with 10⁻⁷ M selegiline significantly enhanced HD-NSC viability, reduced apoptotic and necrotic cell fractions, and upregulated PGC-1α, Nrf2, and Bcl-2 expression compared to untreated cells (P < 0.05). These findings suggest that selegiline mitigates oxidative stress-induced cytotoxicity by activating Nrf2/PGC-1α signaling and promoting anti-apoptotic gene expression, thereby preserving mitochondrial function and enhancing cell survival. Overall, selegiline may represent a promising therapeutic agent for protecting neural progenitor cells and alleviating neuronal damage in neurodegenerative disorders.
    DOI:  https://doi.org/10.14715/cmb/2026.72.5.7
  49. Neurol Sci. 2026 Sep 15. pii: 787. [Epub ahead of print]47(10):
    EBV-associated autoimmune glial fibrillary acidic protein astrocytopathy with lumbosacral leptomeningeal enhancement: a case report and literature review.
    Yueying Liu, Huimin Chen, Miaoxian Xie, Huijing Liu, Jing He, Mingming Zhao, Zeyuan Zhang, Hua Zhang, Shifang Hou.
       BACKGROUND: Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a rare inflammatory central nervous system autoimmune disease. Viral pathogens, most notably Epstein-Barr virus (EBV), represent a major disease trigger. Classic spinal magnetic resonance imaging (MRI) manifestations of GFAP-A are characterized by long-segment T2-weighted hyperintensities surrounding the central canal and patchy intramedullary enhancement, whereas lumbosacral leptomeningeal involvement is extremely rare.
    METHODS: We report a 58-year-old male patient with EBV-associated GFAP-A featuring isolated lumbosacral leptomeningeal enhancement. We consequently conducted a literature review restricted to EBV-associated GFAP-A cases to characterize their clinical manifestations, laboratory examinations, therapeutic regimens, and prognoses.
    RESULTS: The patient presented with fever, low back pain, progressive limb numbness and weakness, and urinary retention. Serum and cerebrospinal fluid (CSF) GFAP-immunoglobulin G (IgG) tests were positive. Concurrently, metagenomic next-generation sequencing detected EBV reads in the CSF, whereas plasma EBV DNA was negative. Contrast-enhanced lumbar MRI demonstrated smooth linear leptomeningeal enhancement along the spinal cord. The patient showed substantial neurological recovery after receiving methylprednisolone pulse therapy, antiviral agents, and rituximab. A literature analysis of 24 cases of EBV-associated GFAP-A indicated a predominance among young and middle-aged males. Prominent clinical features included fever, urinary retention, headache, limb weakness, and tremor, with CSF GFAP-IgG positivity reaching 87.5%. Glucocorticoids, intravenous immunoglobulin, and antiviral agents constituted the first-line therapies.
    CONCLUSIONS: EBV-associated GFAP-A can manifest as isolated lumbosacral leptomeningeal enhancement in the absence of classic intracranial radial perivascular enhancement. Combined antiviral and immunotherapy demonstrates favorable short-term efficacy, whereas long-term, B-cell-targeted maintenance therapy may reduce the risk of relapse.
    Keywords:  EBV infection; GFAP-A; Leptomeningeal enhancement; Rituximab
    DOI:  https://doi.org/10.1007/s10072-026-09390-w
  50. J Neurol. 2026 Sep 18. pii: 604. [Epub ahead of print]273(10):
    What do ALS motor phenotypes measure? A population-based decomposition of their prognostic dimensions.
    Andrea Calvo, Cristina Moglia, Stefano Callegaro, Antonio Canosa, Umberto Manera, Gabriele Mora, Sara Cabras, Francesca Palumbo, Enrico Matteoni, Alessandra Maccabeo, Giorgio Pellegrino, Emilio Minerva, Daniela Pascariu, Fabrizio D'Ovidio, Rosario Vasta, Letizia Mazzini, Fabiola De Marchi, Adriano Chiò.
       BACKGROUND: The ALS-OPM 3.3 classification stratifies incident ALS through three axes: onset region (O), propagation time (P) and motor-neuron pattern (M). We assessed whether OPM 3.3 improves prognostic discrimination over established classifications and characterised how it decomposes their prognostic signal in a population-based cohort.
    METHODS: In the prospective Piedmont and Aosta Valley ALS Register (2000-2022), patients were classified on the three axes; M was operationalised as M_3class (M0 balanced, M1d UMN-predominant, M2d LMN-predominant), with the PLS-spectrum M1p analysed separately. Outcome was survival (death or tracheostomy) from onset. Multivariable Cox models (O, P1(n), M_3class, age, sex) underwent bootstrap optimism-correction and fivefold cross-validation, and were compared against alternative taxonomies and clinical staging systems.
    RESULTS: Amongst 2,738 non-PLS patients (2,561 events, 93.5%), median survival differed across M classes (M0 27.0, M2d 36.0, M1d 41.9 months). OPM 3.3 outperformed the bulbar/spinal dichotomy but matched the classical phenotype (optimism-corrected C-index 0.703, 95% CI 0.685-0.719 vs 0.701). In the arm-proximal cell (95.7% M2d), the O2p protective effect vanished after M adjustment (HR 0.99, 95% CI 0.79-1.24), whilst M2d retained HR 0.83 (95% CI 0.72-0.95), showing prognosis reflects motor-neuron pattern, not anatomy. Adding King's, Milano-Torino (MiToS), or Fine'til 9 (FT9) clinical staging further improved discrimination.
    CONCLUSIONS: OPM 3.3 did not improve discrimination over established phenotypes but decomposed their prognostic signal into independently interpretable dimensions. Favourable prognosis of arm-proximal/flail-arm onset reflects the underlying LMN-predominant phenotype, not onset site. The motor-neuron axis is robust to the treatment of the propagation axis and independent of clinical staging.
    Keywords:  Amyotrophic lateral sclerosis; Disease staging; Motor phenotype; Population-based registry; Prognosis; Survival analysis
    DOI:  https://doi.org/10.1007/s00415-026-14134-z
  51. Molecules. 2026 Aug 28. pii: 3033. [Epub ahead of print]31(17):
    Cholesterol Quantification in Brain and Spinal Cord During Development, Demyelination, and Remyelination.
    Disni Dedunupitiya, Eden P Go, Travis Witte, Ashlynn Elliott, Nishama De Silva Mohotti, Jenna M Williams, Hiroko Kobayashi, Rashmi Binjawadagi, Heather Desaire, Meredith D Hartley.
      Cholesterol in the central nervous system (CNS) is largely unesterified (>99%) and is predominantly present in the myelin sheath (~70% of total CNS cholesterol). However, cholesterol ester accumulation has been observed during neurological disease. In this cross-sectional study, we measured free cholesterol and cholesterol ester levels in the brains and the spinal cords of Plp1-iCKO-Myrf mouse model during postnatal myelination, demyelination, and remyelination using gas chromatography-mass spectrometry with single ion monitoring (GC-MS-SIM) and liquid chromatography-mass spectrometry (LC-MS). Cholesterol levels in healthy mouse brains increased steadily up to 38 weeks of age. In contrast, cholesterol in the healthy spinal cord increased until P42, and then remained steady out to 38 weeks of age. During demyelination, both brain and spinal cord cholesterol levels were significantly reduced compared to healthy mice and did not return to normal cholesterol levels even during remyelination. Semi-quantitative quantification of cholesterol esters during peak demyelination revealed that cholesterol esters comprise 19% of the measured cholesterol pool in the brain and 66% in the spinal cord. Robust methods for internal standard-based quantification of CNS cholesterol and cholesterol esters were developed, which are critical for revealing mechanisms of cholesterol regulation during disease.
    Keywords:  cholesterol; cholesterol esters; demyelination; gas chromatography mass spectrometry (GC-MS); liquid chromatography–mass spectrometry (LC-MS); multiple sclerosis; myelin; myelin repair; remyelination
    DOI:  https://doi.org/10.3390/molecules31173033
  52. Eur J Nucl Med Mol Imaging. 2026 Sep 17.
    Nigrostriatal imaging in patients with clinically uncertain Parkinsonian syndromes: a head-to-head comparison between SPECT, PET, and MRI.
    Gerda Thomsen, Kristoffer Brendstrup-Brix, Claus Svarer, Ulrich Lindberg, Lars H Pinborg, Karen Kettless, Ian Law, Steen G Hasselbalch, Bo Biering-Sørensen, Gitte M Knudsen.
       PURPOSE: Neurodegenerative parkinsonism is characterized by degeneration of the dopaminergic nigrostriatal pathways and a reduction in nigral neuromelanin. Dopamine transporter (DAT) imaging assesses presynaptic striatal dopaminergic function and is typically performed with [123I]FP-CIT SPECT-CT, but has recently also become available with [18F]FE-PE2I PET-CT. Magnetic resonance imaging (MRI) can explore disease-related changes by quantifying neuromelanin and iron deposition associated with the loss of nigral neurons.
    METHODS: In this study, we conducted a head-to-head comparison of [¹²³I]FP-CIT SPECT, [¹⁸F]FE-PE2I PET, and nigral MRI in 35 patients referred for diagnostic DAT imaging. Nigral MRI was performed with neuromelanin-sensitive gradient echo magnetization-transfer contrast MRI and iron-sensitive STrategically Acquired Gradient Echo (STAGE) MRI. Patient satisfaction with SPECT and PET was recorded via questionnaires.
    RESULTS: Eighteen patients were diagnosed with neurodegenerative parkinsonism with a median symptom duration of 29 months. DAT availability as measured with SPECT and PET showed complete concordance across cases, correlated strongly, and demonstrated equally excellent diagnostic performance. Patient questionnaire items were either not different between modalities or in favor of SPECT. Nigral neuromelanin content was reduced in patients with neurodegenerative parkinsonism and provided intermediate diagnostic accuracy, with indications of lower neuromelanin with disease duration. Midbrain iron content did not differ between groups and provided no diagnostic information.
    CONCLUSION: Our findings indicate that in early-stage parkinsonism, DAT neuroimaging with SPECT and PET provides comparable and superior diagnostic value relative to nigral MRI.
    Keywords:  Iron-sensitive MRI; Neuromelanin MRI; Parkinson’s disease; [123I]FP-CIT SPECT-CT; [18F]FE-PE2I PET-CT
    DOI:  https://doi.org/10.1007/s00259-026-08184-8
  53. Nutrients. 2026 Sep 04. pii: 2913. [Epub ahead of print]18(17):
    Serum Biomarkers for Nutritional Monitoring in Motor Neuron Disease: A Longitudinal Cohort Study.
    Sarah A Roscoe, Scott P Allen, Christopher J McDermott, Theocharis Stavroulakis.
      Background: Malnutrition and metabolic dysregulation are common in motor neuron disease (MND) and contribute to accelerated functional decline and reduced survival. Routine serum biochemical analytes can be used to assess nutritional status; however, their interpretation in MND is confounded by systemic inflammation and disease-related metabolic changes. This study investigated the relationship between serum biochemical analytes, inflammatory status, disease severity, progression, and body composition in people living with MND. Methods: In this single-centre, longitudinal prospective cohort study, 19 participants with confirmed MND were assessed at enrolment and at three-month intervals up to nine months. Serum concentrations of albumin, prealbumin, creatinine, transferrin, ferritin, retinol-binding protein, and lipid fractions were measured alongside routine inflammatory markers. Disease severity and progression were assessed using the revised ALS functional rating scale and King's College Staging System. Anthropometry included percentage weight change, body mass index, mid-upper arm circumference, triceps skinfold thickness, arm muscle area, and calf circumference. Participants with evidence of baseline inflammation were excluded from nutritional analyses. Results: Low-grade systemic inflammation was present in 9/19 (47%) of participants at enrolment, most commonly reflected by elevated fibrinogen. In the non-inflammatory sub-cohort (n/N = 10/19), serum creatinine was positively correlated with muscle-related functional subscores (p = 0.007) and declined between enrolment and three months (p = 0.02), showing predominantly negative trajectories by nine months. HDL cholesterol also declined over the nine-month follow-up (p = 0.03) and lipid fractions correlated positively with disease stage (p <0.001-0.02), suggesting evolving metabolic stress. Elevated serum retinol-binding protein was observed in 90% (n/N = 9/10) of participants without inflammation. Biochemical evidence of malnutrition (low transferrin and/or creatinine) was detected in one-third of participants, accompanied by weight loss and reductions in limb anthropometric parameters. Malnutrition risk was identified in 1/10 (10%) of the non-inflammatory sub-cohort using a modified ESPEN-based framework, and in 2/10 (20%) participants using GLIM criteria. Conclusions: Routine serum biochemical analytes provide complementary information on nutritional and metabolic status in MND when interpreted alongside inflammatory markers and anthropometry. Serum creatinine emerged as a longitudinal marker of muscle wasting, reflective of denervation and nutritional depletion, while lipid and retinol-binding protein alterations highlight non-nutritional disease mechanisms that may confound standard biomarker interpretation, informing more targeted nutritional assessments. These findings support a multimodal approach to nutritional monitoring in MND and emphasise the importance of accounting for inflammatory status in biomarker interpretation. Given the small sample size and the limited representation of non-ALS phenotypes, these findings should be regarded as hypothesis-generating and require confirmation in larger, multicentre cohorts with balanced phenotypic representation.
    Keywords:  amyotrophic lateral sclerosis; motor neuron disease; nutritional assessment; nutritional biomarkers; serum
    DOI:  https://doi.org/10.3390/nu18172913
  54. Sci Rep. 2026 08 07. pii: 28591. [Epub ahead of print]16(1):
    Integrating retinal and brain imaging biomarkers for diagnosis of parkinson's disease: findings from a time-lagged cross-sectional persian cohort study.
    Farzane Nikparast, Nooshin Akbari-Sharak, Zohreh Ganji, Ali Shoeibi, Naser Shoeibi, Hoda Zare.
      Parkinson's disease (PD) is a multisystem neurodegenerative disorder with both central and peripheral manifestations. This study aimed to comprehensively characterize structural and functional alterations in the retina and brain, as well as systemic blood biomarkers, in patients with clinically diagnosed PD compared with healthy controls, using a multimodal imaging approach. Blood-derived biomarkers and OCT data were collected from 29 PD patients and 25 healthy participants over an average interval of 2.7 years. MRI scans were performed using a Philips 1.5 Tesla scanner. Retinal and brain structural and perfusion metrics were analyzed using linear regression models adjusted for age, with statistical significance determined through false discovery rate (FDR) correction. The diagnostic performance was assessed using logistic regression, LASSO-penalized logistic regression model and ROC curve analysis. The study indicated that reduced ALT serum is the only significant hematological marker (p = 0.0253). Structural MRI revealed significant volume reductions in the left amygdala and caudate (p = 0.0241 and 0.0035 respectively); However, these findings necessitate careful interpretation due to limitations in spatial resolution. Perfusion MRI showed lower cerebral blood flow in gray matter and the whole brain (p = 0.02) in PD patients. The best imaging biomarker (PCASL total CBF) achieved an AUC of 0.79. A LASSO-penalized logistic regression model integrating left amygdala volume, left caudate volume, and SGPT achieved a significantly elevated AUC of 0.954, with 100% sensitivity and 86.7% specificity. The integration of central and peripheral biomarkers encompasses complementary aspects of Parkinson's disease pathology, providing a more comprehensive diagnostic framework than any singular modality.
    Keywords:  Neuromelanin-sensitive MRI (NM-MRI); Optical coherence tomography (OCT); Parkinson’s disease; Pseudo-continuous arterial spin labeling (PCASL); Structural MRI (sMRI)
    DOI:  https://doi.org/10.1038/s41598-026-66128-6
  55. Comput Biol Chem. 2026 Sep 12. pii: S1476-9271(26)00515-3. [Epub ahead of print]126(Pt 1): 109388
    Parkinson's disease diagnosis using machine learning and multimodal biomarkers: A systematic review.
    Muhammad Imran Khan, Azhar Imran, Ahmad Alshammari.
      Parkinson's disease (PD) is the second most common neurodegenerative disorder and the fastest-growing neurological condition globally, with an estimated 10.5 million people living with PD in 2026 and projections exceeding 14.2 million by 2040 according to the World Health Organization. Despite this staggering burden, diagnosis continues to depend on clinical motor signs that appear only after 60%-80% of dopaminergic neurons in the substantia nigra have been irreversibly lost, and specialist misdiagnosis rates reach 25% at early disease stages even in dedicated movement disorder centers. This systematic review synthesizes evidence from 239 studies drawn from 5847 screened records (2016-2026), critically evaluating unimodal diagnostic approaches encompassing dopamine transporter single-photon emission computed tomography (DAT-SPECT), quantitative magnetic resonance imaging (MRI), alpha-synuclein (α-syn) seed amplification assay (SAA), neurofilament light chain (NfL), genetic risk markers, voice and speech biomarkers, gait and movement metrics, electroencephalography (EEG), and handwriting analysis, alongside their integration into multimodal machine learning (ML) and deep learning (DL) frameworks with explainable artificial intelligence (XAI) components. Across 87 quantitative studies, the α-syn SAA achieved a sensitivity of 84%-92% and specificity of 93%-98% in prodromal cohorts. DAT-SPECT achieved a pooled sensitivity and specificity of approximately 90% but could not differentiate PD from atypical parkinsonian syndromes (APS). Multimodal fusion architectures, particularly cross-attention transformers integrating motor, voice, and gait data, consistently outperformed unimodal approaches by 4%-8% in the area under the receiver operating characteristic curve (AUC), with the largest gains in early stage detection and differential diagnosis tasks. XAI methods, including SHapley Additive exPlanations (SHAP), gradient-weighted class activation mapping (Grad-CAM), and integrated gradients, were reported in only 31% of deep learning studies. This indicates a transparency gap with direct regulatory consequences. Across all modalities, only 22% of studies reported external validation, and multicenter prospective evidence remains scarce. These two deficits, rather than model architecture, are now the principal barriers to clinical adoption. This review provides an actionable roadmap for researchers, clinicians, and regulatory agencies working in the PD diagnostics field.
    Keywords:  Deep learning; Explainable AI; Machine learning; Multimodal biomarkers; Parkinson’s disease; Systematic review; Wearable sensors
    DOI:  https://doi.org/10.1016/j.compbiolchem.2026.109388
  56. Mult Scler Relat Disord. 2026 Sep 12. pii: S2211-0348(26)00957-0. [Epub ahead of print]115 107922
    Platelet-activating factor in multiple sclerosis: From peripheral inflammation to central neurodegeneration.
    Abdullah Baothman, Hayder M Al-Kuraishy, Weam A Elkady, Arafa Musa, Gaber El-Saber Batiha.
      Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease in which peripheral immune activation, blood-brain barrier (BBB) dysfunction, and central nervous system (CNS) injury are closely interconnected. Platelet-activating factor (PAF) is a potent phospholipid mediator involved in inflammation, platelet activation, oxidative stress, and neuronal signaling. Increased PAF levels in the plasma and cerebrospinal fluid (CSF) of patients with MS suggest its involvement in both peripheral and central disease processes. Clinical and experimental evidence supports a working model in which peripheral platelet and neurovascular activation may interact with central PAF/PAF receptor (PAF-R) signaling, where microglial-neuronal communication, glutamate/NMDA-mediated excitotoxicity, synaptic injury, and demyelination may contribute to neural damage. Altered regulation of PAF activity may further enhance these processes. However, several mechanistic links remain derived from experimental models, and some detrimental effects of PAF appear to occur independently of PAF-R. This review integrates the evidence supporting a peripheral-to-central PAF framework in MS and critically evaluates direct PAF-R antagonists, indirect PAF modulators, and exploratory PAF-related candidates. Overall, PAF/PAF-R targeting remains a mechanistically promising but clinically unestablished therapeutic approach requiring further translational investigation.
    Keywords:  Excitotoxicity; Multiple sclerosis; Neuroinflammation; Platelet-activating factor; Platelets
    DOI:  https://doi.org/10.1016/j.msard.2026.107922
  57. Inflammopharmacology. 2026 Sep 15.
    Pharmacological modulation of cGAS-STING-NLRP3 signaling by nano-immunomodulators in Alzheimer and Parkinson disease.
    Mohammed A Abdel-Rasol.
      Neuroinflammation is a central driver of neurodegeneration in Alzheimer's disease (AD) and Parkinson's disease (PD), driven by interconnected pathways involving microglial state dysregulation, inflammasome activation, cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, impaired mitophagy, CD33-TREM2 imbalance, gut-brain axis disruption, and peripheral immune infiltration across a compromised blood-brain barrier (BBB). Conventional anti-inflammatory therapies remain limited by poor CNS delivery, inadequate cell specificity, and the inability to simultaneously modulate multiple inflammatory pathways. Nano-immunomodulators (NIMs) have emerged as a promising strategy to modulate CNS immunity in preclinical models. This review critically evaluates recent advances in NIM-based strategies for AD and PD, including intrinsically therapeutic nanomaterials, targeted delivery systems, and precision gene-regulatory platforms. Intrinsically therapeutic materials, such as polydopamine nanoparticles and biomimetic nanozymes, provide antioxidant and mitochondrial protective functions, whereas BBB-targeted systems, including nanobody-based platforms and engineered exosomes, enhance targeted CNS delivery. Nanotheranostics approaches integrate imaging capabilities with stimuli-responsive release, while precision interceptors aim to simultaneous regulate pathological processes such as amyloid-beta (Aβ)-associated inflammation and cGAS-STING activation. Emerging gene-delivery strategies, including TREM2 mRNA and CD33-targeting lipid nanoparticles, offer opportunities for microglial reprogramming but remain largely restricted to proof-of-concept and early preclinical stages. The review further discusses AI-driven nanomedicine optimization and advanced human-relevant models, including brain-on-a-chip systems and three-dimensional (3D) bioprinting, as tools to improve translational prediction. Currently, AI approaches primarily support candidate selection, formulation optimization, and mechanistic prediction rather than clinical validation. Major challenges for clinical advancement include achieving precise modulation of microglial states beyond the simplified M1/M2 framework, developing context-dependent regulation of NLRP3 and cGAS-STING pathways, establishing gut-CNS therapeutic strategies, improving pluripotent stem cell (iPSC)-based validation platforms, and defining long-term CNS safety frameworks. By integrating molecular mechanisms, AI-assisted nanomedicine, nanoparticle-enabled immune and gene modulation, and advanced preclinical models, this review provides a mechanistic and translational framework for advancing next-generation NIM strategies in AD and PD. This integrated perspective addresses the limitations of previous single-domain analyses focused either on neuroinflammation or nanotechnology and outlines key considerations for translating NIMs from experimental platforms toward clinical applications.
    Keywords:  3D bioprinted brain tissue; AI-driven nanomedicine; Biomimetic nanozymes; Brain-on-a-chip; Exosome nanocarriers; Gene-delivering nanoparticles; Microglial polarization; NLRP3 inflammasome; Nanobody-drug conjugates; Nanotheranostics; Polydopamine nanoparticles; Precision nanomedicine; cGAS-STING pathway
    DOI:  https://doi.org/10.1007/s10787-026-02386-0
  58. Neuroprotection. 2026 Sep 11.
    Repurposing antimicrobial agents for neuroprotection: Mechanisms, clinical potential, and challenges.
    Mohammad Amin Manavi, Mohammadreza Salehi, Razieh Mohammad Jafari, Ramin Goudarzi, Saman Khosravi, Ahmad Reza Dehpour.
      Antimicrobial agents, originally developed for infectious diseases, have become attractive candidates for repurposing in neurodegenerative and neuroinflammatory diseases owing to their anti-inflammatory, antioxidant, immunomodulatory, and neuroprotective activities. In this review, we critically examine the therapeutic potential of selected antimicrobial classes, including tetracyclines (e.g., minocycline), macrolides (e.g., azithromycin), antimalarial agents (e.g., chloroquine/hydroxychloroquine), sulfones (e.g., dapsone), and antiparasitic agents (e.g., ivermectin), in non-infectious neurological diseases. We performed a narrative review of pre-clinical and clinical studies to investigate the effects of these agents on the main neuropathological mechanisms, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired autophagy, and gut-brain axis dysregulation. The available evidence suggests that many of the antimicrobial agents have beneficial effects in a number of neurological disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, and traumatic brain injury. These agents have been shown to modulate microglia activation, to inhibit production of pro-inflammatory cytokines, and to alter intracellular signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells. Furthermore, by reshaping the gut microbiota, antimicrobials modulate immune signaling, alter neurotransmitter levels, and compromise blood-brain barrier integrity-thereby positioning the gut-brain axis as central to their mechanism of action. Repurposing antimicrobial agents is a pragmatic and novel approach to treat complex neurological disorders with available approved drugs. Despite the encouraging evidence, we must carefully manage challenges such as antimicrobial resistance, off-target effects, and regulatory considerations. Further well-designed clinical trials are essential to validate their long-term safety and efficacy in neurodegenerative and neuroinflammatory diseases.
    Keywords:  anti‐bacterial agents; brain‐gut axis; drug repositioning; neurodegenerative diseases; neuroinflammatory diseases; oxidative stress
    DOI:  https://doi.org/10.1002/nep3.70042
  59. Int J Pharm Compd. 2026 Jul-Aug;30(4):30(4): 393-399
    Development and Chemical Stability Assessment of a Methyl-β-Cyclodextrin-Containing Dextromethorphan/ Quinidine Oral Solution for Extemporaneous Compounding.
    Wernli Cedric, Loesch Uli.
      Pseudobulbar affect is a distressing condition frequently observed in patients with amyotrophic lateral sclerosis (ALS), for which a fixed-dose combination of dextromethorphan and quinidine is approved in the United States. In Europe, no commercial product is available, and compounded capsules or suspensions are used; however, capsules may be unsuitable for patients with dysphagia, and suspensions require shaking before administration. The aim of this study was to develop simple fully water-soluble formulation of dextromethorphan hydrobromide and quinidine sulfate using methyl-ß-cyclodextrin as a solubilizing agent and to evaluate its stability under different storage conditions, enabling pharmacies to compound the preparation without complex infrastructure. Preliminary qualitative solubility experiments showed that the dextromethorphan hydrobromide/ quinidine sulfate powder mixture did not dissolve in water without methyl-ß-cyclodextrin. Addition of methyl-ß-cyclodextrin improved dissolution; however, the initial preparation targeting 20 mg/mL dextromethorphan hydrobromide and 10 mg/mL quinidine sulfate in a final volume of 100 mL remained incompletely dissolved. Increasing the final volume to 250 mL yielded a clear formulation containing nominal concentrations of 8.4 mg/mL dextromethorphan hydrobromide and 4.2 mg/mL quinidine sulfate. Three independently prepared batches were stored in amber PET bottles providing light protection and fitted with child-resistant closure at 2-8°C, 15-25°C, and 40°C and analyzed by HPLC for four weeks. HPLC assay values remained within 10% of the corresponding baseline values at each storage condition, and no visible precipitation was observed. The results support the physical clarity and chemical consistency of the tested methyl-ß-cyclodextrin- containing formulation over four weeks under the evaluated storage conditions. Microbiological stability, preservative effectiveness, formal method validation in the author's laboratory, and the extent of cyclodextrin inclusion complexation were not assessed. This formulation may serve as a basis for further pharmaceutical, microbiological, and clinical evaluation of an extemporaneously compounded oral liquid.
    Keywords:  ALS; Compounding pharmacy; Cyclodextrin; Dextromethorphan; Liquid formulation; Quinidine; Solubilization; Stability
  60. J Neurol. 2026 Sep 15. pii: 596. [Epub ahead of print]273(10):
    Comparison of iron and myelin changes in U‑fiber regions of relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorders.
    Yan Xie, Shaolong Wu, Yan Zhang, Chao Ju, Shun Zhang, Yi Wang, Wenzhen Zhu, Meiyun Wang.
       OBJECTIVE: To explore iron and myelin changes in U-fiber regions of relapsing-remitting multiple sclerosis (RRMS) and neuromyelitis optica spectrum disorders (NMOSD) by susceptibility separation imaging, and to evaluate the clinical relevance of these changes.
    METHODS: This study included 119 RRMS patients, 47 NMOSD patients, and 93 healthy controls (HC). The U-fiber region was defined as the white matter within 4 mm beneath the gray-white matter boundary. Susceptibility separation imaging was reconstructed from 3D multi-echo gradient echo data, and total susceptibility, positive susceptibility (χpos) and negative susceptibility (χneg) were extracted from each U-fiber subregion. General linear models were performed to compare these metrics among the three groups. Partial correlation analyses were conducted to explore the associations between susceptibility metrics and clinical characteristics.
    RESULTS: Compared with HC, RRMS patients showed significantly decreased χpos in multiple temporal and limbic U-fiber regions, and significantly increased χneg in widespread U-fiber subregions. However, no significant differences in susceptibility metrics were observed between NMOSD patients and HC in any U-fiber subregion. Notably, after adjusting for potential confounding effects of disease severity and lesion burden, there were no significant differences in susceptibility metrics between RRMS and NMOSD patients. In RRMS patients, χneg in U-fiber subregions was significantly correlated with Expanded Disability Status Scale, particularly in the left superior frontal region.
    CONCLUSION: Susceptibility separation imaging provided surrogate markers suggestive of iron loss and demyelination in the U-fiber region of RRMS patients. These metrics were closely associated with lesion burden and may hold promise as imaging correlates of clinical disability.
    Keywords:  Iron; Multiple sclerosis; Myelin; Neuromyelitis optica spectrum disorders; Susceptibility source separation
    DOI:  https://doi.org/10.1007/s00415-026-14054-y
  61. CNS Neurosci Ther. 2026 Sep;32(9): e71168
    Cannabidiol Ameliorates Blood-Brain Barrier Dysfunction and Inhibits Memory Astrocytes Activation in Mice With Sickness-Like Behaviors.
    Yue Chen, Hui Ma, Qian Long, Xuan Fang, Xiaotong Li, Wenhui Xiao, Xinzhou Deng, Fuze Du, Yifei Tan, Yan Wang, Xiaoxia Jiang, Bo Gao, Xin Qiao.
       BACKGROUND: Blood-brain barrier (BBB) dysfunction has been increasingly implicated in the pathophysiology of depression; however, effective therapeutic strategies targeting this pathology remain limited. This study aimed to investigate the effect of cannabidiol (CBD) on improving depressive-like behaviors and BBB impairment, as well as its underlying mechanism.
    METHODS: Depressive-like behaviors in mice were assessed via exploratory and despair-like tests. BBB integrity was evaluated by examining tight junction protein expression in endothelial cells and AQP4 reduction from the perivascular membrane. Astrocyte activation and neuroinflammation were also measured. The therapeutic effects of a single CBD dose were examined.
    RESULTS: Mice with depressive-like phenotypes showed reduced exploratory behavior and increased despair-like behavior. In the BBB, the expression of tight junction proteins in endothelial cells was downregulated; in astrocytes, decreased AQP4 expression was observed, abnormal activation was enhanced, and neuroinflammation was elevated. A single dose of CBD alleviated all the above pathological changes. Further studies demonstrated that CBD exerted its effects by inhibiting memory astrocyte-associated secondary neuroinflammation, thereby alleviating depressive-like behaviors in mice with depressive-like phenotypes.
    CONCLUSION: Experimental results show that CBD treatment can improve BBB dysfunction in depression and further indicates that targeted inhibition of memory astrocytes-mediated neuroinflammation may promote the treatment of depression.
    Keywords:  BBB; CBD; chronic depression; memory astrocytes; neuroinflammation
    DOI:  https://doi.org/10.1002/cns.71168
  62. Brain Inj. 2026 Sep 18. 1-9
    Caspase-3 dependent, induction of barrier dysfunction and hyperpermeability in blood-brain barrier endothelial cells.
    Himakarnika Alluri, Rickesha L Wilson, Morgan Merriman, Chinchusha Anasooya Shaji, Chen Chen, Gabriela Seplovich, Devendra A Sawant, Chander Peddaboina, Jason H Huang, Binu Tharakan.
       BACKGROUND: Blood-brain barrier (BBB) dysfunction and associated microvascular hyperpermeability lead to brain edema and elevation of intracranial pressure in traumatic and ischemic brain injuries. Pro-inflammatory cytokines, interleukin (IL-1β) and tumor necrosis factor (TNF-α), are up-regulated in such conditions and serve as endogenous activators of caspase-3 and apoptosis. The objective of this study was to comparatively test how these cytokines regulate caspase-3-mediated BBB breakdown/hyperpermeability, and understand if these effects were cell death dependent.
    METHODS: Rat brain microvascular endothelial cells were exposed to IL-1β, TNF-α, or caspase-3 activator, staurosporine (STS). Blood-brain barrier integrity and functions were determined by monolayer permeability, tight junction integrity, and cytoskeletal integrity. The changes in mitochondrial reactive oxygen species (ROS) and caspase-3 activity were evaluated microscopically and fluorometrically, respectively.
    RESULTS: IL-1β, TNF-α, and STS induced caspase-3 activation, tight junction/cytoskeletal disorganization, and monolayer hyperpermeability. These effects were inhibited by a caspase-3 inhibitor, Z-DEVD-fmk. Treatments had no effect on ROS formation.
    DISCUSSION: This comparative study shows that, in BBB endothelial cells, IL-1β, TNF-α, and STS induce tight junction/cytoskeletal disorganization and hyperpermeability via Caspase-3 mediated breakdown of the tight junction proteins. Effects are independent of ROS formation, one of the significant factors that promote blood-brain barrier dysfunctions in neurological disorders.
    Keywords:  Blood-brain barrier dysfunction; cerebral edema; inflammatory cytokines; intracranial pressure; staurosporine; tight junctions; trauma, ischemia
    DOI:  https://doi.org/10.1080/02699052.2026.2733592
  63. Artif Intell Med. 2026 Sep 12. pii: S0933-3657(26)00187-9. [Epub ahead of print]182 103535
    Beyond the field of view: Radiomics and artificial intelligence for organ-specific and systemic disease prediction from localized medical imaging.
    Lixia Wang, Yu Shi, Zengtian Deng, Yufeng Wang, Dante Rigo De Righi, Sehrish Javed, Touseef Ahmad Qureshi, Ju Dong Yang, Yibin Xie, Stephen J Pandol, Debiao Li.
      Radiomics and artificial intelligence (AI) are increasingly used in medical imaging to shift beyond qualitative interpretation toward quantitative disease prediction. Localized medical imaging, including abdominal computed tomography (CT), chest CT, mammography, brain magnetic resonance imaging (MRI), and retinal imaging, may reveal subtle features that reflect not only pathology within the imaged organ but also systemic or distant disease processes. By extracting radiomic features with machine learning or learning imaging representations with deep learning models, previous studies have shown predictive value across neurology, oncology, cardiometabolic disease, and biological aging. This narrative review summarizes recent advances in radiomics and AI for organ-specific and systemic disease prediction from localized imaging. It outlines key methodological steps, including image acquisition, segmentation, harmonization, feature extraction, model development, validation and clinical translation. This review also describes the biological basis linking localized imaging biomarkers to systemic disease processes, such as metabolic dysfunction, inflammation, vascular remodeling, and biological aging. Ongoing challenges include imaging variability, limited generalizability, confounding, reproducibility, interpretability, ethical considerations, and the need for prospective validation. Overall, imaging-based biomarkers have the potential to extend the value of routine scans by enabling earlier risk detection, more individualized risk stratification and targeted follow-up beyond the original field of view.
    Keywords:  Biological age; Data harmonization; Deep learning; Disease prediction; Machine learning
    DOI:  https://doi.org/10.1016/j.artmed.2026.103535
  64. Inflamm Res. 2026 Sep 14. pii: 210. [Epub ahead of print]75(1):
    Autoimmune processes and production of catalytically active antibodies-abzymes in prone to amyotrophic lateral sclerosis FUS(1-359) mice.
    Andrey E Urusov, Marina A Gorobets, Kseniya S Aulova, Anna M Timofeeva, Ludmila B Toporkova, Irina A Orlovskaya, Aleksey A Ustyugov, Georgy A Nevinsky.
       OBJECTIVE: It was shown previously that the development of not only many autoimmune (AIDs) but also neurological and neurodegenerative diseases (NDDs) including multiple sclerosis, tick-borne encephalitis, and schizophrenia in humans and experimental mice models occurs due to a specific destruction of the immune system. This error in the immune system leads to the formation of B lymphocytes producing adverse antibodies-abzymes possessing different catalytic activities.
    METHODS: One of the earliest and statistically reliable index of developments of autoimmune reactions is the appearance in the blood abzymes that are absent in conditionally healthy donors. We investigated the in time changes catalytic activities of Abs-abzymes using standard methods of enzymology.
    RESULTS: It was shown for the first time that, as in the case of various AIDs and NDDs, the early stages of ALS development in FUS(1-359) mice are also associated with the production of catalytic antibodies. CD-1 mice utilized for obtaining FUS(1-359) mice were also used. IgG samples were isolated from the blood of transgenic FUS(1-359) mice and their non-transgenic siblings (CD1) at different times. The first signs of ALS-like symptoms develop at the age of ≥ 2 months of life in FUS(1-359) mice, which was taken as zero time point, and then by ≥ 80 days of age, deep pathology was observed. It was shown for the first time that antibodies from the blood of FUS(1-359) mice exhibit DNase, amylase, phosphatase, and catalase catalytic activities beginning from 2 months of age. However, unlike non-transgenic siblings, the relative activity of mice IgGs was higher in FUS(1-359) mice. All activities of FUS(1-359) mice IgGs began to increase significantly starting from 20 to 30 days after beginning of experiments and achieved maximum upon reaching deep pathology.
    CONCLUSIONS: The data obtained indicate that in the early stages of ALS development in FUS(1-359) mice containing genes associated with this pathology in humans, there is a disruption of the immune system and production of abzymes that destroy components of blood, cells and tissues. One cannot exclude that such autoimmune reactions are important for development of ALS in FUS(1-359) mice.
    Keywords:  Amylase; CD1 mice; Catalase activities of antibodies; Catalytic IgGs; FUS(1-359) mouse model of Amyotrophic lateral sclerosis; Hydrolysis of DNA; Phosphatase
    DOI:  https://doi.org/10.1007/s00011-026-02358-8
  65. Int J Mol Sci. 2026 Aug 25. pii: 7597. [Epub ahead of print]27(17):
    The Oral-Brain Axis: A Unified Framework Linking Trigeminal Sensorimotor Dysfunction, Chronic Stress, Neuroinflammation, and Neurodegeneration.
    Hiroki Toyoda.
      Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) develop over decades, yet their earliest pathogenic drivers remain poorly understood. Epidemiological and experimental animal studies suggest that disturbances in oral sensorimotor regulation, particularly within trigeminal proprioceptive pathways, may contribute to neural dysfunction long before clinical symptoms emerge. The mesencephalic trigeminal nucleus (MesV), the only primary sensory neuron population located entirely within the central nervous system (CNS), links oral proprioception with brainstem and forebrain networks. Chronic occlusal mismatch, impaired mastication, sleep bruxism, and sleep-disordered breathing may generate persistent sensorimotor prediction errors that destabilize MesV-centered circuits and subsequently recruit the locus coeruleus (LC), the brain's principal noradrenergic stress nucleus. This review proposes an oral-brain axis model in which chronic MesV-related prediction error signaling engages LC-dependent stress systems, leading to neuroimmune activation, locus coeruleus-asparagine endopeptidase (LC-AEP) pathway engagement, and downstream proteinopathic processes. Sustained LC activity may facilitate microglial priming, reactive astrocytosis, and neuroinflammatory signaling, creating conditions that favor LC-AEP pathway activation and downstream tau pathology. Epidemiological studies associate tooth loss, reduced occlusal support, and impaired mastication with increased dementia risk, while experimental models of prodromal PD demonstrate early trigeminal sensory-processing abnormalities preceding motor symptoms. Together, these findings support the hypothesis that chronic disturbances in oral sensorimotor homeostasis may increase neurodegenerative vulnerability. This framework identifies potential biomarkers and preventive targets, suggesting that modulation of oral function and neuroimmune pathways may help reduce neurodegenerative risk before irreversible neuronal loss occurs.
    Keywords:  asparagine endopeptidase; locus coeruleus; mesencephalic trigeminal nucleus; neurodegeneration; oral–brain axis; predictive coding
    DOI:  https://doi.org/10.3390/ijms27177597
  66. Front Immunol. 2026 ;17 1901957
    Smoldering neuroinflammation in progressive multiple sclerosis: mechanisms, imaging biomarkers, and therapeutic opportunities.
    Min Wang, Bo-Chi Zhu, Xijing Mao.
      Progressive multiple sclerosis (MS) remains a major therapeutic challenge because disability often continues to accumulate despite effective control of relapses and new focal inflammatory lesions. This dissociation suggests that progression is driven not only by acute inflammation, but also by a distinct process increasingly termed smoldering neuroinflammation. Recent evidence supports chronic active lesions as an important but non-exclusive pathological substrate of this process. These lesions are characterized by persistent lesion-edge inflammation, slowly expanding tissue injury, iron-laden myeloid cells, astrocyte-immune crosstalk, and incomplete repair. Importantly, this inflammatory activity is not restricted to isolated white matter plaques, but is spatially compartmentalized across the central nervous system, involving interactions among white matter lesions, meninges, cortex, and subcortical regions. Advances in susceptibility-based MRI and PET imaging now allow in vivo assessment of imaging-related correlates of this otherwise hidden pathology, including paramagnetic rim lesions (PRLs), slowly expanding lesions (SELs), and TSPO-PET-defined inflammatory activity. Although these biomarkers overlap only partially, they provide complementary insights into lesion composition, structural expansion, and metabolic inflammation. Accumulating studies further suggest that current disease-modifying therapies incompletely control established chronic lesion biology, while other inflammatory-independent or age-related neurodegenerative processes may also contribute to progression. In this review, we discuss the pathological basis, imaging correlates, and therapeutic implications of smoldering neuroinflammation in progressive MS.
    Keywords:  chronic active lesions; multiple sclerosis; paramagnetic rim lesions; progressive multiple sclerosis; smoldering neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1901957
  67. Mol Ther Adv. 2026 Dec 10. 34(4): 201835
    Base editing rescues a hereditary motor neuron disease in mouse and patient-derived iPSC organoid models.
    Keiko Imamura, Shin Yoshioka, Kota Kamizato, Ryosuke Oki, Hiroyuki Hioki, Kayoko Tsukita, Ikuyo Inoue, Rina Shimizu, Mako Takiguchi, Tomoki Sakasai, Aya Okusa, Ran Shibukawa, Takeshi Niki, Satoko Sakurai, Taro Okunomiya, Takayuki Kondo, Tomohisa Kato, Atsushi Miyanohara, Manabu Kakinohana, Takuya Yamamoto, Martin Marsala, Keiji Nishida, Yuishin Izumi, Haruhisa Inoue.
      In hereditary motor neuron diseases (MNDs), including forms of amyotrophic lateral sclerosis (ALS) caused by single-nucleotide variants, effective therapeutic strategies need to address both gain- and loss-of-function mechanisms. Genome editing-based gene therapy represents a promising approach for simultaneously targeting these mechanisms. To establish proof-of-concept for base editing in a hereditary MND, we targeted the P285L variant in the TRK-fused gene (TFG), which causes hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), a disorder that shares clinical and histopathological features with ALS. We identified the optimal adenine base editor by comparing candidate editors in HMSN-P patient-derived induced pluripotent stem cells (iPSCs). We then generated a transgenic mouse model expressing human TFG P285L and evaluated the selected editor by subpial delivery of adeno-associated virus (AAV) vectors to the spinal cord. AAV-mediated base editing prolonged survival, preserved motor neurons, and attenuated axon loss in ventral nerve roots. Treatment with the selected base editing vector reduced TFG aggregation and suppressed neuronal death in HMSN-P iPSC-derived neuromuscular organoids. Collectively, these findings support the therapeutic potential of base editing for hereditary MNDs.
    Keywords:  AAV; ABE; ALS; HMSN-P; MND; base editing therapy; gene therapy; iPSCs; organoids; subpial injection
    DOI:  https://doi.org/10.1016/j.omta.2026.201835
  68. Eur J Neurol. 2026 Sep;33(9): e70759
    Intrathecal Plasma Cell Activity as Measured by the Kappa Free Light Chain Index Is Associated With Retinal Layer Atrophy in Early Multiple Sclerosis.
    Klaus Berek, Martin Schmidauer, Fabian Föttinger, Michael Auer, Thomas Berger, Franziska Di Pauli, Luisa Velez Escola, Thomas Hofer, Barnabas Kremser, Stephanie Mangesius, Jan P Nolte, Marie-Christine Pali, Berthold Pemp, Katharina Stock, Markus Tiefenthaler, Janette Walde, Anne Zinganell, Florian Deisenhammer, Gabriel Bsteh, Harald Hegen.
       BACKGROUND: The relationship between intrathecal kappa free light chain (κ-FLC) synthesis and retinal layer atrophy in multiple sclerosis (MS) is unknown.
    OBJECTIVE: To investigate whether the κ-FLC index is associated with peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell plus inner plexiform layer (GCIPL) thickness.
    METHODS: Patients with newly diagnosed clinically isolated syndrome or relapsing MS and available cerebrospinal fluid (CSF) analysis and optical coherence tomography (OCT) were included. Clinical and magnetic resonance imaging (MRI) data were also assessed. κ-FLC concentrations were measured by nephelometry, and the κ-FLC index was calculated as (CSF κ-FLC/serum κ-FLC)/albumin quotient.
    RESULTS: A total of 100 patients at a median age of 33 (25th-75th percentile: 25-39) years and a female predominance (58%) were included. In multivariable linear regression analysis adjusted for age, sex, disease duration, number of T2-hyperintense and number of contrast-enhancing MRI lesions, the κ-FLC index was associated with pRNFL (log-transformed κ-FLC index: β: -2.51; 95% confidence interval [CI]: -4.01, -1.01; p = 0.001) and GCIPL thinning (log-transformed κ-FLC index: β: -1.24, 95% CI: -2.32, -0.17; p = 0.024).
    CONCLUSIONS: Intrathecal plasma cell activity, as measured by the κ-FLC index, is associated with neuroaxonal damage, as reflected by pRNFL and GCIPL atrophy.
    Keywords:  GCIPL; cerebrospinal fluid; kappa free light chain; multiple sclerosis; optical coherence tomography; pRNFL; retinal layer
    DOI:  https://doi.org/10.1111/ene.70759
  69. Front Aging Neurosci. 2026 ;18 1819248
    Data-driven subtyping of Parkinson's disease using MRI: current insights, challenges, and future directions.
    Anupa A Vijayakumari, Ken E Sakaie, Hubert H Fernandez, Benjamin L Walter.
      Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder marked by diverse motor and non-motor symptom profiles. Traditional symptom-based subtyping shows limited stability and lacks clear biological grounding. Integrating magnetic resonance imaging (MRI) with machine learning (ML) offers a promising avenue for defining biologically informed PD subtypes. This narrative review synthesizes evidence from MRI-based subtyping studies that used structural (T1-weighted), diffusion, functional, or multimodal MRI features as primary inputs for unsupervised or hybrid ML approaches to derive PD subtypes and outlines key methodological challenges and future translational needs. T1-weighted MRI studies consistently identify two to three subtypes characterized by distinct patterns of cortical and subcortical atrophy associated with variation in motor and non-motor symptoms. Although fewer in number, diffusion MRI studies have identified microstructural heterogeneity in PD. However, the findings remain heterogeneous and preliminary, and a stable subtyping framework has yet to be established. Multimodal MRI approaches show that combining modalities provides complementary insights into the neurobiology underlying PD heterogeneity but require further validation. Collectively, MRI-based subtyping shows promise for mapping clinical variability onto neuroanatomical patterns. At present, these subtypes are best viewed as research constructs that illuminate disease variability rather than clinical diagnostic tools. Translation into clinical practice will require addressing critical methodological gaps to achieve the reproducibility and prognostic utility necessary for precision medicine.
    Keywords:  MRI; MRI feature-based subtyping; MRI-based subtypes; Parkinson’s disease; clustering; data-driven subtyping; disease heterogeneity; machine learning
    DOI:  https://doi.org/10.3389/fnagi.2026.1819248
  70. Front Neurosci. 2026 ;20 1913909
    The spectrum of C9orf72 repeat lengths in Portuguese frontotemporal dementia and amyotrophic lateral sclerosis patients: from pathogenic expansions to intermediate alleles.
    Maria Rosário Almeida, Miguel Tábuas-Pereira, Anabela Matos, Ana Santos, Carolina Teixeira, Inês Baldeiras, Marisa Lima, Isabel Santana.
       Introduction: Frontotemporal dementia and amyotrophic lateral sclerosis are clinically distinct disorders that share a common genetic etiology, with pathogenic hexanucleotide repeat expansions in the C9orf72 gene representing the most frequent genetic cause of both conditions. In this study we aim to determine the frequency of C9orf72 repeat expansions in patients with FTD and/or ALS and their at-risk relatives from central Portugal, and to analyze the distribution and repeat size of intermediate alleles within this cohort investigating their potential pathogenicity.
    Methods: Between January 2016 and January 2026, C9orf72 repeat expansions were assessed in 610 patients with the clinical presentation within the spectrum of FTD/ALS and in 63 asymptomatic relatives. C9orf72 repeat expansions were identified using a two-step PCR protocol comprising STR-PCR and RP-PCR, followed by repeat-length sizing with a commercial kit. Capillary electrophoresis traces were subsequently analyzed using AmplideX® PCR/CE Reporter software. Furthermore, carriers of intermediate alleles underwent comprehensive clinical, fluid-biomarker, and neuropsychological characterization to investigate the potential pathogenicity of these alleles.
    Results: Pathogenic C9orf72 expansions were identified in 11% of patients. The vast majority carried long expansions (>145 repeats), whereas three patients exhibited shorter expansions ranging from 38 to 78 repeats. Intermediate alleles were found in seven subjects with heterogeneous clinical presentations. Clinically, these individuals were indistinguishable from carriers of longer expansions.
    Discussion: C9orf72 hexanucleotide repeat expansions are a major genetic cause of FTD, ALS, and FTD-ALS in this cohort of patients, highlighting the importance of genetic testing for accurate counselling and clinical management. These findings support routine C9orf72 testing in all patients with these disorders, particularly those of European ancestry. Our findings also support the emerging view that intermediate C9orf72 repeat expansions may act as a genetic risk factors contributing to a broad spectrum of clinical phenotypes.
    Keywords:  ALS; C9orf72 expansion; FTD; FTD-ALS; intermediate alleles
    DOI:  https://doi.org/10.3389/fnins.2026.1913909
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