bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–09–06
sixty-one papers selected by
Luca Bolliger, lxBio
  1. Microbiota-derived metabolite-GPCR signalling in neurodegeneration.
  2. Use of High-Flow Nasal Cannula in Amyotrophic Lateral Sclerosis Patients Intolerant to Non-Invasive Ventilation: A Case Series.
  3. Mechanistic Characterization of NABi as a Selective Inhibitor of SOD1G93A Aggregation: Structural Basis and Therapeutic Implications for ALS.
  4. Seeds from ALS patients homozygous for the SOD1 D90A mutation transmit two types of SOD1 aggregation and motor neuron disease.
  5. Metabolic and Fluid Biomarkers Support Microglia Activation in Amyotrophic Lateral Sclerosis.
  6. Glutamatergic neuron degeneration in C. elegans models of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
  7. Ginsenosides: potential therapeutic implications in neurodegenerative diseases by inhibiting ferroptosis.
  8. A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases.
  9. Whole-exome sequencing reveals a novel frameshift and a recurrent nonsense SPG11 variant causing rare familial amyotrophic lateral sclerosis type 5 in two consanguineous Pakistani families.
  10. Cortisol Dysregulation as a Major Factor in the Development of Neurodegenerative Diseases, Drug Targets and Therapeutic Prospects: A Comprehensive Review.
  11. Proteomic and Functional Signatures of Phenoconversion in Presymptomatic Amyotrophic Lateral Sclerosis.
  12. Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated gene in French cohorts.
  13. Amyotrophic lateral sclerosis -plus patient with an intermediate-length CACNA1A allele: a Case Report.
  14. Protein Biomarkers in Risk and Prognosis of Amyotrophic Lateral Sclerosis.
  15. Disrupted astrocyte-neuron metabolic coupling in amyotrophic lateral sclerosis.
  16. Military Service and Survival Among Persons With ALS in the U.S. National ALS Registry, 2011-2023.
  17. Implementation of specialised care improves survival in patients with amyotrophic lateral sclerosis.
  18. Data-Driven SuStaIn Model of Disability Progression in Amyotrophic Lateral Sclerosis.
  19. [Atypical forms of amyotrophic lateral sclerosis].
  20. Serum Neurofilament Light Chain and GFAP in Amyotrophic Lateral Sclerosis on a Commercial ECLIA Platform.
  21. Priorities for Advancing Palliative Care for Amyotrophic Lateral Sclerosis: A Consensus Report From a Palliative Care for ALS Working Group in the United States.
  22. Extracellular Vesicles in Neurodegenerative Diseases: A New Frontier in Diagnosis and Therapy.
  23. From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.
  24. CSF Tau and Amyloid Biomarkers in Cognitive Impairment Across the ALS-FTD Spectrum: A Systematic Narrative Review and Evidence Map.
  25. Blood-Brain Barrier Disruption and Edema in Xenopus: Methods for Analysis.
  26. Artificial Intelligence in Neuromuscular Diseases: Opportunities for a Data-Scarce Field.
  27. Pharmacological modulation with the LXR agonist T0901317 attenuates motor pathology in the SOD1G93A mouse model of ALS.
  28. ALSGate: An Efficient Gated Mixture-of-Experts Model for Reliable ALS Detection Using EMG Signals.
  29. Associations of cumulative exposure and longitudinal trajectories of neurofilament light chain with 1-year adverse events in amyotrophic lateral sclerosis: A prospective cohort study.
  30. Deep learning in imaging analysis for multiple sclerosis: Diagnosis and monitoring.
  31. TREM2 as a central hub of neuroimmune-metabolic crosstalk in central nervous system disorders: from microglial biology to therapeutic targeting.
  32. Axonal pathology and impaired axo-glial crosstalk as early drivers of neurodegeneration.
  33. Possible Paraneoplastic Amyotrophic Lateral Sclerosis Presenting as Respiratory Failure in a Breast Cancer Patient: A Case Report.
  34. Increased serum fibroblast growth factor 2 levels, altered peripheral blood inflammatory indicators and their ratios in amyotrophic lateral sclerosis: a clinical exploratory study.
  35. Feto-Maternal Microchimerism and the Brain: Mechanisms, Neurological Implications, and Translational Perspectives.
  36. Repairing the Amyotrophic Lateral Sclerosis Trial Credibility Gap.
  37. Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.
  38. Targeting the vascular interface: beyond crossing the blood-brain barrier.
  39. Computational Insights into Neuromodulation: How Electric Fields Shape Motor Neuron Excitability.
  40. Progress towards a biotypic biomarker profile for amyotrophic lateral sclerosis-frontotemporal spectrum disorders.
  41. The gut neuroepithelial unit as a neurodegeneration-relevant interface in the gut-brain axis.
  42. Role of complement and complement-targeted therapeutics in neurological diseases.
  43. Implications of artificial intelligence in multiple sclerosis theragnostics: current advances and barriers to clinical translation.
  44. Selective targeting of the oligodendroglial GPR17 receptor improves myelin integrity and motor function in female SOD1G93A mice.
  45. Cell-to-Cell Signaling Networks at the Blood-Brain Barrier in Health and Disease.
  46. Prevalence of Slowly Expanding Lesions in Patients With Multiple Sclerosis: A Systematic Review and Meta-Analysis.
  47. UV-programmed gelatin methacryloyl hydrogel microenvironments reveal a bell-shaped vascularization window and enable compartmentalized neuromuscular disease modeling.
  48. The Therapeutic Potential of Purmorphamine Across Disease Models.
  49. Cognitive and motor profiles in biologically defined Parkinson's and Alzheimer's disease.
  50. Artificial intelligence and machine learning in neurogenic lower urinary tract dysfunction and spinal cord injury: current status, emerging technologies, and ethical perspectives.
  51. Can MRI with diffusion-weighted imaging reliably detect cryptorchidism? A systematic review and diagnostic accuracy meta-analysis.
  52. Multimodal MRI biomarkers and machine learning in neuromyelitis optica spectrum disorder: a review.
  53. Focused Ultrasound is Poised to Take Non-Viral Gene Therapies to the Blood-Brain Barrier - and Beyond.
  54. Recent medicinal chemistry efforts of targeting protein kinases for treating neurological conditions of Parkinson's and Alzheimer's diseases.
  55. Delayed appearance of bilateral cerebral peduncle lesions in autoimmune glial fibrillary acidic protein astrocytopathy: A serial MRI case series.
  56. Soluble TREM2 Mediates Blood Brain Barrier Permeability through Astrocyte Reactivity.
  57. Role of STX1A in Parkinson's disease: evidence, mechanistic hypotheses, and translational perspectives.
  58. Rebalancing α-Synuclein Clearance: Novel Therapeutic Frontiers in Parkinson's Disease.
  59. YTHDC1 functions as a molecular chaperone to suppress ALS-linked hnRNPA1 mutants from aggregation.
  60. The APOE4-estrogen-microglia axis in perimenopausal cognitive changes: mechanisms and therapeutic implications.
  61. Mesenchymal Stem Cells and Extracellular Vesicles for Neurodegenerative Diseases: Therapeutic Advances and Challenges.
  1. Neuroscience. 2026 Sep 04. pii: S0306-4522(26)00602-0. [Epub ahead of print]
    Microbiota-derived metabolite-GPCR signalling in neurodegeneration.
    Anshul Sharma, Nidhi Jatana.
      The gut microbiome acts as a primary regulator of host homeostasis, influencing the entire body through bidirectional communication along the gut-brain axis (GBA). Dysbiosis, which is defined as a state of microbial imbalance involving alterations in community composition and function, can disrupt the synthesis of important microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), bile acids and neurotransmitter precursors. This can lead to impaired essential host signalling pathways. There is growing evidence that metabolic alterations associated with dysbiosis contribute to the onset and progression of neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). In this context, G protein-coupled receptors (GPCRs) act as essential molecular transducers that link microbial metabolites to intracellular signalling networks. Aberrant GPCR activation, driven by altered metabolite profiles, modulates key downstream pathways including cAMP, MAPK, PI3K/Akt, NF-κB and Ca2 + signalling. This promotes neuroinflammation, oxidative stress, mitochondrial dysfunction and pathological protein aggregation - hallmark processes underlying neurodegeneration. By identifying convergent and disease-specific signalling pathways, the review highlights mechanistic nodes of therapeutic relevance and discusses GPCR-centric emerging and other microbiome-targeted strategies aimed at restoring metabolic and signalling homeostasis in neurodegenerative disorders.
    Keywords:  G protein-coupled receptors (GPCRs); Gut microbiota dysbiosis; Gut-brain axis; Microbial metabolites; Neurodegenerative diseases; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.09.001
  2. Respirol Case Rep. 2026 Sep;14(9): e70744
    Use of High-Flow Nasal Cannula in Amyotrophic Lateral Sclerosis Patients Intolerant to Non-Invasive Ventilation: A Case Series.
    Fabio Varon-Vega, Carlos Evelio Franco Parra, Doris Fabiola Adame Ochoa, Nancy Uricoechea, Eduardo Tuta-Quintero, María Camila Martinez Ayala.
      Non-invasive ventilation (NIV) is standard respiratory support for amyotrophic lateral sclerosis (ALS), but intolerance may limit its use. High-flow nasal cannula (HFNC) has emerged as a potential alternative in selected patients, but evidence regarding its use remains scarce. We describe 18 ALS patients' management with HFNC between 2014 and 2024 after documented intolerance to NIV. Mean age at HFNC initiation was 65.1 ± 12.5 years, and 66.7% of patients were female. Partial NIV intolerance occurred in 38.9% of cases, while 33.3% tolerated intermittent combined NIV and HFNC. During follow-up, 50.0% of patients required hospitalization, 33.3% experienced respiratory infections, and 27.8% died. Arterial blood gas parameters remained stable, including PaCO2 (p = 0.314). Functional status declined significantly, with Barthel Index decreasing (35.0 ± 20.5 vs. 11.7 ± 11.3; p < 0.001), whereas respiratory muscle strength remained unchanged. HFNC was feasible as home-based support in ALS patients intolerant to NIV, warranting prospective comparative evaluation.
    Keywords:  amyotrophic lateral sclerosis; high‐flow nasal cannula; home care; non‐invasive ventilation; respiratory support
    DOI:  https://doi.org/10.1002/rcr2.70744
  3. ACS Chem Neurosci. 2026 Sep 02. 17(17): 3156-3168
    Mechanistic Characterization of NABi as a Selective Inhibitor of SOD1G93A Aggregation: Structural Basis and Therapeutic Implications for ALS.
    Min-Kyung Nam, Yeram Oh, Yemi Choi, Jieun Lee, Gi Heon Jeong, Sangjun Park, Seung-Ah Yoo, Moonseok Kim, Seongman Kang, Hyangshuk Rhim.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, with familial ALS (fALS) frequently caused by mutations in Cu/Zn superoxide dismutase (SOD1). The G93A mutation, one of the most aggressive forms, promotes the formation of cytotoxic protein aggregates through cross-β-sheet structures, leading to neuronal dysfunction and death. In this study, we investigated the therapeutic potential of NABi (natural Aβ binder and Aβ-aggregation inhibitor), a stable small engineered protein composed of the N-terminal 90 amino acids of SOD1, originally developed to target amyloid-β aggregation in Alzheimer's disease. Given the shared β-sheet-rich aggregation mechanisms between amyloid-β and mutant SOD1 proteins, we hypothesized that NABi could serve as a dual-action therapeutic for both diseases. Through an integrated approach involving structural, biochemical, and cellular analyses, we demonstrate that NABi exhibits a 4-fold greater binding affinity for SOD1G93A compared to SOD1WT, selectively targeting the mutant protein via specific hydrophobic interactions. Structural modeling using AlphaFold2 reveals that the G93A mutation exposes hydrophobic residues that create an optimal binding interface for NABi. Functionally, NABi effectively inhibits SOD1G93A aggregation, as demonstrated by filter trap assays and immunofluorescence microscopy, while maintaining the protein in a soluble, nontoxic state. Importantly, coexpression of NABi reduces SOD1G93A-induced cytotoxicity by approximately 4-fold, significantly enhancing neuronal survival. These findings establish NABi as a promising therapeutic candidate for SOD1G93A-associated familial ALS, demonstrating its capacity to selectively target pathological protein conformations while preserving normal cellular function. Our results support the development of NABi as an innovative pan-therapeutic approach targeting shared aggregation pathways across multiple neurodegenerative diseases.
    Keywords:  Amyotrophic lateral sclerosis; NABi; SOD1G93A; aggregation inhibitor; neurodegenerative diseases; protein aggregation; therapeutic peptide; β-sheet inhibitor
    DOI:  https://doi.org/10.1021/acschemneuro.5c00977
  4. Acta Neuropathol. 2026 Sep 01. pii: 27. [Epub ahead of print]152(1):
    Seeds from ALS patients homozygous for the SOD1 D90A mutation transmit two types of SOD1 aggregation and motor neuron disease.
    Caitlin Henne, Isabelle Sigfridsson, Thomas Brännström, Karin M E Forsberg, Stefan L Marklund, Per Zetterström, Peter M Andersen.
      Mutations in superoxide dismutase-1 (SOD1) are a common cause of amyotrophic lateral sclerosis (ALS). Inheritance is as a rule dominant, but in carriers of the most prevalent mutation, D90A, disease primarily develops in homozygotes. Increasing evidence suggests that prion-like propagation of SOD1 aggregation is the central pathogenic mechanism. Two structurally different strains of aggregates have been found to arise in human SOD1 (hSOD1) transgenic (Tg) mouse models of ALS. Strain A is formed by most mutants including hSOD1G85R and homozygous hSOD1WT Tg mice, whereas homozygous hSOD1D90A Tg mice form a distinct strain B, but also A. Inoculation of strain A and B seed preparations from Tg mice into lumbar spinal cord of adult hSOD1G85R mice induced templated spreading hSOD1 aggregation and premature ALS-like disease. Seeds from an ALS patient carrying the hSOD1G127X truncation mutation likewise transmitted strain A aggregation and disease. In the present study, we investigated whether seeds prepared from spinal ventral horns from six patients homozygous for the hSOD1D90A mutation could transmit aggregation and disease to adult hSOD1G85R Tg mice. Despite the extensive degeneration and loss of motor neurons in the long-lived D90A patients, two of the seeds significantly shortened the survival of the Tg mice, one transmitting A and the other B-pattern hSOD1 aggregation. Nine different preparations from four human controls lacked effects. The results demonstrate that two distinct aggregate strains can arise and propagate in homozygous hSOD1D90A ALS patients, further supporting the hypothesis that prion-like transmission of hSOD1 aggregation is the primary pathogenic mechanism in SOD1-linked ALS.
    Keywords:  ALS; D90A; Prion; SOD1; Transmission
    DOI:  https://doi.org/10.1007/s00401-026-03078-3
  5. Ann Clin Transl Neurol. 2026 Aug 30.
    Metabolic and Fluid Biomarkers Support Microglia Activation in Amyotrophic Lateral Sclerosis.
    Matteo Zanovello, Francesca Serani, Alen Bebeti, Federica Paredi, Giulia Quadrio, Andrea Fortuna, Giacomo Maria Minicuci, Elena Pegoraro, Annachiara Cagnin, Diego Cecchin, Gianni Sorarù.
      Amyotrophic lateral sclerosis is an incurable neurodegenerative disease involving motor neuron degeneration and metabolic and immune dysfunction. We combined clinical data, cerebrospinal fluid biomarkers and fluorodeoxyglucose positron emission tomography with magnetic resonance imaging to investigate the role of reactive microglia in disease pathogenesis. Patients showed increased cerebrospinal fluid levels of neurofilament light chain and chitinases, along with hypermetabolism in the medulla oblongata. Chitinase levels correlated with brainstem metabolism and clinical severity. These findings suggest a link between microglial activation, brainstem hypermetabolism and disease progression in amyotrophic lateral sclerosis, supporting a central role for neuroinflammation in disease pathogenesis.
    Keywords:  ALS; CSF; PET‐MR; chitinase; microglia
    DOI:  https://doi.org/10.1002/acn3.70521
  6. MicroPubl Biol. 2026 ;2026
    Glutamatergic neuron degeneration in C. elegans models of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
    Lexi-Amber Hassell, Mika Gallati, Monica Thoma, Selamawit Asfaw, Anne Church Hart.
      Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) overlap considerably in genetic origin and pathology. Multiple C. elegans models of ALS/FTD have been developed, but the integrity of glutamatergic neurons in these models has not been thoroughly evaluated. Here, we report degeneration of glutamatergic phasmid neurons in animals expressing either wild-type or disease variant V337M human tau, and mild degeneration in animals expressing disease variant M337V human TDP-43. Defects caused by ectopic expression of tau were suppressed by loss of the known modifier, spop-1 , suggesting that SPOP-1-dependent pathways are also involved in glutamatergic neuron degeneration.
    DOI:  https://doi.org/10.17912/micropub.biology.002301
  7. Mol Biol Rep. 2026 Aug 29. pii: 1497. [Epub ahead of print]53(1):
    Ginsenosides: potential therapeutic implications in neurodegenerative diseases by inhibiting ferroptosis.
    Chang Liu, Yanru Zhang.
      A positive correlation exists between the accelerating pace of population aging and the increasing prevalence of neurodegenerative diseases. Conditions such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) profoundly compromise patient quality of life, yet efficacious clinical interventions remain notably limited. The prevention and management of neurodegenerative diseases represent a critical global public health imperative. A comprehensive literature search was performed across PubMed, Web of Science, and Scopus to identify studies on the biological functions, molecular mechanisms, and clinical implications of ginsenosides. The search strategy incorporated MeSH terms and free-text keywords, encompassing "neurodegenerative disease", "ferroptosis", "ginsenosides", "Parkinson's disease", "Alzheimer's disease", "amyotrophic lateral sclerosis", "Huntington's disease" and "multiple sclerosis". From an initial pool of over 400 papers (1998-2026), 107 were selected in this narrative review. Ferroptosis is intricately linked to the pathogenesis of neurodegenerative diseases. Ginsenosides constitute the principal bioactive triterpenoid saponins extracted from plants of the Panax genus, demonstrating broad-spectrum pharmacological efficacy encompassing antitumor, immunomodulatory, anti‑inflammatory, anti‑allergic, anti‑atherosclerotic, antihypertensive, antidiabetic, antistress, and neuroprotective activities. Ginsenosides exert their neuroprotective effects against AD, PD, and ALS predominantly through the modulation of ferroptosis. Herein, this article provides a review of the molecular mechanisms, genetic determinants, signaling cascades, and functional implications of ferroptosis. Ginsenosides represent promising therapeutic agents in neurodegenerative diseases via modulation of iron homeostasis; this paper elucidates mechanistic insights into disease pathogenesis and evaluates their translational therapeutic potential. This narrative review highlights emerging insights that provide novel therapeutic perspectives for neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Ferroptosis; Ginsenosides; Huntington’s disease; Multiple sclerosis; Neurodegenerative disease; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s11033-026-12673-2
  8. Acta Neuropathol Commun. 2026 Sep 01. pii: 182. [Epub ahead of print]14(1):
    A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases.
    Leonie Sowoidnich, Aaron L Norman, Florian Gerstner, Josiane K Siemund, Jannik M Buettner, John G Pagiazitis, Vanessa Dreilich, Konstantin Pilz, Dajun Tian, Charlotte J Sumner, Angela Paradis, George Z Mentis, Christian M Simon.
      Motor neuron (MN) loss is a hallmark of neurodegenerative disorders, yet its assessment remains variable, confounding mechanistic and therapeutic interpretation. To address this, we conducted a systematic review and meta-analysis of spinal muscular atrophy (SMA) mouse studies, revealing 60% variability in reported MN loss, for which spinal cord sampling emerged as a major contributor. Using a whole-segment approach with tissue clearing, MN tracing, and multimodal imaging, we confirmed segment-dependent differences in MN counts. Common MN markers (SMI-32, Nissl) lacked specificity, whereas choline acetyltransferase (ChAT) provided robust labeling in murine and human spinal cords. Deep learning-based whole-mount segmentation enabled unbiased MN quantification and validated manual counts. Integrating analysis with computational modeling established segment sampling as a key driver of variability and revealed degeneration patterns: widespread MN loss in amyotrophic lateral sclerosis (ALS), selective MN loss in severe SMA, and preservation in mild SMA models. These findings establish a framework for reproducible MN quantification.
    Keywords:  4-copy SMN2 Type III-like SMA; Amyotrophic lateral sclerosis; Motor neuron diseases; Motor neuron quantification; Neurodegeneration; SMN∆7; SOD1-G93A; Spinal cord; Spinal muscular atrophy
    DOI:  https://doi.org/10.1186/s40478-026-02415-7
  9. Mol Biol Rep. 2026 Sep 01. pii: 1504. [Epub ahead of print]53(1):
    Whole-exome sequencing reveals a novel frameshift and a recurrent nonsense SPG11 variant causing rare familial amyotrophic lateral sclerosis type 5 in two consanguineous Pakistani families.
    Riaz Ahmad, Muhammad Naeem, Henry Houlden.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both upper and lower motor neurons, disturbing communication between the brain and muscles. So far, few reports have been published for the SPG11-associated ALS, and this is the first documented case from Pakistan.  METHODS: We report a rare subtype of ALS with an autosomal recessive mode of inheritance with juvenile onset before 25 years of age in the five affected individuals from two unrelated families. Whole-exome sequencing was performed to identify disease-causing variants, and selected variants were further prioritized based on predicted pathogenicity and similarity to clinical phenotypes.
    RESULTS: Two homozygous variants within the SPG11 gene were identified as pathogenic according to the ACMG and ClinGen Sequence Variant Interpretation (SVI) Working Group recommendations: a novel truncation (NM_025137.4:c.6738dup, p.Glu2247Ter) variant as validated by Sanger sequencing and a recurrent nonsense (NM_025137.4: c.782C>A, p.Ser261Ter) variant (rs765477482) previously reported in a family affected with autosomal recessive hereditary spastic paraplegia (ARHSP). In silico prediction tools further confirmed their pathogenicity.
    CONCLUSION: Five patients with juvenile-onset ALS born to consanguineous parents were found to have homozygous SPG11 gene variants. Our findings describe the overlapping phenotypes ofSPG11-related autosomal recessive juvenile ALS and ARHSP, suggesting that these disorders show a clear overlapping phenotype with common genetic defects. In clinical practice, it is challenging to distinguish between these two disorders. Additional Mendelian cases should be included to clarify further and investigate whether these represent two diverse diseases caused by variants in a single gene.
    Keywords:   SPG11 ; Amyotrophic lateral sclerosis; Exome sequencing; Hereditary spastic paraplegias; Spatacsin
    DOI:  https://doi.org/10.1007/s11033-026-12618-9
  10. CNS Neurol Disord Drug Targets. 2026 Aug 24.
    Cortisol Dysregulation as a Major Factor in the Development of Neurodegenerative Diseases, Drug Targets and Therapeutic Prospects: A Comprehensive Review.
    Reza Hooshyari Ardakani, Mohadeseh Dashtaki, Seyed-Mahdi Mohamadi-Zarch, Seyyed Majid Bagheri.
      Cortisol, regulated by the hypothalamic-pituitary-adrenal (HPA) axis, is critical for stress response, metabolism, and immune function. Its dysregulation is increasingly implicated in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). This review synthesizes evidence on cortisol's role in neurodegenerative disorders, exploring its mechanisms, clinical implications, and therapeutic potential. This study analyzed preclinical models, clinical studies, and biomarker data to elucidate cortisol's impact on neurodegeneration. Key mechanisms include glucocorticoid and mineralocorticoid receptor-mediated effects on synaptic plasticity, neuroinflammation, and oxidative stress. In AD, elevated cortisol accelerates cognitive decline, hippocampal atrophy, and amyloid-β accumulation. In PD, higher cortisol levels correlate with gait dysfunction and dopaminergic neuron loss. HD shows variable cortisol profiles, with early hypocortisolism shifting to hypercortisolism in later stages, linked to depression. In ALS, elevated cortisol hastens disease progression and neuroinflammation. In MS, HPA axis hyperactivity is associated with cognitive deficits and lesion activity, though it may support remyelination. Chronic stress exacerbates these effects across disorders, promoting neuronal vulnerability. Cortisol dysregulation is a significant contributor to neurodegenerative pathology, acting as both a biomarker and therapeutic target. Emerging interventions, including glucocorticoid receptor antagonists, cortisol synthesis inhibitors, and stress reduction strategies, show promise in mitigating neuronal damage. Personalized, stage-specific therapies and longitudinal studies are needed to optimize cortisol-targeted treatments for neurodegenerative diseases.
    Keywords:  Cortisol; HPA axis; and therapeutic targets; glucocorticoid receptors; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.2174/0118715273466502260813092749
  11. J Clin Neuromuscul Dis. 2026 Sep 01. 28(1): 33-46
    Proteomic and Functional Signatures of Phenoconversion in Presymptomatic Amyotrophic Lateral Sclerosis.
    Steven Lehrer, Peter H Rheinstein.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) likely has a prolonged presymptomatic phase. Identifying blood biomarkers that predict phenoconversion is critical for early intervention.
    METHODS: We analyzed baseline serum proteomics in 270 UK Biobank participants who later developed ALS. A prespecified 19-protein panel was evaluated in relation to time-to-diagnosis. C9orf72 risk was proxied using rs10757668 genotype.
    RESULTS: Neurofilament light rose sharply in the 2-3 years preceding diagnosis (r = -0.37, P < 0.001). Muscle-stress markers, including EDA2R and MYL3, increased earlier, up to 4-6 years before onset. Higher EDA2R levels were associated with reduced grip strength at baseline. A combined 19-protein panel plus genotype predicted phenoconversion within 3 years with an area under the receiver operating characteristic curve of 0.77, outperforming neurofilament light alone.
    CONCLUSIONS: ALS exhibits a measurable molecular prodrome detectable in blood years before diagnosis. Integrated proteomic and genetic profiling may support early identification and trial enrichment strategies.
    Keywords:  C9orf72; UK Biobank; amyotrophic lateral sclerosis; phenoconversion; proteomics
    DOI:  https://doi.org/10.1097/CND.0000000000000567
  12. Acta Neuropathol. 2026 Sep 04. pii: 29. [Epub ahead of print]152(1):
    Familial, neuropathological and cellular analysis identify ARPP21 as a major amyotrophic lateral sclerosis associated gene in French cohorts.
    Brainbank Neuro-CEB neuropathology network
      ARPP21 has recently emerged as a new amyotrophic lateral sclerosis (ALS) associated gene but its pathogenic role remains unclear. In this study we performed familial, clinical, neuropathological and cellular analyses to characterize the recurrent p.P529L and p.P713L variants (also known as p.P563L variant and p.P747L variant, respectively) in our French ALS cohort of 1190 ALS cases and 50 additional family members available for segregation analysis, resulting in the description of 29 ARPP21-linked patients. ARPP21 emerged as the most frequent rare ALS-associated gene in France after exclusion of the four major ALS genes, accounting for 2.7% of familial cases (fALS) and 0.1% of sporadic cases. Age-dependent penetrance reached 45% by age 50 and increased only modestly thereafter, remaining incomplete even at advanced ages. In cellular models, the p.P713L mutant showed aggregation associated with protein hyperphosphorylation and colocalization with the autophagic marker p62. Neuropathological examination of tissue from a p.P529L carrier revealed typical cytoplasmic TDP-43 pathology, together with heterogeneous ARPP21-positive deposits. As ARPP21 antibody also stained granulovacuolar degenerations, ARPP21-positive deposits may reflect neuronal stress rather than mutant ARPP21-specific pathology. Nevertheless, together with previous studies, our findings support ARPP21 as an important ALS-associated gene, and indicate that both p.P529L/p.P563L and p.P713L/p.P747L should be considered pathogenic ALS-causing variants. Incorporating ARPP21 into the routine genetic testing panels for fALS could improve diagnostic yield.
    Keywords:   ARPP21 gene variants; ALS genetics; Aggregation; Hyperphosphorylation; RNA binding protein; TDP-43 neuropathology; miR128-2
    DOI:  https://doi.org/10.1007/s00401-026-03075-6
  13. Front Genet. 2026 ;17 1860828
    Amyotrophic lateral sclerosis -plus patient with an intermediate-length CACNA1A allele: a Case Report.
    Xinyao Gao, Tingting Wang, Sihui Chen, Yuanzheng Ma, Qianqian Wei, Chunyu Li, Huifang Shang, Xueping Chen.
      Amyotrophic lateral sclerosis (ALS), the most common type of motor neuron disease, primarily manifests as progressive weakness, atrophy, fasciculations, bulbar palsy, and pyramidal tract symptoms. Accumulating evidence indicates that the pathological spectrum of ALS extends beyond the pyramidal and neuromuscular motor systems, involving additional brain regions, manifesting as ALS-plus syndrome. We present a case of an elderly woman with bulbar-onset ALS accompanied by cerebellar manifestations and an intermediate-length CACNA1A allele. Based on the Gold Coast criteria, ALS diagnosis was made. Notably, the patient exhibited cognitive impairment and a positive Romberg sign, suggesting a broader phenotypic spectrum. Genetic analysis showed a CAG repeat genotype of 10/20 in the CACNA1A gene. The patient's son carried a 14/20 genotype and displayed isolated cerebellar ataxia without motor neuron features. We reviewed the literature on spinocerebellar ataxia (SCA) co-occurring with motor neuron disease and discussed the uncertain significance of the intermediate-length CACNA1A allele in this context, weighing coincidental co-occurrence against a potential causal link. To our knowledge, this case is the first reported instance of an intermediate-length CACNA1A allele co-occurring with ALS in Chinese population, although the association between the allele and ALS remains unclear.
    Keywords:  ALS-plus syndrome; CACNA1A gene; CAG repeats; SCA; amyotrophic lateral sclerosis; spinocerebellar ataxia
    DOI:  https://doi.org/10.3389/fgene.2026.1860828
  14. Eur J Neurol. 2026 Sep;33(9): e70741
    Protein Biomarkers in Risk and Prognosis of Amyotrophic Lateral Sclerosis.
    Lu Pan, Can Hou, Christina Seitz, Caroline Ingre, Åsa K Hedman, Jose Laffita, Trung Nghia Vu, Yudi Pawitan, Abbe Ullgren, Solmaz Yazdani, John Andersson, Emily E Joyce, Charilaos Chourpiliadis, Anikó Lovik, Yan Chen, Sebastian A Lewandowski, Oscar Fernandez-Capetillo, Myriam Barz, Kristin Samuelsson, Rayomand Press, Fredrik Piehl, Caroline Graff, Anders Mälarstig, Fang Fang.
       BACKGROUND: Plasma and cerebrospinal fluid (CSF) protein biomarkers in amyotrophic lateral sclerosis (ALS) may provide insight into disease mechanisms and yield clinically useful biomarkers.
    METHODS: Overall, 363 proteins in plasma and CSF from 198 patients with ALS and 125 matched controls were profiled using Olink assays. Associations with disease status, survival, and functional decline, as well as longitudinal biomarker stability across the disease course were assessed, together with network and enrichment analyses. ALS risk-associated biomarkers were externally validated in the UK Biobank (UKB).
    RESULTS: Overall, 125 proteins were significantly associated with at least one outcome (i.e., case status, risk, survival, or functional decline), and 21 were associated with three or more outcomes. NEFL was the most robust biomarker in plasma and CSF, alongside TNFRSF12A in plasma and CSF, EDA2R in plasma, and FABP4 in plasma and CSF. Most biomarkers remained stable longitudinally across the disease course. ALS risk-associated biomarkers were replicated in UKB, in which > 3000 plasma proteins were measured in 52,990 participants, including 298 with ALS. Network and enrichment analyses highlighted their roles in immune response and extracellular-matrix remodeling, and their enrichments in the brain and T-cell subsets. Construction of an ALS risk-prediction model achieved an ROC-AUC of 0.72 in the UKB validation cohort.
    CONCLUSIONS: These findings suggest candidate protein biomarkers for ALS risk stratification, early detection, and clinical therapeutic monitoring.
    Keywords:  ALS; Olink; diagnosis; prognosis; proteins
    DOI:  https://doi.org/10.1111/ene.70741
  15. Front Cell Dev Biol. 2026 ;14 1899307
    Disrupted astrocyte-neuron metabolic coupling in amyotrophic lateral sclerosis.
    Áine Bríd Heffernan, Florence Do, Eleanor Carter, Farah Al-Tameemi, Bhuvaneish T Selvaraj, Maria Stavrou.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by progressive loss of motor neurons. In addition to neurodegeneration, ALS is increasingly recognised as a disorder associated with widespread metabolic dysfunction, including hypermetabolism, weight loss, and dyslipidaemia, all of which correlate with disease progression and survival. Astrocytes play a central role in maintaining metabolic homeostasis in the central nervous system by supporting neuronal energy demands, regulating glutamate levels, buffering oxidative stress, and maintaining lipid balance. Emerging evidence suggests that disruption of these supportive astrocytic functions may contribute directly to motor neuron vulnerability in ALS. In this mini-review, we discuss how alterations in astrocyte metabolism may impair astrocyte-neuron metabolic coupling in ALS. We summarise work from human studies and experimental models demonstrating abnormalities in astrocytic glycolysis, mitochondrial function, lactate shuttling, lipid metabolism, and glutamate homeostasis. We highlight growing evidence implicating mitochondrial dysfunction and impaired lipid handling in astrocytes as important contributors to disease progression. We explore how these changes may deprive motor neurons of metabolic and antioxidant support while also promoting excitotoxicity, oxidative stress, and lipotoxicity. We also discuss how recent advances in human induced pluripotent stem cell models, metabolomics, and single-cell transcriptomics are improving our understanding of astrocyte dysfunction in ALS. Finally, we consider current and emerging therapeutic strategies aimed at restoring astrocytic metabolic function. Together, these findings support the idea that progressive failure of astrocyte-mediated metabolic support is an important component of ALS pathogenesis and may represent a promising therapeutic target.
    Keywords:  amyotrophic lateral sclerosis; astrocyte; bioenergetics; cell crosstalk; metabolism; neuron
    DOI:  https://doi.org/10.3389/fcell.2026.1899307
  16. Muscle Nerve. 2026 Aug 30.
    Military Service and Survival Among Persons With ALS in the U.S. National ALS Registry, 2011-2023.
    D Kevin Horton, Jaime Raymond, Theodore Larson, Marc G Weisskopf, Ileana Howard, Paul Mehta.
       INTRODUCTION/AIMS: Military service has been associated with increased risk of amyotrophic lateral sclerosis (ALS) but less is known about survival after diagnosis. We evaluated the association between military service and survival after ALS diagnosis among U.S. National ALS Registry participants.
    METHODS: Participants who completed the Registry's Military History Survey between 2011 and 2023 and had valid ALS diagnosis and mortality follow-up information were eligible. Military service was classified as veteran or nonveteran. Mortality was ascertained through National Death Index linkage. Kaplan-Meier methods evaluated survival distributions, and Cox proportional hazards models estimated adjusted mortality associations.
    RESULTS: Among 8643 participants, 1735 (20.1%) were veterans and 6908 (79.9%) were nonveterans. Veterans were older at diagnosis and reported greater smoking and alcohol use. The median observed time from ALS diagnosis to death or censoring was 3.77 years among veterans and 4.79 years among nonveterans, an approximate 1-year difference; Kaplan-Meier estimated 5-year survival was 47.1% and 57.4%, respectively. Veterans experienced significantly poorer survival than nonveterans (log-rank χ2 = 113.45, p < 0.0001). In the primary adjusted Cox model, military service remained associated with increased mortality (HR 1.25, 95% CI 1.15-1.35; p < 0.0001). Findings were consistent across sensitivity analyses accounting for disease severity, symptom onset site, and delayed Registry entry.
    DISCUSSION: Military service was associated with poorer survival after ALS diagnosis. Veterans had lower 5-year survival and higher mortality hazards than nonveterans, suggesting military history may be an important prognostic factor in ALS.
    Keywords:  National ALS Registry; amyotrophic lateral sclerosis; military service; survival; veterans
    DOI:  https://doi.org/10.1002/mus.70390
  17. Neurol Res Pract. 2026 Sep 02. pii: 73. [Epub ahead of print]8(1):
    Implementation of specialised care improves survival in patients with amyotrophic lateral sclerosis.
    Omar Keritam, Daniel Bormann, Friedrich Haimberger, Diana Gharib, Merve Sener, Felix Gruber, Lukasz Antoniewicz, Ivan Fedak, Andreas Renner, Bernhard Fasching, Sabine Ullrich, Rafael Paternostro, Werner Dolak, Eva K Masel, Othmar Schuhfried, Jakob Rath, Gudrun Zulehner, Martin Krenn, Fritz Zimprich, Hakan Cetin.
       OBJECTIVE: Access to multidisciplinary care influences survival in patients with amyotrophic lateral sclerosis (pwALS). However, real-world data comparing structured specialised care with general neurological management remain limited. We aimed to assess the influence of implementing a specialised outpatient clinic on survival in pwALS.
    METHODS: This retrospective cohort study included pwALS meeting the Gold Coast criteria who were treated at the Department of Neurology of the Medical University of Vienna between January 2009 and July 2023. Demographic and clinical parameters and survival data were obtained from the local ALS registry, the Austrian Federation of Social Insurance databases, and the national mortality database of Statistik Austria. Data were censored in December 2024. Outcomes were compared between patients managed before (general care cohort) and after the establishment of a specialised ALS outpatient clinic in 2018 (specialised care cohort).
    RESULTS: A total of 242 pwALS were included (47.5% female), of whom 43.8% received general neurological care and 56.2% specialised care. Spinal onset ALS was observed in 65.1% and 70.6%, respectively. Baseline demographic and clinical characteristics were comparable between both cohorts. Median survival time was 27.0 months (95% CI 23.0-35.0) in the general care cohort and 40.0 months (95% CI 32.0-47.0) in specialised care cohort (p = 0.0173). This survival difference was driven by patients with spinal onset ALS, whereas no benefit was observed in those with bulbar onset disease.
    CONCLUSIONS: Specialised care was associated with improved survival in this real-world ALS cohort, likely reflecting the cumulative effect of coordinated multidisciplinary management rather than individual interventions.
    Keywords:  ALS; Amyotrophic lateral sclerosis; Motor neuron disease; Multidisciplinary care
    DOI:  https://doi.org/10.1186/s42466-026-00528-x
  18. Ann Clin Transl Neurol. 2026 Aug 30.
    Data-Driven SuStaIn Model of Disability Progression in Amyotrophic Lateral Sclerosis.
    Giammarco Milella, Veria Vacchiano, Vittorio Velucci, Stefano Zoccolella, Rocco Liguori, Giovanni Defazio.
       OBJECTIVE: To determine whether ordinal Subtype and Stage Inference (SuStaIn) applied to routine ALSFRS-R item scores can identify reproducible disability progression patterns in amyotrophic lateral sclerosis (ALS) and provide clinically meaningful staging.
    METHODS: We analysed baseline ALSFRS-R item responses from 866 PRO-ACT participants. Ordinal SuStaIn inferred subtype-specific sequences of functional deterioration and assigned each participant to a subtype and a SuStaIn-derived functional stage. Longitudinal stability was assessed across 3625 consecutive follow-up visit pairs from 697 participants. Structural reproducibility was evaluated in an independent cohort of 301 consecutive ALS patients. Associations of baseline subtype and stage with survival and subsequent ALSFRS-R decline were examined using Cox and piecewise-linear models.
    RESULTS: A three-subtype solution identified fine motor-, gross motor- and bulbar-predominant patterns of early disability. Within each subtype, SuStaIn reconstructed ordered multidomain sequences of functional deterioration and assigned each participant a SuStaIn-derived stage. Subtype assignment was stable across 90.4% of consecutive visit pairs, and stage was non-decreasing in 98.8%. Subtype-specific event ordering was reproduced in the validation cohort. Higher baseline stage was associated with increased mortality risk in the fine motor- and gross motor-predominant subtypes, but not clearly in the bulbar-predominant subtype. Baseline stage showed subtype-dependent, non-linear associations with subsequent functional decline, with acceleration up to mid-stage breakpoints in the fine motor- and gross motor-predominant subtypes and less evident stage-dependent acceleration in the bulbar-predominant subtype.
    INTERPRETATION: Routine ALSFRS-R item-level data can define clinically interpretable ALS progression subtypes and latent SuStaIn-derived functional stages. Joint subtype-stage modelling may refine prognostic stratification and support prognosis-informed trial enrichment.
    Keywords:  SuStaIn; clinical trials; functional phenotyping; latent variable modelling; motor neuron disease
    DOI:  https://doi.org/10.1002/acn3.70519
  19. Zh Nevrol Psikhiatr Im S S Korsakova. 2026 ;126(8): 13-20
    [Atypical forms of amyotrophic lateral sclerosis].
    E E Arbuzova, N E Seksyaev, Yu V Karakulova, N V Selyanina, M A Danilova.
      This article provides a comprehensive overview of contemporary concepts regarding the classical and atypical phenotypes of amyotrophic lateral sclerosis (ALS), with a particular focus on critical diagnostic challenges. The classical variant of the disease is characterized by the progressive involvement of both upper and lower motor neurons, typically presenting with an asymmetric onset and a predictable progression. However, several atypical phenotypes are identified, including syndromes predominantly affecting the lower motor neurons, such as the «hanging hands» and «hanging legs» syndromes, isolated bulbar paralysis, ALS with respiratory onset, and forms with a predominance of upper motor neuron involvement. These atypical variants often mimic other neurological conditions-such as cervical myelopathy, multifocal motor neuropathy, and myasthenia gravis-which can result in significant delays in the accurate diagnosis of ALS. Atypical forms of ALS represent a major source of diagnostic errors in clinical practice. Enhancing healthcare professionals' understanding of the spectrum of phenotypic presentations, alongside the application of contemporary diagnostic criteria, facilitates more timely diagnoses, optimized patient care pathways, and the prompt initiation of pathogenetic therapies, ultimately improving both survival rates and quality of life for affected individuals.
    Keywords:  amyotrophic lateral sclerosis; atypical phenotypes; clinical heterogeneity; motor neuron disease
    DOI:  https://doi.org/10.17116/jnevro202612608113
  20. Muscle Nerve. 2026 Sep 04.
    Serum Neurofilament Light Chain and GFAP in Amyotrophic Lateral Sclerosis on a Commercial ECLIA Platform.
    Nicholas S Streicher.
       INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS), SIMOA-based studies show that baseline serum neurofilament light chain (NfL) predicts the revised ALS Functional Rating Scale (ALSFRS-R) decline rate and survival. The Roche Elecsys electrochemiluminescence immunoassay (ECLIA) reports values approximately six-fold lower; cross-platform comparison confirms comparable performance, but serial clinical-practice data remain limited. We assessed whether ECLIA NfL correlates with the ALSFRS-R decline rate under the sampling conditions of clinical practice, and whether GFAP or S-100B adds prognostic or disease-specific information.
    METHODS: We retrospectively analyzed 58 patients with medical-record-confirmed ALS at an academic center (2022-2026). Serum NfL, GFAP, and S-100B were measured on the Roche Elecsys ECLIA. The NfL-ALSFRS-R correlation was assessed within matching windows; serial NfL was examined in patients with repeat draws.
    RESULTS: First-per-patient NfL median was 7.06 pg/mL (IQR 4.06-17.30). NfL correlated strongly with the ALSFRS-R decline rate (Spearman r = 0.704, n = 31; r = 0.809 within 90 days, n = 17; both p < 0.0001). Fast progressors had 3.7-fold higher mean NfL than slow progressors (17.10 vs. 4.64 pg/mL). NfL showed no correlation with King's clinical stage (r = 0.00). GFAP correlated with age but not with progression rate or disease duration; S-100B showed no association with progression.
    DISCUSSION: Serum NfL on a commercial ECLIA platform retained its strong correlation with progression rate despite unstructured sampling, replicating SIMOA-based findings at platform-specific values. NfL tracked the rate of decline rather than the accumulated disease state; GFAP and S-100B added no prognostic or disease-specific information.
    Keywords:  ECLIA; GFAP; amyotrophic lateral sclerosis; biomarkers; clinical practice; implementation science; monitoring; neurofilament light chain; tofersen
    DOI:  https://doi.org/10.1002/mus.70397
  21. Muscle Nerve. 2026 Aug 31.
    Priorities for Advancing Palliative Care for Amyotrophic Lateral Sclerosis: A Consensus Report From a Palliative Care for ALS Working Group in the United States.
    International Neuropalliative Care Society's Palliative Care for ALS Working Group
      Until there is a cure for amyotrophic lateral sclerosis (ALS), it is imperative that everyone facing this devastating illness receives care to alleviate symptoms and suffering and improve quality of life. Emerging evidence has demonstrated benefits of palliative care for people with ALS, but palliative care is not yet widely available or accessed by people with ALS throughout the disease course. The Palliative Care for ALS Working Group was formed within the International Neuropalliative Care Society, consisting of interprofessional ALS and palliative care clinicians, researchers, advocates, and patients and care partner representatives who are committed to improving palliative care for people living with ALS. The group engaged in a strategic planning process to determine what is needed to advance palliative care for people with ALS over the next 3-5 years. This report outlines the core recommendations from that strategic planning process. Recommendations are divided into five sections: (1) clinician education, (2) clinical service expansion, (3) research, (4) public awareness, and (5) policy change. The aim of this report is to provide ALS and palliative care clinicians, researchers, ALS advocacy organizations, and funders with a road map of priority areas where dedicated focus could significantly advance palliative care for people facing ALS, with the goals of relieving suffering and improving quality of life. The Palliative Care for ALS Working Group is making concrete steps toward these priority areas and will continue to serve as a convening and coordinating body for this work.
    Keywords:  amyotrophic lateral sclerosis (ALS); clinician education; palliative care; public awareness; quality of life
    DOI:  https://doi.org/10.1002/mus.70381
  22. Behav Brain Res. 2026 Sep 04. pii: S0166-4328(26)00431-6. [Epub ahead of print] 116455
    Extracellular Vesicles in Neurodegenerative Diseases: A New Frontier in Diagnosis and Therapy.
    Suleiman Ibrahim Mohammad, Asokan Vasudevan, Ghaleb Oriquat, Tushar B Gajjar, Malathi Hanumanthayya, Sandeep Kumar Shukla, Navin Kumar Tailor, Mirza R Baig, Omar Fadaam, Amir S Abdul.
      Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the progressive disorders of the nervous system that are characterized by the gradual destruction of neurons, the accumulation of misfolded proteins, and the limited effective therapeutic options. In recent years, numerous lines of evidence have emphasized the important role of extracellular vesicles (EVs) in the formation and progression of these diseases. These vesicles are membrane-bound nanoscale structures that are secreted by almost all cell types and play a role in cell-cell communication through the transfer of molecules such as proteins, lipids, and nucleic acids. In neurodegenerative disorders, EVs can facilitate the transport and dissemination of disease-related proteins, including amyloid-β, tau, α-synuclein, mutant huntingtin, SOD1, and TDP-43, thus contributing to the spread of pathological processes in different parts of the nervous system. On the other hand, the ability of these vesicles to cross the blood-brain barrier and reflect molecular changes occurring in the central nervous system makes them valuable candidates for the development of minimally invasive biomarkers. This review reviews the biogenesis, classification, isolation methods, and molecular content of EVs, and analyzes their role in the pathogenesis, diagnosis, and treatment of the most important neurodegenerative diseases. Also, the importance of EV-associated proteins, RNAs, and lipids as emerging diagnostic biomarkers, as well as the therapeutic potential of natural and engineered vesicles as drug delivery systems and regulators of neuroinflammation and neurodegenerative processes, is discussed.
    Keywords:  Alzheimer’s disease; Biomarkers; Drug delivery; Extracellular vesicles; Neurodegenerative diseases; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.bbr.2026.116455
  23. Front Mol Neurosci. 2026 ;19 1921079
    From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases.
    Qiaoqiao Cui, Ke Zheng, Qiyun Liu, Lizhen Wang, Yixin Liu, Ruifang Bai, Wei Zhang, Junhong Guo, Xueli Chang, Juan Wang.
      Microglia are brain-resident myeloid cells that maintain central nervous system homeostasis and respond dynamically to neuronal injury, protein aggregation, and alterations in the local metabolic environment. Single-cell and single-nucleus studies demonstrate that microglial responses in neurodegenerative diseases are highly heterogeneous and cannot be adequately explained by the classical M1/M2 polarization model. Increasing evidence further indicates that metabolic remodeling is not merely a consequence of activation but a determinant of microglial migration, phagocytosis, inflammatory signaling, redox balance, organelle function, and interactions with surrounding neural cells. In this review, we propose a microglial immunometabolic trajectory framework in which metabolic states are viewed as branching and potentially reversible determinants of cellular function rather than fixed stages of a universal disease pathway. We summarize how glucose metabolism, mitochondrial function, lipid metabolism, amino acid metabolism, lysosomal activity, and redox regulation shape microglial plasticity. We further examine relationships among transcriptionally defined states, including disease-associated microglia, microglia associated with neurodegeneration, lipid-droplet-accumulating microglia, and other disease-enriched populations, while emphasizing that transcriptional similarity does not necessarily imply metabolic function or lineage progression. Comparative evidence from Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis indicates that common metabolic regulators, including HIF-1α, mTOR, PKM2, TREM2, APOE, and NLRP3, exert disease-specific effects with unequal mechanistic support. We further distinguish associative metabolic signatures from intervention-based causal evidence and discuss limitations of animal models, immortalized cell lines, postmortem tissue, and induced pluripotent stem cell-derived microglia. Finally, we highlight the need for cell-specific, state-resolved, and temporally precise metabolic interventions that restore defined microglial functions without compromising physiological immune surveillance.
    Keywords:  amino acid metabolism; disease-associated microglia; glucose metabolism; immunometabolism; lipid metabolism; microglia; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnmol.2026.1921079
  24. Brain Behav. 2026 Sep;16(9): e71740
    CSF Tau and Amyloid Biomarkers in Cognitive Impairment Across the ALS-FTD Spectrum: A Systematic Narrative Review and Evidence Map.
    Aasim Ali, Muhammad Arif, Usama Ashraf, Saad Elahi, Aswad Mustafa, Mahad Bin Yasir, Waqar Sarfraz, Asad Ullah Ansari, Hafiz Muhammad Yousaf Masood, Muhammad Asad Shabbir, Armaghana Abdullah, Mukesh Kumar Sharma.
       INTRODUCTION: Cognitive impairment is an important non-motor manifestation of amyotrophic lateral sclerosis (ALS), particularly across the ALS-frontotemporal dementia (ALS-FTD) spectrum. Cerebrospinal fluid (CSF) tau and amyloid biomarkers may reflect nonspecific neurodegenerative injury, concomitant Alzheimer disease (AD) pathology, or distinct cognitive phenotypes. However, available evidence remains limited, fragmented, and methodologically heterogeneous.
    METHODS: This systematic narrative review and semi-quantitative evidence map was conducted according to PRISMA 2020 recommendations. PubMed, Scopus, Web of Science, and Google Scholar were searched from database inception through May 2026. Eligible observational studies reported cognition-specific associations between CSF tau, amyloid, or related neurodegenerative biomarkers and cognitive outcomes in ALS-spectrum populations. Two reviewers independently screened studies, extracted quantitative effect estimates, and assessed risk of bias using the Newcastle-Ottawa Scale. Cross-study consistency was summarized using an exploratory semi-quantitative evidence-coding framework.
    RESULTS: Four observational studies comprising 638 ALS-spectrum participants fulfilled the eligibility criteria. Total tau and p-tau181 showed the most reproducible associations with cognition. Total tau correlated with ECAS total (r = -0.398, P < 0.001) and ALS-specific cognition (r = -0.403, P < 0.001), while adjusted multicenter analyses demonstrated associations between p-tau181 and ECAS total (β = -0.03, p = 0.006) and memory performance (β = -0.04, p = 0.003). Both biomarkers received ++ evidence-map coding. Amyloid findings were more heterogeneous; lower Aβ42/Aβ40 was associated with poorer memory performance (β = 0.20, p = 0.044), but continuous amyloid-cognition associations were not consistently replicated across cohorts (± evidence). Broader CSF protein-ratio findings remained exploratory. Clinical, cognitive, assay, and analytical heterogeneity precluded meta-analysis.
    CONCLUSIONS: The available evidence, although limited and heterogeneous, suggests that total tau may primarily reflect broader neurodegenerative injury, whereas p-tau181 and Aβ42/Aβ40 may be more informative for selected cognitive phenotypes or possible AD co-pathology. These biomarkers should remain research tools until larger, standardized, longitudinal multicenter studies establish their pathological specificity, predictive value, and clinical utility.
    Keywords:  Tau protein; amyloid biomarkers; amyotrophic lateral sclerosis; cognitive impairment; frontotemporal dementia
    DOI:  https://doi.org/10.1002/brb3.71740
  25. Methods Mol Biol. 2026 ;3049 317-325
    Blood-Brain Barrier Disruption and Edema in Xenopus: Methods for Analysis.
    Sydnee Spruiell Eldridge, Amy K Sater.
      The blood-brain barrier (BBB) isolates the brain from pathogens, toxins, and environmental compounds, and it preserves homeostatic control of the neural microenvironment. Thus, it is critical for normal function of the central nervous system throughout vertebrates and in many invertebrate taxa. Disruption or leakage at the BBB is a hallmark of neural injury and many neurodegenerative disorders. This chapter offers a method to assess the integrity of the BBB in live Xenopus tadpoles, by examining the spread of fluorescein introduced by intraventricular injection. Edema often accompanies disruption of the BBB, appearing as an increase in the amount of water present in brain tissue. The chapter, therefore, also includes a method for quantifying brain water weight, which can then be used to evaluate edema. These protocols should be useful for studies modeling neurodegenerative or neurodevelopmental disorders in amphibians.
    Keywords:  Blood–brain barrier; Brain; Edema; Protocol; Xenopus
    DOI:  https://doi.org/10.1007/978-1-0716-5360-9_14
  26. Neurol Ther. 2026 Aug 31.
    Artificial Intelligence in Neuromuscular Diseases: Opportunities for a Data-Scarce Field.
    Shang Ma, Sushan Luo, Huahua Zhong.
      Neuromuscular diseases (NMDs) encompass over 800 distinct entities affecting approximately one in 1000 individuals worldwide, with progressive muscle weakness, atrophy, and motor impairment as primary clinical manifestations. The rarity of most NMDs creates fundamental challenges for artificial intelligence (AI) and machine learning (ML) applications that typically require large-scale datasets. In this narrative review we synthesize the literature published between 2018 and 2025 on AI applications across the NMD spectrum, organized by clinical application domain. We examine how AI has advanced diagnostic capabilities through genetic variant interpretation, muscle magnetic resonance imaging analysis, electromyography-based classification, and computational pathology. In disease monitoring and prognosis, wearable-derived digital biomarkers have achieved regulatory qualification (US Food and Drug Administration [FDA] and European Medicines Agency [EMA]) as clinical trial endpoints for Duchenne muscular dystrophy, while AI-driven survival models for amyotrophic lateral sclerosis (ALS) have been validated across 14 European centers. Proteomic and multi-omics analyses using ML have identified diagnostic panels for ALS. However, most reported models were developed and internally validated on single-center datasets, and few have undergone external or prospective validation or clinical implementation. Despite these achievements, research intensity varies dramatically across NMD subtypes, with ALS and Duchenne muscular dystrophy dominating while myotonic dystrophy, congenital myopathies, and metabolic myopathies remain virtually unexplored. Critical gaps persist in computational pathology, multi-center validation, and clinical translation. In this review, we discuss how federated learning, international collaborative networks (TREAT-NMD, Solve-RD, EURO-NMD), and foundation models can address these challenges, and propose directions for future AI-enhanced clinical studies in this data-scarce field.
    Keywords:  Artificial intelligence; Clinical decision support; Digital biomarkers; Federated learning; Machine learning; Neuromuscular diseases; Rare diseases
    DOI:  https://doi.org/10.1007/s40120-026-01017-8
  27. Neurotherapeutics. 2026 Sep 04. pii: S1878-7479(26)00232-1. [Epub ahead of print]23(5): e01062
    Pharmacological modulation with the LXR agonist T0901317 attenuates motor pathology in the SOD1G93A mouse model of ALS.
    Luis C Fernández-Beltrán, Irene García-Toledo, Karen Javaloyes García, Irene Jiménez-Coca, Jesús Jiménez-Rodríguez, Anna Fernández-Bernal, Juan M Godoy-Corchuelo, Manuel Portero-Otín, Silvia Corrochano.
      Dysregulation of cholesterol metabolism and neuroinflammation are critical drivers of Amyotrophic Lateral Sclerosis (ALS) pathology. Liver X receptors (LXRs) are master regulators of cholesterol homeostasis and immune responses. Here, we evaluated the therapeutic potential of chronic pharmacological modulation using the potent synthetic agonist T0901317 (T0) in the hSOD1G93A mouse model. To assess both long-term functional outcomes and the underlying molecular mechanisms, T0 was administered via two distinct experimental designs. In a longitudinal cohort treated from postnatal day 60 (P60) until the humane endpoint, T0-treated SOD1G93A mice exhibited delayed body weight loss and sustained improvements in neuromuscular strength and motor coordination. Critically, this continuous treatment preserved functional motor unit connectivity, delayed overall clinical progression, and significantly extended median lifespan. While protective in both sexes, the survival benefit was slightly more pronounced in females. Molecular characterization revealed that the early systemic T0 administration successfully engaged canonical LXR targets in the spinal cord, driving a significant transcriptional upregulation of cholesterol efflux pathways and suppressing pro-inflammatory signaling cascades. This response induced a lipid partitioning, evidenced by a significant accumulation of cholesterol esters within the central nervous system, potentially mitigating lipotoxicity. Taken together, these findings demonstrate that T0901317 treatment exerts a significant beneficial effect, highlighting the pharmacological modulation of these lipid and inflammatory networks as a promising therapeutic strategy for ALS.
    Keywords:  Amyotrophic lateral sclerosis; Cholesterol metabolism; Liver X receptor; Neuroinflammation; SOD1
    DOI:  https://doi.org/10.1016/j.neurot.2026.e01062
  28. Healthc Technol Lett. 2026 Jan-Dec;13(1):13(1): e70097
    ALSGate: An Efficient Gated Mixture-of-Experts Model for Reliable ALS Detection Using EMG Signals.
    Sandipa Chowdhury, Sudipto Pramanik, Sudha Bhattacharjee, Motasim Billah.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons, resulting in neuromuscular weakness and paralysis. Electromyography (EMG) is of vital importance for the detection of ALS. In this paper, a refined mixture of experts is proposed that automatically discriminates ALS patients from non-ALS cases using clinical EMG signals from the N2001 EMGLAB open-access dataset. The architecture consists of a 1D convolutional neural network, a temporal convolutional network and a spectrogram-based CNN to collectively learn localised temporal, long-range temporal and spectral features from EMG activity. A gating mechanism dynamically weights expert contributions and performs significantly better than equal-weight fusion. Training with focal loss and exponential moving average stabilisation addresses class imbalance and improves convergence. The proposed approach reached an AUROC of 0.9992, an F1-score of 0.9903 and a balanced accuracy of 0.9905, demonstrating strong discriminative performance and potential for real-time clinical applications.
    Keywords:  amyotrophic lateral sclerosis (ALS); electromyography (EMG); exponential moving average (EMA); focal loss; mixture of experts (MoE); spectrogram‐based CNN; temporal convolutional network (TCN)
    DOI:  https://doi.org/10.1049/htl2.70097
  29. Neurobiol Dis. 2026 Aug 29. pii: S0969-9961(26)00329-3. [Epub ahead of print]229 107584
    Associations of cumulative exposure and longitudinal trajectories of neurofilament light chain with 1-year adverse events in amyotrophic lateral sclerosis: A prospective cohort study.
    Jiahui Zhu, Yuechen Zhang, Bingjie Yang, Qiaoyuan Xiang, Shuqi Hu, Wan Wei, Huixia Zhou, Gaoyi Yang, Hao Zhang.
       BACKGROUND: Baseline neurofilament light chain (NFL) predicts amyotrophic lateral sclerosis (ALS) outcomes, but it does not summarize early repeated biomarker information. We evaluated whether cumulative NFL exposure (cuNFL), calculated over an early monitoring window, and longitudinal NFL trajectory groups were associated with subsequent adverse events in a prospective cohort.
    METHODS: This prospective study enrolled patients with ALS from 32 provinces in China between January 2024 and January 2025. Plasma NFL was measured at baseline, month 1, and month 2. We used K-means clustering to describe longitudinal NFL patterns and multivariable survival models to evaluate prognostic associations. Inverse-probability weighting and causal-forest analyses were used as exploratory, confounding-adjusted analyses of high versus low cuNFL.
    RESULTS: K-means clustering identified three longitudinal NFL groups: Low-Stable (n = 183), Moderate (n = 225), and High-Progressive (n = 100). The High-Progressive group had the shortest event-free survival (P < 0.001). Each 1-SD increment in cuNFL was associated with higher odds of adverse events (adjusted OR 1.99; 95% CI 1.52-2.60; P < 0.001). Using the manuscript-defined 127-event outcome, apparent discrimination was AUC 0.730 for cuNFL and 0.717 for baseline NFL. The paired DeLong comparison was not statistically significant (P = 0.084). Exploratory machine-learning analyses suggested heterogeneity in the association of high cuNFL with outcome by age and respiratory function.
    CONCLUSION: Early repeated NFL measurements summarized as cuNFL and longitudinal trajectory groups were associated with short-term adverse events in this cohort. These findings support further external validation of longitudinal NFL-based risk stratification. They do not establish a causal biological effect or a basis for routine repeated measurement.
    Keywords:  Amyotrophic lateral sclerosis; Causal inference; Cumulative exposure; Longitudinal trajectories; Neurofilament light chain
    DOI:  https://doi.org/10.1016/j.nbd.2026.107584
  30. Caspian J Intern Med. 2026 ;17(2): 242-254
    Deep learning in imaging analysis for multiple sclerosis: Diagnosis and monitoring.
    Abdorreza Naser Moghadasi, Mahsa Owji, Nasim Rezaeimanesh.
      Multiple sclerosis (MS) is an autoimmune disease that affects various parts of the central nervous system and often occurs in young population (between 20-40 years old). Given that MS is a lifelong disease and there is currently no definitive treatment for MS, early diagnosis, initiation of treatment with the most appropriate medication, and patient monitoring are three challenging factors in determining the status of MS patients. Magnetic resonance imaging (MRI) and optical coherence tomography (OCT) are two important and useful imaging methods in all the three aspects of diagnosing, monitoring, and determining the effectiveness of treatment in MS patients. In recent years, the use of artificial intelligence in analyzing MRI and OCT data in these aspects has been rapidly increasing. In this article, we reviewed and discussed the usage of deep learning as a class of machine learning and a method of artificial intelligence for analyzing data obtained from MRI and OCT in MS patients.
    Keywords:  Deep learning; Imaging analysis; Multiple sclerosis
    DOI:  https://doi.org/10.22088/cjim.17.2.242
  31. Front Immunol. 2026 ;17 1912989
    TREM2 as a central hub of neuroimmune-metabolic crosstalk in central nervous system disorders: from microglial biology to therapeutic targeting.
    Yulu Wu, Lian Duan, Luyu Zhang, Shuting Wang, Hongmu Yan, Mingyuan He, Tao Wang, Lili Li, Yuan Gao.
      Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-enriched immunoreceptor that functions as a central regulator of microglial adaptation by integrating immune surveillance, lipid sensing, metabolic reprogramming, and phagocytic responses in the central nervous system (CNS). Through association with the adaptor protein DAP12, TREM2 activates interconnected signaling networks involving the SYK pathway, PLCγ2-mediated Ca2+ signaling, PI3K-AKT-mTOR signaling, NF-κB activation and inflammatory regulatory pathways, thereby shaping microglial survival, migration, clearance capacity, and interactions with surrounding neural and immune cells. Increasing evidence from genetic studies, single-cell transcriptomics, spatial analyses, and human-derived microglial models indicates that TREM2 dysfunction contributes to diverse CNS disorders; however, its biological consequences are highly dependent on disease stage, pathological substrate, cellular context, and microenvironmental cues. In Alzheimer's disease, TREM2 regulates amyloid-β-associated microglial responses, lipid metabolism, and synaptic remodeling, while its effects on tau-driven neurodegeneration remain controversial. In Parkinson's disease, stroke, epilepsy, and amyotrophic lateral sclerosis, TREM2 influences α-Syn clearance, inflammatory resolution, tissue repair, and microglial state transitions, but may exert beneficial or maladaptive effects depending on temporal dynamics and disease-specific stressors. Emerging clinical evidence, including TREM2 variants, soluble TREM2 (sTREM2) biomarkers, and human multi-omics studies, highlights both the translational potential and complexity of targeting this pathway. Herein, this review summarizes the molecular mechanisms, physiological functions, and disease-specific roles of TREM2 in CNS disorders, critically discusses unresolved controversies and species-specific challenges, and evaluates emerging therapeutic strategies toward biomarker-guided and stage-specific modulation of TREM2 signaling. Understanding how to restore appropriate microglial adaptability rather than simply enhance or suppress TREM2 activity may provide a foundation for precision therapies in CNS disorders.
    Keywords:  TREM2; central nervous system diseases; microglia; neuroinflammation; therapeutic targets
    DOI:  https://doi.org/10.3389/fimmu.2026.1912989
  32. Neural Regen Res. 2026 Aug 29.
    Axonal pathology and impaired axo-glial crosstalk as early drivers of neurodegeneration.
    Bastian Bues, Andrew Octavian Sasmita, Shuying Mao, Lina Komarek, Katie O'Mahony, Katja Burk.
       ABSTRACT: Axonal dysfunction is a critical event in neurodegenerative diseases, which can precede neuronal loss. For instance, in multiple sclerosis, chronic demyelination leads to axonal transection and downstream neurological deficits, yet in other neurodegenerative conditions, the causal relationship between axonal pathology and disease progression remains elusive. While defects in axonal transport, cytoskeletal integrity, and organelle trafficking are observed in Alzheimer's disease and the frontotemporal dementia-amyotrophic lateral sclerosis spectrum, a question remains: Are axonal defects merely downstream consequences of somatic neurodegeneration, or do they actively drive pathogenesis? Emerging evidence suggests that early axonal dysfunction may accelerate disease progression through disrupted connectivity, retrograde degeneration, and neuroinflammation. Here, we highlight current evidence on axonal pathophysiology across Alzheimer's disease and frontotemporal dementia-amyotrophic lateral sclerosis. We first outline the makeup of the mature axonal compartment, as well as the processes related to axonal maintenance, which include myelination, glial support, and microtubule-dependent transport mechanisms. We further compare axonal perturbations in Alzheimer's disease and frontotemporal dementia-amyotrophic lateral sclerosis, exploring commonalities as potential convergent mechanisms. Therapeutic strategies to stabilize axons by maintaining microtubule dynamics, restoring energetics, or modulating glial support could therefore theoretically offer neuroprotection if performed selectively on vulnerable neuronal subsets and early in the disease course. Ultimately, by reframing axonal pathology as a primary driver rather than an epiphenomenon, this review underscores the importance of targeting axonal health in neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; amyotrophic lateral sclerosis; axonal pathology; axons; frontotemporal dementia; glia; myelin; neuroinflammation
    DOI:  https://doi.org/10.4103/NRR.NRR-D-26-00462
  33. Clin Case Rep. 2026 Sep;14(9): e73447
    Possible Paraneoplastic Amyotrophic Lateral Sclerosis Presenting as Respiratory Failure in a Breast Cancer Patient: A Case Report.
    Maryam Albaji, Khashayar Ashkboos, Kosar Bagherzadeh.
      A 63-year-old female with metastatic breast cancer presented with acute hypercapnic respiratory failure secondary to severe diaphragmatic dysfunction and mixed upper and lower motor neuron signs. Serum onconeural and neural surface antibody panels were negative, and initial cerebrospinal fluid analysis revealed albuminocytologic dissociation. Immunotherapy with intravenous immunoglobulin (IVIG) produced no clinical improvement, necessitating invasive mechanical ventilation and gastrostomy. Applying the 2021 PNS-Care consensus criteria, the case fulfills criteria for possible paraneoplastic amyotrophic lateral sclerosis (ALS), although coincidental sporadic disease cannot be excluded. A markedly elevated erythrocyte sedimentation rate (ESR) was observed, largely attributable to skeletal metastases and localized pulmonary collapse. Clinicians must maintain a high index of suspicion for motor neuron disease in cancer patients with unexplained hypoventilation.
    Keywords:  amyotrophic lateral sclerosis; breast neoplasms; paraneoplastic syndromes; respiratory insufficiency; seronegativity
    DOI:  https://doi.org/10.1002/ccr3.73447
  34. Front Neurol. 2026 ;17 1859903
    Increased serum fibroblast growth factor 2 levels, altered peripheral blood inflammatory indicators and their ratios in amyotrophic lateral sclerosis: a clinical exploratory study.
    Xiaoting Niu, Meijuan Zhang, Huanjie Huang, Bei Shao, Xun Wang, Zhengyi Cai.
       Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration, leading to muscle weakness, atrophy, and ultimately respiratory failure. Previous research has highlighted the roles of neurotrophic factors and inflammatory responses in ALS pathogenesis; however, their interplay remains poorly understood. This exploratory study aims to elucidate the expression characteristics and correlations of fibroblast growth factor 2 (FGF2) and peripheral blood inflammatory indicators (PBIIs) such as derived neutrophil-to-lymphocyte ratio (dNLR) and systemic inflammatory response index (SIRI) in ALS patients.
    Methods: This was a prospective case-control study, involving ALS patients meeting Gold Coast diagnostic criteria and age- and sex-matched healthy controls (HCs). Serum FGF2 levels were measured using enzyme-linked immunosorbent assay (ELISA), and PBIIs were assessed through routine blood analysis. Statistical analysis was conducted mainly using intergroup comparison, correlation analysis, and multivariate linear regression.
    Results: The results showed significantly elevated levels of FGF2 and PBIIs in ALS patients compared to HCs, with strong correlations between FGF2, PBIIs, clinical staging, and disease progression rates. In multivariate linear regression analysis, PBIIs, especially SIRI, were significantly associated with disease severity and early disease progression. While serum FGF2 and FGF2 to dNLR ratio demonstrated potential as an auxiliary biomarker for later-stage disease.
    Discussion: These findings provide new insights into the molecular mechanisms underlying ALS and suggest practical diagnostic and prognostic tools, reinforcing the importance of targeting neurotrophic and inflammatory pathways in ALS management. This study holds significant promise for advancing both clinical practice and future research endeavors in the field.
    Keywords:  amyotrophic lateral sclerosis; clinical exploratory study; fibroblast growth factor 2; peripheral blood inflammatory indicators; ratio
    DOI:  https://doi.org/10.3389/fneur.2026.1859903
  35. Am J Reprod Immunol. 2026 Sep;96(3): e70317
    Feto-Maternal Microchimerism and the Brain: Mechanisms, Neurological Implications, and Translational Perspectives.
    Nosarieme O Abey.
       PROBLEM: Microchimerism in the brain is a common phenomenon, where in cells cross between mother and fetus during pregnancy, and persist for decades. It has been studied primarily within reproductive immunology and transplantation medicine. The relevance of microchimerism to central nervous system biology, neurological disease, and experimental chimeric modelling has received comparatively little systematic attention. This review sought evidence across the biology of feto-maternal microchimerism, its association with neurological disease, and the emerging field of experimental chimeric brain modelling, to extrapolate a cohesive mechanistic framework.
    METHOD: Research articles in reproductive immunology, neurodevelopment, and neurodegeneration were gathered to assess the potential roles of fetal microchimeric cells (FMc) in brain health and disease. By combining natural microchimerism with experimental chimeric models, a framework for understanding how nonself cells influence the maternal brain was extrapolated and critical mechanisms identified. Searches were conducted across PubMed/MEDLINE, Scopus, and Google Scholar using a dual-concept Boolean.
    RESULTS: The literature reviews show that microchimeric cells cross the blood-brain barrier (BBB), adopt neural and glial phenotypes in the maternal brain parenchyma, and exhibit injury-responsive recruitment in preclinical models. Reciprocally, maternal microchimeric cells (MMc) are present in the offspring brain, where they have been found adopting neural and immune-lineage phenotypes in experimental models. These findings raise the possibility that bidirectional microchimerism influences susceptibility to neurological disease, modulates neuroimmune signaling, and contributes to endogenous repair, although causal mechanisms remain unresolved. Experimental chimeric brain models have extended these principles into therapeutic contexts. Establishing the functional mechanism and directionality requires more prospective longitudinal cohort studies and transcriptional profiling at single-cell resolution in microchimeric brain-resident populations.
    Keywords:  BBB; fetal‐cells; feto–maternal; microchimerism; neuroimmunomodulations; neurological disease
    DOI:  https://doi.org/10.1111/aji.70317
  36. Neurology. 2026 Oct 13. 107(7): e218471
    Repairing the Amyotrophic Lateral Sclerosis Trial Credibility Gap.
    Michael Benatar, Jeffrey D Rothstein, Kelsie Snow, Nadia Sethi, David M Taylor, Kuldip D Dave, Christopher J McDermott, Thomas I Cochrane.
      There is a long history of early- and mid-phase amyotrophic lateral sclerosis (ALS) clinical trial data being used to make claims of clinical benefit that fail to translate into successful phase 3 outcomes. It is suggested that fallacious scientific reasoning is being encouraged by perverse incentives arising from a "clinical trial industrial complex" that greatly influences trial design, data interpretation, and results communication. Recurring fallacies include false premises underlying outcome comparisons, misuse and incorrect interpretation of biomarkers, mismatches between study design and stated objectives, selective reporting of outcomes, over-reliance on post hoc analyses and open-label extension data, and overly optimistic framing of inconclusive data. We argue that these practices, reinforced by misaligned incentives across industry and academia, lead to premature claims of therapeutic promise and tangible harm to patients. To address the resulting ALS clinical trial credibility gap, we call for rigorous adherence to established standards for reporting clinical trial results, clearer distinction between hypothesis generation and hypothesis testing, more measured description of trial results, and more disciplined triage of phase 2 programs. A cultural shift toward scientific skepticism and methodological rigor is essential to accelerate the development of genuinely effective ALS therapies.
    DOI:  https://doi.org/10.1212/WNL.0000000000218471
  37. J Clin Invest. 2026 Sep 01. pii: e199847. [Epub ahead of print]136(17):
    Mitophagy in neuronal health and disease: from mechanisms to neurodegeneration.
    Bishal Basak, Julia F Riley, Neha M Nataraj, Erika Lf Holzbaur.
      Regulation of mitochondrial health is critical for maintaining cellular homeostasis in the nervous system. Damaged mitochondria can have detrimental effects on neuronal health and are thought to be key contributors to the progression of neurodegenerative disorders including Parkinson's disease and amyotrophic lateral sclerosis. To mitigate this damage, multiple quality control mechanisms have evolved to eliminate aged or damaged mitochondria. One such quality control process is autophagy, a process that involves turnover of mitochondria at presynaptic sites and the axon terminal under basal conditions. This highly conserved mechanism sequesters mitochondria from the cytosol within autophagosomes followed by degradation upon fusion with a lysosome. Acute mitochondrial damage activates a selective form of autophagy called mitophagy that involves receptor-mediated engulfment and degradation of the damaged organelle. Multiple mechanisms have been shown to drive efficient mitophagy in neurons and glia, including PTEN induced kinase 1 (PINK1)/Parkin-dependent mitophagy and receptor-mediated mitophagy. Genetic, pathological, and experimental evidence all implicate defects in the removal of damaged mitochondria in the onset or progression of neurodegenerative disease. Both the initiation of PINK1/Parkin-dependent mitophagy and deficits in the removal of damaged mitochondria are linked to activation of neuroinflammatory pathways, including NF-κB and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. In this Review, we discuss the molecular pathways governing mitophagy in neurons and glial cells and how deficits in these pathways may lead to neurodegeneration. We also highlight emerging therapeutic strategies aimed at restoring mitophagy to preserve neuronal homeostasis and function.
    DOI:  https://doi.org/10.1172/JCI199847
  38. J Control Release. 2026 Sep 01. pii: S0168-3659(26)00727-3. [Epub ahead of print] 115323
    Targeting the vascular interface: beyond crossing the blood-brain barrier.
    Ebrahim Sadaqa, Amira Sayed Hanafy.
      Drug delivery to the CNS has traditionally been evaluated by the ability of carriers to cross the blood-brain barrier (BBB). This barrier-centric view has enabled important progress, but it overlooks a therapeutically significant and design-relevant feature of the neurovascular unit: cerebral endothelial cells and pericytes are active regulators of barrier integrity, vascular tone, immune trafficking, amyloid clearance, and perivascular remodeling. In many neurological disorders, the vascular interface is therefore not merely an obstacle to drug access but also part of the pathological process. This review introduces a vascular-interface-guided framework for CNS delivery system design. We discuss how disease-associated vascular phenotypes, including barrier disruption, immune-endothelial activation, vascular-tone dysregulation, and extracellular-matrix/basal-lamina remodeling, define distinct therapeutic entry points at the luminal endothelial surface, within endothelial trafficking pathways, or in the perivascular niche. We further discuss how receptor identity, ligand affinity and valency, particle size, geometry, surface chemistry, and intracellular sorting determine whether nanocarriers undergo transcytosis, recycling, lysosomal degradation, or endothelial retention. Particular emphasis is placed on endothelial-pericyte crosstalk, pericyte-directed delivery, perivascular depot formation, safety constraints, and translational model selection. Finally, we highlight how computational and predictive modeling could help determine when retention-oriented designs should be prioritized over transcytosis-oriented strategies. We propose that next-generation CNS nanomedicines should be designed by considering therapeutic action at luminal, endothelial, and perivascular sites according to the vascular state of disease, rather than being guided solely by parenchymal delivery.
    Keywords:  Blood-brain barrier; CNS drug delivery; Endothelial targeting; Nanomedicine; Neurovascular unit; Pericyte targeting
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115323
  39. IEEE Trans Neural Syst Rehabil Eng. 2026 Aug 31. PP
    Computational Insights into Neuromodulation: How Electric Fields Shape Motor Neuron Excitability.
    Marta Krumina, Sofia Fernandes, Baiba Vilne, Marcin Baczyk.
      Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease characterized by the selective loss of spinal motor neurons (MN). Trans-spinal direct current stimulation (tsDCS) has emerged as a promising noninvasive neuromodulation technique that could provide neuroprotection and slow down disease progression. However, the mechanisms by which tsDCS affects individual MNs remain poorly understood. This study uses computational modeling to explore how low-intensity extracellular electric fields (EEFs), generated by tsDCS, influence the electrophysiological behavior of MNs. Morphologically realistic, multi-compartment models of neonate mouse alpha-MNs were developed in the NEURON simulation environment. Simulations were conducted under different EEF magnitudes, polarities and orientations. At the population level, consistent directional effects on excitability-related properties were limited and depended on stimulation condition. However, analyses of response magnitude showed that EEFs could modulate several properties, including resting membrane potential and rheobase, even when the direction of change varied across neurons. This heterogeneity was associated with neuronal morphology and its alignment with the applied field, with dendritic length and asymmetry affecting sensitivity. Overall, the results suggest that low-intensity EEFs produce modest, morphology-dependent modulation of MN electrophysiological properties, and that variability in neuronal structure and orientation may help explain discrepancies across previous experimental and modeling studies.
    DOI:  https://doi.org/10.1109/TNSRE.2026.3729166
  40. Brain. 2026 Sep 05. pii: awag297. [Epub ahead of print]
    Progress towards a biotypic biomarker profile for amyotrophic lateral sclerosis-frontotemporal spectrum disorders.
    Michael J Strong, Neil Donison, Ammar Al-Chalabi, Bradley Boeve, Elizabeth C Finger, Henne Holstege, Edward D Huey, Edward B Lee, Sarah J Marzi, Caroline McHutchison, Corey T McMillan, Markus Otto, Leonard Petrucelli, Mercedes Prudencio, Tanya Simuni, Maria Carmela Tartaglia, Martin R Turner, Philip Van Damme, David A Wolk.
      Determining the optimal timing of disease-modifying therapies for neurodegenerative disorders will necessitate identification of when the underlying pathobiological process becomes active, well in advance of the point at which clinical manifestions appear. Phenoconversion, the emergence of clinically manifest syndomes, may be preceded by years to decades of silent pathobiological activity that can only be mapped by an array of biomarkers. ALS and FTD, traditionally identified as distinct clinical syndromes, are increasingly recognized to exist along a spectrum of clinical syndromes with shared genetic risk and shared underlying pathology. This clinicopathological spectrum is underpinned by cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) as the common neuropathological hallmark. In contrast, the majority of neuropathologically-defined frontotemporal lobar degeneration (FTLD) is associated with alterations in either TDP-43 metabolism (FTLD-TDP) or of the microtubule associated protein tau (FTLD-tau), with a smaller percentage associated with either autosomal dominant genetic mutations or impairments in the ubiquitin proteasome system. As the field of neurodegenerative disorders increasingly shifts towards the frameworks of a pathobiological definition of disease, there is a growing imperative to develop biomarkers that reflect the varied pathobiologies that underly these disorders, and to determine the sensitivity of such biomarkers to detect the presence of these pathobiologies before phenoconversion. To that end, an international workshop was convened in London, Canada in 2025 to review the evidence for existing or evolving biomarkers suitable for (1) the detection of either ALS or FTD pathobiology prior to phenoconversion and/or (2) predict phenoconversion in at risk individuals. Such biomarkers might be conceptualized as "biotypic biomarkers", capturing their ability to describe an underlying pathophysiology whilst being agnostic to the emergent clinical manifestations. Whereas no single biotypic marker is yet able to predict the emergence of ALS, FTD or their intersection, a multimodal approach to developing a biotypic biomarker profile holds promise for the detection of relevant pathobiological processes. The strength of such an approach would be augmented by also addressing issues of resiliency/susceptibility both in terms of genetic risk susceptibility profiles and developing sensitive biomarkers of genomic and cellular aging. By including such nontraditional markers of disease, a more robust picture of not only the degenerative process but also of those factors that might potentially mitigate or drive a heightened probability of disease can be derived.
    Keywords:  cryptic exons; cryptic proteins; cytoskeletal proteins; epigenetics; neurofilaments; neuroinflammation; telomere
    DOI:  https://doi.org/10.1093/brain/awag297
  41. Transl Neurodegener. 2026 Sep 01. pii: 45. [Epub ahead of print]15(1):
    The gut neuroepithelial unit as a neurodegeneration-relevant interface in the gut-brain axis.
    Siqi Guo, Rui Guo, Qingyu Zhang, Liyuan Fu, Huaxu Zhu, Qichun Zhang.
      Neurodegenerative diseases are increasingly linked to abnormalities in the gut-brain axis, yet the local intestinal interface at which luminal and mucosal perturbations are related with the central nervous system remains poorly defined. The gut neuroepithelial unit (GNU) is proposed as a localized mucosal signalling interface composed of sensory epithelial cells, enteric neurons, glia and adjacent immune-stromal elements that detect, encode and route intestinal information into neural, endocrine and immune outputs. This framework shifts the intestine from being a diffuse upstream modifier of brain pathology to a mesoscopic unit through which microbial products, barrier dysfunction, inflammatory cues and metabolic signals are transformed into disease-relevant gut-to-brain communication. Particularly, in Parkinson's disease and Alzheimer's disease, the GNU may function as a conditional interface that amplifies, filters or biases peripheral signals before they engage central circuits. The GNU therefore provides a tractable framework for mechanistic dissection, translational stratification and peripheral therapeutic targeting in neurodegeneration.
    Keywords:  Gut neuroepithelial unit; Microbiota-gut-brain axis; Neuroimmune communication; Signal encoding; Translational pharmacology
    DOI:  https://doi.org/10.1186/s40035-026-00582-0
  42. Nat Rev Neurol. 2026 Sep 03.
    Role of complement and complement-targeted therapeutics in neurological diseases.
    Marinos C Dalakas, Jan D Lünemann.
      Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains primarily focused on diseases with complement-fixing pathogenic antibodies (such as myasthenia gravis and neuromyelitis optica spectrum disorder), a robust pipeline of emerging treatments holds promise for expanding complement-targeted therapies to a broader spectrum of autoimmune neurological diseases, such as multiple sclerosis and even neurodegenerative diseases such as Alzheimer disease or amyotrophic lateral sclerosis. This Review presents insights into complement biology as it relates to the development or initiation of autoimmune and possibly degenerative diseases affecting the central and peripheral nervous systems or muscle. The effects, merits, risks and challenges of marketed drugs or biologic agents in ongoing phase I-III clinical trials engineered to inhibit proximal or distal components of the complement cascade are also discussed. Anti-complement therapeutics are destined to change the treatment of autoimmune neurologic conditions in which the therapeutic landscape is now becoming crowded with biologic agents targeting other key autoimmunity factors.
    DOI:  https://doi.org/10.1038/s41582-026-01261-4
  43. Mult Scler Relat Disord. 2026 Aug 27. pii: S2211-0348(26)00926-0. [Epub ahead of print]115 107891
    Implications of artificial intelligence in multiple sclerosis theragnostics: current advances and barriers to clinical translation.
    Hooria Noor, Shaafay Humayun, Abrahim Danish Durrani, Ahsan Ahmad.
       BACKGROUND: Artificial intelligence (AI). has been applied across many aspects of multiple sclerosis (MS). theragnostics, from lesion detection in magnetic resonance imaging (MRI)., gait assessment and treatment response prediction to drug repurposing. However, a considerable number of models characterized by high technical performance have yet to be translated into a clinical setting.
    OBJECTIVE: To investigate the translational barriers between AI-based theragnostic applications and their clinical implementation in MS.
    KEY MESSAGES: Many AI-based models have been trained using retrospective data from a single-center source and are rarely externally validated in larger independent populations. Major barriers to translation include technical issues, limited prospective validation, and multi-modality data, poor interoperability, clinical utility, and ethical concerns. In MS particularly, models must remain reliable across various MS phenotypes and disease modifying therapies making translation even more challenging.
    CONCLUSION: High technical performance alone is not sufficient for clinical implementation. Meaningful translation of AI-based theragnostic approaches in MS will require multicenter datasets representative of larger populations, further external validation and transparency. Only through these measures can AI-driven theragnostic approaches evolve from promising research models into clinically meaningful tools for MS care.
    Keywords:  Artificial intelligence; Clinical translation; Machine learning; Multiple sclerosis; Theragnostics
    DOI:  https://doi.org/10.1016/j.msard.2026.107891
  44. Pharmacol Res. 2026 Aug 31. pii: S1043-6618(26)00339-7. [Epub ahead of print]232 108424
    Selective targeting of the oligodendroglial GPR17 receptor improves myelin integrity and motor function in female SOD1G93A mice.
    Stefano Raffaele, Tiziana Bonifacino, Francesca Carolina Mannella, Nhung Nguyen, Carola Torazza, Davide Marangon, Elena Maria Chinosi, Henrik Daa Schrøder, Eva Kildall Hejbøl, Kirsten Madsen, Laura Marchetti, Maria Letizia Trincavelli, Marco Milanese, Davide Lecca, Kate Lykke Lambertsen, Giambattista Bonanno, Maria P Abbracchio, Marta Fumagalli.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no definitive disease-modifying therapies available, underscoring the urgent need to identify novel druggable targets. The G protein-coupled receptor GPR17 is a critical regulator of oligodendrocyte maturation and has emerged as a candidate target in ALS, yet its relevance to human disease and its therapeutic potential remain unclear. Here, we demonstrate that pathological GPR17 upregulation defines a conserved, pathologically immature oligodendroglial state in human ALS that can be pharmacologically leveraged to restore myelin integrity and improve functional outcome in vivo. Publicly available transcriptomics datasets and histological analyses revealed an increased abundance of GPR17-expressing immature oligodendrocytes in post-mortem human spinal cord tissue from ALS cases. Moreover, sustained activation of GPR17 with a selective agonist induced GPR17 internalization in heterologous expression systems and promoted the differentiation of primary oligodendrocyte precursors derived from SOD1G93A mice. Translating these findings in vivo, chronic treatment with a brain-penetrant GPR17 agonist derived from the same pharmacological class significantly extended survival, delayed body weight loss, and improved motor performance in female SOD1G93A mice, whereas male mice showed no therapeutic benefit. These effects were associated with restored oligodendrocyte maturation, preserved myelin integrity, motor neuron survival, and attenuated reactive gliosis in the spinal cord of female SOD1G93A mice, while milder effects were observed in males. Together, these findings establish oligodendroglial GPR17 as a conserved and pharmacologically actionable target in ALS and show that sustained in vivo GPR17 agonism can reprogram altered oligodendroglial states and slow disease progression in a sex-dependent manner.
    Keywords:  Amyotrophic lateral sclerosis; GPR17 receptor; Oligodendrocytes; Remyelination; SOD1G93A mice
    DOI:  https://doi.org/10.1016/j.phrs.2026.108424
  45. Arterioscler Thromb Vasc Biol. 2026 Sep 03.
    Cell-to-Cell Signaling Networks at the Blood-Brain Barrier in Health and Disease.
    Joseph H McCarty.
      The blood-brain barrier (BBB) is a highly specialized interface between the central nervous system and the peripheral circulation, crucial for maintaining neuronal homeostasis and protecting the brain parenchyma from potentially harmful blood-borne substances. This review examines the molecular and cellular organization of the BBB and explores how defective cell adhesion and signaling networks lead to BBB pathologies. I discuss the intricate architecture of brain endothelial cells within the context of the larger multicellular neurovascular unit, highlighting the roles of pericytes, astrocytes, as well as ECM (extracellular matrix) proteins and growth factors in vascular basement membranes. Recent advances in understanding endothelial cell tight junction dynamics, transport mechanisms, and communication pathways within the neurovascular unit are presented, with a particular emphasis on astrocyte-endothelial communication. Furthermore, I detail how abnormal astrocyte-endothelial signaling leads to BBB breakdown and contributes to various neurological disorders. In summary, this review synthesizes current knowledge of BBB biology, with particular emphasis on recent discoveries in signaling pathways, intercellular adhesion, and dynamic regulatory mechanisms that govern barrier function. By integrating findings from functional studies across multiple models, this review provides critical insights into both fundamental BBB biology and the potential development of translational approaches for treating human cerebrovascular disorders. Understanding these complex mechanisms not only advances our knowledge of normal brain homeostasis but also illuminates promising therapeutic targets and strategies for addressing conditions ranging from stroke to neurodegenerative diseases, ultimately paving the way for more effective clinical interventions that can preserve or restore BBB integrity.
    Keywords:  astrocytes; blood-brain barrier; cell adhesion; endothelial cells; tight junctions
    DOI:  https://doi.org/10.1161/ATVBAHA.126.324590
  46. Neurology. 2026 Oct 13. 107(7): e218474
    Prevalence of Slowly Expanding Lesions in Patients With Multiple Sclerosis: A Systematic Review and Meta-Analysis.
    Andreas Liampas, Artemios Artemiadis, Vasilis-Spyridon Tseriotis, Ferran Prados, Paolo Preziosa, Alberto Calvi, Georgios Hadjigeorgiou, Maria A Rocca, Massimo Filippi, Olga Ciccarelli.
       BACKGROUND AND OBJECTIVES: Chronic active lesions (CALs) reflect chronic inflammation in multiple sclerosis (MS). Slowly expanding lesions (SELs) are CALs identified on conventional MRI by linear, concentric expansion over time, while paramagnetic rim lesions (PRLs) are CALs characterized by a paramagnetic rim on susceptibility-sensitive MRI. However, the prevalence of SELs and their overlap with PRLs remain unclear. The aims of this study were to (1) estimate the proportion of SELs among all T2 lesions and the proportion of patients with at least 1 SEL and (2) assess the proportion of SELs overlapping with PRLs.
    METHODS: We systematically searched PubMed, Scopus, Web of Science, and Embase on February 1, 2026, for studies evaluating SELs in MS. At least 2 authors independently assessed study eligibility. Primary outcomes were the pooled proportion of SELs among T2 lesions and the proportion of patients with at least 1 SEL. We estimated mean per-patient volumes of SELs and total T2 lesions and the proportion of SELs overlapping with PRLs. Random-effects generalized linear mixed-effects models and inverse-variance methods were used, with between-study heterogeneity assessed using τ2 and I2 and robustness using sensitivity analyses. Univariable meta-regression explored heterogeneity. PROSPERO: CRD42024603778.
    RESULTS: Of 5,980 records, 20 studies comprising 4,786 patients with MS were included (mean age: 43.6 ± 6.3 years; 63.7% female). Sample sizes varied by outcome. SELs accounted for 14% (95% CI 10-21) of all T2 lesions, and 78% (67-85) of patients had at least 1 SEL. After sensitivity analysis, per-patient mean volumes were 1.42 mL (0.79-2.06) for SELs and 10.6 mL (8.53-12.67) for total T2 lesions. In total, 11% (6-20) of SELs overlapped with PRLs. In subgroup analyses, proportions of SELs were similar in relapsing-remitting and progressive MS (15%), but the proportion of patients with at least 1 SEL was higher in progressive MS. Between-study heterogeneity was high across analyses with no significant sources identified.
    DISCUSSION: Although SELs represent a minority of T2 lesions, most patients have at least 1 SEL and a subset overlaps with PRLs, suggesting a partial correspondence between these 2 imaging markers of chronic inflammatory activity. Limitations include possible publication bias, high unexplained heterogeneity, differences in SEL identification methods, and differences in MRI time point number/timing.
    DOI:  https://doi.org/10.1212/WNL.0000000000218474
  47. Biomaterials. 2026 Aug 31. pii: S0142-9612(26)00612-5. [Epub ahead of print]338(Pt A): 124588
    UV-programmed gelatin methacryloyl hydrogel microenvironments reveal a bell-shaped vascularization window and enable compartmentalized neuromuscular disease modeling.
    Chun-Chuan Ni, Chun-Sheng Yu, Shih-Yen Wei, Jun-Zhi Dai, Chih-Ling Chang, Hsiao-Chien Ting, Chia-Yu Chang, Ying-Chieh Chen.
      Matrix mechanics and microarchitecture jointly regulate tissue morphogenesis and functional maturation; however, defining their combined effects remains challenging when microenvironmental tuning requires changes in material composition. Here, we establish a UV-programmable gelatin methacryloyl (GelMA) hydrogel system in which ultraviolet exposure coordinates changes in construct architecture, pore morphology, and apparent mechanical properties within a constant material formulation. This framework enables systematic mapping of biological responses to UV-programmed architectural-mechanical microenvironments without compositional confounders. In vivo subcutaneous implantation reveals a nonlinear, bell-shaped vascularization response to UV-programmed GelMA hydrogel properties, identifying a narrow microenvironmental window that supports blood-containing vessel formation, human-derived vascular structures, and host-perfused vascular integration. For neuromuscular modeling, a structurally stable UV-defined regime was selected to support long-term compartmentalized co-culture of human induced pluripotent stem cell-derived myoblasts and motor neuron spheroids. Within this same UV-defined compartmentalized neuromuscular microenvironment, amyotrophic lateral sclerosis (ALS)-derived constructs exhibit impaired myogenic maturation, reduced neuromuscular junction (NMJ)-like structural organization, and altered contractile responsiveness compared with gene-corrected Healthy controls. Pharmacological treatment with the FDA-approved drug Riluzole partially restores these disease-associated phenotypes. Together, these findings establish UV-programmed GelMA hydrogels as an adaptable architectural-mechanical platform for identifying vascularization-permissive microenvironments and supporting compartmentalized neuromuscular disease modeling.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Compartmentalized neuromuscular model; Light-programmed hydrogel microenvironment; Micropatterned gelatin hydrogel; Neuromuscular junction (NMJ)
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124588
  48. J Cell Mol Med. 2026 Sep;30(17): e71349
    The Therapeutic Potential of Purmorphamine Across Disease Models.
    Ashis Dhar, Ahnaf Dil Sharar, Saikarthik Papisetty, Mohammad Bydon, F M Moinuddin.
      Purmorphamine (PUR) is a trisubstituted purine compound that selectively activates Smoothened receptor, thereby initiating Sonic Hedgehog (Shh) signalling-a pathway critical for embryonic patterning, neuronal specification and tissue regeneration across multiple organ systems. Dysregulation of Shh signalling has been implicated in degenerative diseases yet therapeutic interventions targeting this pathway remain limited. PUR demonstrates broad therapeutic efficacy across diverse preclinical disease models by activating both canonical GLI-mediated transcription and non-canonical Shh pathways, resulting in neuroprotection, reduced neuroinflammation, enhanced blood-brain barrier integrity and tissue regeneration. In contrast to previous assumptions that Shh pathway activation requires endogenous ligand binding, PUR bypasses this requirement through direct Smoothened engagement, offering a pharmacologically tractable approach to pathway modulation. Preclinical studies demonstrate that PUR enhances motor neuron survival in amyotrophic lateral sclerosis models, protects dopaminergic neurons in Parkinson's disease, reverses behavioural abnormalities in autism spectrum disorder, promotes neurovascular repair following stroke, restores myelin integrity in multiple sclerosis models and drives osteogenic differentiation in bone tissue engineering applications. Beyond its established Smoothened agonist activity, recent evidence identifies PUR as a positive allosteric modulator of the secretin receptor, expanding its therapeutic scope to include cardiovascular applications such as hypertension management through enhanced nitric oxide bioavailability.
    Keywords:  Alzheimer; amyotrophic lateral sclerosis; autism; neurodegeneration; purmorphamine; small‐molecule; smoothen agonist; sonic hedgehog; stroke
    DOI:  https://doi.org/10.1111/jcmm.71349
  49. J Parkinsons Dis. 2026 Sep 02. 1877718X261477521
    Cognitive and motor profiles in biologically defined Parkinson's and Alzheimer's disease.
    Daniel Zarhin, Noa Bregman, Tamara Shiner, Anat Mirelman, Roy N Alcalay, Avner Thaler.
      BackgroundParkinson's disease (PD) patients may harbor coexisting Alzheimer's disease (AD) pathology that accelerates cognitive and motor decline. Defining biomarker-defined AD in PD is important for prognosis, patient counseling, and trial stratification.ObjectiveTo determine the prevalence of AD biomarker positivity in α-synuclein seed amplification assay (αSyn-SAA) positive PD and assess its impact on cognitive and motor progression.MethodsWe analyzed data from the Parkinson's Progression Markers Initiative, a multinational prospective cohort of de novo PD patients. Baseline CSF biomarkers included αSyn-SAA, amyloid-β1-42 (Aβ1-42), and phosphorylated tau181 (p-tau181). AD biomarker positivity was defined by a low Aβ1-42/high p-tau181 profile using the CSF Aβ1-42/p-tau181 ratio (<39.2). αSyn-SAA-positive PD participants with and without AD biomarker positivity were compared. Outcomes included cognition, Montreal Cognitive Assessment (MoCA), neuropsychological testing, and MDS-UPDRS motor scores over follow-up.ResultsAmong 449 αSyn-SAA-positive PD patients, 42 (9.3%) met AD biomarker criteria (PD-AD). Baseline cognition and motor scores did not differ between PD-AD and PD without AD biomarkers (PD-nonAD). Over time, PD-AD patients showed greater cognitive decline, with lower MoCA scores and higher MCI prevalence at 5 years. At 8 years, PD-AD patients also demonstrated worse motor outcomes. MoCA <24 predicted AD biomarker positivity (PPV 15%; OR 6.1). APOE ε4 status was not associated with cognition.ConclusionsBiomarker-defined AD identifies a distinct PD subgroup with accelerated cognitive and motor decline, independent of APOE ε4. A ratio-based CSF Aβ1-42/p-tau181 framework offers a practical approach to detect AD copathology in PD and refine prognostic stratification.
    Keywords:  amyloid; biomarkers; cognition; dementia; neurodegeneration
    DOI:  https://doi.org/10.1177/1877718X261477521
  50. Front Urol. 2026 ;6 1931923
    Artificial intelligence and machine learning in neurogenic lower urinary tract dysfunction and spinal cord injury: current status, emerging technologies, and ethical perspectives.
    Patrick M F Levien, Jürgen Pannek.
      Artificial intelligence (AI) and machine learning are increasingly applied across urology, with particular promise for the management of neurogenic lower urinary tract dysfunction (NLUTD) in individuals with spinal cord injury (SCI). There is also particular promise in the management of NLUTD, a complex, lifelong condition affecting individuals with SCI and also occurring in the context of multiple sclerosis, Parkinson's disease, and other neurological disorders. This article provides a comprehensive analysis of AI's current and emerging role in neuro-urology, with dedicated focus on the specific challenges and opportunities presented by NLUTD and SCI. We review the epidemiological and clinical burden of neurogenic bladder dysfunction. We further examine AI applications in uro-oncology, functional urology, digital pathology, and robotic surgery, integrating these with the specialized perspective of neuro-urology. The particular vulnerability of individuals with SCI to algorithmic bias, access inequity, and assistive technology dependency is critically discussed. We identified five key domains where AI may transform care for patients with NLUTD: automated urodynamic interpretation including detection of detrusor overactivity and detrusor-sphincter dyssynergia, predictive risk stratification for renal deterioration, closed-loop neuromodulation, remote digital monitoring, and AI-assisted rehabilitation support. Alongside the substantial opportunities, we articulate the ethical, moral, and societal responsibilities that accompany AI integration in this population, emphasizing that patients with SCI and NLUTD deserve not merely inclusion in AI development but active partnership as co-designers of the technologies that will shape their lives.
    Keywords:  artificial intelligence; autonomic dysreflexia; clinical decision support; closed-loop neuromodulation; deep learning; detrusor-sphincter dyssynergia; digital twin; health equity
    DOI:  https://doi.org/10.3389/fruro.2026.1931923
  51. Abdom Radiol (NY). 2026 Aug 29.
    Can MRI with diffusion-weighted imaging reliably detect cryptorchidism? A systematic review and diagnostic accuracy meta-analysis.
    Sagar Yadav, Udit Khurana, Varun Sharma, Shubham Singh Bais, Aakash Yadav, Krishn Kant Bhardwaj.
       PURPOSE: Non-palpable undescended testes require accurate localisation, but the role of magnetic resonance imaging (MRI) combined with diffusion-weighted imaging (DWI) remains uncertain. We evaluated the diagnostic accuracy of MRI-DWI for detecting clinically non-palpable undescended testes.
    METHODS: This PROSPERO (CRD420261411862) registered review searched PubMed, Embase, Web of Science, and CENTRAL to June 6, 2026. Eligible diagnostic-accuracy studies assessed MRI-DWI against diagnostic laparoscopy or operative exploration. Two reviewers extracted 2 × 2 data, and assessed QUADAS-2 risk of bias. Sensitivity and specificity were pooled using bivariate random-effects models, with hierarchical summary receiver operating characteristic (HSROC) analysis, likelihood ratios, diagnostic odds ratios, and Fagan nomograms used to summarise diagnostic performance.
    RESULTS: Fifteen studies were included. In seven testis-level studies (340 testes), pooled sensitivity and specificity were 92.6% (95% CI 88.4-95.3%) and 94.3% (85.6-97.9%) and the HSROC area under the curve (AUC) was 0.957. In eight patient-level studies (1782 patients), pooled sensitivity and specificity were 86.7% (77.1-92.7%) and 85.8% (68.8-94.3%) and the HSROC AUC was 0.917. Positive MRI-DWI increased post-test probability on the Fagan nomogram, but a negative result left a residual probability of 21%. Heterogeneity was minimal at the testis level but substantial at the patient level analysis. Deeks' test suggested small-study effects only in the testis-level analysis.
    CONCLUSIONS: MRI-DWI shows good-to-excellent accuracy and can support localization, operative planning, and counselling. However, a negative MRI-DWI result does not safely exclude the presence of a viable or otherwise at-risk undescended testis and leaves a clinically meaningful residual probability of disease. Therefore, negative imaging should not be used to omit operative exploration. MRI-DWI should be regarded as an adjunctive localisation tool rather than a replacement for diagnostic laparoscopy, which remains necessary for definitive evaluation.
    Keywords:  Cryptorchidism; Diagnostic test accuracy; Diffusion-weighted imaging; Magnetic resonance imaging; Undescended testis
    DOI:  https://doi.org/10.1007/s00261-026-05765-x
  52. Front Neurol. 2026 ;17 1751426
    Multimodal MRI biomarkers and machine learning in neuromyelitis optica spectrum disorder: a review.
    Jiahui Zhang, Haoyou Xu, Min Zhao, Zequan Zheng, Yuanqi Zhao.
      Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing inflammatory demyelinating disease of the central nervous system that can result in substantial cumulative neurological disability. Magnetic resonance imaging (MRI) plays a central role in lesion detection, differential diagnosis, and longitudinal assessment. However, conventional MRI may not fully capture subtle tissue damage and may show substantial overlap with related inflammatory demyelinating disorders in clinically ambiguous cases. Reliable imaging biomarkers reflecting disease burden, progression, and prognosis remain limited. This narrative review summarizes current evidence on conventional MRI features and advanced quantitative MRI biomarkers in NMOSD. We found that advanced techniques, including diffusion tensor imaging, morphometric analyses of T1 imaging, and resting-state functional MRI have revealed structural, microstructural, and functional abnormalities beyond lesions visible on conventional MRI. Furthermore, imaging-based machine learning applications have shown promising performance in differential diagnosis, particularly in distinguishing NMOSD from multiple sclerosis. However, findings across studies vary in the distribution, magnitude, and clinical relevance of reported abnormalities, likely reflecting differences in disease stage, acquisition protocols, and analytical methods. Additionally, most available studies remain limited by small cohorts, methodological heterogeneity, and insufficient external validation. Evidence for relapse prediction and treatment monitoring remains comparatively limited. Future research should prioritize multicenter prospective validation, harmonized imaging protocols, clearer separation of disease subgroups, and integration of imaging with clinical, serological, cerebrospinal fluid, and ophthalmic biomarkers before routine clinical implementation.
    Keywords:  differential diagnosis; imaging biomarkers; machine learning; multimodal MRI; neuromyelitis optica spectrum disorder
    DOI:  https://doi.org/10.3389/fneur.2026.1751426
  53. Cell Biomater. 2026 May 20. pii: 100461. [Epub ahead of print]
    Focused Ultrasound is Poised to Take Non-Viral Gene Therapies to the Blood-Brain Barrier - and Beyond.
    Eden N Gordon, Anna C Debski, Victoria R Breza, Matthew R Hoch, Nareen Z Anwar, Khondamir Imomnazarov, Alec J Batts, Matthew R DeWitt, Natasha D Sheybani, Richard J Price.
      The blood-brain barrier (BBB) offers a highly specialized protective boundary for the brain, but severely limits therapeutic delivery, posing major challenges for treating neurological diseases and solid tumors. Focused ultrasound (FUS) has emerged as a powerful tool to noninvasively and transiently disrupt the BBB to enable localized delivery of drugs and gene therapies. More commonly paired with viral vectors like adeno-associated virus (AAV), FUS is now being explored with non-viral vectors such as polymeric and lipid nanoparticles, which offer tunable chemistry, repeat dosing potential, and capability to deliver varying cargos. Upon promising advances, future directions aim to improve safety, target immune modulation, and integrate diagnostic imaging for theranostic potential. Overall, the convergence of FUS and non-viral nanocarrier technologies represents a transformative approach for precise, minimally invasive, and accessible gene delivery to the central nervous system.
    DOI:  https://doi.org/10.1016/j.celbio.2026.100461
  54. RSC Adv. 2026 Sep 02.
    Recent medicinal chemistry efforts of targeting protein kinases for treating neurological conditions of Parkinson's and Alzheimer's diseases.
    Rajwinder Kaur, Damanpreet Kaur Lang, Ankita Sood, Thakur Gurjeet Singh, Balakumar Chandrasekaran, Mahmoud A Al-Sha'er.
      The human genome encodes a wide variety of protein kinases that regulate multiple cellular functions. These enzymes play a crucial role in amplifying and propagating intracellular signals during signal transduction. Dysregulation of protein kinase signaling is associated with vascular diseases, inflammatory disorders, cancer, and various neurological conditions. Kinase-targeted therapies have already demonstrated clinical efficacy in oncology and inflammatory diseases, prompting growing interest in their potential application in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Several kinases, including PDK1, CK1, CK2, c-Abl, p38 MAPK, PKA, GSK-3β, PINK1, and ROCK, have been implicated in the pathogenesis of AD and PD, highlighting their potential as therapeutic targets. However, the development of kinase inhibitors for central nervous system (CNS) disorders remains challenging due to limited blood-brain barrier (BBB) penetration and cytochrome P450-mediated metabolism. This review summarizes protein kinase targets involved in AD and PD, discusses kinase inhibitors under preclinical and clinical investigation, and highlights emerging strategies to overcome pharmacokinetic and therapeutic limitations in the development of disease-modifying therapies.
    DOI:  https://doi.org/10.1039/d6ra03269a
  55. J Neurol Sci. 2026 Aug 27. pii: S0022-510X(26)00437-5. [Epub ahead of print]490 126155
    Delayed appearance of bilateral cerebral peduncle lesions in autoimmune glial fibrillary acidic protein astrocytopathy: A serial MRI case series.
    Yusuke Akitomi, Kensuke Takahashi, Yuta Komori, Shuichiro Mitsuchi, Akatsuki Kubota, Jun Mitsui, Ryo Kurokawa, Akio Kimura, Takayoshi Shimohata, Wataru Satake.
      Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is an immune-mediated inflammatory disorder of the central nervous system. Although delayed magnetic resonance imaging (MRI) abnormalities have been reported in patients with GFAP-A, the anatomical distribution of brain lesions that become apparent on follow-up MRI remains unclear. We retrospectively reviewed three patients with cerebrospinal fluid anti-GFAPα immunoglobulin G-positive GFAP-A who underwent serial brain MRI. The patients ranged in age from 40 to 80 years and were clinically heterogeneous: patients 1 and 2 required ventilatory support, whereas patient 3 had a milder course and improved without immunotherapy. Initial brain MRI performed 10-21 days after symptom onset showed leptomeningeal or periventricular radial linear enhancement and/or T2-weighted imaging (T2WI)/fluid-attenuated inversion recovery (FLAIR) hyperintensities in the supratentorial white matter, deep gray matter, or brainstem. Definite bilateral cerebral peduncle involvement was not evident in the corresponding initial axial midbrain images. Follow-up brain MRI performed on days 31-59 revealed bilateral cerebral peduncle T2WI/FLAIR hyperintensities in all three patients. Pathological plantar reflexes were documented during the subacute phase in two patients, although coexisting spinal cord lesions detected during follow-up may also have contributed to these signs. Previous reports have described delayed non-enhancing T2WI/FLAIR abnormalities and brainstem involvement in GFAP-A. However, whether the cerebral peduncles are involved as part of these delayed MRI abnormalities remains unclear. Thus, bilateral cerebral peduncle lesions may represent a delayed non-enhancing MRI manifestation of GFAP-A. Careful assessment of the cerebral peduncles on follow-up MRI may help characterize the evolving lesion distribution.
    Keywords:  Autoimmune glial fibrillary acidic protein astrocytopathy; Brainstem; Cerebral peduncle; Corticospinal tract; Magnetic resonance imaging; Meningoencephalomyelitis
    DOI:  https://doi.org/10.1016/j.jns.2026.126155
  56. Res Sq. 2026 Aug 27. pii: rs.3.rs-10730833. [Epub ahead of print]
    Soluble TREM2 Mediates Blood Brain Barrier Permeability through Astrocyte Reactivity.
    Samuel Martinez-Meza, Brandon A Sealy, Lillie Lopez, Douglas F Nixon, Joan W Berman.
      The Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein predominantly expressed by cells of the myeloid lineage. In the CNS, it is mainly expressed by microglia and macrophages, where it regulates their reactive state. This protein can be shed to release soluble TREM2 (sTREM2), which is increased in the cerebrospinal fluid of people with neurocognitive disorders. However, it remains unknown how sTREM2 contributes to neuropathogenesis. We examined the effects of sTREM2 on the inflammatory state of astrocytes, and how these impact blood-brain barrier (BBB) integrity using an in vitro BBB model composed of primary human Brain Microvascular Endothelial Cells (BMVEC) and primary human astrocyte cells. We found that sTREM2 induced an inflammatory state in astrocytes, characterized by increased AKT phosphorylation, NF-kB activation, and upregulation of activation markers including GFAP, all consistent with a reactive astrocyte (RA) phenotype. In addition, we found an increase in BBB permeability when astrocytes were exposed to sTREM2 that correlated with decreased levels of the tight junction (TJ) protein Occludin in BMVEC from the BBB. sTREM2 promoted release of astrocyte-derived molecules implicated in BBB disruption, with Matrix Metalloproteinases-2 (MMP2) appearing to be a major contributor to the loss of barrier integrity. Our findings demonstrate a novel role for sTREM2 in BBB dysfunction in the context of neuropathogenesis.
    DOI:  https://doi.org/10.21203/rs.3.rs-10730833/v1
  57. Front Aging Neurosci. 2026 ;18 1905708
    Role of STX1A in Parkinson's disease: evidence, mechanistic hypotheses, and translational perspectives.
    Rui Xu, Rui Li, Hongmei Li, Qingyun Li, Yanping Li, Gang Wu, Xiaolin Dong.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of substantia nigra dopaminergic neurons, α-synuclein pathology, and widespread synaptic dysfunction. Syntaxin-1A (STX1A), a presynaptic Qa-SNARE protein, is essential for synaptic vesicle fusion and also interacts with proteins involved in ion-channel regulation and neuronal excitability. Several animal, extracellular-vesicle, and peripheral-blood studies have reported reduced STX1A abundance in PD. However, the available evidence is predominantly cross-sectional and does not establish whether STX1A downregulation is a cause of PD pathology, a consequence of neuronal and synaptic loss, or a peripheral correlate of disease. This narrative review critically evaluates evidence linking STX1A to PD and distinguishes experimentally supported observations from mechanistic hypotheses. Potential relationships with calcium dysregulation, mitochondrial injury, ferroptosis, and neuroimmune signaling are discussed as testable models rather than established pathways. Direct evidence connecting STX1A to the gut-brain axis in PD is currently lacking and is therefore considered primarily as a future research direction. The biomarker and therapeutic potential of STX1A remains preliminary because diagnostic performance, disease specificity, longitudinal stability, and causal relevance have not been adequately validated. Future studies using cell-type-specific STX1A manipulation, rescue experiments, electrophysiology, and multicenter longitudinal cohorts are required to define the biological and clinical significance of STX1A in PD.
    Keywords:  Parkinson’s disease; SNARE complex; biomarker; calcium signaling; synaptic dysfunction; syntaxin-1A
    DOI:  https://doi.org/10.3389/fnagi.2026.1905708
  58. Neuromolecular Med. 2026 Aug 31. pii: 51. [Epub ahead of print]28(1):
    Rebalancing α-Synuclein Clearance: Novel Therapeutic Frontiers in Parkinson's Disease.
    Maryam Jabeen, Huma Hameed, Syed Muhammad Ahmad, Tehreem Mushtaq, Mahtab Ahmad Khan, Anam Hameed.
      Parkinson's disease (PD), the second most common neurodegenerative condition, develops because of abnormal protein misfolding and aggregation of α-synuclein with its subsequent intercellular spread. Such pathological changes lead to disruption of neuronal homeostasis and contribute to neuronal degeneration. During normal conditions, α-synuclein clearance is controlled by different types of lysosomal degradation, namely, macro autophagy, chaperone-mediated autophagy (CMA), micro autophagy, and the ubiquitin-proteasome system. Malfunction of these systems results in increased α-synuclein secretion due to exosome-dependent, direct, and damage-induced mechanisms, which, in turn, promotes enhanced intercellular propagation, inflammation, mitochondrial dysfunction, blood-brain barrier leakage, and neuronal cell death. Although several approaches targeting α-synuclein clearance have shown biological activity in preclinical or early clinical studies, consistent disease-modifying efficacy has not yet been established, owing to challenges including target specificity, blood brain barrier penetration, biological heterogeneity, and the limited sensitivity of clinical endpoints. Recent research indicates that successful treatment is more related to restoring the balance of these two processes than to manipulating one of them.In this review, it is proposed that a systems-level approach can be taken where PD is understood as a disease characterized by the imbalance in proteostasis. Potential treatment modalities include small molecules targeting lysosome function (ambroxol, rapamycin, TFEB activators), CMA enhancers, gene therapy, and antibodies against extracellular α-synuclein. Furthermore, new modalities like molecular glue degraders, allostery-based stabilization of α-synuclein tetramers, engineered decoy particles, and bispecific antibodies represent some other possible routes towards multimodal disease modification.
    Keywords:  Autophagy; Extracellular Propagation; Lysosomal Dysfunction; Nanoparticles; Parkinson’s Disease; α-Synuclein
    DOI:  https://doi.org/10.1007/s12017-026-08948-3
  59. Nat Commun. 2026 08 21. pii: 9357. [Epub ahead of print]17(1):
    YTHDC1 functions as a molecular chaperone to suppress ALS-linked hnRNPA1 mutants from aggregation.
    Kang Ren, Mingjie Cheng, Qiudan Luo, Boxin Zhang, Haosheng Zhang, Zhe Li, Yuxin Liu, Yujie Wang, Ting Kang, Xiaoming Dai, Jiong Chen, Yuanming Cheng, Liangqian Huang.
      Proteostasis failure drives multiple neurodegenerative disorders (NDs), and ATP-independent chaperone pathways that support neuronal proteostasis remain poorly defined. Here, we identify the N6-methyladenosine (m6A)-binding protein YTHDC1 as an ATP-independent molecular chaperone, whose activity is mediated by a highly acidic polyaspartate/glutamate (polyD/E) segment. YTHDC1 prevents protein misfolding and aggregation, unfolds kinetically trapped substrates, and resolubilizes pre-formed aggregates. Deletion of the polyD/E segment abolishes these activities, whereas aromatic-cage mutants retain chaperone activity, demonstrating independence from m6A recognition. We identify the amyotrophic lateral sclerosis (ALS)-associated RNA-binding protein hnRNPA1 as a YTHDC1 client. YTHDC1 maintains liquid-like hnRNPA1 condensates, delays fibrillization of disease-associated mutants, and limits stress-granule sequestration, while mitigating mutant hnRNPA1-induced neurite growth defects in primary neurons. These findings define a proteostatic function of YTHDC1 and highlight its chaperone activity as a potential target for mitigating protein aggregation in ALS-related NDs.
    DOI:  https://doi.org/10.1038/s41467-026-77016-y
  60. Front Immunol. 2026 ;17 1925850
    The APOE4-estrogen-microglia axis in perimenopausal cognitive changes: mechanisms and therapeutic implications.
    Liuqing Shi, Chuntong Zhou, Huan Han, Mei Lu, Mingjie Li, Junjing Miao, Shiyu Feng, Xin Zhou, Haiyang Chen, Lu Ren.
      Alzheimer's disease (AD) exhibits marked sex differences, with women bearing a disproportionate burden of disease, particularly after midlife. Among the major factors contributing to this vulnerability, the apolipoprotein E ϵ4 allele (APOE4) and the abrupt endocrine transition of perimenopause have emerged as two critical and potentially synergistic drivers of neurodegeneration. Microglia, the resident immune cells of the central nervous system, lie at the center of this interaction because they integrate genetic, hormonal, metabolic, and inflammatory signals that shape amyloid clearance, synaptic remodeling, and neuroimmune homeostasis. Accumulating evidence indicates that APOE4 impairs microglial phagocytosis, disrupts lipid handling and lysosomal function, promotes pro-inflammatory activation, and compromises neurovascular integrity. In parallel, estrogen normally restrains microglial inflammatory signaling and supports phagocytic, metabolic, and reparative functions through estrogen receptor-dependent pathways. During perimenopause, fluctuating estrogen deficiency removes these protective constraints, thereby increasing the susceptibility of microglia to APOE4-driven dysfunction. This review synthesizes current evidence supporting an integrated pathogenic framework centered on the "APOE4-estrogen deficiency-microglia axis." We discuss how this axis promotes chronic neuroinflammation, synaptotoxicity, amyloid and tau pathology, mitochondrial dysfunction, blood-brain barrier disruption, and large-scale network disconnection, ultimately accelerating cognitive decline in women. We also summarize relevant experimental models, including APOE-targeted murine paradigms, ovariectomy and accelerated ovarian failure models, human induced pluripotent stem cell-derived microglia, and emerging single-cell and spatial omics approaches. Finally, we highlight translational opportunities, including precision hormone-based interventions, selective estrogen receptor modulation, TREM2-centered microglial therapies, APOE4-directed molecular and genetic strategies, and biomarker-guided multi-target interventions during the perimenopausal "window of opportunity." By integrating molecular mechanisms with translational perspectives, this review proposes a precision medicine framework for preventing or delaying neurodegenerative progression in high-risk perimenopausal women.
    Keywords:  Alzheimer’s disease; ApoE4; cognitive decline; estrogen deficiency; microglia; neuroinflammation; perimenopause
    DOI:  https://doi.org/10.3389/fimmu.2026.1925850
  61. Int J Nanomedicine. 2026 ;21 628071
    Mesenchymal Stem Cells and Extracellular Vesicles for Neurodegenerative Diseases: Therapeutic Advances and Challenges.
    Luming Pan, Baocai Liu, Jingjia Xu, Xupeng Mu, Lianlian Fan.
      Mesenchymal stem cells (MSCs), as a type of adult stem cells, exhibit robust self-renewal, multi-lineage differentiation, paracrine and immunomodulatory capacities, demonstrating broad application prospects in the treatment of neurodegenerative diseases. This review systematically summarizes the mechanisms of action, therapeutic advances and comparative analyses of various MSCs and their derived extracellular vesicles (EVs) in Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and discusses the optimization effects of gene modification and pretreatment on therapeutic efficacy. This article not only highlights the advantages of various MSCs and their corresponding EVs, but also provides unique insights into their differentiated therapeutic potential and mechanism of action, which have not been fully elucidated in previous studies. Meanwhile, although current research results are encouraging, this paper also critically points out that existing studies suffer from insufficient elucidation of mechanisms and lack of large-scale clinical trials. Finally, the article prospects future directions of MSC-based therapeutic strategies, including mechanism deepening, treatment optimization and standardization system construction, to promote their translation into clinical application. However, most of the current evidence is still preclinical, and the recognized clinical efficacy in humans is still limited. This is a narrative review. Literature was screened from Web of Science and PubMed by thematic relevance and research quality, without systematic review protocol or meta-analysis.
    Keywords:  clinical application; extracellular vesicles; genetic engineering modification; mesenchymal stem cells; neurodegenerative diseases
    DOI:  https://doi.org/10.2147/IJN.S628071
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