bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–10–25
sixty-two papers selected by
Luca Bolliger, lxBio
  1. The Role of Astrocytes in the Inflammatory Response in Neurodiseases.
  2. OGT regulates RNA-binding protein nucleocytoplasmic partitioning, but this fails in amyotrophic lateral sclerosis.
  3. Data-driven progression trajectories across clinical subtypes of amyotrophic lateral sclerosis.
  4. Factors associated with post-tracheostomy survival in Amyotrophic Lateral Sclerosis.
  5. Peripheral and cerebrospinal fluid inflammatory markers in sporadic amyotrophic lateral sclerosis an exploratory cross-sectional association study.
  6. Molecular recognition of axonal injury-associated candidate hub genes and predicted inhibitors across Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
  7. Tau isoform mapping across tissues and biofluids reveals a signature distinguishing Alzheimer's disease from amyotrophic lateral sclerosis.
  8. Cryo-EM advances in TDP-43 amyloid fibrils structure determination.
  9. Cerebrospinal fluid amyloid and neurodegeneration biomarkers in the diagnosis and prognosis of amyotrophic lateral sclerosis: a multicohort observational study.
  10. Understanding Holistic Patient-Relevant Measurement in Amyotrophic Lateral Sclerosis: A Mixed-Methods Content Validity and Exploratory Rasch Analysis of Selected Clinical Outcome Assessments.
  11. Serum p-tau181 and p-tau217 levels in adolescents and adults with 5q spinal muscular atrophy.
  12. Cellular senescence in ageing and neurodegenerative disorders: Molecular mechanisms, biomarkers, and therapeutic strategies.
  13. Plasma Proteomic Signatures Predict Incident Amyotrophic Lateral Sclerosis: A Prospective Study Stratified by C9orf72 Expansion.
  14. Plasma Lipidome Is Dysregulated in Amyotrophic Lateral Sclerosis and Associated With Life-Course Adiposity Polygenic Risk.
  15. ABCD-Trial: study protocol for a randomized, double-blind, placebo-controlled study in patients with Amyotrophic lateral sclerosis for the evaluation of efficacy and safety of B-Cell Depletion with rituximab (ABCD).
  16. The role of nanomedicine in infectious diseases of the central nervous system: a narrative review.
  17. Neuromelanin-sensitive magnetic resonance imaging in the diagnosis and assessment of Parkinson's disease.
  18. Neurotransmitter-defined cerebral vulnerability patterns in frontotemporal lobar degeneration (FTLD).
  19. Nose-to-brain drug delivery: A new frontier in targeted therapeutics.
  20. Linking protein misfolding and heat stress: a common role for the kynurenine pathway.
  21. State transitions in amyotrophic lateral sclerosis: mechanistic convergence and biomarker-guided stratification.
  22. Blood-brain barrier junctional proteins as potential biomarkers of cerebral ischaemia and reperfusion injury.
  23. Early micro- and nanoscale microglial responses to blood-brain barrier modulation by transcranial focused ultrasound.
  24. End-of-life care of patients with amyotrophic lateral sclerosis and home mechanical ventilation: the national population-based DISCOVERY study.
  25. Mitochondrial dysfunction in neurology: biomarkers and clinical implications.
  26. Intelligent exogenous predictive networks for nonlinear Parkinson's disease model involving delay with effects of immunotherapy.
  27. Locus coeruleus abnormalities on neuromelanin-sensitive MRI in Parkinson's disease: a systematic review and meta-analysis.
  28. Altered IL-23/IL-17A immune axis in Parkinson's disease: An exploratory analysis.
  29. Dissociable associations of free-water fraction and DTI-ALPS index with disease manifestation and mutation carrier status in Parkinson's disease.
  30. Diagnostic performance and methodological heterogeneity of neuromelanin-sensitive MRI in Parkinson's disease: A systematic review and meta-analysis.
  31. Hierarchical deep learning-radiomics fusion for differentiating Parkinson's disease from atypical Parkinsonism using FP-CIT imaging.
  32. Tiny Travelers, Big Impact: Physiological Effects of Extracellular Vesicles on the Blood-Brain Barrier.
  33. Regional blood-brain barrier dysfunction maps to lower performance in cognitive ageing.
  34. Reassessment of the DTI-ALPS index in focal epilepsy.
  35. Enzyme-Targeted Therapeutics for Neurological Disorders.
  36. Methamphetamine-Induced Oxidative Stress and Inflammatory Markers as Indicators of Blood-Brain Barrier Disruption.
  37. Cross-species molecular stratification enables T cell receptor diagnosis of Parkinson's disease.
  38. Genetic architecture of MRI-derived cervical spinal cord morphology reveals sensory-motor axis and systemic disease associations.
  39. Lower fibrinogen and fibrinogen-to-albumin ratio in migraine with white matter hyperintensities: implications for microvascular vulnerability.
  40. MiR‑204‑5p modulates glial morphology and apomorphine‑induced rotational asymmetry without dopaminergic neuroprotection in a preclinical mouse model of Parkinson's disease.
  41. A critical mechanistic synthesis of PINK1-mediated mitophagy signaling and its therapeutic targeting in Parkinson's disease neurodegeneration.
  42. Live and Heat-Killed Lactiplantibacillus plantarum HY7715 Attenuate D-Galactose-Induced Aging-Related Brain Changes and Blood-Brain Barrier Disruption with Gut Microbiota Modulation in Mice.
  43. Neural stem cell transplantation in progressive multiple sclerosis: STEMS study long-term outcomes.
  44. Eye-movement-based machine learning for identifying Parkinson's disease dementia in a retrospective cohort: an interpretable model-development study.
  45. Drosophila Models of Human Neurodegenerative Diseases.
  46. Oxidative signaling thresholds shape vulnerability in the central and peripheral nervous systems.
  47. Parkinson's at the brain border.
  48. Microglial Labeling in Mouse Spinal Cord Injury: A Review of Timing, Efficacy, and Specificity.
  49. The blood-brain tumor barrier as a spatial immune checkpoint in glioblastoma: leukocyte entry, perivascular retention, and therapeutic implications.
  50. Mechanistic Evaluation of Psilocybin in Neurodegenerative Disorders: Relevance of 5-HT2A Receptors and Downstream Pathways.
  51. Cytoplasmic TDP-43 Accumulation in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.
  52. Single cell landscape of sex differences in the different courses of multiple sclerosis.
  53. Microglia in Perioperative Neurocognitive Disorders: Pathogenic Mechanisms and Emerging Concepts of Microglial Heterogeneity.
  54. Case Report: Herbal nutritional intervention in a critically ill ALS patient with multidrug-resistant infection.
  55. Therapeutic mechanistic framework of mesenchymal stem cell-derived extracellular vesicles in neurodegenerative diseases.
  56. Matching developmental timelines of fish, frog, mouse and human brains.
  57. Multi-cohort meta-analysis, single-cell and Mendelian randomization analyses with experimental validation identify RHBDF2 as a shared mediator of ulcerative colitis and blood-brain barrier disruption.
  58. Astaxanthin alleviates Parkinson's disease via dual regulation of tryptophan metabolism: central STAT3/IDO1 inhibition and gut microbiota remodeling.
  59. An Automated Framework Using Magnetic Resonance Imaging Feature Masking and Support Vector Machine for Schizophrenia Classification.
  60. Correlation Between Cognitive Function and Serum Irisin Levels in Parkinson's Disease Patients.
  61. Caregiver Contributions to Self-Care in Parkinson's Disease: A Qualitative Descriptive Study.
  62. Gait characteristics in people with central nervous system disorders under dual-task experimental paradigms: a scoping review.
  1. MedComm (2020). 2026 Nov;7(11): e71069
    The Role of Astrocytes in the Inflammatory Response in Neurodiseases.
    Shijun Peng, Lepeng Wang, Jia Ouyang, Ruen Liu.
      Astrocytes have emerged as central regulators of neuroinflammation, extending far beyond their traditional roles as structural and metabolic support cells. In neurological disorders, astrocytes undergo reactive remodeling that encompasses morphological, transcriptional, metabolic, and functional changes. Rather than fitting into a fixed A1/A2 dichotomy, reactive astrocytes exist along a disease-, region-, and stage-dependent continuum shaped by local pathology and intercellular crosstalk. This review summarizes how astrocytes contribute to neuroinflammatory processes in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, central nervous system injury, infection, multiple sclerosis, epilepsy, and autism spectrum disorder. We highlight convergent mechanisms, including cytokine and chemokine release, complement activation, glutamate and ion homeostasis disruption, oxidative stress, metabolic reprogramming, and blood-brain barrier regulation, while emphasizing disease-specific astrocytic programs. We further discuss astrocyte interactions with microglia, neurons, oligodendrocytes, endothelial cells, and peripheral immune cells, as well as key regulatory pathways, epigenetic remodeling, and lipid-dependent metabolic signaling. Finally, we evaluate current and emerging astrocyte-targeted therapeutic strategies, including metabolic modulation, receptor targeting, gene editing, nanodelivery, and gut-brain axis interventions. Defining functionally validated astrocyte states and developing biomarker-guided, stage-adaptive therapies may enable more precise intervention in neuroinflammatory and neurodegenerative diseases.
    Keywords:  astrocytes; glial cell crosstalk; neuroinflammation; neurological diseases; therapeutic targeting
    DOI:  https://doi.org/10.1002/mco2.71069
  2. iScience. 2026 Nov 20. 29(11): 117807
    OGT regulates RNA-binding protein nucleocytoplasmic partitioning, but this fails in amyotrophic lateral sclerosis.
    Yiran Wang, Lisa Fournier, Benjamin Wymann, Kevin Talbot, Raphaëlle Luisier, Rickie Patani.
      O-linked N-acetylglucosamine transferase (OGT) catalyzes the O-linked β-N-acetylglucosamine (O-GlcNAc) modification to proteins and has been implicated in a range of diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and currently incurable neurodegenerative disorder. However, the precise mechanisms by which OGT influences ALS pathogenesis remain largely unresolved. In this study, we used human-induced pluripotent stem cell (hiPSC)-derived spinal motor neurons (hiPSC-MNs), the principal cell type that undergoes degeneration in ALS, to systematically reveal that OGT-related mechanisms regulate RNA-binding protein (RBP) nucleocytoplasmic compartmentalization. Using a combination of antisense oligonucleotide (ASO) technology and small molecular pharmacology, we reveal two distinct regulatory mechanisms of RBP compartmentalization, including by intron-retaining transcript-mediated sequestration and O-linked N-acetylglucosaminylation (O-GlcNAcylation)-mediated nuclear transport. We finally examine the tractability of manipulating OGT activity in the ALS context but demonstrate that the OGT-related mechanisms governing RBP localization in healthy hiPSC-MNs are impaired in the context of ALS-causing VCP and TARDBP mutations.
    Keywords:  O-GlcNAcylation; OGA; OGT; RNA-binding protein; amyotrophic lateral sclerosis; nucleocytoplasmic localization
    DOI:  https://doi.org/10.1016/j.isci.2026.117807
  3. J Neurol Sci. 2026 Oct 16. pii: S0022-510X(26)00506-X. [Epub ahead of print]491 126224
    Data-driven progression trajectories across clinical subtypes of amyotrophic lateral sclerosis.
    Pooled Resource Open-Access ALS Clinical Trials Consortium
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) exhibits substantial clinical heterogeneity; however, conventional classifications based on the predominant site of involvement may not fully capture patterns of disease progression. This study aimed to identify data-driven subtypes of ALS and reconstruct their temporal progression using item-level scores from the ALS Functional Rating Scale-Revised (ALSFRS-R).
    METHODS: Baseline data from 3067 participants in the Pooled Resource Open-Access ALS Clinical Trials database were analyzed. Subtype and Stage Inference (SuStaIn) was applied to ALSFRS-R item scores to identify subtypes and infer their progression trajectories. Internal consistency was evaluated using complexity and sensitivity analyses. Longitudinal stability was assessed at 180 and 365 days. Associations with functional decline and survival were examined using adjusted statistical models.
    RESULTS: Three clinically interpretable subtypes were identified, characterized by predominant upper-limb, lower-limb, or bulbar involvement. These subtypes exhibited distinct, consistent progression patterns across the analyses. Subtype stability was moderate short-term but limited longer-term; stage progression was largely monotonic. The bulbar subtype showed more rapid functional decline at both 180 and 365 days. Higher SuStaIn stage was associated with increased mortality. In an exploratory stage-stratified analysis, poorer survival was observed in the bulbar subtype than in the upper-limb subtype within the lower-stage group.
    CONCLUSIONS: This study reconstructed ALS subtype-specific functional progression trajectories and inferred disease stage using a widely accessible clinical scale. SuStaIn-derived subtypes characterized patterns of functional heterogeneity, and higher stage was associated with increased mortality. Further prospective comparative validation is needed to establish the prognostic and clinical utility of this framework.
    Keywords:  ALSFRS-R; Amyotrophic lateral sclerosis; Bulbar predominant; Clinical subtypes; SuStaIn
    DOI:  https://doi.org/10.1016/j.jns.2026.126224
  4. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Oct 19. 1-10
    Factors associated with post-tracheostomy survival in Amyotrophic Lateral Sclerosis.
    Alessandra Maccabeo, Sara Cabras, Stefano Callegaro, Maria Ida Pateri, Francesca Pili, Antonio Canosa, Umberto Manera, Francesca Palumbo, Enrico Matteoni, Giorgio Pellegrino, Emilio Minerva, Alessandro Ciravegna, Giulia Gianferrari, Monica Puligheddu, Cristina Moglia, Fabiola De Marchi, Letizia Mazzini, Jessica Mandrioli, Giuseppe Borghero, Adriano Chiò, Andrea Calvo, Rosario Vasta.
       OBJECTIVE: To identify demographic and clinical factors associated with post-tracheostomy survival using three well-characterized cohorts of patients with Amyotrophic Lateral Sclerosis (ALS).
    METHODS: ALS patients from the Piemonte and Valle d'Aosta ALS Register (PARALS) diagnosed between 1995-2019 interval who underwent tracheostomy were included. A multivariable Cox proportional hazards model was used to identify factors associated with post-tracheostomy survival. Significant findings were tested in two independent cohorts, the Emilia-Romagna Region ALS Register (ERRALS) and an incident ALS cohort from South Sardinia.
    RESULTS: A total of 449 patients from PARALS underwent tracheostomy during the study period, with a median post-tracheostomy survival of 16.3 months (IQR 4.0-45.0). Younger age at tracheostomy was associated with longer survival (HR 1.03 per one-year increase, 95%CI1.01-1.05, p = 0.001), as being married/cohabiting (HR 0.78, 95%CI0.61-0.98, p = 0.033), a longer diagnosis-to-tracheostomy interval (HR 0.84 per one-year increase, 95%CI0.79-0.90, p < 0.001) and a lower ALS Functional Rating Scale slope from onset to tracheostomy (HR 1.13 per one-unit increase, 95%CI1.03-1.25, p = 0.012). These associations were replicated in the independent cohorts, when data were available. Additionally, discharge to nursing homes was associated with poorer survival in the Sardinian cohort (HR 4.23, 95%CI2.49-7.19; p < 0.001), whereas a more recent year of tracheostomy was associated with longer survival in the ERRALS cohort (HR 0.95, 95%CI0.90-0.99; p = 0.019).
    DISCUSSION: We identified multiple factors associated with post-tracheostomy survival in ALS patients, encompassing clinical and demographic characteristics at tracheostomy as well as local factors influencing peri- and post-operative care. These findings may support decision-making and clinician-patient communication in the advanced stages of ALS.
    Keywords:  Amyotrophic Lateral Sclerosis; Motor neuron disease; prognosis; tracheostomy
    DOI:  https://doi.org/10.1080/21678421.2026.2742815
  5. Neurol Sci. 2026 Oct 17. pii: 865. [Epub ahead of print]47(11):
    Peripheral and cerebrospinal fluid inflammatory markers in sporadic amyotrophic lateral sclerosis an exploratory cross-sectional association study.
    Agnieszka Wełnicka-Wesołowska, Karolina Łuczkowska, Przemysław Nowacki, Edyta Paczkowska, Agnieszka Meller, Karolina Machowska-Sempruch, Bogusław Machaliński, Monika Gołąb-Janowska.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with an ambiguous etiology, whose onset may be linked to innate immune system activation outside the central nervous system (CNS). We investigated the association between peripheral blood and CNS inflammatory parameters in 45 sporadic ALS patients compared to 30 controls, analyzing peripheral blood tests (C-reactive protein [CRP], blood count, fibrinogen) and cerebrospinal fluid (CSF) immunological measures (Tumor Necrosis Factor alpha [TNF-α], TNF receptor type 1 [TNFR-1], CRP) alongside clinical characteristics. Results revealed significantly higher concentrations of TNFR-1 in the CSF of ALS patients compared to the control group (1,029.5 ± 176.0 vs. 846.1 ± 167.5 pg/ml; p < 0.0001). This difference remained significant in multivariable logistic regression adjusting for age and sex (OR 1.82 per 100 pg/ml increment, 95% CI 1.26-2.63; p = 0.0015). In an exploratory ROC analysis, CSF TNFR-1 discriminated patients from controls with an AUC of 0.78 (95% CI 0.67-0.88). TNFR-1 correlated with age (R = 0.32, p = 0.038), associations with disease severity and a lower concentration in bulbar-onset disease were exploratory and not robustly significant. Plasma and CSF CRP concentrations did not differ significantly between groups, but strongly correlated with each other in both ALS (R = 0.83) and control (R = 0.82) cohorts, indicating a disease-non-specific relationship. CSF TNFR-1 is independently associated with sporadic ALS and warrants further investigation as a candidate disease-associated inflammatory biomarker. Given the limitations, our findings do not prove diagnostic accuracy or causality. Longitudinal studies with disease controls and blood-CSF barrier integrity measures are needed.
    Keywords:  Amyotrophic lateral sclerosis - pathogenesis; Biomarker; Inflammation of the central nervous system; Neuroinflammation; TNF receptor 1
    DOI:  https://doi.org/10.1007/s10072-026-09480-9
  6. In Silico Pharmacol. 2026 ;14(3): 259
    Molecular recognition of axonal injury-associated candidate hub genes and predicted inhibitors across Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
    Ayesha Naseer, Naveed Iqbal, Ishrat Bibi, Syed Ali Raza Shah, Misbah Khalid, Ayesha Khalid.
      Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) have converging molecular pathologies such as neuroinflammation, mitochondrial dysfunction, and axonal degeneration, but do not have broadly effective disease-modifying therapies. A novel computational strategy was used in this study with an integrated in-silico pipeline to determine common candidate hub genes across AD, PD, and ALS and to computationally screen candidate inhibitors. The gene expression datasets were retrieved from the Gene Expression Omnibus database and analyzed with limma R package for blood-derived gene expression datasets for AD (GSE63060), PD (GSE99039) and ALS (GSE112680). A multi-dataset intersection analysis revealed 138 genes commonly upregulated and 0 commonly downregulated genes, which were functionally enriched in immune regulation, apoptotic signaling and mitochondrial instability pathways. Protein-protein interaction network analysis identified three key genes (MMP9, PTPN6 and TNFRSF1A) as high-confidence candidate hub genes for AD, PD, and ALS. The ZINC library of 34,853 compounds was screened for drug-like properties using QikProp to yield 16,466 drug-like compounds. Based on the comparative screening results, the structure of MMP9 (PDB ID: 8K5Y) was chosen for further analysis and two of the selected compounds ZINC04582833, ZINC00047690 were identified as the two highest ranked compounds with docking scores of - 10.4 and - 9.7 kcal/mol respectively. Both complexes were further evaluated by 100 ns MD simulations, showing RMSD profile stability, maintained secondary structure for both complexes. The results in this study make ZINC04582833 and ZINC00047690 computationally prioritized candidates for shared neurodegenerative targets for experimental validation.
    Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00774-6.
    Keywords:  Alzheimer's disease; Amyotrophic lateral sclerosis; Differential gene expression analysis; Molecular docking; Molecular dynamics simulation; Neurological diseases; Parkinson's disease
    DOI:  https://doi.org/10.1007/s40203-026-00774-6
  7. Nat Commun. 2026 Oct 22. pii: 10745. [Epub ahead of print]17(1):
    Tau isoform mapping across tissues and biofluids reveals a signature distinguishing Alzheimer's disease from amyotrophic lateral sclerosis.
    Samir Abu-Rumeileh, Henning Großkopf, Arthur Guthknecht, Alexander Mensch, Dirk Osterloh, Antonia Ratti, Julian Conrad, Caroline Stapf, Julia Krippner, Patrick Oeckl, Gisela Stoltenburg-Didinger, Alessio Maranzano, Petra Steinacker, Christopher M Weise, Lorenzo Barba, Lucio D'Anna, Hans-Wolfgang Klafki, Jens Wiltfang, Vincenzo Silani, Lutz Froelich, Nicola Ticozzi, Lucrezia Hausner, Dietmar Rudolf Thal, Jochen Hans Weishaupt, Ingolf Lachmann, Federico Verde, Markus Otto.
      Blood phosphorylated tau 217 (p-tau217) accurately detects Alzheimer's disease (AD) pathology but is also elevated in amyotrophic lateral sclerosis (ALS), likely reflecting peripheral (big) tau released from muscle. Assays selectively measuring brain-derived (BD-) tau and BD-p-tau217 are therefore needed. We analysed serum BD-tau and p-tau217 in ALS (n = 139), AD (n = 101) and controls (n = 75) using direct immunoassays and after BD-Tau immunoprecipitation (BD-Tau-IP), and tau species in brain (n = 16), spinal cord (n = 11) and muscle (n = 10) by targeted mass spectrometry. With the direct immunoassays, BD-tau and p-tau217 were increased in AD and ALS versus controls. After BD-Tau-IP, BD-tau and BD-p-tau217 were elevated in AD only, improving diagnostic accuracy. Mass spectrometry revealed a central-to-peripheral shift from BD-tau to big tau predominance, with exclusively big p-tau217 detected in muscle. Selective detection of BD-tau species improves the specificity of blood AD biomarkers by reducing peripheral tau confounding.
    DOI:  https://doi.org/10.1038/s41467-026-78390-3
  8. Neurobiol Dis. 2026 Oct 17. pii: S0969-9961(26)00405-5. [Epub ahead of print] 107659
    Cryo-EM advances in TDP-43 amyloid fibrils structure determination.
    Zhengdong Xu, Xi Chen, Wenjuan Yi.
      TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein whose pathological aggregation characterizes a spectrum of neurodegenerative disorders known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and chronic traumatic encephalopathy (CTE). Recent breakthroughs in cryo-electron microscopy (cryo-EM) have revolutionized our understanding of these diseases by resolving the atomic structures of TDP-43 amyloid fibrils. These structural insights have been pivotal in elucidating the transition from functional liquid-liquid phase separation (LLPS) to irreversible solid-state aggregation. This review synthesizes key cryo-EM findings from 2019 to 2026, encompassing fibrils formed by the full-length low-complexity domain, disease-relevant core fragments, and filaments extracted directly from patient tissues, as well as the pathological implications of distinct structural polymorphs. These findings not only deepen our understanding of the brain science aspects of the pathogenesis of TDP-43 proteinopathies, but also provide an important structural basis for the development of specific conformational diagnostic methods and targeted therapeutic drugs.
    Keywords:  Amyloid; Brain science; Cryo-EM; TDP-43; TDP-43 proteinopathies
    DOI:  https://doi.org/10.1016/j.nbd.2026.107659
  9. EBioMedicine. 2026 Oct 20. pii: S2352-3964(26)00395-6. [Epub ahead of print] 106511
    Cerebrospinal fluid amyloid and neurodegeneration biomarkers in the diagnosis and prognosis of amyotrophic lateral sclerosis: a multicohort observational study.
    Kazuki Obara, Shorena Janelidze, Daisuke Ito, Linda Karlsson, Munetaka Yamamoto, Andrea Mastrangelo, Sinh Tran, Koyo Tsujikawa, Yosuke Nishio, Tomoo Ogi, Veria Vacchiano, Rocco Liguori, Ryoichi Nakamura, Naoki Atsuta, Gen Sobue, Christer Nilsson, Piero Parchi, Masahisa Katsuno, Niklas Mattsson-Carlgren.
       BACKGROUND: Neurofilament light chain (NfL) is an established biomarker for amyotrophic lateral sclerosis (ALS). However, it remains unclear whether biomarkers reflecting amyloid-β metabolism (Aβ), tau (phosphorylated tau, pTau), and astrogliosis (glial fibrillary acidic protein, GFAP) can complement NfL in clinical applications. It is also unclear how Alzheimer's disease (AD) co-pathology affects disease progression in ALS.
    METHODS: We studied 264 patients with ALS and 164 disease-control participants, analysing baseline cerebrospinal fluid (CSF) NfL, Aβ peptides, pTau181, pTau217, and GFAP. A two-step diagnostic strategy was examined in individuals with intermediate NfL values, using machine-learning models. Prognostic associations were evaluated using linear mixed-effects and Cox models adjusted for established predictors; survival was additionally examined in pooled analyses including an external ALS cohort (n = 153).
    FINDINGS: Patients with ALS exhibited higher CSF NfL, Aβ38, Aβ40, Aβ42, pTau181, and pTau217 than controls, even within Aβ-negative subgroups. NfL discriminated ALS from controls with an AUC of 0.85 (0.82-0.88), which increased to 0.90 (0.88-0.92) in machine-learning models incorporating additional biomarkers. The machine-learning models maintained a high positive predictive value (0.90) for classifying cases with intermediate NfL values. Significant Aβ × NfL interactions were observed for longitudinal functional decline, and pooled survival analyses showed stronger associations between NfL and survival in the Aβ-positive ALS subgroup (14%) than in the Aβ-negative ALS subgroup (HR 4.02 [2.17-7.45] vs 1.62 [1.36-1.92]).
    INTERPRETATION: Multiple biomarker assessments can reduce misclassification of individuals with intermediate NfL values. CSF Aβ positivity modified the association between baseline NfL and disease progression. Personalised diagnosis and prognosis based on fine-grained co-pathology evaluation may enhance clinical management of ALS.
    FUNDING: This study was primarily supported by JST SPRING (JPMJSP2125). A complete list of funding organisations is provided in Acknowledgements.
    Keywords:  Amyloid beta-Peptides; Amyotrophic lateral sclerosis; Clinical trials as topic; Machine learning; Neurofilament light; Survival
    DOI:  https://doi.org/10.1016/j.ebiom.2026.106511
  10. Neurol Ther. 2026 Oct 21.
    Understanding Holistic Patient-Relevant Measurement in Amyotrophic Lateral Sclerosis: A Mixed-Methods Content Validity and Exploratory Rasch Analysis of Selected Clinical Outcome Assessments.
    William B Nowell, Nadine McGale, Oren Levy, Krystian Przydzial, Nick Patel, Sophie Cleanthous, Jinsy A Andrews, Diana Rofail.
       INTRODUCTION: Living with amyotrophic lateral sclerosis (ALS) has a profound impact on function and health-related quality of life (HRQoL). This mixed-methods study aimed to cognitively debrief selected ALS outcome measures to investigate their relevance and conduct exploratory Rasch Measurement Theory (RMT) analyses to assess targeting.
    METHODS: Semi-structured interviews were conducted (January-September 2024) with people living with ALS (PLwALS) and clinicians to cognitively debrief selected patient- and clinician-reported outcome (PRO and ClinRO) measures. The PRO measures debriefed with PLwALS were Rasch Overall ALS Disability Scale (ROADS), 5-item ALS Assessment Questionnaire (ALSAQ-5), and Neurological Fatigue Index for Motor Neurone Disease (NFI-MND). ROADS and ClinRO ALS Functional Rating Scale-Revised (ALSFRS-R) were debriefed with clinicians. Interview transcripts were qualitatively analyzed; structured codes were used to compile data on item relevance and comprehensiveness. Exploratory RMT analysis was conducted using quantitative data from PLwALS responses to evaluate selected PRO psychometric properties.
    RESULTS: Qualitative analysis of interviews with 31 PLwALS found that PROs were meaningful and relevant, and identified the relevance of individual items. Clinicians (n = 10) endorsed ALSFRS-R as a relevant and meaningful measure, and supported ROADS' conceptual coverage and response category. RMT analysis indicated evidence of good targeting, reliability, and item fit for the PROs, with some exceptions for ALSAQ-5.
    CONCLUSION: This study supports the use of ALSFRS-R, ROADS, ALSAQ-5, and NFI-MND to measure meaningful aspects of ALS, with support for ALSAQ-5 qualified by its limited measurement precision. Scores from these measures can provide important insights into the lived experience of PLwALS, characterizing disease progression and HRQoL.
    Keywords:  Amyotrophic lateral sclerosis; Clinical outcome assessments; Lived experience; Qualitative analysis; Quantitative analysis
    DOI:  https://doi.org/10.1007/s40120-026-01058-z
  11. J Neurol. 2026 Oct 21. pii: 672. [Epub ahead of print]273(11):
    Serum p-tau181 and p-tau217 levels in adolescents and adults with 5q spinal muscular atrophy.
    Caroline Deborah Stapf, Zeljko Uzelac, Louise Iterbeke, Arthur Guthknecht, Lorenzo Barba, David Strube, Anna Kölsch, Kathleen Kleeberg, Thomas Kendzierski, Andreas Roos, Petra Steinacker, Samir Abu-Rumeileh, Kristl G Claeys, Jochen Weishaupt, Alexander Mensch, Markus Otto.
       BACKGROUND: Reliable blood biomarkers for longitudinal monitoring in adolescent and adult 5q spinal muscular atrophy (SMA) are lacking. Phosphorylated tau (p-tau) species are elevated in serum in amyotrophic lateral sclerosis (ALS), where they may reflect peripheral nerve and muscle pathology. We aimed to investigate serum p-tau181 and p-tau217 as longitudinal biomarkers in adolescent and adult SMA and assessed associations with clinical parameters.
    METHODS: In this retrospective multi-centre study, we assessed serum p-tau181 and p-tau217 levels in adults with 5q SMA under treatment with nusinersen or risdiplam, comparing levels with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and non-neurodegenerative disease controls. Associations with motor function, respiratory capacity, creatine kinase (CK), and neurofilament light chain (NfL) were assessed using linear mixed-effects models adjusted for age and sex.
    RESULTS: Serum p-tau181 was higher in SMA than in disease controls (β = -0.48, 95%-CI -0.81 to -0.15), but lower than in ALS (β = 0.99, 95%-CI 0.58 to 1.39) and AD (β = 0.56, 95%-CI 0.11 to 1.00). P-tau181 declined from baseline to FUP2 (Δ median -1.80 pg/mL, IQR -5.90 to 2.10); p-tau217 showed no longitudinal change. P-tau181 and p-tau217 were positively associated with motor function, functional status, respiratory capacity, and CK, with no association with NfL. In exploratory analyses, higher baseline p-tau181 was associated with greater HFMSE decline (β = 1.79, 95%-CI 0.59 to 2.99).
    CONCLUSIONS: Serum p-tau181 and p-tau217 appear to reflect ongoing muscle turnover in adult SMA, declining as muscle mass decreases. Higher baseline p-tau181 was associated with subsequent functional deterioration, suggesting potential utility as a biomarker of active denervation and disease monitoring.
    Keywords:  Motor neuron disease; Phosphorylated tau (p-tau181; p-tau217); Serum biomarkers; Spinal muscular atrophy
    DOI:  https://doi.org/10.1007/s00415-026-14194-1
  12. Prog Neuropsychopharmacol Biol Psychiatry. 2026 Oct 23. pii: S0278-5846(26)00383-0. [Epub ahead of print] 111985
    Cellular senescence in ageing and neurodegenerative disorders: Molecular mechanisms, biomarkers, and therapeutic strategies.
    Aanchal Verma, Ahsas Goyal, Neetu Agrawal, Harlokesh Narayan Yadav.
      Cellular senescence has been increasingly associated with neurodegenerative disorders, potentially linking ageing-related cellular impairment with mitochondrial dysfunction, chronic inflammation, and disrupted intercellular signalling. The present study aims to explore the increasing relevance of cellular senescence among key cell types, including neurons, astrocytes, neural progenitor cells, microglia and oligodendrocyte-lineage cells across neurodegenerative ailments such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. This review discusses the findings of pre-clinical and clinical studies which suggest that senescence-associated features may contribute to neurodegeneration. Further, it provides an overview of the biomarkers used in the identification of senescence in the CNS. Also, the review examines senotherapeutic treatment approaches, highlighting their actions on different CNS cell types and the growing clinical evidence. It also points out the challenges in translating these approaches to clinical application, such as targeting specific cell types and the lack of suitable biomarkers. Collectively, present findings suggest that senescence-associated alterations may contribute to neurodegeneration, although their effects appear to vary across cell types and diseases.
    Keywords:  Ageing; Neurodegenerative; Senescence; Senolytics; Senomorphics
    DOI:  https://doi.org/10.1016/j.pnpbp.2026.111985
  13. J Cachexia Sarcopenia Muscle. 2026 Oct;17(5): e70405
    Plasma Proteomic Signatures Predict Incident Amyotrophic Lateral Sclerosis: A Prospective Study Stratified by C9orf72 Expansion.
    Wei-Ming Su, Qing-Qing Duan, Nan Zhang, Sheng-Yi He, Ru-Yin Liu, Xiang-Jin Wen, Xiao-Jing Gu, Yi Wang, Bei Cao, Yong-Ping Chen.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder for which reliable preclinical biomarkers to predict disease onset are currently lacking. Plasma proteomics offers a promising avenue for early detection. The identification of plasma proteins and pathways associated with incident ALS holds potential to improve early diagnosis, enable risk stratification and provide insights into disease mechanisms.
    METHODS: Employing the Olink Explore platform, we quantified 2920 plasma proteins within a prospective cohort of UK Biobank participants. Multivariate Cox proportional hazards regression was utilized to identify proteins associated with incident generalized ALS, C9-ALS (C9orf72-associated ALS) and non-C9-ALS. Enrichment analysis was conducted to delineate the biological pathways implicated by the identified proteins. Associations between plasma protein levels and the age at onset (AAO) of ALS were assessed via linear regression, while a multivariate Cox model was employed to evaluate the relationships between protein levels and ALS survival. We subsequently assessed potential causal relationships using Mendelian randomization (MR) and colocalization and analysed protein cross-sectional temporal patterns in ALS.
    RESULTS: In this prospective cohort study, we followed 52 584 participants from the UK Biobank for a mean of 11.8 years. During this period, 291 (0.55%) incident cases of ALS were identified, among whom 34 individuals carried the C9orf72 hexanucleotide repeat expansion mutation. Nine proteins demonstrated associations with all-type ALS risk (FDR < 0.05): NEFL (HR: 2.897), CSRP3 (HR: 1.233), MYBPC1 (HR: 1.352), MEGF10 (HR: 1.744), MYOM3 (HR: 1.289) and THBS4 (HR: 1.570) were identified as risk factors, whereas EGFLAM (HR: 0.402), ITGAV (HR: 0.284) and CD248 (HR: 0.573) exhibited protective effects. NEFL (HR: 2.742) and three additional proteins were primarily associated with non-C9-ALS, while only NEFL (HR: 4.403) and COL5A1 (HR: 3.072) showed significant associations with C9-ALS. When combined with age and sex, these proteins yielded area under the curve (AUC) values exceeding 0.750 for predicting ALS at 3, 5 and 10 years. Furthermore, elevated NEFL levels were correlated with an earlier onset of non-C9-ALS and began to increase approximately 9.27 years prior to diagnosis, reaching a peak 1-2 years before clinical presentation in non-C9ALS cases via cross-sectional temporal analysis. Pathway analysis implicated muscle-related, extracellular matrix, energy metabolism and inflammatory pathways.
    CONCLUSIONS: This investigation uncovers extensive alterations in plasma proteins associated with ALS risk, revealing potential novel biomarkers for both sporadic and C9orf72-linked forms of the disease. These results enhance our comprehension of early ALS pathogenesis and provide a foundation for subsequent biomarker identification and the development of targeted therapeutic strategies.
    Keywords:   C9orf72 ; NEFL; amyotrophic lateral sclerosis; plasma proteomics; risk prediction
    DOI:  https://doi.org/10.1002/jcsm.70405
  14. J Cachexia Sarcopenia Muscle. 2026 Oct;pii: e70410. [Epub ahead of print]17(5): e70410
    Plasma Lipidome Is Dysregulated in Amyotrophic Lateral Sclerosis and Associated With Life-Course Adiposity Polygenic Risk.
    Linjing Zhang, Leyuan Zhang, Yongping Zheng, Zhenhuang Zhuang, Lu Tang, Wei Zheng, Kailin Xia, Shan Ye, Tielun Yin, Tao Huang, Dongsheng Fan.
       OBJECTIVE: Although both pre-symptomatic adiposity and dysregulated lipid metabolism are implicated in amyotrophic lateral sclerosis (ALS), the mechanistic pathways linking adiposity to disease remain unclear. This study aimed to investigate how genetic predisposition to adiposity might influence ALS through specific lipid metabolic pathways.
    METHODS: We conducted mass spectrometry-based quantitative lipidomics on plasma from 104 ALS patients and 78 age- and sex-matched controls. Life-course adiposity polygenic risk scores (PRS) for birth weight, body fat percentage, appendicular lean mass and whole-body fat-free mass were constructed. Associations and PRS-by-disease interaction effects on the lipidome were evaluated.
    RESULTS: Compared to controls, ALS patients exhibited widespread lipid dysregulation. Seventy-eight lipid species were significantly altered (FDR  < 0.05, |Cohen's d| > 1.0), characterized by a predominant decrease in acylcarnitines (75% of species) and distinct shifts within sphingolipid and glycerophospholipid subclasses. A three-acylcarnitine candidate panel (C10:0, C12:0 and C18:2) using fivefold analysis with feature selection repeated within each training fold yielded an overall out-of-fold AUC of 0.958. Exploratory PRS-by-disease-status analyses identified 16 nominal interaction signals, including 13 acylcarnitines; no significant mediation effect of lipids between PRS and ALS risk was detected.
    CONCLUSION: These findings identify robust ALS-associated plasma lipid alterations, and our exploratory findings suggest that genetic predisposition to adiposity may shape the pattern of lipid metabolic disruption in ALS, offering new insights into the disease's metabolic pathophysiology.
    Keywords:  adiposity; amyotrophic lateral sclerosis; gene–environment interaction; lipidomic; polygenic risk score
    DOI:  https://doi.org/10.1002/jcsm.70410
  15. Trials. 2026 Oct 20. pii: 615. [Epub ahead of print]27(1):
    ABCD-Trial: study protocol for a randomized, double-blind, placebo-controlled study in patients with Amyotrophic lateral sclerosis for the evaluation of efficacy and safety of B-Cell Depletion with rituximab (ABCD).
    Friederike Ufer, Rosa Rössling, Annika Spottke, Robert Németh, Tamara Schaprian, Nadja Kemmerling-de Coninck, Anna Gamez, Rebecca Sterl, Pia Naumann, Nikolaus Behr, André Maier, Thomas Meyer, Patrick Weydt, Harald Prüss.
       BACKGROUND: The exact disease-causing mechanisms in ALS remain incompletely understood. A possible cause is inflammation of neurons. Compared to other neurodegenerative diseases, neuroinflammation is pronounced in ALS, presumably leading to disease progression and neuronal death. Patients with ALS can have neuronal autoantibodies and most notably antibody-producing cells in the cerebrospinal fluid. The CD20-binding therapeutic antibody rituximab targets these antibody-producing B-cells. Rituximab is a medication commonly used in neurology. Single patients with ALS have already been treated with rituximab, which was well tolerated. We therefore want to evaluate safety and efficacy of a treatment with rituximab in ALS patients in a double-blind placebo-controlled trial. With this trial we aim for slower disease progression and unveiling disease-causing mechanisms in ALS.
    METHODS: A total of 52 male and female patients older than 18 years with active sporadic ALS and disease duration of less than 24 months who are on a stable dose of riluzole (50 mg BID) should be included. Patients requiring assisted ventilation of any kind or have a known intolerance to the study medication rituximab are excluded. The study medication rituximab or placebo should be administered over a period of 52 weeks at 4 distinct time points, followed by a follow-up period of 79 weeks with 4 visits. Treatment efficacy should be evaluated using the ALS functioning scale ALSFRS-R-SE at every study visit (except safety visits). Safety will be assessed through regular laboratory analyses, adverse event (AE) and serious adverse event (SAE) monitoring, and CD20+ B-cell kinetics. The primary endpoint is the change in the ALS Functional Rating Scale-Revised (ALSFRS-R-SE) from baseline to week 79. Trial sites will be at Charité/DZNE Berlin and DZNE Bonn.
    DISCUSSION: ALS is a rapidly progressive neurodegenerative disease with limited treatment options. Recent preclinical in vivo studies suggest that B-cell-mediated autoimmunity contributes to disease progression. This trial will evaluate whether rituximab, which specifically depletes CD20+ B-cells, can slow ALS progression and provide insights into disease mechanisms.
    TRIAL REGISTRATION: The trial was registered in the German WHO-recognized primary register Deutsches Register Klinische Studien DRKS (German Clinical Trials Register) on 3/07/2023 under registration number DRKS00030948.
    Keywords:  Amyotrophic lateral sclerosis; Autoantibody; Autoimmune CNS disorder; Neurodegeneration; Rituximab
    DOI:  https://doi.org/10.1186/s13063-026-10022-z
  16. Nanomedicine (Lond). 2026 Oct 17. 1-23
    The role of nanomedicine in infectious diseases of the central nervous system: a narrative review.
    Stephanie Somerville, Horacio Bach.
      Infectious diseases in the central nervous system (CNS) are a global health problem, causing significant morbidity and mortality. One of the main challenges in treating CNS infections is the blood-brain barrier (BBB), which limits drug delivery to the brain. During infections, brain-resident immune cells, release inflammatory mediators, which further contribute to neuroinflammation and damage. Nanomedicine offers an alternative for CNS treatment that has been explored in several types of infections. Across preclinical studies, nanomedicine approaches have demonstrated substantial improvements in CNS delivery and therapeutic outcomes, including reductions in brain pathogen burden of up to 3 log10 colony-forming units, increases in brain drug concentrations of 3-4-fold, and survival improvements of up to 100% in selected infection models. However, the literature remains fragmented across pathogens, nanomaterial platforms, and experimental models, with few direct comparisons and limited clinical validation. This review provides a comprehensive, up-to-date synthesis of the current evidence, integrating emerging nanomedicine strategies across major CNS infections while highlighting common therapeutic approaches, clinical applications, limitations, and key gaps that must be addressed to advance these technologies toward clinical translation. It also highlights advances and techniques in nanomedicine for treating brain infections, discusses clinical applications, and promotes innovation and future directions.
    Keywords:  Central nervous system; infection; lipid-based nanoparticles; liposomes; nanostructured-lipid carriers; solid lipid nanoparticles
    DOI:  https://doi.org/10.1080/17435889.2026.2749655
  17. Front Neurol. 2026 ;17 1908455
    Neuromelanin-sensitive magnetic resonance imaging in the diagnosis and assessment of Parkinson's disease.
    Die Zhang, Aishanjiang Yusufujiang, Hongyan Li.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized primarily by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc); noradrenergic neurons in the locus coeruleus (LC) are also frequently affected. Because clinical motor symptoms usually emerge only after substantial neurodegeneration has occurred, there is a compelling need for noninvasive imaging biomarkers capable of detecting early pathological changes. Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) generates neuromelanin-related image contrast in the SNpc and LC and can indirectly reflect the structural integrity of these catecholaminergic nuclei. Current evidence suggests that NM-MRI may be useful for distinguishing patients with PD from healthy controls, supporting the differential diagnosis of selected atypical parkinsonian syndromes and essential tremor, assessing disease stage, monitoring longitudinal change, and evaluating high-risk individuals in the prodromal phase. This review provides an updated account of recent advances in the use of NM-MRI for diagnostic support, differential diagnosis, prodromal assessment, longitudinal monitoring, multimodal imaging, and artificial intelligence-based analysis, and discusses its clinical role relative to other imaging and fluid biomarkers. Combining NM-MRI with complementary imaging measures, such as quantitative susceptibility mapping and diffusion MRI, and with automated analytical methods may further enhance pathological characterization and quantitative assessment. However, the available evidence is derived largely from single-center or case-control studies with limited sample sizes. Substantial variability may arise from differences in scanners, magnetic field strengths, acquisition protocols, and analytical methods, while independent external validation and prospective multicenter longitudinal evidence remain limited. The biological basis of the NM-MRI signal has not been fully established, and artificial intelligence models developed for NM-MRI remain vulnerable to overfitting, limited interpretability, and limited cross-center generalizability. Accordingly, NM-MRI cannot currently serve as a stand-alone diagnostic tool for PD or replace diagnosis based on comprehensive clinical assessment. It is better regarded as a promising complementary imaging biomarker and research tool. Before NM-MRI can be widely used for routine clinical diagnosis, disease monitoring, or as a clinical trial outcome measure, acquisition and analytical methods must be further standardized, and its performance must be evaluated in large, prospective, multicenter longitudinal studies.
    Keywords:  Parkinson’s disease; imaging biomarker; multimodal imaging; neuromelanin-sensitive magnetic resonance imaging; substantia nigra
    DOI:  https://doi.org/10.3389/fneur.2026.1908455
  18. J Neurol. 2026 Oct 21. pii: 673. [Epub ahead of print]273(11):
    Neurotransmitter-defined cerebral vulnerability patterns in frontotemporal lobar degeneration (FTLD).
    Marlene Tahedl, Alison Toomey, Naser Mandal, Sarah Mangan, We Fong Siah, Ee Ling Tan, Orla Hardiman, Jana Kleinerova, Mary Clare McKenna, Siobhan Hutchinson, Jasmin Lope, Peter Bede.
       BACKGROUND: Frontotemporal dementia syndromes encompass a genetically, clinically and radiologically heterogeneous set of conditions with distinctive clinical and imaging characteristics. The main FTD phenotypes exhibit strikingly different disease burden patterns with a predilection to specific brain regions and relative sparing of others. The apparent selectivity of cerebral involvement in FTD has not been fully elucidated.
    METHODS: A prospective neuroimaging study has been undertaken with a uniform imaging protocol to characterise atrophy patterns in ALS-FTD, behavioural variant FTD, nonfluent variant primary progressive aphasia, and semantic variant primary progressive aphasia and evaluate associations with physiological neurotransmitter receptor expression maps. Anatomical correlations between focal volume loss and a large panel of neurotransmitters were systematically evaluated and associations ranked.
    RESULTS: Associations were noted with GABAergic, opioid, cannabinoid, microglial and acetylcholine systems in ALSFTD-C9NEG. Correlations were observed with opioid, glutaminergic, and synaptic vesicle glycoprotein 2A receptor populations in ALSFTD-C9POS. Atrophy in bvFTD showed predilection to serotonergic, glutaminergic, opioid, GABAergic and cannabinoid circuits. Volume loss in nfvPPA colocalised with GABAergic, opioid, microglial, serotonergic, cannabinoid, acetylcholine, glutaminergic and dopaminergic networks. A multitude of neurotransmitter populations are implicated in svPPA including opioid, serotonergic, GABAergic, dopaminergic, and microglial systems.
    DISCUSSION: The distinctive neuroimaging signatures of FTD phenotypes exhibit spatial associations with physiological neurotransmitter receptor density maps. The propensity of atrophy to specific brain regions in FTD subtypes may be defined by neurotransmitter populations. Our findings indirectly support the notion of neurotransmitter-system defined connectivity-based disease propagation in FTD.
    Keywords:  ALS; Amyotrophic lateral sclerosis; FTD; Frontotemporal dementia; MRI; Neuroimaging; Neurotransmitter systems; Spatial correlations
    DOI:  https://doi.org/10.1007/s00415-026-14216-y
  19. Iran J Basic Med Sci. 2026 ;29(11): 1617-1630
    Nose-to-brain drug delivery: A new frontier in targeted therapeutics.
    Karakavalasa Svvs Sai Sampath, Rama Devi Korni.
      Delivering therapeutics to the Central Nervous System (CNS) remains a major challenge in drug development, largely because the blood-brain barrier (BBB) limits brain exposure for most systemically administered agents. Among alternative delivery routes, intranasal administration has attracted significant interest because it leverages direct anatomical connections between the nasal cavity and the brain, thereby reducing reliance on BBB permeability. This review examines the nasal route, focusing on how olfactory and trigeminal neural pathways contribute to drug transport into the CNS. Rather than assuming a single dominant route, the relative roles of extracellular perineural diffusion, intracellular neuronal transport, perivascular movement, and cerebrospinal fluid-associated distribution are evaluated in light of existing experimental evidence. Key factors that limit or enhance intranasal brain delivery-including mucociliary clearance, local enzymatic activity, drug physicochemical properties, formulation design, and patient-specific variability-are discussed with attention to their practical implications. Recent advances in formulations, such as mucoadhesive and in situ gelling systems, particulate and lipid-based carriers, dendrimers, and stimuli-responsive platforms, are reviewed alongside developments in nasal delivery devices that influence regional deposition.
    Keywords:  Brain targeting; Central nervous system- targeting; Intranasal; Nanoparticle; Nose-to-brain
    DOI:  https://doi.org/10.22038/ijbms.2026.93677.20210
  20. Metab Brain Dis. 2026 Oct 21. pii: 243. [Epub ahead of print]41(1):
    Linking protein misfolding and heat stress: a common role for the kynurenine pathway.
    Dorothy Wasike, Petra Majerova, Timotej Jankech, Andrej Kovac.
      The kynurenine pathway (KP) of tryptophan metabolism is emerging as a key regulator of immune response, neuroinflammation, and neurodegeneration. Tryptophan-derived metabolites influence multiple processes, including excitotoxicity, oxidative stress, mitochondrial dysfunction, and protein aggregation, which are underlying mechanisms in major neurological disorders. Dysregulation of the KP leads to an imbalance between neuroactive metabolites such as kynurenic acid quinolinic acid and 3-hydroxykynurenine, contributing to neuronal dysfunction and disease progression. This imbalance is associated with chronic proteinopathies such as Alzheimer's disease and Parkinson's disease, where persistent neuroinflammation and excitotoxicity sustain the activation of KP and subsequent neurodegeneration. Importantly, KP activation is not only limited to chronic conditions but may also occur in acute neurological insults such as heatstroke, where impaired thermoregulation contributes to systemic inflammatory responses, oxidative stress, and disruption of the blood-brain barrier. Consequently, this facilitates the influx of peripheral kynurenine into the brain and its conversion into neuroactive metabolites, linking peripheral immune activation and neuronal injury. These findings highlight KP as a mechanistic bridge between acute and chronic neuropathological processes. In addition, the KP involvement in NAD⁺ production links immune activation and cellular energy metabolism, subsequently increasing neuronal vulnerability, particularly under stress. Emerging evidence further supports the potential of KP metabolites as diagnostic biomarkers for disease progression and severity, as well as possible therapeutic targets. Targeting key enzymes within the KP may offer novel strategies to reduce neurotoxicity and restore metabolic balance, which subsequently improves clinical outcomes.
    Keywords:  Heat stress; Heatstroke; Kynurenine pathway; Neurodegenerative diseases; Neuroinflammation; Protein misfolding; Proteinopathies; Tryptophan metabolism
    DOI:  https://doi.org/10.1007/s11011-026-02011-7
  21. Neuroscience. 2026 Oct 23. pii: S0306-4522(26)00706-2. [Epub ahead of print]
    State transitions in amyotrophic lateral sclerosis: mechanistic convergence and biomarker-guided stratification.
    Mo Nasb, Dan Yang, Tayyab Hamid Malik, Dandan Xu, Lamis Dayoub, Jing Zhou, Yan Zhao.
       BACKGROUND: Biological heterogeneity is a major obstacle to therapeutic development in amyotrophic lateral sclerosis (ALS). Cross-sectional pathway labels do not show whether a mechanism is active or treatment-relevant in an individual patient.
    METHODS: We conducted a structured critical narrative review informed by the Scale for the Assessment of Narrative Review Articles. MEDLINE, Embase, PubMed, and CENTRAL were searched for English-language literature published from 1 January 2015 to 7 August 2026; seminal earlier studies were identified by citation tracking. Human genetic, pathological, longitudinal biomarker, multi-omic, imaging, neurophysiological, and interventional evidence was prioritized. Evidence was appraised by human proximity, temporality, replication, mechanistic specificity, and treatment relevance.
    RESULTS: Evidence supports interacting RNA/proteostasis, nucleocytoplasmic-transport, glial-inflammatory, and energetic-metabolic processes, but current evidence does not yet support the use of any candidate state for individual treatment assignment. The most mature temporal example is loss of TDP-43 splicing repression before neurofilament elevation in genetically at-risk individuals. Nucleocytoplasmic-transport evidence is strongest in C9orf72 disease; inflammatory and metabolic signals are confounded by disease burden and systemic illness; and the gut-brain axis remains a context-dependent amplifier. We propose prespecified transition rules, evidence grades, and biomarker-by-treatment interaction tests.
    CONCLUSIONS: A state-transition model becomes clinically useful when longitudinal measurements add value beyond clinical predictors and injury markers and prospectively identify differential treatment benefit.
    Keywords:  Amyotrophic lateral sclerosis; Biomarkers; Disease progression; Narrative review; Patient stratification; Precision medicine
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.10.036
  22. IBRO Neurosci Rep. 2026 Dec;21 955-962
    Blood-brain barrier junctional proteins as potential biomarkers of cerebral ischaemia and reperfusion injury.
    Meaad Almusined, Pragati Kakkar, Nadira Y Yuldasheva, Hema Viswambharan, Tarun Kakkar, Sikha Saha.
       Background: Cerebral ischaemia/reperfusion (CI/R) damage involves obstructing the blood supply to the brain, followed by restoring cerebral circulation through thrombolytic treatment. The blood-brain barrier (BBB) is a specialised structure separating the brain from peripheral blood circulation and plays an important role in brain function. However, little is known about CI/R-induced BBB damage and changes in circulatory biomarkers.
    Methods and results: This novel study aims to examine the changes in BBB tight-junctional (TJ) proteins (Zonula occludens-1, Occludin and Claudin-5) in the hippocampus of the brain and determine the levels of these proteins in a mouse model of CI/R induced by bilateral common carotid occlusion. Expressions of BBB TJ proteins in the hippocampus were examined by immunohistochemistry and Western blotting. The levels of these proteins in blood serum were measured by Enzyme-Linked Immunosorbent Assay.
    Conclusion: The results showed a significant decrease in BBB TJ proteins in the hippocampus, with increased levels of these proteins in blood serum in ischaemic mice as compared to sham-operated mice suggesting that these proteins can be used as potential biomarkers for the diagnosis of CI/R injury.
    Keywords:  Biomarker; Blood-brain barrier; Brain ischaemia; Stroke; Tight junction protein
    DOI:  https://doi.org/10.1016/j.ibneur.2026.09.021
  23. Theranostics. 2026 ;16(16): 9322-9345
    Early micro- and nanoscale microglial responses to blood-brain barrier modulation by transcranial focused ultrasound.
    Elisa Gonçalves de Andrade, Jared VanderZwaag, Rikke Hahn Kofoed, Katherine Picard, Keelin Henderson Pekarik, Micaël Carrier, Fernando González Ibáñez, Mohammadparsa Khakpour, Kullervo Hynynen, Isabelle Aubert, Marie-Ève Tremblay.
      Modulation of the blood-brain barrier (BBB) using transcranial focused ultrasound with intravenous microbubbles (FUS) has progressed to clinical trials. Guided by magnetic resonance imaging (MRI), FUS significantly increases local BBB permeability for approximately 6-24 h in mice, with an ensuing mild inflammation. Microglia, as the immune cells of the brain, are stimulated by FUS-BBB modulation, although the timing and nature of their responses remain unclear. In this study, we characterized the cellular (i.e., density, distribution, and morphology) and subcellular (i.e., ultrastructure) microglial alterations early after FUS-BBB modulation.
    Methods: We targeted the hippocampi of adult, male mice with MRI-guided FUS in the presence of intravenous microbubbles. At 1 h and 24 h after FUS-BBB modulation, we investigated i) the density and distribution of ionized calcium-binding adaptor molecule 1 (Iba1)-positive (+) microglia; ii) the morphology of Iba1+ soma and processes; and iii) the microglial organelles and contacts using scanning electron microscopy.
    Results: Microglial density and distribution were unchanged at 1 h and 24 h. However, FUS-BBB modulation was associated with elongated microglial cell bodies at both time points. At 1 h, microglia shifted to compact shapes with stubby processes, whereas at 24 h, they were larger, with fewer processes. At the nanoscale, microglia preserved interactions with blood vessels, but they increased their contacts with swollen astrocytic endfeet at 1 h and 24 h. By 24 h after FUS-BBB, microglia contacted pre-synaptic elements and extracellular space pockets less frequently, with ultrastructural indications of changes in metabolic demand and lysosomal activity.
    Conclusion: At 1 h and 24 h after FUS-BBB, traits of microglial surveillance were maintained, despite a shift in morphology associated with injury shielding in a subset of cells. FUS-BBB modulation appears to temporarily modify lysosomal, but not phagocytic properties, of microglia and to reduce ultrastructural indications of pre-synaptic remodeling early after treatment.
    Keywords:  blood-brain barrier modulation; focused ultrasound; microglia; scanning electron microscopy; ultrastructure
    DOI:  https://doi.org/10.7150/thno.131051
  24. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Oct 21. 1-8
    End-of-life care of patients with amyotrophic lateral sclerosis and home mechanical ventilation: the national population-based DISCOVERY study.
    Mikaela Dalkvist, Karin Ersson, Stefan Bergström, Magnus Ekström, Össur Ingi Emilsson, Ludger Grote, Caroline Ingre, Ulf Kläppe, Staffan Lundström, Ingela Nygren, Josefin Sundh, Andreas Palm.
      Background: Home mechanical ventilation (HMV), including noninvasive ventilation (NIV) and invasive ventilation (IV), is increasingly used in people with amyotrophic lateral sclerosis (pwALS), but its impact on end-of-life care remains unclear. Objective: To examine whether ventilation pathway (NIV or IV) influences symptom prevalence and relief during the final week of life in pwALS. Secondary objectives were to assess end-of-life discussions, place and cause of death, and anticipated death. Methods: This national, population-based retrospective cohort study included pwALS using HMV in the Swedish National Quality Registry for Respiratory Failure (Swedevox), cross-linked with the Swedish Register of Palliative Care, which contains staff-reported end-of-life data, and other national registries. Results: Among 652 pwALS, 609 received NIV (mean age 66 years, 42% female) and 43 IV (mean age 60 years, 42% female). Anxiety and breathlessness were more common in the NIV group (76% vs 48% and 72% vs 31%, both p < 0.001), while prevalence and relief of other symptoms were similar between groups. Most patients had end-of-life discussions (NIV 87%, IV 92%). NIV patients more often died in specialized palliative wards (22% vs 7%, p = 0.023). Most deaths were due to ALS (96%) and were anticipated (NIV 94%, IV 88%). Conclusions: In pwALS with HVM, NIV was associated with higher rates of anxiety and breathlessness in the final week of life, but the ventilation pathway did not influence overall symptom relief. End-of-life communications and cause of death were similar; place of death differed by ventilation pathway; however, most deaths were anticipated.
    Keywords:  amyotrophic lateral sclerosis; end-of-life care; home mechanical ventilation; invasive ventilation; non-invasive ventilation
    DOI:  https://doi.org/10.1080/21678421.2026.2747563
  25. Nat Rev Neurol. 2026 Oct 23.
    Mitochondrial dysfunction in neurology: biomarkers and clinical implications.
    Elena Rossini, Matteo Garibaldi, Michael G Hanna, Robert D S Pitceathly, Chiara Pizzamiglio.
      Mitochondrial dysfunction is increasingly recognized as a shared downstream pathogenic mechanism across a wide spectrum of neurological disorders, ranging from primary mitochondrial diseases to conditions including amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease, multiple sclerosis, hereditary ataxias and idiopathic inflammatory myopathies. This Review examines the role of mitochondrial biomarkers in improving diagnostic accuracy, patient stratification and monitoring of disease progression and therapeutic response. Primary mitochondrial diseases are presented as proof-of-concept models of impaired oxidative phosphorylation, providing a framework for biomarker identification and validation with translational relevance to other neurological diseases. Mitochondrial biomarkers can be broadly categorized into four domains: fluid biomarkers, reflecting metabolic alterations and stress signalling; genetic biomarkers, capturing mitochondrial DNA integrity and dynamics; multi-omics approaches, integrating transcriptomic, proteomic and metabolomic signatures; and imaging biomarkers, enabling in vivo assessment of structural and functional consequences of mitochondrial dysfunction. Across disorders, these biomarkers reveal shared disturbances in bioenergetics, redox homeostasis, mitochondrial genome maintenance and inflammatory signalling. However, clinical implementation remains limited by methodological heterogeneity, biological variability and reduced disease specificity. Integrated, multimodal biomarker strategies, combined with longitudinal validation, will be essential for supporting precision medicine and guiding the development of therapies to target mitochondrial pathways in neurology.
    DOI:  https://doi.org/10.1038/s41582-026-01274-z
  26. Comput Biol Chem. 2026 Oct 21. pii: S1476-9271(26)00628-6. [Epub ahead of print]126(Pt 2): 109501
    Intelligent exogenous predictive networks for nonlinear Parkinson's disease model involving delay with effects of immunotherapy.
    Naveed Ishtiaq Chaudhary, Aqib Mukhtar, Iqra I Chaudhary, Muhammad Asif Zahoor Raja.
      Artificial intelligence is used to simulate, solve, or approximate the dynamics of complex neurodegenerative diseases through accurate prediction. Parkinson's disease (PD) is a progressive disorder caused by the loss of dopaminergic neurons, leading to motor impairments such as muscle stiffness, tremors, and Bradykinesia. In this study, artificial intelligence-driven nonlinear autoregressive exogenous neural networks (AI-NARX-NN) are applied to the existing mathematical model reflecting the dynamics of innate as well as adaptive immune responses to PD under immunotherapy (IAIR-PDI). The IAIR-PDI model is characterized by a delay differential system of five classes representing the densities of healthy neurons, affected neurons, extracellular alpha-syn, activated microglia, and activated T cells. The performance of the AI-NARX-NN is investigated in scenarios of active immunization, passive immunization, and no treatment in the IAIR-PDI model. In the active immunization case, short antigenic peptide vaccination is given to the patients that mimics alpha-syn to generate antibodies, whereas in the passive immunization case, antibody vaccination is given directly to PD patients. The simulation results, including mean-square-error-based convergence curves, histograms, error correlation, solution plots, and corresponding absolute errors, confirm strong agreement between the AI-NARX-NN predictions and the reference numerical solutions, supporting the accuracy of the proposed scheme for the IAIR-PDI model with different time delays.
    Keywords:  Active & passive immunization; Alpha-synuclein; Immunotherapy; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.compbiolchem.2026.109501
  27. J Neurol. 2026 Oct 22. pii: 680. [Epub ahead of print]273(11):
    Locus coeruleus abnormalities on neuromelanin-sensitive MRI in Parkinson's disease: a systematic review and meta-analysis.
    Jiale Zhao, Naibijiang Abuliezi, Rurui Wei, Yihan Sun, Alimire Aikemu, Junyan Lei, Yanyan Wu, Beisha Tang, Jifeng Guo, Qinfen Wu.
      Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) enables in vivo assessment of locus coeruleus (LC) integrity, but findings in Parkinson's disease (PD) vary across cohorts and methods. We searched PubMed/MEDLINE, Embase, Web of Science Core Collection and Scopus from inception to 5 September 2026 and pooled independent PD-healthy control (HC) comparisons using random-effects models. Sixty-five reports were included, of which 17 contributed to at least one main pooled outcome. The primary LC-signal analysis included 14 independent cohorts (1,078 participants with PD and 543 HCs) and showed lower LC signal in PD (Hedges' g = - 0.95, 95% confidence interval (CI) - 1.32 to - 0.57; P = 0.00011). Between-study heterogeneity was substantial (I2 = 88.4%), and the 95% prediction interval crossed zero (- 2.28 to 0.38). The LC-volume analysis included five independent cohorts (215 participants with PD and 134 HCs) and likewise showed lower values in PD (g = - 0.87, 95% CI - 1.13 to - 0.62; P = 0.00071; I2 = 0%). The negative mean LC-signal effect was preserved across sensitivity analyses, but every specification-level prediction interval crossed zero. Of the 65 reports, 64 yielded 243 secondary-outcome records, of which 102 contained directly usable quantitative information; however, no additional outcome cluster simultaneously met the criteria for construct compatibility, cohort independence and numerical poolability. LC NM-MRI shows group-level differences in PD, but LC-signal differences vary across settings. These comparisons do not establish individual diagnostic accuracy. Clinical translation will require harmonized acquisition, analysis and reporting, together with independent, multicentre and longitudinal validation. This review was registered with PROSPERO (CRD420261498031).
    Keywords:  Locus coeruleus; Meta-analysis; Neuromelanin-sensitive MRI; Parkinson’s disease; Systematic review
    DOI:  https://doi.org/10.1007/s00415-026-14226-w
  28. Parkinsonism Relat Disord. 2026 Oct 22. pii: S1353-8020(26)00853-9. [Epub ahead of print]153 109026
    Altered IL-23/IL-17A immune axis in Parkinson's disease: An exploratory analysis.
    Saikat Dey, Nikhitha Sreenivas, Thrinath Mullapudi, Shweta Prasad, Ravi Yadav, Pramod Kumar Pal, Jitender Saini, Monojit Debnath.
       OBJECTIVE: Parkinson's disease (PD) is a progressive neurodegenerative disorder with a multifactorial basis. Immune dysregulation, both in the periphery and the brain, has been suggested to contribute to neurodegeneration in PD. Recent research has suggested a crucial role of T lymphocytes, especially the Th17 lineage, in α-synuclein-mediated neurodegenerative disorders. Whether Th17 cells exhibit pathogenic potential in PD is not adequately known. In this study, the role of cytokines that regulate the commitment, development, pathogenic transformation, and effector function of Th17 cells was examined in patients with PD.
    METHODS: This case-control study was conducted on 46 patients with PD and an equal number of age and sex-matched healthy controls (HC). The serum levels of five Th17-pathway-related cytokines, such as IL-1β, IL-6, TNF-α, IL-23, and IL-17A, were measured in all the study participants by Multiplex Suspension Assay. The serum cytokine levels were compared between patients with PD and HC.
    RESULTS: Serum levels of IL-6 (p < 0.001), IL-23 (p < 0.001), TNF-α (p = 0.027), and IL-17A (p = 0.004) were significantly elevated in patients with PD compared to HC. Importantly, IL-6 levels showed a significant positive correlation with TNF-α, IL-23, and IL-17A levels, while IL-23 levels positively correlated with the levels of IL-17A.
    INTERPRETATION: The findings suggest elevated levels of inducer, mediator, and effector cytokines of the inflammatory Th17 cells in PD. Furthermore, the significant positive correlation between IL-23 and IL-17A suggests an activated IL-23/IL-17A immune axis in PD.
    Keywords:  Cytokines; IL-23/IL-17A axis; Neuroinflammation; Parkinson's disease; Th17 pathway
    DOI:  https://doi.org/10.1016/j.parkreldis.2026.109026
  29. Jpn J Radiol. 2026 Oct 22.
    Dissociable associations of free-water fraction and DTI-ALPS index with disease manifestation and mutation carrier status in Parkinson's disease.
    Chang Liu, Xi Liu, Meng Dong, Wenze Li, Hongfa Zhang, Lu Zhang, Yuqing Zhang, Yangmei Chen.
       PURPOSE: Parkinson's disease (PD) is a biologically heterogeneous disorder. Diffusion MRI-derived free-water fraction (FWf) and DTI-ALPS index have been proposed as biomarkers of PD-related brain alterations; however, their relationships with clinical disease manifestation and genetic susceptibility remain unclear. This study investigated whether substantia nigra pars compacta (SNc) FWf and DTI-ALPS indices show different associations with disease status and mutation carrier status across the PD continuum.
    MATERIALS AND METHODS: Diffusion MRI data from the Parkinson's Progression Markers Initiative were analyzed, including healthy controls (HCs), non-manifesting mutation carriers (NMCs), and patients with sporadic or genetic PD. A 2 × 2 factorial analysis of covariance was performed to assess the effects of disease status and mutation carrier status on SNc FWf and DTI-ALPS indices. Exploratory longitudinal associations between baseline imaging measures and 4-year clinical outcomes were examined using multivariable linear regression with adjustment for the corresponding baseline clinical measures.
    RESULTS: Among 284 participants (63 HCs, 48 NMCs, 126 sporadic PD patients, and 47 genetic PD patients), mean SNc FWf showed a significant main effect of disease status, whereas mutation carrier status and the interaction effect were not significant. Sporadic PD patients exhibited higher SNc FWf than HCs and NMCs. In contrast, the left-sided DTI-ALPS index was associated with mutation carrier status. NMCs had lower left-sided DTI-ALPS indices than HCs and sporadic PD patients. In the exploratory longitudinal analysis, higher baseline mean SNc FWf was associated with a higher 4-year MDS-UPDRS Part II score, although this association was not significant when the analysis was restricted to participants with manifest PD.
    CONCLUSIONS: SNc FWf and DTI-ALPS may capture complementary aspects of PD heterogeneity. SNc FWf appears more closely related to clinical disease expression, whereas DTI-ALPS index may reflect differences associated with genetic susceptibility. Further validation in larger mutation-stratified and longitudinal cohorts is warranted.
    Keywords:  Analysis along the perivascular space; Free water; Genetic susceptibility; Parkinson’s disease; Substantia nigra
    DOI:  https://doi.org/10.1007/s11604-026-02105-3
  30. Neuroimage Clin. 2026 Oct 21. pii: S2213-1582(26)00142-7. [Epub ahead of print]52 104082
    Diagnostic performance and methodological heterogeneity of neuromelanin-sensitive MRI in Parkinson's disease: A systematic review and meta-analysis.
    Rayo Akande, Thomas Kustermann, Štefan Holiga, Judith Anzures-Cabrera, Gennaro Pagano.
       BACKGROUND: Parkinson's disease (PD) diagnosis remains primarily clinical and is often delayed until substantial neurodegeneration has occurred. Neuromelanin-sensitive MRI (NM-MRI) assesses the integrity of neuromelanin-rich nuclei affected in PD, the substantia nigra pars compacta (SNpc) and locus coeruleus (LC), but its diagnostic performance, technical determinants, and translational applicability remain unclear amid heterogeneity. We aimed to quantify diagnostic accuracy, determine whether performance varies across methodological approaches, and contextualise evidence from clinically relevant settings.
    METHODS: We systematically reviewed NM-MRI diagnostic studies through December 2025. QUADAS-2 assessed risk of bias. Sensitivity and specificity were jointly pooled using a bivariate model, and AUC using random-effects meta-analysis. Subgroup analyses and exploratory meta-regressions assessed methodological heterogeneity; broader clinical evidence was synthesised qualitatively.
    RESULTS: Thirty-nine studies were included. Across 20 PD-versus-healthy-control (HC) studies (878 PD; 690 HCs), pooled sensitivity was 89.03% (95% CI 86.01-91.45%), specificity 87.02% (95% CI 82.76-90.34%), PLR 6.86, NLR 0.126, and DOR 54.37. Across 32 studies (1411 PD; 1086 HCs), pooled AUC was 0.909 (95% CI 0.884-0.929; I2 = 64.6%). No significant unadjusted differences emerged by sequence, dimensionality, segmentation, or measurement type. NM-MRI abnormalities were detectable across prodromal, early- and advanced-stage PD, although global measures showed limited discrimination between disease stages. Subregional measures captured phenotypic variation, genotype discrimination was limited, and PD-versus-ET/APS performance was promising but variable, within small, heterogeneous evidence bases.
    CONCLUSION: NM-MRI is a promising non-invasive imaging biomarker for PD, with strong discrimination across diverse methodological approaches. Harmonised acquisition and analysis, externally validated diagnostic thresholds, and prospective multicentre studies in clinically representative populations are needed to support future clinical implementation.
    Keywords:  Candidate imaging biomarker; Diagnosis; Meta-analysis; Neuromelanin-sensitive MRI; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.nicl.2026.104082
  31. Parkinsonism Relat Disord. 2026 Oct 15. pii: S1353-8020(26)00848-5. [Epub ahead of print]153 109021
    Hierarchical deep learning-radiomics fusion for differentiating Parkinson's disease from atypical Parkinsonism using FP-CIT imaging.
    Jun Kim, Young Jae Kim, Kawngwoo Park, Kwang Gi Kim.
       BACKGROUND: Parkinson's disease (PD) and atypical Parkinsonism (AP) are challenging to differentiate, particularly in the early stages, because of overlapping motor symptoms and similar dopaminergic neurodegenerative patterns. We developed an interpretable artificial intelligence (AI) framework integrating deep learning and radiomics using automatically extracted striatal regions of interest (ROIs) from FP-CIT imaging for the differential diagnosis of Parkinsonian disorders.
    METHODS: A total of 228 participants, including healthy controls (HC), patients with PD, and patients with AP, were retrospectively analyzed. Striatal ROIs were automatically extracted from FP-CIT images using a hotspot-based bounding-box algorithm. Radiomics features and deep learning-derived imaging features were integrated using a hierarchical late fusion framework. Hierarchical classification was performed in two stages: HC versus Parkinsonism, followed by PD versus AP. Model interpretability was evaluated using Grad-CAM and SHAP analyses.
    RESULTS: Across five random seeds, the validation-selected late-fusion model achieved a mean held-out test accuracy, F1-score, and ROC-AUC of 0.906, 0.942, and 0.969, respectively, for Stage 1 (HC vs. parkinsonism) and 0.815, 0.669, and 0.880 for Stage 2 (PD vs. AP). The ablation analysis showed modest improvements in mean accuracy and F1-score over the deep learning-only model in both stages. Grad-CAM provided qualitative visualizations of the image regions contributing to model predictions, while SHAP identified stage-dependent radiomics importance profiles primarily involving voxel-intensity distributions and texture heterogeneity.
    CONCLUSION: The proposed framework demonstrated promising internal performance for the hierarchical classification of Parkinsonian disorders and provided exploratory information regarding the image regions and radiomics features contributing to model predictions. These findings support the feasibility of integrating deep learning and radiomics for FP-CIT image analysis; however, independent multicenter validation is required before its external generalizability and clinical utility can be established.
    Keywords:  Atypical parkinsonism; Dopamine transporter imaging; Explainable artificial intelligence; Parkinson's disease; Radiomics
    DOI:  https://doi.org/10.1016/j.parkreldis.2026.109021
  32. Microcirculation. 2026 Oct;33(7): e70091
    Tiny Travelers, Big Impact: Physiological Effects of Extracellular Vesicles on the Blood-Brain Barrier.
    Linda Lin, Manisha Patil, Simon Hawke, Felix Marsh-Wakefield, Georges E Grau.
      The blood-brain barrier [BBB] is a highly specialized structure that regulates the influx and efflux of nutrients and metabolic waste to maintain homeostasis of the central nervous system. This selective permeability of the BBB is sustained by tight junctions that are supported by pericytes and astrocytes. Recently, extracellular vesicles have emerged as mediators of intercellular communication across and within the BBB. This review examines the bidirectional transport of EVs across the BBB and the distinct functional impacts of blood-borne EVs. On the luminal side, circulating EVs derived from platelets, erythrocytes, and leukocytes convey systemic signals to the neurovasculature. Platelet-derived EVs deliver growth factors and lipid mediators that promote vascular repair and modulate adaptive immunity during endothelial disruption. Erythrocyte-derived EVs selectively shed surface markers like CD47 to regulate cellular turnover while simultaneously providing phosphatidylserine that maintains hemostasis and nitric oxide bioavailability. Meanwhile, leukocytic-derived EVs protect and transport immunological cargo, such as MHC complexes and cytokines, functioning as critical sensors and amplifiers of immune surveillance at the vascular interface. Together, these circulating EV populations influence endothelial signaling, transporter expression, and tight junction integrity from the vascular side. Conversely, on the abluminal side, the roles of brain parenchymal-derived EVs secreted by astrocytes, pericytes, neurons, and microglia are explored in regulating local neurovascular coupling, vascular tone, and endothelial responsiveness. Within this microenvironment, astrocyte-derived EVs provide neurotrophic and neuroprotective support by delivering angiogenic factors and cytoprotective chaperone proteins like HSP70 to protect cells from mechanical and oxidative stress. Pericyte-derived EVs preserve microvascular barrier integrity by transporting regulatory microRNAs and angiopoietin-1 to directly upregulate endothelial tight junction proteins. Furthermore, neuron-derived EVs participate in activity-dependent signaling, transferring vital microRNAs to endothelial cells to promote vascular stability and support synaptic plasticity. By framing the BBB as an active communication system, this review underscores how peripheral and central EVs integrate systemic and neural environments, highlighting their fundamental roles in BBB physiology and, beyond, their profound implications as biomarkers of CNS distress and programmable vehicles for targeted drug delivery.
    DOI:  https://doi.org/10.1111/micc.70091
  33. Brain Commun. 2026 ;8(5): fcag342
    Regional blood-brain barrier dysfunction maps to lower performance in cognitive ageing.
    Sheida Mirloo, Sheizaf Shpilberg, Noam Druker, Rotem Saar-Ashkenazy, Ofer Prager, Shai Baruch Neustaedter, Gal Ben-Arie, Ilan Shelef, Lyna Kamintsky, Yonatan Serlin, Danielle K Sandsmark, Alon Friedman, Hadar Shalev.
      Age-related cognitive decline is a common and growing public health challenge, associated with loss of independence, reduced quality of life, increased caregiver burden and substantial healthcare and societal costs. Yet cognitive decline in ageing is heterogeneous, and current clinical constructs do not reliably capture the underlying biological mechanisms or predict progression to dementia. This cross-sectional study examined whether blood-brain barrier dysfunction (BBBD) provides a biologically supported correlate of cognitive performance beyond clinical diagnosis. The study included 46 patients with mild cognitive impairment (MCI), 46 age-matched controls and 43 young controls. BBBD was assessed using dynamic contrast-enhanced MRI in 42 patients with MCI and all controls, alongside volumetric brain analysis. Standardized NeuroTrax cognitive assessment data were analysed for 41 MCI patients and 19 age-matched controls. BBBD was analysed using the BBBdetect software (Emagix Inc, Nova Scotia, Canada), quantifying voxelwise and region-wise blood-brain barrier permeability; volumetric analysis was performed using the Volbrain software; and cognitive performance was stratified into low- and high-performance subgroups based on modified z-scores. Compared with young controls, the older cohort (MCI patients combined with age-matched controls) showed significantly greater BBBD volume and regional extent. Permeability increased with age and showed marked inter-individual variability. Across participants, lower cognitive performance was associated with a greater number of regions exhibiting BBBD. Receiver operating characteristic analysis identified domain-specific spatial patterns of BBBD linked to poor performance in memory, executive, attention, verbal and motor domains, implicating frontal, cingulate, hippocampal, basal ganglia and cerebellar regions. In contrast, volumetric analyses revealed expected age-related reductions in grey and white matter and cortical thickness along with increased ventricular volume; however, these structural changes showed weak to no associations with cognitive performance. These findings suggest that BBBD is widespread in ageing and that regional BBBD maps to domain-specific cognitive deficits. BBBD thus emerges as a biologically relevant biomarker of age-related cognitive impairment and a potential therapeutic target for preserving cognitive function in ageing.
    Keywords:  MRI; biomarkers; mild cognitive impairment; neuropsychological tests
    DOI:  https://doi.org/10.1093/braincomms/fcag342
  34. Eur Radiol Exp. 2026 Oct 23. pii: 162. [Epub ahead of print]10(1):
    Reassessment of the DTI-ALPS index in focal epilepsy.
    Stefanie Chambers, Leo Hofer, Mario Tranfa, Patric Kienast, Julia Shawarba, Radheshyam Stepponat, Judith Jud, Susanne Aull-Watschinger, Ekaterina Pataraia, Florian Ph S Fischmeister, Frederik Barkhof, Gilbert Hangel, Karl Rössler, Giuseppe Pontillo, Gregor Kasprian, Lukas Haider.
       OBJECTIVE: Recent evidence highlights the limited specificity of diffusion tensor imaging (DTI) along perivascular spaces (ALPS) as a noninvasive glymphatic biomarker because microstructural tract degeneration and crossing-fiber geometry confound it. We aimed to reassess the interpretation of the DTI-ALPS index in people with focal epilepsy.
    MATERIALS AND METHODS: Seventy-nine people with drug-resistant focal epilepsy (PWFE) underwent comprehensive presurgical work-up and 3-T magnetic resonance imaging (MRI). Etiologies included MRI-negative epilepsy, malformations of cortical development, temporal lobe epilepsy, and low-grade epilepsy-associated tumors. DTI preprocessing was conducted using QSIPrep with automated region-of-interest (ROI) placement. Linear regression models and Wilcoxon signed-rank tests were used to assess group differences and associations with clinical variables. Twenty-five age- and sex-matched healthy controls were included for comparison.
    RESULTS: Seventy-nine patients (28.6 years ± 11.3 [mean ± standard deviation]; 47 men, 32 women) and 25 healthy controls (mean age, 26.7 years ± 4.2; 11 men, 14 women) were evaluated. DTI-ALPS findings were more abnormal in lesions in proximity to the ROI (p = 0.014), implicating local white matter disruption as a modifier, which was further corroborated by reduced postoperative values. No associations were identified with disease duration, sex, or normalized gray-or white matter volumes.
    CONCLUSION: Our results demonstrate a distance-dependent correlation of DTI-ALPS values to the seizure onset zone in focal epilepsy, whilst no significant associations to disease duration or normalized brain volumes were found. Together, these findings suggest that local disruption of fiber tracts may act as important modifiers of this measure and warrant caution in the interpretation of the DTI-ALPS index.
    KEY POINTS: Question Microstructural changes may significantly confound the interpretation of the DTI-ALPS index as a surrogate parameter for glymphatic system dysfunction in epilepsy. Findings No significant differences in the DTI-ALPS index were observed comparing PWFE with healthy controls; however, lesion proximity and post-operative status significantly alter the metric. Relevance statement Local white-matter disruption and microstructural architecture may significantly alter the DTI-ALPS index; therefore, caution is warranted when interpreting the index as a glymphatic biomarker in focal epilepsy.
    Keywords:  Diffusion tensor imaging; Epilepsy (partial); Glymphatic system; Magnetic resonance imaging; Malformations of cortical development
    DOI:  https://doi.org/10.1186/s41747-026-00799-8
  35. J Med Chem. 2026 Oct 22. 69(20): 23111-23226
    Enzyme-Targeted Therapeutics for Neurological Disorders.
    Leonardo Massignan, Lokesh Kanduru, Sara Ziadat, David Uehling, Donald F Weaver, Mark A Reed.
      Neurological disorders represent one of the leading causes of disability and mortality worldwide, and their prevalence is expected to increase substantially with population aging. Despite major advances in neuroscience, effective disease-modifying therapies remain unavailable for most chronic disorders of the central nervous system (CNS), highlighting the need for novel therapeutic strategies. Enzymes are attractive drug targets because they regulate fundamental processes including neurotransmission, signal transduction, energy metabolism, protein homeostasis, epigenetic regulation, lipid metabolism, and cellular detoxification. This review summarizes the major classes of druggable CNS enzymes, discuss clinically approved drugs and emerging investigational agents, and evaluate therapeutic opportunities across neurodegenerative, neurodevelopmental, neuropsychiatric, cerebrovascular, and neuro-oncologic diseases. Key challenges including blood-brain barrier penetration, target selectivity, off-target pharmacology, and clinical translation are also examined. By integrating diverse enzyme-targeting modalities across multiple neurological disorders, this review highlights both the progress achieved to date and the substantial opportunities that remain for future CNS drug discovery.
    Keywords:  Blood-brain barrier; Central nervous system; Clinical translation; Drug discovery; Enzyme inhibitors; Medicinal chemistry; Neurodegeneration; Neurological disorders; Target selectivity; Target validation
    DOI:  https://doi.org/10.1021/acs.jmedchem.6c01274
  36. Rep Biochem Mol Biol. 2025 Aug;14(2): 171-180
    Methamphetamine-Induced Oxidative Stress and Inflammatory Markers as Indicators of Blood-Brain Barrier Disruption.
    Mushtaq Talib Abood, Mustafa Taha Mohammed.
       Background: Methamphetamine (METH) abuse has been linked to neurotoxicity, oxidative stress, and dysfunction of the blood-brain barrier (BBB), potentially leading to cognitive impairments. This study aimed to evaluate the association between METH use, oxidative stress biomarkers, inflammation (NF-κB), endothelial permeability (MLCK), and memory impairment.
    Methods: A total of 150 male participants, aged 18-50 years, were recruited, including 75 METH users and 75 age-matched healthy controls. Serum levels of myosin light chain kinase (MLCK, NCBI Gene ID: 4638), nuclear factor kappa B (NF-κB, NCBI Gene ID: 4790), total oxidant status (TOS), total antioxidant capacity (TAC), catalase activity (CAT), and oxidative stress index (OSI) were measured. Receiver operating characteristic (ROC) curves and logistic regression were used to analyze biomarker sensitivity and risk association.
    Results: MLCK and NF-kB were significantly elevated in METH users compared to controls (p< 0.001*). TOS and OSI were higher, while TAC and CAT were lower in METH users (p< 0.001*). ROC analysis revealed MLCK (AUC = 0.978) and NF-kB (AUC = 0.959) as sensitive biomarkers for BBB dysfunction. Logistic regression indicated increased odds of memory impairment with elevated MLCK (OR = 1.246) and NF-kB (OR = 1.452), though these associations were not statistically significant (p > 0.05).
    Conclusions: Chronic METH use is associated with oxidative stress, inflammation, and increased BBB permeability, implicating MLCK and NF-kB as potential biomarkers for neurovascular damage and cognitive decline. Larger studies are warranted to confirm these associations.
    Keywords:  Blood-Brain Barrier; Catalase; Cognitive Dysfunction; Inflammation; Methamphetamine; Myosins; NF-kappa B; Oxidative Stress; Protein Kinases
    DOI:  https://doi.org/10.66224/rbmb.14.2.171
  37. Genome Med. 2026 Sep 29. pii: 161. [Epub ahead of print]18(1):
    Cross-species molecular stratification enables T cell receptor diagnosis of Parkinson's disease.
    Jiayu Chen, Xian Xia, Yuruo Zhang, Xiaoge Tong, Yue Liang, Xiangding Fan, Qinghao Meng, Yihong Wei, Gang Hu.
       BACKGROUND: Developing peripheral blood-based diagnostic models for idiopathic Parkinson's disease (iPD), particularly those leveraging the T-cell receptor (TCR) repertoire, has long been considered infeasible because patient-derived TCRs appear to lack convergent sequence motifs. We reasoned that this apparent absence of shared TCR features likely reflects both insufficient sample sizes and unaccounted immune heterogeneity within the iPD population.
    METHODS: We reconstructed TCR repertoires from the two largest iPD cohorts currently available, anchoring them with three mechanistically distinct mouse models to stratify patients into model-anchored informed subtypes. Within these data-driven subtypes, we trained subtype-specific, multimodal multi-instance classifiers.
    RESULTS: We demonstrated that iPD patients can be successfully stratified into model-anchored informed subtypes. Furthermore, the trained subtype-specific, multimodal multi-instance classifiers achieved an Area Under Curve (AUC) exceeding 0.8 for both subtypes.
    CONCLUSIONS: Our findings underscore the critical role of disease stratification in enabling TCR repertoire-based modeling in neurodegenerative diseases.
    Keywords:  Diagnosis; Machine learning; Parkinson’s disease; T-cell receptor
    DOI:  https://doi.org/10.1186/s13073-026-01776-x
  38. Nat Commun. 2026 09 16. pii: 10904. [Epub ahead of print]17(1):
    Genetic architecture of MRI-derived cervical spinal cord morphology reveals sensory-motor axis and systemic disease associations.
    Zhuopin Sun, Jiru Han, Zachary F Gerring, Victoria E Jackson, Oneil G Bhalala, Gustavo M Jarola, Ian H Harding, Thiago J R Rezende, Melanie Bahlo.
      The spinal cord is critical to motor, sensory, autonomic function, and increasingly implicated in neurological disease and human health, yet its genetic architecture remains largely unexplored. We perform large-scale phenotyping of the upper cervical spinal cord (C1-C3) structure using brain magnetic resonance imaging from over 80,000 UK Biobank participants, extracting shape metrics including cross-sectional area, diameters, and eccentricity. We identify a total of 179 independent genome-wide significant variants, with cervical spinal cord morphology showing moderate to high SNP-based heritability (0.16 to 0.42). We also uncover sex-specific genetic signals, highlighting potential biological sex differences in spinal cord development. In addition, spinal cord structure is associated with a wide range of neurological, metabolic, and systemic conditions, such as multiple sclerosis, neuropathies, diabetes, and attention-deficit/hyperactivity disorder. These findings establish the cervical spinal cord as a genetically informative and health relevant structure, offering opportunities to study its role in disease mechanisms and human health.
    DOI:  https://doi.org/10.1038/s41467-026-77419-x
  39. BMC Neurol. 2026 Jul 22. pii: 653. [Epub ahead of print]26(1):
    Lower fibrinogen and fibrinogen-to-albumin ratio in migraine with white matter hyperintensities: implications for microvascular vulnerability.
    Aslıhan Baran.
       BACKGROUND: White matter hyperintensities (WMH) are increasingly recognized as imaging markers of migraine-related cerebral small-vessel injury. However, the biological correlates underlying WMH in migraine remain poorly defined. The relationship between WMH and the fibrinogen-to-albumin ratio (FAR), a composite hemostatic marker, has not yet been evaluated.
    METHODS: In this cross-sectional study, 69 patients with migraine were included after exclusion of systemic inflammatory and vascular confounders. WMH presence was assessed using brain magnetic resonance imaging (MRI). Plasma fibrinogen and albumin levels were measured during the interictal period, and FAR was calculated. C-reactive protein (CRP) and inflammatory indices derived from complete blood counts were also analyzed. Multivariable regression analyses were performed with adjustment for age and sex.
    RESULTS: Patients with WMH had significantly lower fibrinogen levels and FAR compared to those without WMH (p = 0.003 and p = 0.004, respectively). After adjustment for age and sex, WMH remained independently associated with lower fibrinogen levels and FAR (p = 0.002 for both). No differences were observed in CRP or other systemic inflammatory markers.
    CONCLUSIONS: WMH in migraine were independently associated with lower fibrinogen levels and FAR. These findings suggest that WMH in migraine may reflect microvascular vulnerability associated with altered hemostatic balance rather than systemic inflammation. Further longitudinal studies are needed to clarify the underlying mechanisms and clinical implications.
    Keywords:  Endothelial dysfunction; Fibrinogen; Fibrinogen-to-albumin ratio; Hemostasis; Migraine; White matter hyperintensities
    DOI:  https://doi.org/10.1186/s12883-026-05202-y
  40. Metab Brain Dis. 2026 Oct 22. pii: 244. [Epub ahead of print]41(1):
    MiR‑204‑5p modulates glial morphology and apomorphine‑induced rotational asymmetry without dopaminergic neuroprotection in a preclinical mouse model of Parkinson's disease.
    Catarina Serra-Almeida, Ana Vale, Inês Tomé-Ribeiro, Marta Barão, Ana Clara Cristóvão, Lino Ferreira, Liliana Bernardino.
      Parkinson's disease (PD) is characterized by progressive nigrostriatal dopaminergic degeneration and a dysregulated neuroinflammatory environment. Here, we investigated whether intranigral delivery of a microRNA‑204‑5p mimic (miR‑204-5p) at the time of lesion modulates dopaminergic‑dependent rotational asymmetry, glial morphology, and striatal medium spiny neurons (MSNs) recruitment in a unilateral 6‑OHDA mouse model. Adult C57BL/6 mice received a unilateral striatal 6‑OHDA injection and simultaneous intranigral infusion of a synthetic miR‑204‑5p mimic or vehicle, and apomorphine‑induced rotations, rotarod performance, TH immunohistochemistry, high‑content morphometric analyses of GFAP‑positive astrocytes and IBA1‑positive microglia, and c‑Fos/DARPP‑32 expression were assessed four weeks later. In 6‑OHDA‑lesioned mice, miR‑204-5p treatment significantly reduced apomorphine‑induced contralateral rotations relative to 6‑OHDA alone, while TH‑positive neuron counts in the substantia nigra and TH‑positive fiber density in the striatum remained comparably reduced across all lesioned groups. Intranigral miR‑204-5p delivery in 6‑OHDA‑lesioned animals was associated with increased astrocytic and microglial branching complexity along the nigrostriatal axis and with a higher proportion of striatal DARPP‑32‑positive MSNs expressing c‑Fos during dopaminergic stimulation, without a change in total c‑Fos‑positive cell counts. These findings indicate that miR‑204‑5p mimic administration can modulate glial morphology and apomorphine‑induced rotational asymmetry in a severely denervated nigrostriatal system without detectable dopaminergic neuroprotection as assessed by TH immunostaining. This exploratory study supports further investigation of glial mechanisms in miR-based approaches to PD.
    Keywords:  6-OHDA; Glial remodeling; Medium spiny neuron activity; Parkinson’s disease; miR-204-5p
    DOI:  https://doi.org/10.1007/s11011-026-02012-6
  41. Exp Neurol. 2026 Oct 18. pii: S0014-4886(26)00446-2. [Epub ahead of print]408 116078
    A critical mechanistic synthesis of PINK1-mediated mitophagy signaling and its therapeutic targeting in Parkinson's disease neurodegeneration.
    Abida Khan, Talha Jawaid, Zia Ur Rehman, Mohammed Kanan Alshammari, Md Afroz Bakht, Faiyaz Shakeel, Mohammed Zawiah, Mohd Imran.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder that is associated with loss of dopaminergic neurons, mitochondrial dysfunction and disruption of cellular homeostasis. PTEN-induced kinase 1 (PINK1) plays a crucial role in mitochondrial quality control by regulating mitophagy, mitochondrial dynamics, and calcium signaling to maintain neuronal bioenergetic homeostasis. This review critically evaluates the molecular pathways underlying PINK1-mediated mitochondrial integrity and the mechanisms by which loss-of-function mutations contribute to the pathogenesis of PD. Familial early-onset PD is strongly associated with pathogenic PINK1 mutations identified through genetic studies. Therapeutic approaches targeting the PINK1 pathway are examined, including adeno-associated virus (AAV)-based gene delivery, direct small-molecule PINK1 activation (MTK458), and indirect modulation of mitophagy and mitochondrial homeostasis by compounds such as curcumin, resveratrol, cannabidiol, gastrodin, and quercetin. Moreover, the complementary restoration of mitochondrial homeostasis through the modulation of downstream targets, such as transcription factor EB (TFEB) activation and BCL2-interacting protein 3-like (BNIP3L/NIX)-mediated mitophagy, is discussed as an indirect therapeutic strategy. Another important finding is that PD is a biologically and clinically heterogeneous disease that requires biomarker-directed and genotype-stratified therapeutic development. Finally, major translational issues are critically evaluated, including challenges related to blood-brain barrier penetration, target specificity, and long-term safety of mitochondrial modulators.
    Keywords:  Mitochondrial dysfunction; Mitophagy; Oxidative stress; PINK1/Parkin; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.expneurol.2026.116078
  42. J Microbiol Biotechnol. 2026 Oct 21. 36 e2609057
    Live and Heat-Killed Lactiplantibacillus plantarum HY7715 Attenuate D-Galactose-Induced Aging-Related Brain Changes and Blood-Brain Barrier Disruption with Gut Microbiota Modulation in Mice.
    Jimin Baik, Hyeonjun Gwon, Joo-Yun Kim, Jae-Jung Shim, Jae-Hwan Lee.
      Aging is associated with changes in systemic homeostasis, intestinal barrier integrity, and brain function. This study investigated the effects of Lactiplantibacillus plantarum HY7715 on aging-related alterations in a D-galactose-induced accelerated aging mouse model. Male C57BL/6J mice were administered D-galactose for 8 weeks and orally treated with live or heat-killed HY7715. D-galactose increased circulating advanced glycation end products (AGEs), blood-brain barrier (BBB) permeability, hippocampal inflammation, and aging-related molecular changes, while impairing cortical and colonic tight junction-associated markers. Both live and heat-killed HY7715 reduced serum AGE levels, Evans blue leakage, and hippocampal inflammatory responses, while restoring CLDN5 immunoreactivity, tight junction-associated gene expression, and antioxidant-related gene expression. HY7715 also attenuated senescence- and apoptosis-related changes in the hippocampus and colonic tight junction- and inflammation-related gene expression changes. Gut microbiota analysis showed taxon-specific changes following HY7715 treatment, including significant increases in Bifidobacterium in both HY7715-treated groups, whereas live HY7715 was associated with significant changes in microbial community structure. Several microbial taxa were correlated with serum AGEs, BBB permeability, and neuroinflammation-related parameters. Together, these results show that both live and heat-killed HY7715 attenuated multiple aging-related changes in the D-galactose-induced accelerated aging model, accompanied by changes in gut microbiota composition.
    Keywords:  Blood-brain barrier; D-galactose-induced accelerated aging; Gut microbiota; Gut-brain axis; Intestinal barrier; Lactiplantibacillus plantarum HY7715
    DOI:  https://doi.org/10.4014/jmb.2609.09057
  43. Stem Cell Res Ther. 2026 Jul 22. pii: 371. [Epub ahead of print]17(1):
    Neural stem cell transplantation in progressive multiple sclerosis: STEMS study long-term outcomes.
    Maria A Rocca, Angela Genchi, Matteo Azzimonti, Irene Gattuso, Elisabetta Pagani, Loredana Storelli, Paolo Vezzulli, Elena Brambilla, Roberto Santangelo, Raffaella Greco, Fabio Ciceri, Roberto Furlan, Lucia Moiola, Andrea Falini, Gianvito Martino, Massimo Filippi.
       BACKGROUND: To evaluate the long-term safety and potential neuroprotective effects of human fetal neural precursor cell transplantation in individuals with progressive multiple sclerosis.
    METHODS: This retrospective observational study assessed long-term follow-up data (median 5.7 years) from participants in a first-in-human phase I trial (NCT03269071) investigating neural cell transplantation in progressive multiple sclerosis. Clinical and radiological available data were collected and compared to baseline values and reference populations.
    RESULTS: Long-term follow-up data were available for 11 of 12 patients. No serious adverse events related to cell transplantation occurred, confirming long-term safety. Although physical disability progressed over time, cognition remained stable compared to baseline. Five patients developed new T2-hyperintense brain lesions without associated contrast enhancement. Long-term gray matter atrophy rates were lower than those observed during the initial two years post-transplantation. Rates of gray and white matter atrophy approximated those of age-matched healthy individuals and patients with early-stage multiple sclerosis, with a trend for a lower atrophy rate compared to a control cohort with progressive disease. These structural findings were consistent with stable levels of circulating biomarkers of neurodegeneration.
    CONCLUSIONS: The findings support the long-term safety of fetal neural cell transplantation in progressive multiple sclerosis. Although exploratory in nature, the stability of cognitive function, reduced brain atrophy, and consistent biomarker profiles support the hypothesis of a possible neuroprotective effect that warrants further investigation in a controlled clinical trial setting.
    Keywords:  Biomarkers; Brain atrophy; Multiple sclerosis; Stem cells; Transplantation
    DOI:  https://doi.org/10.1186/s13287-026-05148-5
  44. Front Aging Neurosci. 2026 ;18 1935091
    Eye-movement-based machine learning for identifying Parkinson's disease dementia in a retrospective cohort: an interpretable model-development study.
    Jing Wu, Qing Liu, Song Yang, Yuqing Zhang, Yuanlu Shu, Junwen Wang, Min Wu, Tian Tian.
       Background: Parkinson's disease dementia (PDD) is a major non-motor complication of Parkinson's disease (PD), but conventional cognitive screening is influenced by education, language, motor impairment, fatigue, and testing conditions. We developed and interpreted machine-learning models using eye-movement and demographic features to identify PDD among patients with PD.
    Methods: In this retrospective single-center study, 486 patients were screened between December 2024 and February 2025. After exclusions, 297 patients with idiopathic PD were analyzed, including 84 without dementia and 213 with PDD. Thirteen machine-learning algorithms were trained using demographic and task-derived eye-movement variables. Performance was assessed using ROC AUC, PR AUC, classification metrics, calibration, the Brier score, and decision-curve analysis. SHapley Additive exPlanations (SHAP) were used to interpret the final model.
    Results: Patients with PDD showed poorer cognitive performance and abnormalities in antisaccade inhibition, saccade execution, and fixation stability. Seven predictors were retained: age, sex, education level, antisaccade accuracy, mean overlap-saccade completion duration, mean gap-saccade velocity, and lateral-gaze deviation duration >4°. Logistic regression and elastic net achieved the highest test-set ROC AUCs (both 0.962), while logistic regression had the lowest Brier score (0.077). A radial basis function support vector machine (SVM) was retained as the primary classifier for detailed evaluation because it provided balanced performance across threshold-dependent metrics and could capture potentially nonlinear relationships and interactions. In the test set, the SVM achieved a ROC AUC of 0.947 and PR AUC of 0.979. Accuracy, sensitivity, specificity, and F1 score were 0.867, 0.870, 0.857, and 0.904, respectively. SHAP identified education, antisaccade accuracy, mean overlap-saccade completion duration, mean gap-saccade velocity, and lateral-gaze deviation duration >4° as the leading contributors.
    Conclusion: A seven-feature model combining demographic and eye-movement measures showed promising internal discrimination of PDD from PD without dementia. Eye-movement-based machine learning may complement clinical cognitive assessment, but external validation in larger and more representative cohorts is required before clinical use.
    Keywords:  Parkinson’s disease dementia (PDD); cognitive screening; eye movement; machine learning; support vector machine (SVM)
    DOI:  https://doi.org/10.3389/fnagi.2026.1935091
  45. Curr Opin Insect Sci. 2026 Oct 23. pii: S2214-5745(26)00155-0. [Epub ahead of print] 101639
    Drosophila Models of Human Neurodegenerative Diseases.
    Jasmine Speranza, Charlotte Gale-Rogers, Abigail C Stretch, Ryan J H West.
      In his book Insects and the Life of Man: Collected Essays on Pure Science and Applied Biology, Sir V. B. Wigglesworth examined how a fundamental understanding of insect physiology and biology can be applied to some of society's greatest challenges, including human health. Here we reflect on how, in the 50 years since his book's publication, Drosophila melanogaster have played a critical role in advancing our understanding of human neurodegenerative diseases. Focusing on Parkinson's disease, Huntington's disease, and the frontotemporal dementia / amyotrophic lateral sclerosis spectrum, we examine the role Drosophila have played in elucidating fundamental mechanisms of neurodegeneration, identifying therapeutic targets, and dissecting the complex interplay that exists between genetics and environmental factors. Together these studies highlight how Drosophila models continue to provide critical insight into the molecular mechanisms underpinning neurodegeneration and provide a fundamental pre-clinical model in which we can accelerate research into human neurodegenerative conditions.
    DOI:  https://doi.org/10.1016/j.cois.2026.101639
  46. PLoS Biol. 2026 Oct;24(10): e3004032
    Oxidative signaling thresholds shape vulnerability in the central and peripheral nervous systems.
    Shuji Wakatsuki, Toshiyuki Araki.
      Neurodegeneration is frequently associated with oxidative stress, yet the mechanisms that convert reactive oxygen species (ROS) into irreversible degenerative signals remain incompletely understood. Neurons in the central and peripheral nervous systems often differ in their responses to injury, but these differences cannot be reduced to a simple contrast between weak and strong antioxidant capacity. This Essay proposes that neuronal vulnerability is shaped by multilayered signaling thresholds comprising ROS production, antioxidant and thiol buffering, redox-sensitive signal detection, molecular gating, and commitment to degeneration, survival, or repair. This framework may help explain selective neuronal vulnerability in neurodegenerative diseases and identify intervention points downstream of global ROS suppression.
    DOI:  https://doi.org/10.1371/journal.pbio.3004032
  47. J Exp Med. 2026 Nov 02. pii: e20261409. [Epub ahead of print]223(11):
    Parkinson's at the brain border.
    Henry Kim, Tsogt-Itgel Munkhbat, Max A Tischfield.
      Parkinson's disease is increasingly recognized as a disorder that extends beyond neurons. In this issue of JEM, Stevenson et al. (https://doi.org/10.1084/jem.20251245) highlight the functional consequence of α-synuclein aggregates at the brain border, uncovering their active role in reshaping lymphatic integrity and the neuroimmune macroenvironment.
    DOI:  https://doi.org/10.1084/jem.20261409
  48. Glia. 2026 Dec;74(12): e70240
    Microglial Labeling in Mouse Spinal Cord Injury: A Review of Timing, Efficacy, and Specificity.
    Ruth Colbert, Julia Di Stefano, Dearbhaile Dooley.
      Traumatic spinal cord injury (SCI) is a complex and disabling condition with no curative therapy currently available. The mechanical damage of the primary injury phase is followed and exacerbated by a secondary injury phase, characterized by the release of free radicals and pro-inflammatory cytokines that lead to chronic inflammation. Microglia, as the resident immune cells of the central nervous system, play a critical role in orchestrating this inflammatory response. Studying their dynamics after SCI not only deepens our understanding of injury pathology but also advances the development of microglia-targeted immunotherapies. However, trauma-induced transcriptional and phenotypic changes mean that markers used to identify homeostatic microglia may be unreliable when applied to their reactive counterparts. Another major challenge lies within discriminating resident microglia from infiltrating monocyte-derived macrophages (MDM), which permeate the blood-spinal cord barrier (BSCB) after injury. In this review, we examine three key variables for selecting appropriate strategies for labeling microglia in mice: (i) time (in relation to injury); (ii) efficacy (within the chosen murine SCI model); and (iii) specificity (to microglia). We discuss the transcriptional landscape of murine microglia pre-injury and its alteration post-injury, evaluate the strengths and limitations of commonly used markers, and highlight emerging tools and approaches for studying microglia in preclinical murine SCI research.
    Keywords:  antibody markers; microglia; mouse; neuroinflammation; reporter mice; spinal cord injury
    DOI:  https://doi.org/10.1002/glia.70240
  49. Front Immunol. 2026 ;17 1957858
    The blood-brain tumor barrier as a spatial immune checkpoint in glioblastoma: leukocyte entry, perivascular retention, and therapeutic implications.
    Fangbo Lin.
      Glioblastoma (GBM) combines heterogeneous vascular dysfunction with a predominantly myeloid immune landscape. This Mini Review focuses on a specific problem: vascular permeability is not equivalent to productive leukocyte access. Entry requires endothelial capture, chemokine-guided arrest, transendothelial migration, release from perivascular sites, intratumoral dispersion, target recognition, and sustained effector function. Human tissue and spatial studies show regionally distinct neurovascular and myeloid states, whereas much of the causal evidence for trafficking and retention remains preclinical. We therefore distinguish published observations from a hypothesis-generating model in which the blood-brain tumor barrier (BBTB) and perivascular myeloid niche can act as coupled but separable checkpoints. The main conceptual advance is not the already recognized heterogeneity of the BBTB, but the argument that leakage-based imaging should not be used as a surrogate for immune-cell entry and that each trafficking stage requires its own pharmacodynamic readout. We summarize regional BBTB states, differential lymphoid and myeloid access, and selected strategies-vascular normalization, myeloid reprogramming, local cell delivery, and focused ultrasound-while emphasizing their evidence limits. Clinical translation will require spatially registered human sampling, explicit model provenance, and tests that can reject individual components of the framework.
    Keywords:  blood-brain tumor barrier; glioblastoma; immunotherapy resistance; leukocyte trafficking; neurovascular unit; perivascular myeloid niches; spatial immune checkpoint; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2026.1957858
  50. CNS Neurol Disord Drug Targets. 2026 Oct 14.
    Mechanistic Evaluation of Psilocybin in Neurodegenerative Disorders: Relevance of 5-HT2A Receptors and Downstream Pathways.
    Sheekha Chaudhary, Sanchit Dhankhar, Monika Saini, Thakur Gurjeet Singh, Samrat Chauhan, Viney Kumar.
      More than fifty million individuals worldwide are experiencing neurodegenerative disorders, which include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and frontotemporal dementia. These disorders have a significant role in the gradual degradation of cognition and motor skills. Most current treatment approaches have little effect on changing the course of the disease and are largely symptomatic. Psilocybin, a naturally occurring tryptamine alkaloid from psilocybin mushrooms, has become a promising medicinal agent because of its hallucinogenic, neuroprotective, and neuroplastic properties. After being metabolically transformed into its active form, psilocin, it primarily activates serotonin 5-HT2A receptors. This modulates glutamatergic neurotransmission and neurotrophic signaling pathways such as BDNF/TrkB and mTOR, which regulate synaptic remodeling, dendritic complexity, neurogenesis, neuroinflammatory response, and default mode network connectivity, all of which are linked to depression and dementia. Preclinical research studies demonstrate that psilocybin increases hippocampal plasticity, restores dendritic complexity, lowers proinflammatory cytokine levels, and promotes fear extinction in experimental models of stress, ischemic stroke, and neurodegeneration. Emerging clinical studies also indicate that individuals with moderate cognitive impairment, early-onset Alzheimer's disease, and Parkinson's disease may see long-term decreases in anxiety and depression as well as improvements in cognitive function, frequently after a single dose administration. Additionally, psilocybin has demonstrated promise in treating mental comorbidities that often accompany neurodegenerative illness, such as treatment-resistant depression, drug use disorders, and obsessive-compulsive disorder. However, there are still significant obstacles to overcome, such as optimizing dosing schedules, assessing safety issues such as temporary perceptual abnormalities and cardiovascular consequences, and translating preclinical results into extensive phase -III clinical studies. This review incorporates the most recent data on psilocybin's chemistry, pharmacology, metabolism, and mechanistic actions; it highlights the drug's therapeutic potential across a variety of neurodegenerative diseases and emphasizes the necessity of carefully planned randomized controlled trials to determine clinical efficacy, long-term safety, and its place in multimodal treatment approaches.
    Keywords:  5-HT2A receptor; Psilocybin; alzheimer’s disease; neurodegenerative disorders; neuroplasticity; parkinson’s disease
    DOI:  https://doi.org/10.2174/0118715273491538261009064612
  51. Can J Neurol Sci. 2026 Oct 21. 1-7
    Cytoplasmic TDP-43 Accumulation in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay.
    Alexandre Paquet, Lydia Touzel-Deschênes, Vincent Roy, Jean-Denis Brisson, Jean Mathieu, Nicolas Dupré, Stephan Saikali, François Gros-Louis.
       BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare, early-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, spasticity and peripheral neuropathy. It is caused by biallelic mutations in the SACS gene, which encodes sacsin, a large protein involved in cytoskeletal organization and mitochondrial homeostasis, and protein quality control. Despite advances in understanding sacsin biology, the molecular mechanisms underlying neurodegeneration in ARSACS remain incompletely understood. Here, we report the first neuropathological evidence of pathological TAR DNA-binding protein 43 (TDP-43) accumulation in ARSACS.
    METHODS: Available postmortem brain tissue from a genetically confirmed ARSACS patient homozygous for the Quebec founder mutation (SACS c.8844delT) was analyzed by immunohistochemistry, immunofluorescence and biochemical fractionation.
    RESULTS: Neurons in the prefrontal cortex, motor cortex and cerebellum exhibited cytoplasmic phosphorylated dot-like TDP-43 (pTDP-43) aggregates with reduced nuclear localization. Biochemical fractionation further identified detergent-insoluble TDP-43 species in ARSACS tissue. Additional pathological features included increased neurofilament accumulation, vacuole-like neuronal changes, Purkinje cell loss and p62-positive cytoplasmic inclusions. Similar dot-like cytoplasmic pTDP-43 aggregates were observed in a second ARSACS case.
    CONCLUSION: These findings identify pTDP-43 as a previously unrecognized pathological feature of ARSACS. While the patient exhibited no clinical or histopathological signs of amyotrophic lateral sclerosis, the presence of atypical pTDP-43 aggregates observed in ARSACS may represent a rare, secondary, early-stage or potentially underrecognized manifestation of TDP-43 pathology rather than a defining hallmark of the disease. Further studies in additional patients and experimental ARSACS models will be required to determine the prevalence and mechanistic basis of TDP-43 abnormalities in this disorder.
    Keywords:  ARSACS; TDP-43; ataxia; cerebellum; neurofilaments; neurons
    DOI:  https://doi.org/10.1017/cjn.2026.10695
  52. Biol Sex Differ. 2026 Jul 24. pii: 170. [Epub ahead of print]17(1):
    Single cell landscape of sex differences in the different courses of multiple sclerosis.
    Irene Soler-Sáez, Borja Gómez-Cabañes, Rubén Grillo-Risco, Cristina Galiana-Roselló, Lucas Barea-Moya, Héctor Carceller, María de la Iglesia-Vayá, Sara Gil-Perotin, Vanja Tepavčević, Marta R Hidalgo, Francisco García-García.
       BACKGROUND: One of the major challenges in addressing multiple sclerosis is to understand its progression trajectory. The pathological process transitions from acute phases predominantly driven by inflammation to progressive clinical profiles where neurodegeneration takes precedence. It is known that sex plays a crucial role in this heterogeneity; females are two to three times more likely to suffer from multiple sclerosis, while males suffer from more rapid neurodegeneration with greater severity.
    RESULTS: To gain insight into the sex-based molecular differences, we processed single cell datasets from the central nervous system and the peripheral blood, covering the different courses of multiple sclerosis. We generated cell-type specific landscapes, including gene signatures from differentially expressed genes, functional profiling, pathway activation, and cell-cell communication networks for females, males, and their sex differential profiles. Among our findings, we revealed that female neurons may exhibit protective mechanisms against neurodegeneration. In the inflammatory-predominant forms, female immune cells present an inflammatory core driven by the AP-1 transcription factor, while male adaptive immune cells exhibit higher mitochondrial impairment. Conversely, larger differences are reported in CD8 + T cells progressive forms, with males exhibiting cytolytic profiles that may promote neurodegeneration. Complete results can be explored in the interactive webtool https://irsoler.shinyapps.io/cbl-atlas-ms/ .
    CONCLUSIONS: We identified cell-type specific sex differences in brain and immune cells that vary in the spectrum of multiple sclerosis. We consider this molecular description a valuable resource to promote future targeted approaches considering the sex of the individual.
    Keywords:  Central nervous system; Excitotoxicity; Inflammation; Multiple sclerosis; Myelin recovery; Neurodegeneration; Peripheral immune system; Sex differences; scRNA-seq
    DOI:  https://doi.org/10.1186/s13293-026-00957-y
  53. Neurochem Res. 2026 Oct 20. pii: 298. [Epub ahead of print]51(6):
    Microglia in Perioperative Neurocognitive Disorders: Pathogenic Mechanisms and Emerging Concepts of Microglial Heterogeneity.
    Han Wang, Xinyi Wang, Qijie Ai, Daqing Pei.
      Perioperative neurocognitive disorders (PND) comprise a spectrum of cognitive disturbances after anesthesia and surgery, affecting learning, memory, and executive function. Although systemic inflammation, surgical trauma, anesthetic exposure, and patient vulnerability have been implicated in PND, the mechanisms linking perioperative stress to persistent cognitive changes remain incompletely understood. Microglia, as resident immune cells of the central nervous system, are important regulators of neuroimmune interactions and may contribute to PND through alterations in inflammatory signaling, synaptic regulation, vascular function, metabolism, and epigenetic programs. In this Overview, we summarize current evidence regarding microglial involvement in PND across five interconnected domains: neuroinflammation, blood-brain barrier dysfunction, microglia-neuron communication, mitochondrial and metabolic regulation, and epigenetic remodeling. We further discuss emerging single-cell transcriptomic and multi-omic studies indicating that microglial responses are heterogeneous, dynamic, and context dependent rather than adequately described by the traditional M1/M2 framework. We propose that PND involves complex interactions among peripheral immune activation, neurovascular dysfunction, microglial state transitions, and neuronal vulnerability. Finally, we highlight current challenges in translating microglial mechanisms into clinical applications and discuss future directions for identifying biomarkers and developing context-specific perioperative neuroprotective strategies.
    Keywords:  Microglia heterogeneity; Microglia-neuron crosstalk; Neuroinflammation; Perioperative neurocognitive disorders
    DOI:  https://doi.org/10.1007/s11064-026-04926-0
  54. Front Med (Lausanne). 2026 ;13 1912856
    Case Report: Herbal nutritional intervention in a critically ill ALS patient with multidrug-resistant infection.
    Meng Wang, Chihim Mak, Xinjie Li, Shaoyu Li, Chunyan Cui, Defeng Cai, Zhiwei Liang, Tao Lu, Qingshun Jia, Xiangming Shao, Yong Ma, Guanghui Fan, Kejin Li, Wenzhi Mai, Chihang Mak, Nan Liu.
      We report a retrospective single case of a female patient with a 9-year history of amyotrophic lateral sclerosis (ALS) who presented with respiratory failure due to a multidrug-resistant organism (MDRO) infection, predominantly Klebsiella pneumoniae (KP), and who showed significant clinical improvement during a comprehensive treatment regimen that included an adjunctive herbal nutritional intervention. The objective of this retrospective single-case report was to describe the clinical course of this patient following a nutritional intervention with two herbal beverages: Sang Shen Pu Gong Ying (SSPGY) and Wu Zhi Mao Tao Hong Zao (WZMTHZ). The patient was admitted in critical condition and managed in three phases: initial antibiotics with occasional herbal beverages, daily herbal beverages, and a combination of herbal beverages with intermittent antibiotics. Retrospective analysis of clinical data revealed significant improvements post-intervention. Body weight increased from 26 kg to 35.5 kg at discharge and 39 kg at the 6-week follow-up. Vital signs normalized, with no detectable KP in the final hospital phase. Inflammatory markers, including C-reactive protein and white blood cell count, decreased markedly. Neurological status, as indicated by neurofilament light chain (NfL) levels, improved, and the patient showed respiratory autonomy and positional changes. Nutritional markers, total protein and creatinine, also improved. This case documents clinical improvements, including extended ventilator-free breathing periods, in an ALS patient with MDRO infection following a combined therapeutic approach. Although concurrent medical interventions were administered in real-world clinical practice, these findings suggest the potential value of this adjunctive intervention, warranting further systematic investigation. Clinical Trial Registration: identifier ITMCTR2024000322.
    Keywords:  Klebsiellapneumoniae (KP); amyotrophic lateral sclerosis (ALS); herbal nutritional intervention; multidrug-resistant organism (MDRO); respiratory failure
    DOI:  https://doi.org/10.3389/fmed.2026.1912856
  55. Extracell Vesicles Circ Nucl Acids. 2026 ;7(3): 1653-1680
    Therapeutic mechanistic framework of mesenchymal stem cell-derived extracellular vesicles in neurodegenerative diseases.
    Gunjan Bawne, Magdalena J Lorenowicz.
      Neurodegenerative diseases are a spectrum of progressive disorders unified by chronic neuroinflammation, oxidative and mitochondrial stress, and accumulation of misfolded proteins that ultimately drive neuronal dysfunction and loss. Despite recurring convergence on these pathogenic processes, therapeutic progress has remained limited, underscoring the need for interventions capable of targeting convergent pathogenic pathways rather than single downstream features. Mesenchymal stromal/stem cells (MSCs) have emerged as promising therapeutic candidates through their paracrine actions that modulate inflammatory and cellular stress responses within the nervous system. Increasing evidence indicates that extracellular vesicles released by MSCs (MSC-EVs) are key mediators of these effects, transferring regulatory RNAs, lipids, and proteins that reprogram recipient cells, attenuate neuroinflammatory cascades, and support neuronal survival. MSC-EVs can recapitulate key therapeutic mechanisms of their parent cells and may offer potential advantages in safety, scalability, and delivery across the blood-brain barrier. While MSC-EVs are promising candidates for treating these diseases, the molecular mechanisms underlying their effects are still emerging. In this review, we synthesise evidence from experimental models to develop a mechanistic framework describing how MSC-EVs modulate interconnected regulatory modules that shape neuroinflammation with blood-brain barrier dysfunction, oxidative and mitochondrial stress, and dysregulated proteostasis with loss of neurotrophic support. We further discuss how this modular perspective may inform strategies to mitigate infection-associated neurodegenerative trajectories, with particular attention to post-SARS-CoV-2 neurological sequelae. By integrating these mechanistic insights, this review provides a conceptual foundation for the rational optimisation and bioengineering of MSC-EV-based therapies targeting convergent regulatory pathways in neurodegeneration.
    Keywords:  Neurodegenerative diseases; SARS-CoV-2; extracellular vesicles; mesenchymal stromal cells; neuroinflammation; proteostasis; redox homeostasis; signal transduction
    DOI:  https://doi.org/10.20517/evcna.2026.54
  56. Anim Cells Syst (Seoul). 2026 ;30(1): 587-599
    Matching developmental timelines of fish, frog, mouse and human brains.
    Hyun Jung Park, Hosung Jung.
      The overall structure and development of the central nervous system (CNS) are highly conserved among vertebrates. Peak neurogenesis generally precedes the main wave of astrogliogenesis; exuberant synapses are formed and pruned during critical periods; and the neurotransmitter gamma-aminobutyric acid (GABA) shifts from depolarizing to hyperpolarizing as the brain matures. The sequence of these key developmental events is broadly similar across vertebrate model organisms, including mouse, Xenopus, and zebrafish. Despite this overall similarity, the relative duration of each event varies substantially, and key events such as live birth in mammals do not occur in fish or frogs. These differences must be considered when translating findings from one species to another. In this review, we compare several developmental events that are relevant to modeling human diseases in animal models, including microglial colonization and blood-brain barrier formation. We also present comparative developmental timelines as a resource for translational neuroscience research.
    Keywords:  GABA-A polarity switch; Microglial colonization; Xenopus; blood–brain barrier; zebrafish
    DOI:  https://doi.org/10.1080/19768354.2026.2742604
  57. Front Synaptic Neurosci. 2026 ;18 1970578
    Multi-cohort meta-analysis, single-cell and Mendelian randomization analyses with experimental validation identify RHBDF2 as a shared mediator of ulcerative colitis and blood-brain barrier disruption.
    Jiongjiong Cheng, Aman Xu.
       Background: Ulcerative colitis (UC) is increasingly associated with central nervous system comorbidities, including cognitive decline and dementia, yet the molecular mechanisms linking intestinal inflammation to brain dysfunction remain unclear. Blood-brain barrier (BBB) disruption is a plausible convergence point, but the mediators involved are largely unknown.
    Methods: We performed random-effects meta-analyses of five human UC bulk-transcriptome cohorts (1,130 UC and 508 control samples) and three mouse BBB-disruption (BBBD) cohorts, followed by cross-species orthologue mapping to identify shared genes. The cellular context of candidate genes was resolved by single-cell RNA-sequencing analysis of human UC colonic mucosa (GSE214695) and paired human BBB-intact/BBB-opened brain samples (GSE208074), combined with scTenifoldKnk in-silico gene knockout. Summary-data-based Mendelian randomization (SMR) integrating whole-blood cis-eQTL and FinnGen GWAS data was used to assess causal relevance to dementia. Findings were validated in dextran sulfate sodium (DSS)-induced colitis in mice preventively treated with the ADAM17 inhibitor GW280264X, with Evans blue assessment of BBB permeability.
    Results: Four genes-TNF, RHBDF2, PILRA and CXCL16-were significantly and concordantly up-regulated in both UC and BBBD, forming a protein-protein association module organized around the sheddase ADAM17. RHBDF2, the essential activating chaperone of ADAM17, was predominantly up-regulated in colonic epithelial cells in UC, whereas its strongest inferred regulatory impact at the human BBB mapped to endothelial cells, affecting complement, microglial and angiogenic programs. Genetically predicted higher expression of RHBDF2 and PILRA was associated with increased risk of all-cause and Alzheimer's dementia. In DSS-induced colitis, preventive administration of GW280264X attenuated intestinal inflammation, reduced cerebral Evans blue extravasation and lowered brain Rhbdf2, Adam17 and Tnfα protein levels.
    Conclusion: Integrative transcriptomic, genetic and experimental evidence identifies an RHBDF2-ADAM17-TNFα axis as a plausible mechanistic bridge between ulcerative colitis and blood-brain barrier disruption and a candidate therapeutic target.
    Keywords:  ADAM17; GW280264X; Mendelian randomization; RHBDF2/iRhom2; TNFα; blood–brain barrier; meta-analysis; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fnsyn.2026.1970578
  58. Food Res Int. 2026 Dec 01. pii: S0963-9969(26)02424-5. [Epub ahead of print]245(Pt 2): 120737
    Astaxanthin alleviates Parkinson's disease via dual regulation of tryptophan metabolism: central STAT3/IDO1 inhibition and gut microbiota remodeling.
    Jing Shi, Guifa Wang, Xiaochen Zhang, Nan Zhang, Kening Zhang, Qing Wang, Yuanzheng Wang, Tongtong Li, Meilan Xue, Zhenxia Sha.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder with limited disease-modifying treatments. Dysregulation of tryptophan metabolism via the gut-brain axis has emerged as a key pathogenic mechanism. Astaxanthin (AX), a dietary ketocarotenoid abundant in Haematococcus pluvialis and marine organisms, possesses potent antioxidant and anti-inflammatory properties; however, it remains unclear whether AX exerts neuroprotection in PD through specific modulation of tryptophan metabolism via the signal transducer and activator of transcription 3 (STAT3)/ indoleamine 2,3-dioxygenase 1 (IDO1) pathway and gut microbiota remodeling. In this study, an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced mouse model of PD was used to evaluate the neuroprotective effects of AX. AX ameliorated motor deficits, attenuated dopaminergic neuron loss in the substantia nigra (SN), suppressed neuroinflammation, and enhanced mitophagy. Mechanistically, AX directly inhibited STAT3 activation and downregulated IDO1 expression in the brain, reducing the conversion of tryptophan to neurotoxic quinolinic acid (QUIN). Concurrently, AX reshaped the gut microbiota by enriching Lactobacillus, which redirected tryptophan metabolism toward the production of neuroprotective indole derivatives, including indole-3-propionic acid (IPA) and indole-3-acetic acid (IAA). Fecal microbiota transplantation (FMT) from AX-treated donors recapitulated key aspects of these effects, including suppression of signal transducer and activator of transcription 3(STAT3)/ indoleamine 2,3-dioxygenase 1(IDO1), elevation of IPA/IAA, and improvement of motor function, confirming that the gut microbiota mediates AX's neuroprotective action. These findings demonstrate that AX alleviates PD pathology through a dual mechanism: central inhibition of the STAT3/IDO1 pathway to block neurotoxic quinolinic acid production, and peripheral gut microbiota remodeling to enhance neuroprotective indole derivatives. This study positions AX as a promising functional food ingredient targeting tryptophan metabolism for PD intervention.
    Keywords:  Astaxanthin; Gut-brain axis; Mitophagy; Neuroinflammation; Parkinson's disease; Tryptophan metabolism
    DOI:  https://doi.org/10.1016/j.foodres.2026.120737
  59. J Vis Exp. 2026 Oct 21.
    An Automated Framework Using Magnetic Resonance Imaging Feature Masking and Support Vector Machine for Schizophrenia Classification.
    Jun Liu, Cong Fu, Liping Liu.
      Automated classification of schizophrenia can improve the quality of life for people with schizophrenia and reduce social costs. At present, however, the usual standards for diagnosing mental illnesses are still based on the subjective assessment of psychiatrists and lack objective quantitative biomarkers for early detection. Neuroimaging-based machine learning has achieved some success, but the existing models have not addressed the high dimensionality of small-sample magnetic resonance imaging (MRI) studies. These data characteristics are prone to sub-optimal automatic feature extraction and weak out-of-sample generalization. Based on the above problems, an automated classification pipeline that combines MRI feature engineering with a support vector machine (SVM) classifier to accurately differentiate patients with schizophrenia is introduced. First, to address inter-subject anatomical differences, comprehensive brain preprocessing and spatial alignment were performed. Then, intensity-based statistical features were derived from the preprocessed volumes, reduced in the input space via background masking to remove non-brain tissues, and subsequently aggregated into atlas-based regional features. A refined feature matrix is then fed into an SVM to construct the optimal separating hyperplane for final classification. This study adopted an 80:20 train-test split strategy, with five-fold cross-validation performed exclusively on the training set for model selection and hyperparameter tuning, followed by final performance evaluation on the held-out test set. Using the public COBRE dataset, the final SVM model achieved an accuracy of 96.7% on the held-out test set. This framework is expected to evolve into an objective, data-driven auxiliary diagnostic tool for schizophrenia and to provide timely treatment decision support in clinical practice.
    DOI:  https://doi.org/10.3791/72337
  60. Brain Behav. 2026 Oct;pii: e71848. [Epub ahead of print]16(10):
    Correlation Between Cognitive Function and Serum Irisin Levels in Parkinson's Disease Patients.
    Meilin Gui, Lixia Qin, Lingling Lv, Jinduo Huang, Shenglan Hu, Kexin Chen, Xing Wang, Yiwen Zhou, Beisha Tang, Hainan Zhang, Chunyu Wang.
       INTRODUCTION: Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD) that markedly reduces patients' quality of life. Given the clinical heterogeneity of PD-related cognitive impairment (PDCI), further clarification of clinical and circulating biological factors associated with cognitive status may help improve our understanding of cognitive dysfunction in PD.
    METHODS: In this cross-sectional study, 243 patients with PD and 90 age- and sex-matched healthy controls (HCs) were enrolled. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA), and patients with PD were classified into the PD with cognitive impairment (PDCI) and PD without cognitive impairment (PDNCI) groups. Based on motor symptoms, PD patients were further divided into three subtypes: tremor-dominant (TD), postural instability and gait disorder (PIGD), and indeterminate subtype (IND). Group comparisons and logistic regression analyses were performed to examine factors associated with cognitive impairment.
    RESULTS: Serum irisin levels did not differ significantly between patients with PD and healthy controls (p = 0.478). Compared with PDNCI patients, those with PDCI had lower serum irisin levels. Among motor subtypes, the PIGD group showed a higher prevalence of cognitive impairment (68.8% vs. 46.2%, p < 0.001) and significantly lower irisin levels compared with the TD group [3.25 (2.62-4.14) vs. 4.12 (3.42-5.07) µg/mL, p < 0.001]. Serum irisin levels were weakly but positively associated with memory performance, and this association remained significant after FDR correction across the five cognitive domains (r = 0.194, FDR-adjusted p = 0.010). Compared with patients in the TD-high irisin group, those in the PIGD-low irisin group had higher odds of concurrent cognitive impairment (OR = 6.065, 95% CI: 2.974-18.638, p = 0.002).
    CONCLUSION: Cognitive impairment was common among patients with PD, particularly those with the PIGD subtype. The PIGD subtype and lower serum irisin levels were associated with the presence of PDCI. In the joint-category analysis, patients in the PIGD-low-irisin group had higher odds of concurrent cognitive impairment than those in the TD-high-irisin group.
    Keywords:  Parkinson's disease; cognitive impairment; irisin; motor subtypes
    DOI:  https://doi.org/10.1002/brb3.71848
  61. J Nurs Scholarsh. 2026 Nov;pii: e70141. [Epub ahead of print]58(6):
    Caregiver Contributions to Self-Care in Parkinson's Disease: A Qualitative Descriptive Study.
    Petralito Monica, Caruso Rosario, Tedesco Chiara, Castaldo Anna, Muttillo Giovanni, Ioannis Ugo Isaias, Bonvegna Salvatore, Caniglia Arturo, Cuoco Angela, Vellone Ercole, Pucciarelli Gianluca.
       INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, and is characterized by motor symptoms such as bradykinesia, rigidity, and reduced movement automaticity. Caregiver contributions (CC) to self-care in PD represent an important resource for supporting people with PD. However, this topic has not yet been fully explored.
    AIM: To explore CC to self-care in PD across the domains of CC to self-care maintenance, monitoring, and management.
    METHOD: A qualitative study design was conducted using a combined deductive and inductive approach. An initial deductive framework guided the analysis, while an inductive process allowed the identification of additional codes emerging from the interview data.
    RESULTS: Twenty semi-structured interviews were conducted. Caregivers of people with PD were 75% women, with a mean age of 63.7 years, and were 90% spouses and 95% living with the patient. The analysis showed that the CC to self-care emerges across all domains: in self-care maintenance, through support for medication adherence, physical activity, safety, and diet; in self-care monitoring, through support in daily activities, routine symptom monitoring, and alert system monitoring; and in self-care management, through symptom management strategies and caregiver attitudes. More broadly, this contribution also emerged in relation to caregiving difficulties, interactions with healthcare professionals, and the information that guides self-care.
    DISCUSSION-CONCLUSION: The findings from this study showed that caregivers of persons with PD play a significant role in CC to self-care maintenance, monitoring, and management, particularly through non-pharmacological strategies.
    CLINICAL RELEVANCE: These data are fundamental for guiding educational interventions aimed at the caregivers of patients with PD.
    DOI:  https://doi.org/10.1111/jnu.70141
  62. Front Aging Neurosci. 2026 ;18 1807030
    Gait characteristics in people with central nervous system disorders under dual-task experimental paradigms: a scoping review.
    Haizhe Jin, Jiahao Zhang, Xinyi Meng, Jianing Li, Su Meng, Quanwei Fu.
       Background: Dual-task (DT) paradigms are widely used for gait assessment in patients with central nervous system diseases. However, previous studies have primarily focused on specific diseases and a limited range of DT paradigms, making it difficult to obtain an overall understanding of the application patterns of different paradigms and their associated gait changes. This scoping review aimed to identify and classify the DT paradigms used in DT gait studies of Alzheimer's disease (AD), Parkinson's disease (PD), and stroke; describe the application and distribution of these paradigms across studies of different diseases; further examine changes in gait characteristics under different DT paradigms.
    Methods: The Web of Science Core Collection, PubMed, and the Cochrane Library were systematically searched for relevant studies published between January 1, 2005, and April 30, 2026. DT paradigms were classified, and their distribution was mapped by disease category. Dual-task cost (DTC) for gait speed, stride length, and cadence was also summarized descriptively.
    Results: A total of 84 studies were included, and 26 DT paradigms were identified, including 21 cognitive tasks, four motor tasks, and one combined cognitive-motor task. Serial subtraction by 3s and 7s were more frequently used in studies of PD, whereas the counting task was more frequently used in studies of AD. The verbal fluency task was relatively evenly distributed across studies of the three diseases, whereas the object-carrying task was used primarily in studies of PD and stroke. Among the paradigms included in the descriptive synthesis, mean gait speed DTC was numerically highest under the verbal fluency task in patients with AD, under serial subtraction by 7s in patients with PD and healthy controls, and under the counting task in patients with stroke. Available data on stride length and cadence were relatively limited.
    Conclusion: The paradigms used in DT gait studies of AD, PD, and stroke were primarily concentrated in a small number of commonly used paradigms, and their distribution was uneven across diseases. The descriptive DTC findings suggest that patterns of gait change may differ according to disease and DT paradigm.
    Keywords:  central nervous system diseases; cognitive–motor interference; dual-task cost; dual-task paradigm; gait analysis
    DOI:  https://doi.org/10.3389/fnagi.2026.1807030
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