bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–08–30
74 papers selected by
Luca Bolliger, lxBio
  1. Unraveling Neurodegeneration: Common Molecular Mechanisms and Novel Therapeutic Concepts in Major Neurodegenerative Disorders.
  2. Combination Pharmacology for ALS: A Mechanistic Rationale.
  3. Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation.
  4. Bridging the gap: neuroinflammation and the dawn of precision medicine in amyotrophic lateral sclerosis.
  5. High-dose methylcobalamin in amyotrophic lateral sclerosis: mechanistic rationale, translational evidence, and clinical implications.
  6. Theranostic Innovative Strategies for Brain Diseases: New Insights on Neurovascular Unit-Associated Pathological Changes in Neurodegenerative Disorders and Aging.
  7. Targeting Mitochondrial Fission Produces Both Neuroprotective and Detrimental Effects in the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis.
  8. Drosophila: An Emerging New Approach Method (NAM) for Studying Amyotrophic Lateral Sclerosis (ALS).
  9. Hospital-to-Home Neurological Transition Care: A Scoping Review Across Selected Chronic Neurological Disorders.
  10. The Role of Neurofilaments in Diagnosis and Monitoring of Amyotrophic Lateral Sclerosis.
  11. Long-term survival in amyotrophic lateral sclerosis - data from a population-based registry in Rhineland-Palatinate, Germany.
  12. Diagnostic Delay in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis Comparing Time From Symptom Onset to Diagnosis in Bulbar-Onset Versus Limb-Onset Disease.
  13. ALS: An Organism-Wide Bioenergetic Failure Due to Mitochondrial Dysfunctions?
  14. Effects Of Ethanol on the Structure and Function of the BBB and Their Roles in Central Nervous System Diseases.
  15. Detection of TDP-43 Proteinopathies in Brain and Cerebrospinal Fluid Using Seed Amplification Assay.
  16. Task-Evoked Prefrontal Hemodynamics During Cognitive Assessment in Amyotrophic Lateral Sclerosis Using fNIRS.
  17. K16ApoE-mediated delivery across the blood-brain barrier: mechanisms, applications, and translational challenges.
  18. The Microbiota-Gut-Brain Axis and Nutritional Interventions in Amyotrophic Lateral Sclerosis: Pathophysiological Mechanisms, Neuroinflammation, and Non-Motor Manifestations-Scoping Review.
  19. Targeting Neutrophil Extracellular Traps in Neuroinflammation: A Therapeutic Perspective on Neurodegenerative Diseases.
  20. Functional Activity of TDP-43: A Direct Biomarker for ALS.
  21. Pridopidine Mediated Sigma-1 Receptor Activation and Therapeutic Implications in Neurodegenerative Diseases.
  22. Therapeutic Challenges and Future Breakthroughs in Amyotrophic Lateral Sclerosis: From Precision Medicine to Innovative Trial Design.
  23. Exploration of reliable assessment of respiratory function in amyotrophic lateral sclerosis.
  24. Exosomal innovations in neurodegenerative disorders: Emerging insights and intranasal route.
  25. The HDAC Inhibitor Butyrate Reduces SOD1 Aggregation and Improves Motor Function in C. elegans and Cellular Models of ALS.
  26. TDP-43-Associated Neurodegenerative Disease Conceptualization and Integrated Staging: A Review.
  27. GLP-1 and GIP class drugs have neuroprotective properties in Alzheimer's and Parkinson's disease.
  28. Ferulic Acid and Brain Health: A Defender Against Alzheimer's Disease, Parkinson's Disease, and Neuroinflammation.
  29. Splicing modulation of ATXN2 as a therapeutic strategy to regulate Ataxin-2 protein levels in ALS.
  30. Palliative Care Involvement in Hospitalized Amyotrophic Lateral Sclerosis Patients.
  31. Systematic Design and Evaluation of Nasal Drug Delivery for Central Nervous System Disease from Experimental to Clinical Application.
  32. Feasibility study on a noninvasive assessment of ALS patient emotional state.
  33. Clinical, Social, and Healthcare Factors Associated with Nutritional Status in Amyotrophic Lateral Sclerosis: A Multidimensional Approach.
  34. Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43.
  35. Theory of mind impairment related to C9orf72 repeat expansion in amyotrophic lateral sclerosis: a case-control study.
  36. Ultraviolet radiation and neurodegeneration: molecular mechanisms underlying dual neuroprotective and neurotoxic effects.
  37. Metabolic connectivity alterations in amyotrophic lateral sclerosis: Individual network analysis based on Wasserstein distances.
  38. NLRP3 Inflammasome and Inflammation-Related Proteins Expression Characterized in Non-Cultivated Versus Cultivated Peripheral Blood Cells of Patients with Amyotrophic Lateral Sclerosis.
  39. Evaluating the Incremental Value of Three-Dimensional Conformer Descriptors for Blood-Brain Barrier Permeability Prediction Using the B3DB Benchmark Dataset.
  40. Esterified Cholesterol Conjugates Enable LNP-Mediated mRNA Delivery to the Blood-Brain Barrier Following Intravenous Administration.
  41. Are Signal Peptides Hidden Regulators of Neurodegenerative Disease?
  42. Low expression of PDGFR-β impairs the blood-brain barrier and accelerates cellular aging in the hippocampal region.
  43. The Eye as a Window to Neurodegeneration: Oxidative Stress, Optic Nerve Vulnerability, and Retinal Biomarkers-A Scoping Review.
  44. Quantitative Structural Thresholds for Blood-Brain Barrier Permeability Derived from Experimental logBB Measurements.
  45. Multitargeted drug strategies for Alzheimer's and Parkinson's diseases.
  46. Generation of two iPSC lines from ALS patients harboring C9orf72 hexanucleotide repeat expansions.
  47. Quercetin as a Hypothesized Involvement of VMAT2 in Neurodegenerative Diseases-Mechanistic Insight and Therapeutic Applications.
  48. DeepBBB: A Data-Composition-Aware Graph Screening Workflow for BBB-Focused CNS Library Construction and Prospective PAMPA-BBB Evaluation.
  49. The sleep-deprived blood-brain barrier: Does the Brain's gatekeeper adapt or merely fail slowly?
  50. Methodological insights and clinical outcomes in ALS and FTLD: lessons from the SPIN cohort.
  51. JP1 peptide modulates oxidative stress and autophagy via Keap1-Nrf2-ARE in ALS model mice.
  52. EXPRESS: Disentangling MRI-derived blood-brain barrier leakage into vascular permeability and surface area.
  53. Overcoming the blood-brain barrier for therapeutics targeting neurodegenerative diseases: a patent review (2020-present).
  54. Cognitive and behavioral manifestations of the C9orf72 mutation in Amyotrophic Lateral Sclerosis: an age, education, and gender-matched cohort study.
  55. 3D U-net for volumetric segmentation of spinal cord MRI in degenerative disorders.
  56. Benzothiazole-driven molecular probes and therapeutics for neurodegenerative diseases: focus on amyloid-beta (Aβ), tau, and α-synuclein.
  57. Recent advances in MR neuroimaging: toward quantitative and AI-driven brain and spinal cord imaging.
  58. Lipid Metabolism in Central Nervous System Diseases: Pathological Mechanisms and Therapeutic Advances.
  59. The Prospective Regulatory Functions of lncRNAs and Their ceRNA Networks in the Development of Motor Neurons and Associated Diseases.
  60. Low vs high frequency deep brain stimulation for Parkinson's disease-associated motor symptoms: A systematic review and meta-analysis of randomized control trials.
  61. SARS-CoV-2 disrupts the integrity of a human blood-brain barrier model in the absence of infection.
  62. Diagnosing multiple sclerosis: implementation and unintended effects of the 2024 McDonald criteria.
  63. Sex-dependent dopaminergic vulnerability may contribute to sex differences in Parkinson's disease risk.
  64. Epilepsy-Linked Gut Microbiota and Metabolic Signatures in Acquired Epilepsy: The Focus on Short-Chain Fatty Acid and Tryptophan Metabolism.
  65. Metformin in Neurodegenerative Diseases: Mechanisms and Therapeutic Implications.
  66. Bypassing the Blood-Brain Barrier: A Dual-Axis Framework for Alzheimer's Disease Utilizing Glymphatic-Lymphatic Clearance and In Situ Chaperone Synthesis.
  67. Biallelic SIGMAR1 variants in early-onset distal hereditary motor neuropathy: A Japanese case series.
  68. CA-IV-directed small-molecule shuttle enables targeted brain delivery of biologics.
  69. Diagnostic Accuracy of Artificial Intelligence Models for Detecting Odontogenic Keratocytes on CBCT Imaging: A Systematic Review and Meta-Analysis.
  70. Current Targeted Nanoparticle Therapy for Alzheimer's Disease: Current Advances and Future Prospects.
  71. From neuroinflammation to immune reprogramming: Nanozyme-Integrated nanoplatforms for neuroimmune modulation in Parkinson's disease.
  72. Neuron-derived SPP1 instructs microglia to limit degeneration.
  73. Microphysiological modeling of the Blood-CSF barrier for biopharmaceutical transport and sequestration: evaluation of PEG-induced accumulation and vacuolation in the choroid plexus epithelium.
  74. Pathogenesis-Driven Drug Repurposing with a Self-Nanoemulsifying Delivery System for Parkinson's Disease.
  1. Brain Behav. 2026 Aug;16(8): e71615
    Unraveling Neurodegeneration: Common Molecular Mechanisms and Novel Therapeutic Concepts in Major Neurodegenerative Disorders.
    Fatemeh Sadat Aldaghi, Zakieh Siahpoosh, Zivar Salehi, Farhad Mashayekhi, Shabnam Sohrabnezhad.
       PURPOSE: Although Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Huntington's disease (HD) present with markedly different clinical phenotypes, these neurodegenerative diseases (NDDs) appear to converge on a shared set of underlying molecular disturbances. This review sought to integrate disease-specific causative triggers with shared pathogenic pathways, focusing on neuroinflammatory signaling, oxidative imbalance, mitochondrial impairment, and disrupted protein homeostasis, in order to support multi-target, disease-modifying therapeutic strategies.
    METHOD: Relevant classical and contemporary literature, encompassing original research and review articles on the molecular basis of AD, PD, ALS, MS, and HD, was reviewed and synthesized narratively, with attention to how neuroinflammatory and oxidative stress pathways intersect, reinforce one another through mitochondrial and inflammasome-driven feedback, and recur across the five conditions.
    FINDING: In each disorder, persistently activated microglia and astrocytes secreted inflammatory mediators and reactive oxygen species, engaged the NLRP3 inflammasome, and progressively destabilized cellular homeostasis through a self-perpetuating cycle linking neuroinflammation and oxidative stress. Disease-specific lesions nonetheless persisted: amyloid-β and tau pathology in AD; α-synuclein aggregation with iron-driven mitochondrial damage in PD; RNA-binding protein dysfunction, proteostatic collapse, and excitotoxicity in ALS; inflammatory demyelination and axonal bioenergetic failure in MS; and mutant huntingtin-driven transcriptional and mitochondrial disruption in HD. These distinct triggers ultimately converged on shared downstream cascades.
    CONCLUSION: Recognizing this shared pathogenic foundation supports multi-target therapies-such as Nrf2 activation, NLRP3 inhibition, mitochondria-targeted antioxidants, and gene-based interventions-that extend across diagnostic boundaries, though challenges in intervention timing, patient stratification, and clinical translation remain unresolved.
    Keywords:  disease‐modifying therapies; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammation; oxidative stress; protein aggregation
    DOI:  https://doi.org/10.1002/brb3.71615
  2. Int J Mol Sci. 2026 Aug 19. pii: 7404. [Epub ahead of print]27(16):
    Combination Pharmacology for ALS: A Mechanistic Rationale.
    Jeffrey Rosenfeld, Shiran Salomon-Zimri, Ferenc Tracik.
      Amyotrophic lateral sclerosis (ALS) involves multiple converging pathogenic mechanisms, including glutamate excitotoxicity, oxidative and endoplasmic-reticulum stress, mitochondrial dysfunction, neuroinflammation, iron dysregulation, and altered microRNA processing. Expecting a single pharmacologic intervention to meaningfully alter such a complex disease has proven overly optimistic and is reflected by the modest clinical benefits of approved monotherapies. This review outlines the mechanistic foundation and translational rationale for combination pharmacology in ALS. Drawing from paradigms in oncology, infectious disease, and other neurological disorders, it explores how rational multi-target strategies, whether synergistic, complementary, or pathway-divergent, may better address the multifactorial biology of ALS. The review also discusses recent mechanistic examples and design principles for advancing this therapeutic paradigm.
    Keywords:  ALS; clinical trials; combination therapy; mechanistic rationale; neurodegeneration
    DOI:  https://doi.org/10.3390/ijms27167404
  3. Brain Sci. 2026 Aug 04. pii: 828. [Epub ahead of print]16(8):
    Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic Translation.
    Shaoshuai Lu, Ziyang Chen, Yanyan Wang, Hongsheng Bian, Shuang Yu, Lili Huang.
      O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification that couples hexosamine biosynthesis pathway flux to protein function in neurons and glia. This reversible cycling, catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), integrates glucose, glutamine, acetyl-CoA, and nucleotide metabolism with synaptic activity, mitochondrial adaptation, transcriptional regulation, proteostasis, and neuroimmune signaling. Dysregulated O-GlcNAc cycling has been implicated in major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington's disease (HD), through effects on disease-related proteins, autophagy, mitochondrial function, and inflammatory networks. However, available evidence does not support a universal model in which global O-GlcNAc elevation is uniformly protective or global reduction is uniformly pathogenic. In this mechanistic narrative review, we integrate disease-specific and substrate-focused findings while distinguishing relatively mature translational evidence from model-based or hypothesis-generating observations. We propose a state-resolved framework in which disease-relevant O-GlcNAc states are interpreted across biological contexts, substrate/site specificity, and intervention dynamics. This framework helps reconcile divergent findings across experimental systems and highlights the limitations of indiscriminate global pathway modulation. Although OGA inhibitors represent the most advanced therapeutic strategy, their broad substrate effects underscore the need for pharmacodynamic biomarkers, human validation, brain-targeted delivery, and state-resolved approaches. Moving from bulk O-GlcNAc measurements toward precise correction of disease-relevant O-GlcNAc states across defined biological contexts will be essential for translating this biology into clinically meaningful interventions.
    Keywords:  O-GlcNAcylation; OGA inhibitors; brain energy metabolism; neurodegenerative diseases; precision therapy; proteostasis; synaptic plasticity
    DOI:  https://doi.org/10.3390/brainsci16080828
  4. Transl Neurodegener. 2026 Aug 24. pii: 40. [Epub ahead of print]15(1):
    Bridging the gap: neuroinflammation and the dawn of precision medicine in amyotrophic lateral sclerosis.
    Lu Tang, Dongsheng Fan.
      Neuroinflammation is no longer a secondary feature of amyotrophic lateral sclerosis (ALS), but rather a disease-modifying process that actively shapes the motor neuron vulnerability from the earliest stages of pathology. Central and peripheral immune cells, including microglia, astrocytes, and infiltrating T lymphocytes, adopt context-dependent states that can be neuroprotective or neurotoxic depending on disease stage and genetic background. These states are driven by discrete molecular programs, such as cGAS-STING-mediated innate immune sensing, NLRP3 inflammasome activation, and RIPK1-dependent necroptotic signaling, which represent tractable therapeutic targets. The repeated failure of broad-spectrum immunosuppressive trials reflects a fundamental mismatch between the non-selective interventions and the mechanistically distinct immune states of diseases. Converging transcriptomic, genetic, and immunophenotypic evidence supports the existence of putative neuroimmune endotypes in ALS, though this framework remains a working hypothesis pending prospective validation in biomarker-stratified cohorts. Advances in the following three domains are needed for realizing precision immunotherapy: standardized biomarker panels (including cerebrospinal fluid chitinases and TSPO-PET) to stratify patients by inflammatory subtype; pharmacodynamic readouts to confirm target engagement before interpreting clinical outcomes; and adaptive platform trial designs capable of evaluating mechanism-matching interventions in defined subgroups. This review integrates ALS-associated neuroinflammation with emerging precision medicine strategies, arguing that the central translational question is no longer whether or not to target neuroinflammation, but how, when, and in whom neuroinflammation should be targeted.
    Keywords:  Amyotrophic lateral sclerosis; Biomarker; Immunotherapy; Microglia; Neurodegeneration; Neuroimmune endotype; Neuroinflammation; Precision medicine
    DOI:  https://doi.org/10.1186/s40035-026-00572-2
  5. Neurodegener Dis Manag. 2026 Aug 27. 1-12
    High-dose methylcobalamin in amyotrophic lateral sclerosis: mechanistic rationale, translational evidence, and clinical implications.
    Alexandre Almeida da Silva, Camila Castelo Branco Pupe, Júlio César Claudino Dos Santos.
      Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder characterized by selective degeneration of upper and lower motor neurons, driven by converging mechanisms including glutamatergic excitotoxicity, mitochondrial dysfunction, oxidative stress, calcium dyshomeostasis, impaired RNA metabolism, and neuroinflammation. In the absence of effective disease-modifying therapies, high-dose methylcobalamin has emerged as a candidate intervention based on its pleiotropic neurobiological effects. A structured literature search was conducted in PubMed/MEDLINE and ScienceDirect to identify peer-reviewed studies published between January 2017 and December 2025 addressing the mechanistic, preclinical, and clinical effects of methylcobalamin in ALS. Preclinical evidence suggests that methylcobalamin modulates homocysteine metabolism, supports S-adenosylmethionine-dependent methylation pathways, preserves mitochondrial integrity, attenuates oxidative stress, and promotes axonal regeneration. Experimental and translational findings further indicate that its therapeutic effects may be strongly dose dependent, particularly under ultra-high-dose regimens capable of overcoming limitations in central nervous system delivery. Clinical trials evaluating ultra-high-dose methylcobalamin demonstrate a potential attenuation of functional decline in patients treated during early disease stages, although effects on survival and respiratory outcomes remain inconsistent. This narrative review integrates molecular mechanisms, experimental evidence, biomarker research, and clinical trial data to examine the translational relevance, stage dependency, and therapeutic implications of high-dose methylcobalamin in ALS.
    Keywords:  Amyotrophic lateral sclerosis; motor neuron disease; neurodegeneration; neuroprotection; vitamin B12
    DOI:  https://doi.org/10.1080/17582024.2026.2713755
  6. Int J Mol Sci. 2026 Aug 11. pii: 7165. [Epub ahead of print]27(16):
    Theranostic Innovative Strategies for Brain Diseases: New Insights on Neurovascular Unit-Associated Pathological Changes in Neurodegenerative Disorders and Aging.
    Giulia Terribile, Matilda Pedrinazzi, Irene Frigerio, Giulio Sancini, Romina Combi.
      Central nervous system (CNS) disorders represent a significant healthcare challenge, with aging as the primary risk factor. Current clinical management remains predominantly symptomatic, as late-stage diagnosis and the blood-brain barrier (BBB) limit therapeutic efficacy. This review synthesizes emerging innovations in neurotheranostics-integrated diagnostic and therapeutic platforms-focusing on the neurovascular unit (NVU) as a central pathogenic driver and target. Evidence indicates that NVU and BBB dysfunction are early events in Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases, often preceding classic neuropathological hallmarks. The review highlights the potential of nanotechnology, engineered nanoparticles (NPs) and microRNAs (miRNAs) as precision tools for early detection and targeted CNS delivery. Additionally, it discusses the transformative impact of artificial intelligence (AI) in facilitating personalized, predictive care. Transitioning from a generic "one-pill-for-one-disease" model to a patient-centered strategy targeting early NVU alterations is essential. Integrating AI, nanotechnology and NVU-focused strategies offers a promising path toward effective, personalized disease-modifying therapies.
    Keywords:  aging; nanomedicine; neurodegenerative disorders; neurovascular unit; theranostic
    DOI:  https://doi.org/10.3390/ijms27167165
  7. Biology (Basel). 2026 Aug 07. pii: 1334. [Epub ahead of print]15(16):
    Targeting Mitochondrial Fission Produces Both Neuroprotective and Detrimental Effects in the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis.
    Maria Ciuro, Chantal Rovetto, Angela A Sirna, Salvatore Giunta, Giampiero Leanza, Rosario Gulino.
      Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by progressive motor neuron (MN) degeneration and severe skeletal muscle atrophy. Despite extensive research, the mechanisms driving disease onset and progression remain incompletely understood. While MN loss is a defining feature of ALS, increasing evidence indicates that mitochondrial dysfunction contributes to disease pathogenesis. Here, we investigated the hypothesis that Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp-1, may exert neuroprotective properties in the SOD1G93A mouse model of ALS. Treatment was initiated prior to symptomatic onset to assess its potential disease-modifying effects. Mdivi-1 administration resulted in partial preservation of spinal MNs, however, this benefit did not translate into functional improvement. Moreover, treated animals exhibited exacerbated muscle atrophy, increased cytoplasmic localization of TDP-43 in MNs and compromised synaptic plasticity. Drp-1 expression was reduced in SOD1 mice and further decreased following Mdivi-1 treatment, suggesting that mitochondrial dynamics may already be compromised in this model. Overall, our results also highlight possible off-target effects of Mdivi-1 and point to a context-dependent role of mitochondrial dynamics in ALS.
    Keywords:  Mdivi-1; SOD1G93A mouse model; TAR DNA-binding protein 43; amyotrophic lateral sclerosis; dynamin-related protein 1; mitochondrial dynamics; motor neurons; physiology; skeletal muscle atrophy; synaptic plasticity
    DOI:  https://doi.org/10.3390/biology15161334
  8. Cells. 2026 Aug 08. pii: 1432. [Epub ahead of print]15(16):
    Drosophila: An Emerging New Approach Method (NAM) for Studying Amyotrophic Lateral Sclerosis (ALS).
    Sasha Leggett, Nitesh Sanghai, Chuying Ru, Paul C Marcogliese, Geoffrey K Tranmer.
      Drosophila melanogaster (D. melanogaster), or fruit flies, are a commonly used model organism in the study of neurodegenerative diseases (NDs). Their short lifespan, low cost, genetic tractability, and conserved signaling and developmental pathways make them ideal for studying NDs and associated biochemical pathways. Further, flies offer the advantage of high-throughput exploratory drug and genetic screening without stringent ethical constraints. Therefore, D. melanogaster serves as an ideal organism for preliminary drug screening before transitioning to toxicity and efficacy studies in vertebrate models. Following the recent plan by the United States FDA (US FDA) and the National Institutes of Health (NIH) to progressively phase out preclinical drug testing in vertebrate animals and introduce New Approach Methodologies (NAMs), D. melanogaster has the potential to become part of the conventional drug testing pipeline in the future. This literature review focuses on the use of D. melanogaster models as a powerful, low-cost model organism to study superoxide dismutase 1 (SOD1)- and TAR DNA-binding protein 43 (TDP-43)-linked Amyotrophic Lateral Sclerosis (ALS), as well as previous efforts to screen drugs in SOD1- and TDP-43-expressing Drosophila models.
    Keywords:  Drosophila melanogaster; United States FDA; amyotrophic lateral sclerosis; neurodegenerative diseases; new approach methodologies
    DOI:  https://doi.org/10.3390/cells15161432
  9. Med Sci (Basel). 2026 Jul 28. pii: 445. [Epub ahead of print]14(4):
    Hospital-to-Home Neurological Transition Care: A Scoping Review Across Selected Chronic Neurological Disorders.
    Rocco Salvatore Calabrò, Andrea Calderone, Daniele Ravi, Carmelo Galipò, Maria Felicita Crupi, Angelo Quartarone.
       BACKGROUND: Returning home after neurological hospitalization, rehabilitation, or specialist care transfers responsibility to patients, caregivers, and community services. We mapped mechanisms and gaps across dementia/Alzheimer's disease and related dementias (ADRD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).
    METHODS: Following JBI guidance and PRISMA-ScR, eligibility was derived using population-concept-context. We included empirical reports involving adults with a target condition, a post-discharge, return-home, rehabilitation, telehealth, caregiver, treatment, respiratory, or palliative continuity component, and post-transition patient, caregiver, service, safety, rehabilitation, equity, or implementation outcomes. Five databases were searched through to 11 May 2026. Two reviewers independently screened records; charting and classification were verified by R.S.C., A.C., and A.Q.
    RESULTS: Of 24,417 records, 69 reports were included: Dementia/ADRD, 28; PD, 10; MS, 9; and ALS, 22. Eighteen were core transition reports (26.1%), 14 return-home/community re-entry reports (20.3%), 16 adjacent continuity reports (23.2%), and 21 companion/secondary reports (30.4%). Dementia/ADRD provided discharge-anchored evidence; PD and MS mapped functional carry-over; ALS mapped adjacent respiratory, telehealth, and palliative continuity.
    CONCLUSIONS: The main contribution is an operational cross-disease framework separating direct discharge, return-home, adjacent-continuity, and companion evidence while linking mechanisms to disease-specific pathways. This framework maps disease-specific functions, not comparative effectiveness. The proposed frameworks are author-derived and hypothesis-generating. Future studies should use explicit anchors, standardized outcomes, longer follow-up, and equity-sensitive implementation measures addressing caregiver workload, digital access, feasibility, and sustainability. They inform testable, context-sensitive intervention designs for future neurological transition-care research and practice.
    Keywords:  Parkinson’s disease; amyotrophic lateral sclerosis; continuity of care; dementia; multiple sclerosis; post-discharge follow-up; selected chronic neurological disorders; transitional care
    DOI:  https://doi.org/10.3390/medsci14040445
  10. J Clin Med. 2026 Aug 10. pii: 6196. [Epub ahead of print]15(16):
    The Role of Neurofilaments in Diagnosis and Monitoring of Amyotrophic Lateral Sclerosis.
    Anwen Davies, Andrew Bentley, Andras Bikov.
      Background: Amyotrophic lateral sclerosis (ALS), the most common type of motor neurone disease (MND), is a devastating diagnosis that often leads to mortality within 2-5 years of symptom onset. Respiratory failure and aspiration pneumonia both associated with respiratory muscle weakness are the most common causes of death. Difficult to diagnose and devastating in its prognosis, much research has aimed to identify a reliable biomarker to diagnose ALS, prognosticate and improve enrolment into clinical trials to further research efforts. Over the last few decades, neurofilaments (NFs) have emerged as promising biomarkers, especially neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH). This review aims to summarise the current evidence for use of NFs as biomarkers in ALS. Current Evidence: Higher levels of NFL and pNFH are measured in CSF than in serum, and levels in CSF and serum are correlated. High CSF NFL, serum NFL and CSF pNFH levels could differentiate patients with ALS from healthy controls, other neurological disease, neurodegenerative controls (without MND), other MND subtypes and ALS disease mimics; however, studies reported a high degree of heterogeneity irrespective of which media or NFs have been used. The number of studies examining NFs to predict respiratory failure in patients with ALS is low. Conclusions and Future Directions: Despite numerous studies consistently reporting higher NF levels in ALS compared to various controls, their clinical value is limited due to high heterogeneity of the results and inconsistencies in proving its prognostic value. Further understanding the relationship between NF levels and respiratory failure is paramount to improve the quality of life of patients with ALS and increase survival.
    Keywords:  amyotrophic lateral sclerosis; biomarker; motor neuron disease; neurofilament heavy chain; neurofilament light chain; neurofilaments; respiratory failure
    DOI:  https://doi.org/10.3390/jcm15166196
  11. BMC Neurol. 2026 Aug 27. pii: 546. [Epub ahead of print]26(1):
    Long-term survival in amyotrophic lateral sclerosis - data from a population-based registry in Rhineland-Palatinate, Germany.
    Joachim Wolf, Anton Safer, Ulrich Stefenelli, Johannes C Woehrle, Matthias Maschke, Wilfred A Nix, Armin J Grau.
       BACKGROUND: Data on long-term survival in amyotrophic lateral sclerosis (ALS) is scarce. In a population-based ALS cohort in Germany we evaluated long-term survival and assessed key factors influencing long-term survival, including demographic and clinical variables that are available at an early stage of the disease.
    METHODS: Data from patients in the prospective, population-based ALS-registry Rhineland-Palatinate were analyzed. Survival was evaluated separately for time from symptom onset and time from diagnosis. Patient demographic and disease-related variables were analyzed in relation to survival probability using the Kaplan-Meier method and Cox proportional hazards regression.
    RESULTS: Data from 200 incident ALS patients (106 men and 94 women) were included in the study. The median age of the patients was 68 years (range 23-85 years; mean age 65.8 years; standard deviation 10.5 years). The median survival time was 2.5 years from symptom onset and 1.5 years from diagnosis. 12% of the patients survived for at least ten years from first manifestation of symptoms. Multivariate statistics revealed that younger age, a low progression rate, the absence of frontotemporal dementia and a long interval between symptom onset and diagnosis were predictors of long survival.
    CONCLUSIONS: 12% of ALS patients are still alive ten years after the onset of symptoms, which is important for advance planning of patient care. In our analysis demographic and clinical variables available at an early stage of the disease have emerged as valuable predictive factors.
    TRIAL REGISTRATION: ClinicalTrials.gov (NCT01955369; registered retrospectively 28/09/2013).
    Keywords:  Amyotrophic lateral sclerosis; Long-term survival; Population-based register; Prognostic factors
    DOI:  https://doi.org/10.1186/s12883-026-05325-2
  12. Cureus. 2026 Jul;18(7): e113188
    Diagnostic Delay in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis Comparing Time From Symptom Onset to Diagnosis in Bulbar-Onset Versus Limb-Onset Disease.
    Yousaf Saeed, Maryam Fatima, Munib Ur Rehman, Muhammad Hamza Aslam.
      Diagnostic delay is a recognized challenge in amyotrophic lateral sclerosis (ALS), depriving patients of timely access to disease-modifying therapy and multidisciplinary care. Although several individual cohorts have reported diagnostic delay separately for bulbar-onset and limb-onset ALS, few studies have directly compared the two, and their estimates have not been pooled. We aimed to compare time from symptom onset to diagnosis in bulbar-onset versus limb-onset ALS. We searched PubMed and Cochrane CENTRAL (Cochrane Central Register of Controlled Trials) from inception through April 2026 for studies reporting diagnostic delay separately for the two onset types. Where upper- and lower-limb onset were reported separately, these were combined into a single limb-onset group using standard formulae; medians with interquartile ranges were converted to means and standard deviations using the method of Wan et al. A random-effects meta-analysis (DerSimonian-Laird) pooled studies reporting a usable measure of dispersion by onset group, with the remaining studies summarized narratively. The outcome was the mean difference (MD) in diagnostic delay in months, where a negative value indicates faster diagnosis in bulbar onset; heterogeneity was quantified with I² and risk of bias with the Newcastle-Ottawa Scale. In total, 13 studies (898 bulbar-onset and 2,438 limb-onset patients from eight countries) met the inclusion criteria; nine contributed to the meta-analysis, as four reported no usable measure of dispersion and were summarized narratively. Bulbar-onset patients were diagnosed significantly faster than limb-onset patients (MD = -4.42 months; 95% confidence interval -5.73 to -3.11; p < 0.001), with moderate heterogeneity (I² = 56%). The direction of effect was consistent across all studies, and the pooled estimate was stable on leave-one-out analysis. The four non-pooled studies were each directionally consistent. Bulbar-onset ALS is diagnosed approximately 4 months faster than limb-onset ALS, likely because distinctive bulbar symptoms prompt earlier specialist referral whereas limb weakness is attributed to more common musculoskeletal or orthopedic conditions. Strategies raising awareness of limb-onset ALS among primary care and orthopedic physicians are warranted.
    Keywords:  amyotrophic lateral sclerosis; bulbar onset; diagnostic delay; limb onset; meta-analysis
    DOI:  https://doi.org/10.7759/cureus.113188
  13. Biomolecules. 2026 Aug 01. pii: 1126. [Epub ahead of print]16(8):
    ALS: An Organism-Wide Bioenergetic Failure Due to Mitochondrial Dysfunctions?
    Hiroshi Mitsumoto, Hélène Blasco, Philippe Corcia, Vincenzo Silani.
      Amyotrophic lateral sclerosis (ALS) is a devastating and invariably fatal disease for which currently available disease-modifying therapies provide only modest benefit. Defining its underlying pathogenesis is therefore essential for the development of effective treatments. Increasing evidence indicates that ALS is not restricted to motor neurons but involves multiple neuronal and glial systems, extending to peripheral organs, often at subclinical levels. These multisystem alterations may precede overt neurological symptoms by years and are accompanied by metabolic disturbances, including progressive weight loss and hypermetabolism. In peripheral tissues, ongoing cellular turnover and associated immune and inflammatory responses may further increase energy demand. Within this framework, mitochondrial dysfunction emerges as a central mechanism underlying impaired bioenergetics and systemic metabolic failure. Mitochondria not only regulate energy production but also contribute to oxidative stress, which in turn exacerbates mitochondrial injury, creating a self-amplifying cycle. Importantly, many genetic forms of familial ALS directly affect mitochondrial pathways, and similar biochemical abnormalities are observed in sporadic ALS. These shared features suggest that mitochondrial dysfunction represents a common pathway across ALS subtypes. Targeting upstream mechanisms of mitochondrial impairment may therefore provide a unifying strategy for understanding ALS pathogenesis and developing effective therapies.
    Keywords:  ALS; MND; amyotrophic lateral sclerosis; bioenergetics; frontotemporal systemic disease; hypothalamus; metabolic disease; mitochondria; mitochondrial associated membrane (MAM); motor neuron disease; multisystem involvement
    DOI:  https://doi.org/10.3390/biom16081126
  14. Mini Rev Med Chem. 2026 Aug 06.
    Effects Of Ethanol on the Structure and Function of the BBB and Their Roles in Central Nervous System Diseases.
    Yuqi Peng, Tianyuan Ye, Dongmei Qi, Xiaorui Cheng.
      The blood-brain barrier (BBB) plays a vital role in maintaining brain homeostasis, as its proper function and structural integrity are essential. Communication between endothelial cells and nearby perivascular cells, which include pericytes, astrocytes, microglia, and oligodendrocytes, is key to the overall structure and function of the BBB. When ethanol is consumed, it raises the permeability of the BBB, leading to significant damage that can adversely affect brain health. This article reviews how ethanol interacts with the body, detailing the various mechanisms through which it alters the BBB's structure and function. We particularly highlight how ethanol damages endothelial cells, activates astrocytes and microglia, disrupts the differentiation and survival of oligodendrocyte precursor cells (OPCs), triggers neuroimmune responses, inhibits glucose transport, modifies blood pressure, and increases blood flow. Moreover, we examine how different levels of ethanol consumption influence the risk of developing conditions like Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. Interestingly, moderate alcohol intake may lower the odds of these diseases, while excessive drinking can heighten the risk. The effects of ethanol exposure on BBB permeability can also vary due to factors like sex, age, and genetics. Research suggests that estrogen is important for preserving the integrity of the BBB and protecting against neural damage, whereas high levels of ethanol intake may worsen BBB impairment, especially in individuals with the ApoE4 genotype. In summary, this article focuses on the mechanisms by which ethanol impacts the BBB, with the goal of offering insights that could assist in preventing and treating central nervous system diseases, particularly AD.
    Keywords:  Alcohol; Alzheimer's disease; Parkinson’s disease; Stroke; blood-brain barrier; brain
    DOI:  https://doi.org/10.2174/0113895575464650260731052107
  15. Curr Issues Mol Biol. 2026 Aug 13. pii: 824. [Epub ahead of print]48(8):
    Detection of TDP-43 Proteinopathies in Brain and Cerebrospinal Fluid Using Seed Amplification Assay.
    Katsuya Satoh, Mika Inada Shimamura, Takeshi Fujimoto, Michio Kitayama, Akio Akagi, Yasushi Iwasaki, Yuu Satoh, Katsuhiro Ichinose, Akira Satoh, Ikuko Takahashi Iwata, Ichiro Yabe.
      Misfolded TAR DNA-binding protein 43 (TDP-43) is the primary pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While seed amplification assays (SAAs), such as real-time quaking-induced conversion (RT-QuIC), have shown promise in detecting misfolded TDP-43 in cerebrospinal fluid (CSF) and olfactory mucosa, technically accessible methodologies are urgently required for widespread clinical application. We developed a streamlined, non-immunoprecipitation-based TDP-43 RT-QuIC assay to assess seeding activity in brain tissue and CSF. We evaluated its diagnostic performance using CSF from patients with TDP-43 proteinopathies and control subjects, and further examined its association with neurofilament light chain (NfL) and tau-related biomarkers. In CSF analysis, the assay demonstrated positive seeding activity in 70% (21/30) of patients with ALS and dementia, 50% (5/10) of patients with FTLD, and 40% (8/20) of patients with ALS alone. The assay exhibited excellent specificity, yielding negative results in >99% (199/200) of control samples, including those with autoimmune or electrophysiological abnormalities. Furthermore, CSF analysis demonstrated significantly higher NfL levels in TDP-43 SAA-positive cases compared to SAA-negative cases (p < 0.0008). The highest NfL concentrations were observed in the SAA-positive ALS with dementia and ALS cohorts, contrasting with lower levels in FTLD. Tau-related biomarkers exhibited no significant differences between the groups. Our streamlined, non-immunoprecipitation TDP-43 RT-QuIC assay provides highly specific detection of pathological TDP-43 seeding activity. While the assay detects the underlying TDP-43 proteinopathy rather than distinguishing between ALS and FTLD clinical phenotypes, its technical simplicity and combined utility with NfL measurements offer a robust, scalable framework for biomarker development. This approach provides a practical foundation for future multi-center validation and international standardization efforts.
    Keywords:  TDP-43; amyotrophic lateral sclerosis; biomarkers; frontotemporal lobar degeneration; seeding amplification assay
    DOI:  https://doi.org/10.3390/cimb48080824
  16. Brain Sci. 2026 Aug 21. pii: 895. [Epub ahead of print]16(8):
    Task-Evoked Prefrontal Hemodynamics During Cognitive Assessment in Amyotrophic Lateral Sclerosis Using fNIRS.
    Saqer Alshehri, Bartu Atabek, Terry Heiman-Patterson, Hasan Ayaz.
      Background/Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease increasingly recognized for extra-motor manifestations, including cognitive dysfunction involving frontal cortical systems. Conventional clinical assessments are primarily behavioral and may not capture subtle alterations in the neural systems that support cognitive performance. This pilot study examined whether wearable functional near-infrared spectroscopy (fNIRS) could detect task-evoked prefrontal hemodynamic differences during the King-Devick Task (KDT), a rapid oculomotor number-naming task that engages visual scanning, attention, processing speed, and verbal response production. Methods: Sixteen participants, including seven individuals with ALS and nine age-matched healthy controls (HC), completed four progressively difficult KDT conditions while prefrontal cortical activity was recorded. Results: As task difficulty increased, response times became slower across participants, while accuracy remained preserved and behavioral performance did not differ significantly between groups. Prefrontal oxygenated hemoglobin (HbO) responses increased with task difficulty across all prefrontal optodes, supporting task-evoked cortical engagement. In contrast, deoxygenated hemoglobin (HbR) responses showed a group-specific pattern in the left dorsolateral prefrontal cortex: individuals with ALS demonstrated progressively increasing HbR responses across difficulty conditions, whereas HC showed relatively stable responses, with group differences emerging at higher difficulty levels. Conclusions: These findings suggest a dissociation between preserved behavioral performance and altered prefrontal hemodynamic regulation in ALS. The observed HbR pattern may reflect differences in cortical recruitment, neurovascular coupling, oxygen extraction, vascular responsiveness, or the efficiency of cortical resource allocation during increasing cognitive-motor demands. Wearable fNIRS may therefore complement behavioral assessments by revealing task-evoked neural alterations that are not evident from performance measures alone.
    Keywords:  King-Devick Task (KDT); amyotrophic lateral sclerosis (ALS); cognitive assessment; functional near-infrared spectroscopy (fNIRS); neuroergonomics; prefrontal cortex (PFC)
    DOI:  https://doi.org/10.3390/brainsci16080895
  17. Neuroscience. 2026 Aug 25. pii: S0306-4522(26)00585-3. [Epub ahead of print]615 144-157
    K16ApoE-mediated delivery across the blood-brain barrier: mechanisms, applications, and translational challenges.
    Sengodan Amudha, Sivaraj Ramasamy, Israel V M V Enoch.
      The blood-brain barrier (BBB) supporting the health of the central nervous system does this by limiting molecular exchange between circulation and brain tissue, although unfortunately this same restriction prevents therapeutically relevant macromolecules from entering the brain. Consequently, a number of protein-based therapies with success in peripheral tissues including enzymes, antibodies and biologics are unsuccessful in treating neurological disorders. The most recently described example is K16ApoE, a synthetic peptide that combines a polylysine-associated moiety with the receptor binding domain of apolipoprotein E (apoE), suggested to facilitate systemic delivery of large biomolecules across the BBB. Here, we review evidence that co-administration of K16ApoE with therapeutic proteins can mediate high concentrations of this protein in brain tissue, which can yield significant substrate clearance (pathological storage) and profound neurologic improvement and survival benefits in animal models of late-infantile neuronal ceroid lipofuscinosis (LINCL; CLN2 disease). In addition to applications in lysosomal storage disorders, the peptide has shown efficacy in promoting delivery of chemotherapeutic agents, antibodies and biologics related to brain tumors and neurodegenerative diseases. However, broad limitations persist including dose-dependent toxicity or nonspecific BBB permeability and immunogenicity as well high levels of uncertainty in referencing animal findings to humans. This review provides an integrated critical perspective on K16ApoE by connecting its proposed delivery mechanisms with therapeutic efficacy, toxicity, and translational barriers. In particular, we examine the unresolved balance between receptor-associated endothelial transport and transient BBB modulation and propose a mechanism-safety-translation framework to guide the rational development of K16ApoE and related peptide shuttles.
    Keywords:  Blood–brain barrier transport; Lysosomal storage disorders; Macromolecular drug delivery; Neurodegenerative disease therapeutics; Peptide-mediated delivery; Receptor-mediated transcytosis
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.08.042
  18. Pathophysiology. 2026 Aug 10. pii: 59. [Epub ahead of print]33(3):
    The Microbiota-Gut-Brain Axis and Nutritional Interventions in Amyotrophic Lateral Sclerosis: Pathophysiological Mechanisms, Neuroinflammation, and Non-Motor Manifestations-Scoping Review.
    Elena Sanchis-Sanchis, José Enrique de la Rubia Ortí, David Sancho-Cantus, Cristina Cunha-Pérez, Jorge Casaña-Mohedo.
      Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder in which systemic pathophysiological alterations significantly contribute to disease progression and non-motor manifestations, such as depression and anxiety. The microbiota-gut-brain axis represents a critical bidirectional pathway in which intestinal dysbiosis and epithelial barrier disruption catalyze central neuroinflammation. This scoping review synthesizes evidence from 43 empirical and analytical studies across 28 countries and maps the findings under the WHO International Classification of Functioning (ICF) framework. Pathophysiological data reveal a profound taxonomic shift in patients with ALS, characterized by severe depletion of neuroprotective, butyrate-producing genera (Akkermansia and Prevotella) and enrichment of pro-inflammatory Enterobacteriaceae. This dysbiotic state leads to structural damage to the intestinal mucosa, alteration of Paneth cells, and downregulation of tight junction proteins (zonulin), triggering a "leaky gut" phenomenon. Subsequent systemic translocation of lipopolysaccharides (LPS) induces TLR4-mediated endotoxemia, microglial hyperactivation, and accelerated motor neuron apoptosis. Conversely, therapeutic modulation via Fecal Microbiota Transplantation (FMT), psychobiotics, and metabolic interventions (ketogenic or Mediterranean diets) has demonstrated significant efficacy in restoring epithelial integrity, mitigating mitochondrial hypermetabolism, and reducing emotional distress. This review identifies a critical research gap in the microstructural characterization of the enteric nervous system in ALS. Incorporating microbiome-targeted biomarkers into clinical protocols is crucial for implementing a stratified, multi-systemic therapeutic strategy aimed at enhancing patient prognosis and psychological well-being.
    Keywords:  Amyotrophic Lateral Sclerosis; intestinal permeability; microbiota–gut–brain axis; neuroinflammation; pathophysiology; psychobiotics
    DOI:  https://doi.org/10.3390/pathophysiology33030059
  19. Brain Sci. 2026 Jul 27. pii: 792. [Epub ahead of print]16(8):
    Targeting Neutrophil Extracellular Traps in Neuroinflammation: A Therapeutic Perspective on Neurodegenerative Diseases.
    Iolanda Masalskiene Costa, Alexandre Kanashiro, Giovanna Siqueira Favi Barros, Ana Julia Monteiro, Caio Santos Bonilha, Giovane Galdino, Flavio Protasio Veras.
      Neuroinflammation is a complex process involved in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. Neutrophils, although traditionally considered peripheral immune cells, have emerged as active participants in the immunopathology of the central nervous system (CNS) through the release of neutrophil extracellular traps (NETs), structures composed of decondensed chromatin embedded with pro-inflammatory proteins. Evidence suggests that NETs play a dual role: they are protective against pathogens but can also induce tissue damage when produced in excess. Several pathways are involved in their formation, including vesicle-mediated release (vital NETs), the lytic NADPH oxidase (NOX)-dependent pathway, and the mitochondrial pathway. Targeting NETs therapeutically, through the use of NETosis inhibitors, NET-degrading strategies, or blockade of neutrophil migration, has shown promise in reducing neuroinflammation/neurodegeneration and improving neurological outcomes in experimental models. This review aims to investigate both the protective and deleterious roles of NETs and how this knowledge may reveal new therapeutic strategies to modulate neurodegenerative diseases and preserve neural integrity, offering valuable insights for potential applications in clinical practice.
    Keywords:  inflammatory response; innate immunity; neurodegenerative disorders; neuroinflammation; neutrophil extracellular traps; neutrophils
    DOI:  https://doi.org/10.3390/brainsci16080792
  20. Biosensors (Basel). 2026 Aug 17. pii: 446. [Epub ahead of print]16(8):
    Functional Activity of TDP-43: A Direct Biomarker for ALS.
    Kirti Shila Sonkar, Vito Levi D'Ancona, Jade Cramp, Hannah Shilling, Ellie Giles, Tyler Howell-Bray, Becky Fillingham, Merit E Cudkowicz, Avindra Nath, Jeffrey D Rothstein, Robert Bowser, Barbara Borroni, James D Berry, Ghazaleh Sadri-Vakili, Emanuele Buratti, Ian P Thrippleton.
      TDP-43 dysfunction is a defining feature of amyotrophic lateral sclerosis (ALS), yet no biofluid biomarker directly measures its functional activity. We developed a serum-based homogeneous time-resolved FRET (hTR-FRET) assay that quantifies TDP-43 RNA binding activity using synthetic UU-rich RNA probes. We analyzed 1080 serum samples from controls, sporadic ALS, and genetic subgroups (C9orf72, SOD1) across multiple biorepositories. Cross-sectionally, TDP-43 functional activity was elevated in ALS (mean 390 a.u.) versus controls (302 a.u.), yielding AUC = 0.79. Genotype means were 392 a.u. (sporadic), 382 a.u. (C9orf72), and 323 a.u. (SOD1); a 366 a.u. threshold achieved 95% specificity against controls. Longitudinally, Target ALS showed a modest but significant inverse correlation between TDP-43 activity and ALSFRS-R, while other cohorts exhibited similar non-significant trends. Elevated signal in serum likely reflects increased extracellular release of probe-competent TDP-43 species during cell death and exosomal shedding, rather than restored intracellular nuclear splicing function. This assay provides a proof-of-concept platform for the direct functional measurement of probe-competent TDP-43 species in serum. While it demonstrates moderate group-level discrimination, individual diagnostic performance requires prospective validation. The assay may support exploratory applications in genotype stratification and progression monitoring in future clinical studies.
    Keywords:  RNA-binding function; TDP-43; amyotrophic lateral sclerosis; functional proteomics; hTR-FRET; serum biomarker
    DOI:  https://doi.org/10.3390/bios16080446
  21. Neurol Int. 2026 Jul 29. pii: 144. [Epub ahead of print]18(8):
    Pridopidine Mediated Sigma-1 Receptor Activation and Therapeutic Implications in Neurodegenerative Diseases.
    Ahmed I Anwar, Abdul-Rahman A Hegazi, Hamsa Priya Bhuchakra, Joshua R Nelson, Ty L Birdsong, Cy J Fontenot, Majed Zeibo, Moiz M Fazal-Ur-Rehman, Harrison P Bieber, Claudia J Spring, Joshua L Smith, Ibraheem A Hachem, Taranjit Singh, M Farris Sawaya, Kevin S Murnane, Alan D Kaye.
      Neurodegenerative diseases are targets for pridopidine therapy, which aims to improve quality of life through neuroprotective mechanisms that involve sigma-1 receptor (S1R) activation. Neurodegenerative motor and cognitive diseases are influenced by dopamine imbalance, where disruptions in pathways contribute to states that are hyperkinetic or hypokinetic, while current dopaminergic treatments are symptomatic rather than disease-modifying, especially for Huntington's disease and Amyotrophic lateral sclerosis. This review summarizes the mechanisms underlying pridopidine-mediated neuroprotection and examines the current evidence supporting its therapeutic potential. The S1R is an endoplasmic reticulum-mitochondria-associated chaperone involved in homeostasis of calcium, stress regulation, and mitochondrial function. Pridopidine is a small lipophilic molecule that crosses the blood-brain barrier and acts as an S1R agonist, with minimal dopamine D2 receptor occupancy. Activation of S1R by pridopidine modulates calcium signaling and enhances anti-apoptotic activity. Collectively, available evidence suggests that pridopidine may improve motor outcomes and slow disease progression in Huntington's disease and amyotrophic lateral sclerosis, supporting its promise as a disease-modifying therapeutic strategy.
    Keywords:  Huntington’s disease; S1R; amyotrophic lateral sclerosis; neurodegeneration; pridopidine; sigma-1-receptor
    DOI:  https://doi.org/10.3390/neurolint18080144
  22. Drug Des Devel Ther. 2026 ;20 626069
    Therapeutic Challenges and Future Breakthroughs in Amyotrophic Lateral Sclerosis: From Precision Medicine to Innovative Trial Design.
    Yutong Wei, Jie Wang, Yanan Ji, Tongxin Shang, Yuntian Shen, Hualin Sun, Yong Cai.
      Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous and fatal neurodegenerative disorder, for which clinical management and drug development have long faced formidable challenges. Since the approval of riluzole and edaravone, dozens of promising drug candidates that showed efficacy in preclinical models have failed in Phase III trials, highlighting an urgent need for systematic re-evaluation of the field. This review provides a comprehensive summary of the major limitations of current clinical therapies for ALS. These include the modest survival benefit of riluzole, the narrow eligible population for edaravone, and the complex trajectory of sodium phenylbutyrate-taurursodiol, which received accelerated approval but was subsequently voluntarily withdrawn after its confirmatory Phase III trial failed to meet its primary endpoints. On this basis, we discuss four major challenges that contribute to clinical trial failures: disease heterogeneity, paucity of reliable biomarkers, insufficient translational validity of preclinical models, and inherent flaws in conventional trial designs. Subsequently, we discuss emerging therapeutic strategies, encompassing precision medicine and gene therapy (exemplified by the development of the antisense oligonucleotide tofersen for SOD1-ALS), targeting protein homeostasis, modulation of neuroinflammation, metabolic and energetic support, neuroprotection and regeneration, as well as multi-target combination approaches. Innovative trial designs, including adaptive platform trials (exemplified by the HEALEY ALS Platform Trial), enrichment designs, sequential designs, N-of-1 trials, and virtual clinical trials are fundamentally reshaping the drug development paradigm in ALS. In conclusion, ALS treatment is at a historic turning point from a "one-size-fits-all" approach toward "precisely stratified" medicine. Future success depends on establishing multimodal biomarker panels, implementing genetic testing-guided individualized therapy, developing combination regimens, and integrating patient-reported outcomes with palliative care. Although substantial challenges remain, the clinical success of Tofersen provides evidence that precision therapeutic strategies may gradually transform ALS management toward a more individualized and disease-modifying approach.
    Keywords:  amyotrophic lateral sclerosis; biomarkers; challenges; clinical treatment; clinical trial design; gene therapy
    DOI:  https://doi.org/10.2147/DDDT.S626069
  23. Neurol Sci. 2026 Aug 28. pii: 742. [Epub ahead of print]47(9):
    Exploration of reliable assessment of respiratory function in amyotrophic lateral sclerosis.
    Nan Hu, Lei Zhang, Huihong Tian, Jianfeng Ding, Dongchao Shen, Xunzhe Yang, Liying Cui, Jingwen Niu, Mingsheng Liu.
       OBJECTIVE: To identify potentially useful objective indicators for early assessment of respiratory dysfunction in amyotrophic lateral sclerosis (ALS).
    METHODS: Forty ALS patients were enrolled and followed every 3 months for one year. Baseline assessments included dyspnea complaints, ALSFRS-R, the ALS Respiratory Symptom Score (ARES), physical examination (including lower lung mobility), phrenic nerve conduction studies, diaphragm ultrasound, and multi-region ultrasound fasciculation detection. Forced vital capacity (FVC%) was also measured. Logistic regression (binary outcomes) and linear regression (continuous outcomes) were used to identify predictors of respiratory decline at 6 and 12 months.
    RESULTS: At 6 months, decreased right lower lung mobility (β = 1.771, 95%CI:1.047-2.495, p = 0.038), bulbar fasciculations (OR = 2.198, 95%CI:1.527-2.868, p = 0.001), and lumbosacral fasciculations (OR = 2.117, 95%CI:1.516-2.839, p = 0.001) independently predicted a higher post-progression rate. At 12 months, cervical fasciculations predicted a higher post-progression rate (OR = 1.644, 95%CI:1.130-2.157, p = 0.017). Traditional measures (FVC%, diaphragm ultrasound, phrenic CMAP) showed limited short-term predictive value.
    CONCLUSION: Lower lung mobility on physical examination and ultrasound-detected fasciculations in bulbar, cervical, and lumbosacral regions are potentially valuable objective markers for predicting disease progression in ALS. These exploratory findings suggest they may complement conventional pulmonary function tests, but require validation in larger independent cohorts.
    Keywords:  Amyotrophic lateral sclerosis; Fasciculations; Phrenic nerve; Prognosis; Respiratory function; Ultrasound
    DOI:  https://doi.org/10.1007/s10072-026-09358-w
  24. Biochem Biophys Res Commun. 2026 Aug 21. pii: S0006-291X(26)01238-6. [Epub ahead of print]834 154474
    Exosomal innovations in neurodegenerative disorders: Emerging insights and intranasal route.
    Rajashree Hirlekar, Srushti Agnihotri, Shalom Sathe, Mangal Nagarsenkar.
      Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and Multiple Sclerosis (MS), represent a substantial and growing global health burden, collectively accounting for millions of disability-adjusted life years (DALYs) worldwide and severely impacting cognition, mood, behavior, and motor function. Current therapies, particularly small-molecule drugs, are challenged by the blood-brain barrier (BBB), resulting in poor central nervous system (CNS) bioavailability, systemic adverse effects, and suboptimal patient adherence, underscoring the urgent need for novel delivery platforms. Exosomes, endogenous nanoscale extracellular vesicles (30-150 nm) derived from sources such as mesenchymal stem cells, neural stem cells, and immune cells, have emerged as highly promising biogenic drug carriers owing to their low immunogenicity, inherent biocompatibility, cargo versatility (proteins, mRNA, miRNA), and unique innate ability to cross the BBB, positioning them as superior alternatives to synthetic nanocarriers such as liposomes, niosomes, and solid lipid nanoparticles for targeted CNS delivery. This review provides a comprehensive overview of exosome biology and therapeutics for AD, PD, and MS, covering classification, isolation and characterization methods, drug-loading strategies and a comparative analysis of administration routes (intravenous, intracerebral, intrathecal, intra-arterial, and intranasal). Particular emphasis is placed on the intranasal route, which offers a non-invasive, direct nose-to-brain pathway via the olfactory and trigeminal nerves, effectively bypassing the BBB while minimizing systemic exposure. The review also examines the dual therapeutic and pathological roles of exosomes in BBB function, and emphasizes preclinical and early clinical evidence across AD, PD, and MS. Finally, the review outlines the major manufacturing, regulatory, and standardization hurdles that must be addressed including GMP-grade scale-up, consistent particle-based dosing benchmarks, and large placebo-controlled trials before intranasal exosome therapeutics can progress from promising preclinical candidates to approved disease-modifying treatments for neurodegenerative disorders.
    Keywords:  Blood-brain barrier; Exosomes; Intranasal drug delivery; Neurodegenerative diseases; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154474
  25. Int J Cell Biol. 2026 ;2026 3022967
    The HDAC Inhibitor Butyrate Reduces SOD1 Aggregation and Improves Motor Function in C. elegans and Cellular Models of ALS.
    Fiona C Dresel, Martin Michaelis, Campbell W Gourlay.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by motor neuron loss and protein aggregation, commonly driven by mutations in superoxide dismutase 1 (Sod1). Recent evidence implicates gut microbiota-derived metabolites, such as butyrate, in modulating neurodegeneration, but the underlying mechanisms remain unclear. Here, we demonstrate that sodium butyrate (NaB), a histone deacetylase inhibitor and microbial metabolite, ameliorates ALS-related phenotypes in C. elegans and mammalian cell models expressing mutant isoforms of Sod1 linked to ALS. NaB treatment prevented Sod1 aggregation and restored motor function and axonal integrity in transgenic worms overexpressing Sod1G85R. Mechanistically, NaB recapitulated the effects of the pan-HDAC inhibitor trichostatin A, suggesting HDAC inhibition as key to reducing Sod1 aggregation and its downstream effects. Application of NaB or the HDAC inhibitor valproic acid also prevented aggregation of Sod1A4V, Sod1G85R or Sod1G37R in transfected human neuroblastoma cells. These findings support a conserved neuroprotective role for NaB and HDAC inhibitors via their antiaggregation activity. Our findings also verify C. elegans and neuroblastoma cell lines as excellent research tools to explore the mechanisms underlying the antiaggregation action of NaB and HDAC inhibitors, as well as their potential for future therapeutic development.
    DOI:  https://doi.org/10.1155/ijcb/3022967
  26. JAMA Neurol. 2026 Aug 24.
    TDP-43-Associated Neurodegenerative Disease Conceptualization and Integrated Staging: A Review.
    Michael Benatar, Sami Barmada, Gregory A Jicha, Clotilde Lagier-Tourenne, Jenna Gregory, Ammar Al-Chalabi, Bradley F Boeve, Clifford R Jack, William W Seeley, Nicholas J Maragakis, Joanne Wuu, Zane Zeier, Chiadi Onyike, Joe Lewcock, Collin Hovinga, Paymaan Jafar-Nejad, Olga Uspenskaya, Adam Simmons, Susan E Browne, Jonathan Rohrer, Leonard Petrucelli, Jacquelyn Shapiro, Deb Scharper, Adam Boxer, Lyle W Ostrow, Adam M Staffaroni, Penny Dacks, Martin R Turner, Kuldip D Dave, Martina de Majo, Laura Mitic, Stephanie Fradette, Samantha Budd Haeberlein, Tanya Simuni, Billy Dunn, Corey T McMillan, Edward B Lee.
       Importance: Classifying disease based on underlying pathobiology rather than clinical phenotype has implications for the development of biomarkers and therapy development.
    Observations: Transactive response DNA-binding protein 43 kDa (TDP-43) pathology is observed across a range of clinically defined neurodegenerative disorders including limbic predominant age-related encephalopathy (LATE), most cases of amyotrophic lateral sclerosis (ALS), inclusion body myositis, multisystem proteinopathy, and approximately half the cases of frontotemporal dementia (FTD). Despite this shared biology, the current nosology for these neurodegenerative disorders is based on their distinct clinical phenotypes. An alternative approach recognizes the central role of TDP-43 pathology in disease pathogenesis, reserving the use of clinical terms like ALS, FTD, or LATE to describe phenotypic manifestations of underlying pathobiology. This approach also recognizes the converging biomarker and neuropathological data indicating that pathology begins presymptomatically, before the overt clinical manifestations of disease appear.
    Conclusions and Relevance: In proposing a pathobiological definition of disease, the goal is to provide a road map for developing biomarkers that accurately reflect the underlying pathobiology of disease and for advancing therapeutic candidates that effectively target fundamental disease mechanisms.
    DOI:  https://doi.org/10.1001/jamaneurol.2026.2812
  27. Front Neurosci. 2026 ;20 1906426
    GLP-1 and GIP class drugs have neuroprotective properties in Alzheimer's and Parkinson's disease.
    Christian Hölscher.
      Alzheimer's and Parkinson's disease are two CNS diseases with a large unmet need for disease-modifying therapies. Recently, two phase 3 clinical trials testing the GLP-1 analogue Semaglutide (Wegovy, Ozempic) in patients with Alzheimer's disease did not show improvements. This failure should not have been a surprise, since it has been known for many years that Semaglutide does not cross the blood-brain barrier (BBB) and enters the brain only in very small amounts. It is designed to stay in the blood stream and has a very long half-life in the blood (168 h). The GLP-1 analogue Liraglutide (Victoza), in contrast, has a much shorter half-life (13 h), and a phase 2 clinical trial showed improvements in cognitive tests after 1 year of treatment. GLP-1 receptor agonists have been tested in clinical trials in Parkinson's patients, and a similar picture emerged. Drugs that can cross the BBB well (exenatide, lixisenatide) show good protection, while a drug that cannot cross the BBB showed no effects (NLY01). Clearly, when treating CNS diseases, it is of importance to get the drug into the brain to ensure target engagement. This review will look at the clinical trials that have been conducted in more detail, describe the mode of action as derived from preclinical trials, and discuss novel strategies for getting GLP-1 receptor agonists into the brain to successfully treat CNS diseases.
    Keywords:  Alzheimer’s; BBB; CNS; GIP; GLP-1; Parkinson’s; incretins
    DOI:  https://doi.org/10.3389/fnins.2026.1906426
  28. Curr Top Med Chem. 2026 Aug 13.
    Ferulic Acid and Brain Health: A Defender Against Alzheimer's Disease, Parkinson's Disease, and Neuroinflammation.
    Niraj Kumar Singh, Ghaleb Oriquat, Ishika Jain, Mahima Chaudhary, Yasser Mohsen Khlyl, Navin Kumar Tailor.
      Neuroinflammation is the body's immune reaction that occurs inside the central nervous system to keep brain cells balanced and healthy. Uncontrolled and chronic neuroinflammation can start damaging neuronal cells and lead to neurodegenerative diseases. Glial cells, especially microglia and astrocytes, play an important role in this process. Microglia act as immune guards of the brain, shifting between protective and harmful states depending on certain signals such as NADPH oxidase 2, histone deacetylases, and transforming growth factor. Astrocytes support neurons and maintain the blood-brain barrier. During injury or stress, they become overactive and release numerous chemicals that make inflammation worse. Further, neuroinflammation is controlled by several signalling pathways, including NF-κB, PI3K/Akt, and MAPK. When these systems lose their balance, they cause ongoing inflammation and oxidative stress, which eventually harm brain cells. During the progression of neurodegenerative disorders, especially Alzheimer's Disease (AD) and Parkinson's Disease (PD), overactive microglia and astrocytes release large amounts of cytokines, reactive oxygen species, and inflammasome components that speed up neuron loss. The constant interaction between NF-κB, NLRP3, and oxidative stress worsens this damage, linking faulty molecular signals with the progression of these disorders. Ferulic acid, a natural antioxidant found in grains, fruits, and vegetables, has shown remarkable protective effects on the brain. It is biologically synthesized from aromatic amino acids L-phenylalanine and L-tyrosine through the shikimate pathway. By clearing free radicals and stopping lipid damage, ferulic acid protects neurons from degeneration. Experimental studies have shown that ferulic acid offers significant antioxidant and anti-neuroinflammatory effects and prevents the accumulation of harmful proteins, such as Aβ and α-synuclein, in the brain. Furthermore, ferulic acid has a strong capacity to modulate several cellular and molecular signaling pathways, including Nrf2/HO-1, NF-κB, and MAPK, which are closely linked to the development and progression of neurodegenerative disorders such as AD and PD. Interestingly, ferulic acid inhibits the generation of pro-inflammatory mediators, ameliorates mitochondrial dysfunction, prevents apoptosis, and consequently protects cholinergic and dopaminergic neurons in the brain, thereby exhibiting remarkable neuroprotective effects. Thus, the current review addressed that ferulic acid is considered a promising natural compound that could be an alternative natural phytoconstituent for the prevention and management of neuroinflammationassociated neurodegenerative disorders like AD and PD.
    Keywords:  Alzheimer’s disease; Ferulic acid; Neuroglia; Neuroinflammation; Oxidative stress; Parkinson’s disease
    DOI:  https://doi.org/10.2174/0115680266493487260611111705
  29. Neurobiol Dis. 2026 Aug 24. pii: S0969-9961(26)00327-X. [Epub ahead of print] 107582
    Splicing modulation of ATXN2 as a therapeutic strategy to regulate Ataxin-2 protein levels in ALS.
    Nicolette Heinsinger, Yi Wang, Steve Grauer, Zuo Zhang, Jacky Wong, Vladimir Simov, Marina Bukhtiyarova, Xi Ai, Craig Parish, Rebecca Meier Klein, Jason Uslaner, Sean Smith, Yuan Tian.
      ATXN2 is associated with an increased risk of Amyotrophic Lateral Sclerosis (ALS), while down-regulation of ATXN2 has been shown to mitigate TDP-43 proteinopathy in ALS models. In this study, we demonstrated that Ataxin-2 protein levels were upregulated in rNLS8 mice following doxycycline withdrawal, which coincided with TDP-43 overexpression, phosphorylation, and aggregation. To reduce Ataxin-2 protein levels, we explored the approach of splicing modulation at the RNA level. Through bioinformatical analysis, we identified an alternative 5' splicing site of ATXN2 in intron 8. This alternative splicing results in an additional 47 base pairs at the 3' end after Exon 8. The insertion of the extra nucleotides causes a frameshift that leads to reduced mRNA production and, consequently, protein levels. Following the discovery of this alternative splicing site, we conducted an antisense oligonucleotide (ASO) micro-walk to screen ASOs targeting this region. We identified ASOs that specifically modulate this splicing, including those that either enhance or inhibit alternative splicing. We validated that the ASOs that promote alternative splicing and reduce constitutive splicing can lower Ataxin-2 protein levels, which in turn decreases TDP-43 aggregation and stress granule formation in a cell-based model of TDP-43 toxicity. Furthermore, we confirmed that reducing Ataxin-2 levels via previously validated ASO delivery ameliorated TDP-43 pathology in rNLS8 mice. The discovery of ATXN2 alternative splicing, along with the confirmation of splicing modulation using ASOs in human cell-based assays, provides evidence for a proof-of-principle strategy to modulate Ataxin-2 protein levels for the treatment of ALS.
    Keywords:  ALS; ASO splicing modulation; ATXN2; Alternative splicing; Constitutive splicing; Stress granules; TDP-43; iPSC-derived neurons; qPCR; rNLS8; ∆NLS-TDP43
    DOI:  https://doi.org/10.1016/j.nbd.2026.107582
  30. Int J Environ Res Public Health. 2026 Aug 19. pii: 1081. [Epub ahead of print]23(8):
    Palliative Care Involvement in Hospitalized Amyotrophic Lateral Sclerosis Patients.
    Sumeet Bhardwaj, Anita Chakraborty, Jillian Mead, Kalli Stilos.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with significant physical, psychological, and social distress. Given its terminal nature and high symptom burden, early integration of palliative care is essential. The inpatient Palliative Care Consult Team (PCCT) provides specialist palliative care to hospitalized patients with ALS. Hospitalizations are common throughout the ALS disease trajectory, particularly as patients experience progressive functional decline, respiratory compromise, and increasing care needs, making inpatient encounters important opportunities for specialist palliative care involvement. To extend palliative care beyond the inpatient setting and facilitate earlier involvement, an ALS ambulatory clinic was established in 2018. Despite the importance of palliative care, limited data describes its involvement among hospitalized ALS patients. This retrospective review examines the relationship between the PCCT and ALS patients admitted to a tertiary care facility between 2006-2019. Data collected included patient demographics, referral indications, clinical course, and disposition. Most patients referred to the PCCT had poor functional status and a guarded prognosis at initial consultation. Symptom management and support for complex decision-making were leading reasons for referral. Approximately half of patients died in the hospital within three months of referral. Most deaths occurred within one week, underscoring the importance of timely palliative care.
    Keywords:  Amyotrophic Lateral Sclerosis; hospitalized patients; multidisciplinary care; palliative care consult service; symptom management
    DOI:  https://doi.org/10.3390/ijerph23081081
  31. Pharmaceutics. 2026 Jul 25. pii: 916. [Epub ahead of print]18(8):
    Systematic Design and Evaluation of Nasal Drug Delivery for Central Nervous System Disease from Experimental to Clinical Application.
    Xi-Rui Zhou, Yi Zhang, Qianqian Kong, Ziyue Wang, Yiming Luo, Hao Huang, Wensheng Qu, Zhiyuan Yu, Xiang Luo.
      Disorders of the central nervous system (CNS) are intricate and often resistant conditions that create a significant global impact, affecting millions of individuals each year. The blood-brain barrier (BBB) acts as a protective mechanism for the brain against external substances, but it also prevents most therapeutic agents from entering the CNS, leading to inadequate drug absorption and reduced effectiveness after diagnosis. Nasal drug delivery has emerged as a viable approach to bypass the BBB, facilitating direct access to the brain through the olfactory and trigeminal nerve routes. Although considerable research focuses on innovative nasal formulations with proven clinical promise, a critical gap persists: a systematic framework that bridges laboratory breakthroughs with clinical implementation. This review addresses this unmet need by integrating recent basic research advances with practical clinical requirements. We summarize nasal transport pathways, targeted design strategies, formulation optimization, and device engineering. Crucially, we propose a structured clinical evaluation framework built upon five essential pillars: targeting precision, pharmacokinetic performance, multi-organ safety profiling, device-drug clinical compatibility, and anatomical translation from animal models to humans. By mapping current research capabilities against clinical readiness criteria, this framework identifies translational bottlenecks and provides actionable guidance to accelerate the bench-to-bedside transition of intranasal drug delivery systems for CNS disorders.
    Keywords:  blood–brain barrier; central nervous system; clinical application; clinical evaluation; drug design; molecular biology; nasal delivery system; olfactory nerve pathway; trigeminal nerve pathway
    DOI:  https://doi.org/10.3390/pharmaceutics18080916
  32. Front Digit Health. 2026 ;8 1886561
    Feasibility study on a noninvasive assessment of ALS patient emotional state.
    Marc Garbey, Quentin Lesport, Gülşen Öztosun, Megan Heidebrecht, Kamyab Pirouz, Elham Bayat.
       Introduction: Objective assessment of emotional responsiveness in Amyotrophic Lateral Sclerosis (ALS) remains limited despite its importance for personalized care. This study investigated whether non-invasive speech analysis could identify digital biomarkers associated with emotional coping behaviors in ALS patients.
    Methods: We analyzed 28 ALS patient visits using clinician-rated emotional concern scores, ALS Functional Rating Scale-Revised (ALS-FRS-R), forced vital capacity (FVC), and speech acoustic features. We also evaluated the reliability of large language models (LLMs), including ChatGPT, Gemini, and Claude, for automated concern assessment. Patients were classified relative to functional impairment as congruent, muted, or excessive responders.
    Results: LLMs failed to provide reliable or reproducible assessments of patient concern without expert clinical supervision. Subjective concern levels also showed discordance with objective respiratory measures such as FVC. Excessive responders were predominantly male and required significantly greater clinician interaction time, while muted responders were predominantly female. Acoustic analysis revealed distinct vocal profiles between groups. Muted responders demonstrated high loudness and sharpness with low roughness and fluctuation, whereas excessive responders showed the opposite profile. These findings suggest that dysarthria may function as an acoustic filter modulating emotional expression.
    Discussion: Speech-derived acoustic biomarkers may enable objective identification of emotional coping phenotypes in ALS and support earlier, personalized psychosocial interventions. The findings also highlight important limitations of current LLM-based clinical interpretation tools in unsupervised settings.
    Keywords:  affective computing; amyotrophic lateral sclerosis; clinical trial; generative language; natural language processing; signal analysis; telemedicine
    DOI:  https://doi.org/10.3389/fdgth.2026.1886561
  33. Biomedicines. 2026 Aug 15. pii: 1838. [Epub ahead of print]14(8):
    Clinical, Social, and Healthcare Factors Associated with Nutritional Status in Amyotrophic Lateral Sclerosis: A Multidimensional Approach.
    Diogo Sousa-Catita, Paulo Mascarenhas, Cátia Oliveira, Miguel Grunho, Filipe Gonçalves, Jorge Fonseca.
      Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where malnutrition significantly worsens clinical outcomes. We performed a multidimensional analysis to identify clinical, social, and healthcare factors associated with nutritional vulnerability in a real-world setting. Methods: This cross-sectional study included 97 adults with ALS recruited through a national association (APELA) and a hospital-based outpatient consultation (ANOC). Nutritional status was assessed using the Mini Nutritional Assessment (MNA®), Body Mass Index (BMI), and Global Leadership Initiative on Malnutrition (GLIM) criteria. Associations with total MNA® scores were evaluated using a prespecified multivariable linear model with HC3 robust standard errors and bootstrap validation to assess inferential stability. Results: Malnutrition prevalence was high, with 42.3% of participants classified as moderately malnourished and 43.3% as severely malnourished under GLIM criteria. Mean MNA® score was 19.69 (SD 4.53). In the adjusted model, ANOC recruitment was associated, after adjustment, with a 4.477-point lower MNA® score compared with APELA (HC3 95% CI -7.071 to -1.884; p<0.001). Other sociodemographic and clinical factors yielded imprecise estimates. Although explanatory power was modest (Adjusted R2=0.067; optimism-corrected R2=-0.005), the recruitment setting remained a robust correlate across sensitivity analyses. Conclusions: Recruitment setting emerged as the most consistent adjusted correlate of MNA® scores, likely reflecting differences in clinical case mix and referral pathways in the Portuguese healthcare context. These findings highlight nutritional vulnerability in ALS as a multifaceted construct that should be interpreted in relation to both clinical and healthcare-contextual factors. This study supports considering systemic factors and the need for longitudinal research that incorporates comprehensive functional and social metrics to optimize multidisciplinary nutritional interventions.
    Keywords:  GLIM criteria; MNA; amyotrophic lateral sclerosis; multidimensional vulnerability; multidisciplinary care; nutritional status
    DOI:  https://doi.org/10.3390/biomedicines14081838
  34. Nat Biomed Eng. 2026 Aug 26.
    Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43.
    Huishan Guo, Alexandre Savard, Charlotte Manser, Kallol Dutta, James A Taylor, Maxime W C Rousseaux, Silvia Pozzi, Jean-Pierre Julien, Stephen Baird, Derrick Gibbings.
      In neurodegenerative diseases such as frontotemporal dementia and amyotrophic lateral sclerosis, pathological forms of proteins such as Tau and TDP-43 accumulate within large heterogeneous inclusions inside cells. Current strategies to eliminate such aberrant protein species in patients encounter three main challenges: crossing the blood-brain barrier and plasma membrane, specifically recognizing pathological forms of proteins, and engaging mechanisms to eliminate large entities. Here we fuse LC3A, a central protein in the recruitment of substrates into autophagosomes, to cytoplasm-stable antibodies. These engineered autophagy receptors, targeting Tau or TDP-43, are delivered using small extracellular vesicles and reduce pathology in models, including Tau P301S adult primary mouse neurons, TDP-43G298S iPSC-derived motor neurons and after intravenous injection in Tau P301S mice. Similarly, adeno-associated-virus-mediated delivery in TDP-43ΔNLS mice enhances clearance of pathological TDP-43. This targeted degradation strategy allows delivery into the brain while capitalizing on the specificity of antibodies and the ability of autophagy to degrade large intracellular entities.
    DOI:  https://doi.org/10.1038/s41551-026-01774-9
  35. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Aug 24. 1-11
    Theory of mind impairment related to C9orf72 repeat expansion in amyotrophic lateral sclerosis: a case-control study.
    Francesca Palumbo, Barbara Iazzolino, Antonio Canosa, Umberto Manera, Rosario Vasta, Maurizio Grassano, Enrico Matteoni, Sara Cabras, Alessandra Maccabeo, Giorgio Pellegrino, Filippo Giai Merlera, Anastasia Dei Giudici, Stefano Callegaro, Luisa Balz, Cristina Moglia, Adriano Chiò, Andrea Calvo, Dorothée Lulé.
      Objective: To investigate cognitive and affective theory of mind (ToM) in amyotrophic lateral sclerosis (ALS) patients carrying the C9orf72 repeat expansion (C9orf72+), compared with matched non-mutated (C9orf72-) ALS patients and healthy controls (HCs). Methods: We assessed 34 C9orf72+ ALS patients, 34 C9orf72- ALS patients matched for sex, age, education, and cognitive category, and 34 HC matched for sex, age, and education. Participants underwent neuropsychological evaluation, including the Story-Based Empathy Task (SET), assessing cognitive ToM (Intention Attribution, IA), affective ToM (Emotion Attribution, EA), and Causal Inference (CI). Results: C9orf72+ patients showed lower SET-global score than C9orf72- patients (p = 0.028). Compared with HC, C9orf72+ showed lower score in SET-global score and all SET subtests (all p < 0.05). C9orf72+ cognitively normal differed from HC in SET-global score, IA, and EA (all p < 0.038), whereas C9orf72- cognitively normal did not differ from HC. Multiple linear regression analyses indicated that ALS-specific cognitive domains only explained ∼25% of ToM variance, with no association with demographic, clinical, or behavioral variables. Cluster analysis identified three cognitive profiles based on SET performance, with the most impaired cluster showing the highest proportion of C9orf72+ patients (68%). Conclusion: C9orf72-mutated ALS patients showed more pronounced impairment in cognitive and affective ToM than non-mutated ALS patients, independent of demographic, clinical, and cognitive features. These findings, although requiring confirmation on larger samples, suggest that ToM dysfunction may represent a sensitive marker of cognitive involvement in ALS-C9orf72-associated disease, particularly in its affective component.
    Keywords:  ALS-FTD spectrum; Amyotrophic lateral sclerosis; C9orf72 hexanucleotide repeat expansion; social cognition; theory of mind
    DOI:  https://doi.org/10.1080/21678421.2026.2694499
  36. Front Cell Neurosci. 2026 ;20 1909393
    Ultraviolet radiation and neurodegeneration: molecular mechanisms underlying dual neuroprotective and neurotoxic effects.
    Shreya Praharaj, Eshika Chakraborty, Gayathri Mahalingam.
      Ultraviolet radiation exhibits a complex, often contradictory link to neurodegeneration risk/progression, spanning clinically diagnosed diseases [Parkinson's Disease (PD), Alzheimer's Disease (AD), Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS)] or intermediate phenotypes (decreased neurogenesis, loss of hippocampal volume). The aim of this review is to highlight the dual impact of UV radiation by collecting and synthesizing experimental (preclinical and translational) evidence as well as epidemiological evidence. Current literature exhibits a clear dichotomy: while Vitamin D is capable of exerting a potent neuroprotective effect via anti-oxidant and anti-inflammatory pathways, chronic and intense UV radiation exposure actually hastens the progression or even drives neurodegeneration via a variety of mechanisms. UV radiation exerts its effects through various interconnected pathways: DNA damage pathways, ROS mediated pathways, vitamin D signaling and the skin-brain axis, which unifies both protective and degenerative effects of UV radiation. Owing to the increasing occurrence of neurodegenerative diseases in the general population, these pathways and mechanisms must be leveraged in future research to develop novel therapeutic and preventive strategies. Investigation of biomarkers linked to certain genetic and environmental factors that could provide a link to predisposition toward neurodegeneration and standardization of UV radiation dosimetry (exposure dose/duration) across experimental or pre-clinical studies must also be prioritized.
    Keywords:  DNA damage; neurodegeneration; neuroinflammation; oxidative stress; ultraviolet radiation; vitamin D signalling
    DOI:  https://doi.org/10.3389/fncel.2026.1909393
  37. Imaging Neurosci (Camb). 2026;4:pii: IMAG.a.1343. [Epub ahead of print]4
    Metabolic connectivity alterations in amyotrophic lateral sclerosis: Individual network analysis based on Wasserstein distances.
    Chunmeng Tang, Joke De Vocht, Philip Van Damme, Koen Van Laere, Michel Koole.
      Molecular connectivity analysis with positron emission tomography (PET) imaging offers a promising approach for characterising brain network alterations in neurodegenerative disorders. In this study, we introduce Wasserstein distance (WD) as an alternative to Kullback-Leibler divergence similarity estimation (KLSE) for constructing single-subject metabolic connectivity networks. Using 18F-FDG PET data from 167 individuals with amyotrophic lateral sclerosis (ALS), 36 healthy volunteers (HV), and 25 ALS mimics, we generated WD- and KLSE-based connectivity matrices across 77 atlas-defined brain regions and evaluated corresponding graph theory-based nodal metrics. WD- and KLSE-derived nodal measures were strongly correlated, indicating methodological consistency. Compared with HVs, age-matched subjects in the ALS group (ALSamHV) showed significant alterations in frontal, temporal, cerebellar, and occipital network nodes, with WD-based metrics revealing differences across more brain regions than the KLSE-based approach. Support vector machine classification of ALSamHV vs. HV demonstrated that both connectivity approaches matched voxel-wise PET performance with accuracy higher than 0.80 (yet significantly lower than voxel-wise data, p<0.05 ), while significantly outperforming image-based classification for ALS vs. ALS mimics ( p<0.01 ), with WD achieving the highest accuracy of 0.65 ( p<0.001 ). These findings support WD-based metabolic connectivity as a sensitive, data-efficient framework for detecting disease-related network alterations and motivate its application to a broader range of PET tracers and cohorts.
    Keywords:  Wasserstein distance; amyotrophic lateral sclerosis (ALS); brain FDG PET; individual brain network; metabolic connectivity
    DOI:  https://doi.org/10.1162/IMAG.a.1343
  38. NeuroSci. 2026 Jul 23. pii: 84. [Epub ahead of print]7(4):
    NLRP3 Inflammasome and Inflammation-Related Proteins Expression Characterized in Non-Cultivated Versus Cultivated Peripheral Blood Cells of Patients with Amyotrophic Lateral Sclerosis.
    Denis Shevchuk, Yulia Kuzmenko, Mariya Zakharova, Vadim Karpov, Elizaveta Starodubova, Anastasia Latanova.
       BACKGROUND: Cell and mouse models studies demonstrate NLRP3 inflammasome involvement in amyotrophic lateral sclerosis (ALS) neuroinflammation. Peripheral blood mononuclear cells (PBMCs) are a promising, yet understudied, source of in vivo inflammasome activation biomarkers. Our study reviewed the literature on PBMC-based inflammasome studies of ALS and other neurodegenerative diseases and tested different conditions for PBMC handling to evaluate inflammasome and inflammation-related protein expression in these cells.
    METHODS: Expression of NLRP3 inflammasome components and inflammation-related proteins was analyzed by Real-time qPCR and Western blot in non-cultivated/cultivated PBMCs of 23 ALS patients and 20 Healthy controls. IL-1β and IL-18 levels were measured in plasma and cultivated PBMC supernatants by ELISA.
    RESULTS: Cultivation of PBMCs decreased expression of inflammasome components and inflammation-related cytokines on the mRNA but not protein level. NLRP3 mRNA expression was significantly higher in ALS-cultivated PBMCs. In both ALS and Healthy controls, IL-18 was detected in plasma, and IL-1β in supernatants of cultivated PBMCs.
    CONCLUSIONS: Our findings suggest that PBMC handling conditions, i.e., cell cultivation, may determine particular parameters associated with NLRP3 inflammasome expression and activation pathway, so they should be carefully selected for PBMC-based studies of inflammasome in neurodegenerative and non-neurological disorders and taken into account when interpreting the study results.
    Keywords:  Interleukin-18; Interleukin-1β; NLRP3 inflammasome; amyotrophic lateral sclerosis; biomarkers; inflammation; peripheral blood mononuclear cells
    DOI:  https://doi.org/10.3390/neurosci7040084
  39. Pharmaceutics. 2026 Aug 17. pii: 1018. [Epub ahead of print]18(8):
    Evaluating the Incremental Value of Three-Dimensional Conformer Descriptors for Blood-Brain Barrier Permeability Prediction Using the B3DB Benchmark Dataset.
    Saurabh Tiwari, Katarzyna Mądra-Gackowska, Marcin Gackowski, Łukasz Szeleszczuk.
      Background/Objectives: Predicting blood-brain barrier (BBB) permeability remains a major challenge in central nervous system (CNS) drug discovery. Three-dimensional (3D) conformer-derived molecular descriptors are often proposed as improvements over conventional two-dimensional (2D) topological representations; however, their incremental predictive value remains unclear. Methods: Here, we systematically evaluated six molecular feature sets comprising curated 2D Mordred descriptors, Morgan/ECFP4 fingerprints, 3D conformer-derived descriptors, and their combinations, using LightGBM regression on the B3DB benchmark dataset (1054 compounds with experimental logBB values). The model performance was assessed using 30 independent random splits and 30 Murcko scaffold-based splits. Results: The 2D descriptor model achieved mean test R2 values of 0.567 ± 0.060 and 0.418 ± 0.085 under random and scaffold splitting, respectively, whereas the 3D descriptor model performed substantially worse (0.430 ± 0.066 and 0.298 ± 0.097, respectively). Incorporating 3D descriptors into the 2D feature set yielded only a marginal improvement under random splitting (+0.008 R2; p = 0.039), which disappeared during scaffold-based validation (p = 0.599). Similarly, adding 3D descriptors to the combined 2D + fingerprint representation did not yield any significant benefits. Fingerprints alone exhibited pronounced scaffold fragility, with the mean R2 decreasing from 0.441 to 0.312 between the random and scaffold evaluations. SHAP analysis identified TopoPSA (NO) as the dominant predictor (mean |SHAP| = 0.332), highlighting the central role of desolvation in BBB permeation. Applicability domain analysis showed that 94.8% of the test compounds fell within the structural coverage of the training set. Conclusions: Overall, on the B3DB benchmark and under the descriptor implementation evaluated here, 3D conformer descriptors provided limited incremental value and no scaffold-robust advantage over well-curated 2D molecular representations for BBB permeability predictions.
    Keywords:  3D conformers; BBB permeability; LightGBM; blood–brain barrier; logBB; machine learning; molecular descriptors
    DOI:  https://doi.org/10.3390/pharmaceutics18081018
  40. Adv Mater. 2026 Aug 23. e74762
    Esterified Cholesterol Conjugates Enable LNP-Mediated mRNA Delivery to the Blood-Brain Barrier Following Intravenous Administration.
    Zeru Tian, Xu Wang, Alexis Pacheco Benitez, Erick Guerrero, Yaou Duan, Jingwen Wei, Lukas Farbiak, Daniel J Siegwart.
      The blood-brain barrier (BBB) plays a critical role in maintaining central nervous system homeostasis by regulating molecular and cellular exchange between the brain and peripheral circulation. While most delivery strategies focus on crossing the BBB, targeting brain endothelial cells directly may offer a complementary and more controlled alternative for therapeutic intervention. This study presents a ligand-free lipid nanoparticle (LNP) platform that enables efficient mRNA delivery to the brain endothelium via systemic administration. A modular synthesis strategy was used to generate a chemically diverse library of cholesterol-based lipids. Screening of 486 LNPs identified an optimized four-component formulation consisting of C6O2B2 (novel cholesterol-based lipid), DODAP, DSPC, and DMG-PEG, which achieves high transfection efficiency in brain endothelial cells without the incorporation of free cholesterol or disruption of BBB integrity and function, such as those utilized in focused ultrasound (FUS) techniques. This BBB-targeting LNP platform avoids neuronal and glial transfection, thereby offering a noninvasive, and scalable approach for cerebrovascular gene delivery. The work establishes a new class of cholesterol-based lipids and provides a foundation for next-generation RNA therapeutics targeting BBB-associated diseases.
    Keywords:  blood–brain barrier (BBB); brain endothelial cells; cholesterol‐based lipid; lipid nanoparticles (LNPS); mRNA delivery; systemic administration
    DOI:  https://doi.org/10.1002/adma.74762
  41. Biomedicines. 2026 Aug 07. pii: 1781. [Epub ahead of print]14(8):
    Are Signal Peptides Hidden Regulators of Neurodegenerative Disease?
    Maciej Karbownik, Marcin Fidura, Renata Perlikowska.
      Canonical signal peptides (SPs) are short N-terminal sequences that direct nascent proteins into the secretory pathway, but their role extends far beyond protein targeting. Advances in sequencing and computational tools have enabled their systematic identification across proteomes, highlighting SPs as critical regulators of protein biogenesis, including endoplasmic reticulum (ER) targeting, translocation, folding, and proteostasis. Clinically, mutations affecting SP function underlie a distinct group of human disorders, while SP-derived fragments are emerging as diagnostic biomarkers and therapeutic targets. In biotechnology, SPs are engineered to enhance recombinant protein production and serve as molecular tags for intracellular delivery. Together, these developments position SPs at the intersection of fundamental cell biology, medicine, and biotechnology. While this review primarily focuses on canonical SPs, it also considers selected non-canonical targeting and topogenic sequences whose dysfunction contributes to protein misfolding, impaired ER translocation, disrupted degradation pathways, and altered intracellular trafficking in neurodegenerative diseases. Aberrations involving both conventional SPs and alternative targeting/topogenic elements contribute to pathological protein aggregation, a hallmark of major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington Disease (HD), prion diseases, and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); in multiple sclerosis (MS) is primarily an inflammatory demyelinating disease, where abnormal protein exposure, potentially linked to misprocessed SPs, can activate immune responses. By synthesizing current knowledge, the review explores how alterations in targeting determinants influence key proteostasis pathways, acting as upstream modulators of disease-relevant molecular cascades. It further discusses the emerging concept that SP-derived fragments may participate in intercellular communication, adding an additional layer of regulatory complexity.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; drug development; prion diseases; protein targeting; secretory pathway dysfunction; therapeutic targets
    DOI:  https://doi.org/10.3390/biomedicines14081781
  42. Biochem Biophys Res Commun. 2026 Aug 18. pii: S0006-291X(26)01220-9. [Epub ahead of print]834 154456
    Low expression of PDGFR-β impairs the blood-brain barrier and accelerates cellular aging in the hippocampal region.
    Haichao Chen, Le Zhang, Xiaoling Zhu, Cheng Gu, Fulin Gao.
       BACKGROUND: Platelet-Derived Growth Factor Receptor Beta (PDGFR-β), a key marker of cerebrovascular pericytes, plays a crucial role in regulating pericyte function and maintaining the stability of the blood-brain barrier (BBB). Recent studies suggest that abnormalities in the PDGFR-β signaling pathway may be closely associated with the onset and progression of neurodegenerative diseases. However, the causal relationship and specific mechanisms by which PDGFR-β gene deficiency directly leads to systemic pathological alterations in the hippocampal microenvironment, subsequently causing impaired neurogenesis and cellular senescence, remain unclear.
    METHODS: Using PDGFR-β heterozygous knockout (PDGFR-β+/-) mice, we systematically examined pericyte coverage, BBB integrity, cellular senescence markers, and hippocampal neurogenesis.
    RESULTS: PDGFR-β ± mice exhibited significant pericyte loss, reduced tight junction proteins, impaired vascular basement membrane, and increased BBB permeability in the hippocampus. These changes were accompanied by elevated DNA damage response, increased p16-positive senescent cells, and markedly reduced numbers of SOX2-positive neural stem/progenitor cells and DCX-positive immature neurons in the hippocampus.
    CONCLUSION: Our findings establish that PDGFR-β haploinsufficiency drives pericyte loss and BBB breakdown, leading to hippocampal cellular senescence and impaired neurogenesis. This highlights vascular instability as a key driver of brain aging and positions pericyte dysfunction as a critical link between genetic susceptibility and age-related cognitive decline.
    Keywords:  Aging; Blood-brain barrier; Neurogenesis; Pericytes; Platelet-derived growth factor receptor β
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154456
  43. Antioxidants (Basel). 2026 Jul 30. pii: 948. [Epub ahead of print]15(8):
    The Eye as a Window to Neurodegeneration: Oxidative Stress, Optic Nerve Vulnerability, and Retinal Biomarkers-A Scoping Review.
    Giustino Varrassi, Y Van Tran, Giacomo Farì, Miguel Narvaez Encinas, Alberto Corriero, Filomena Puntillo, Phong Van Pham, Matteo Luigi Giuseppe Leoni.
      Neurodegenerative diseases represent a major and growing global health burden characterized by progressive neuronal dysfunction, axonal degeneration, and irreversible neural tissue loss. Increasing evidence identifies oxidative stress as one of several interacting pathogenic mechanisms in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and several optic neuropathies. Interest has increasingly focused on the brain-retina axis, as the retina and optic nerve share structural, metabolic, and molecular features with the central nervous system and may provide accessible insights into neurodegeneration. This scoping review mapped current evidence on oxidative stress in neurodegeneration, emphasizing cranial nerve involvement, optic nerve vulnerability, retinal ganglion cell degeneration, visual dysfunction, oxidative biomarkers, and emerging therapeutic strategies. The review followed established methodological frameworks and PRISMA-ScR recommendations; no formal risk-of-bias appraisal was undertaken, consistent with scoping-review methodology. The literature shows that oxidative stress interacts with mitochondrial dysfunction, neuroinflammation, impaired mitophagy, ferroptosis, and altered bioenergetics, contributing to neuronal injury in cerebral and retinal disorders. Retinal ganglion cells appear particularly vulnerable because of their high metabolic demands and reliance on oxidative phosphorylation. Glaucoma and other optic neuropathies share molecular signatures with central neurodegenerative diseases. Retinal imaging and oxidative biomarkers show promise for diagnosis, monitoring, and stratification. The evidence base is nonetheless dominated by preclinical work; biomarker performance is inconsistent across matrices and assay platforms and most antioxidant clinical trials have been negative. Oxidative stress is therefore best regarded as one interacting node of a broader pathogenic network rather than a universal or predominant driver and the brain-retina continuum as a mechanistically plausible but not yet clinically validated framework for biomarker-guided neuroprotection.
    Keywords:  biomarkers; glaucoma; mitochondria; neurodegenerative diseases; neuroinflammation; optic nerve diseases; oxidative stress; precision medicine; retina; retinal ganglion cells
    DOI:  https://doi.org/10.3390/antiox15080948
  44. Pharmaceutics. 2026 Aug 06. pii: 967. [Epub ahead of print]18(8):
    Quantitative Structural Thresholds for Blood-Brain Barrier Permeability Derived from Experimental logBB Measurements.
    Saurabh Tiwari, Katarzyna Mądra-Gackowska, Marcin Gackowski, Łukasz Szeleszczuk.
      Background/Objectives: Rules for predicting blood-brain barrier (BBB) permeability, including the CNS multiparameter optimization (CNS MPO) score, Lipinski's Rule of Five, and Veber's rules, were developed using relatively limited datasets and have not been systematically re-evaluated using modern large-scale experimental databases. Using the B3DB database, which contains 1058 experimentally measured logBB values, we derived quantitative, data-driven structural thresholds for BBB permeability and benchmarked them against established heuristic rules. Methods: Six key physicochemical properties were calculated for all compounds, and optimal classification thresholds were identified through exhaustive optimizations. Decision trees and scaffold analyses were used to generate interpretable medicinal chemistry guidelines. Results: The topological polar surface area (TPSA) emerged as the strongest single predictor of BBB permeability, with an optimal threshold of 66.8 Å2 (AUC = 0.731, 95% CI: 0.689-0.771). This threshold outperformed the approximated CNS MPO ≥ 4 (AUC = 0.625), Lipinski's Rule of Five (AUC = 0.546), and Veber rules (AUC = 0.566). A simple two-parameter rule combining TPSA < 67 Å2 and H-bond donors ≤ 1 achieved 96.6% precision for BBB-permeable compounds while maintaining an AUC of 0.720. Decision tree analysis further confirmed TPSA as the dominant determinant of BBB permeability, whereas scaffold analysis identified the molecular frameworks associated with highly permeable and impermeable compounds. External validation provided preliminary support for the improved specificity of the proposed rule, compared with existing approaches. Conclusions: These findings suggest that the commonly applied TPSA threshold of 90 Å2 may be overly lenient. A data-driven threshold of approximately 67 Å2 substantially improved the discrimination of BBB permeability across the entire dataset. Compounds with TPSA values between 67 and 90 Å2 should be assessed on a case-by-case basis, considering the ionization state and active transport potential, rather than being automatically classified as BBB-permeable. These experimentally grounded rules offer a practical framework for the early-stage design of CNS leads.
    Keywords:  B3DB; BBB permeability; CNS MPO; TPSA; blood–brain barrier; decision tree; logBB; rule-based prediction; scaffold analysis
    DOI:  https://doi.org/10.3390/pharmaceutics18080967
  45. Z Naturforsch C J Biosci. 2026 Aug 31.
    Multitargeted drug strategies for Alzheimer's and Parkinson's diseases.
    Azmat Ullah Khan, Abdullah Abdullah, Syeda Farwa Naqvi, Hadia Tahir, Hira Khalid, Hina Sarfraz, Yousaf Khan.
      Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are multifactorial diseases that are characterized by several interconnected pathological mechanisms, such as the aggregation of amyloid-beta (Aβ), hyperphosphorylation of tau, accumulation of α-synuclein, oxidative stress, mitochondrial dysfunction, neuroinflammation, and neurotransmitter imbalance. Conventional single-target therapies failed to produce significant clinical effects due to the fact that they target only individual disease pathways. Thus, the multitarget-directed ligand (MTDL) strategy has become an attractive therapeutic option, and MTDLs can act on several pathological targets simultaneously. Recent advances in multitarget drug development for AD and PD targeting compounds targeting Aβ, BACE1, MAO-B, cholinesterases, metal-ion dyshomeostasis, oxidative stress, and inflammatory pathways are reviewed. A few potential candidates, such as GV-971, Prasinezumab, Huperzine A, curcumin derivatives, and hybrids of MAO-B inhibitors, have shown neuroprotective and cognitive effects in preclinical and clinical studies. There are significant advances in the clinical pipeline, with over 180 clinical trials for AD and over 130 clinical trials for PD testing multitarget or disease-modifying strategies. The review also highlights the growing importance of computer-aided drug design (CADD), artificial intelligence (AI), and machine learning (ML) in speeding up the discovery of MTDL, optimizing their pharmacokinetic profiles, and predicting multitarget interactions. However, there are still major obstacles to be overcome, such as the ability to cross the blood-brain barrier, optimizing the pharmacokinetics, the difficulties of transferring from the animal to the human model, and the complexity of the regulatory process. New strategies based on nanomedicine, biomarker-driven trials, personalized medicine, and drug repurposing will enhance therapeutic precision and clinical success.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; multitarget-directed ligands
    DOI:  https://doi.org/10.1515/znc-2026-0116
  46. Stem Cell Res. 2026 Aug 22. pii: S1873-5061(26)00181-9. [Epub ahead of print]95 104085
    Generation of two iPSC lines from ALS patients harboring C9orf72 hexanucleotide repeat expansions.
    Dide Wu, Ana Kojic, Jay P Ross, Dong Li, Parker Walther, Neelam Goyal, Jacinda Sampson, Joseph C Wu.
      The GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene constitutes the leading genetic driver of amyotrophic lateral sclerosis (ALS). This fatal neurodegenerative disorder is characterized by the systematic loss of both the upper and lower motor neurons across both the central and peripheral nervous systems. This work describes the successful reprogramming of two human induced pluripotent stem cell (iPSC) lines originating from two independent ALS patients, both of whom carry a C9orf72 HRE mutation. Validation of the two established iPSC lines confirmed the expression of pluripotency markers, normal karyotypes, and successful trilineage differentiation. Consequently, these lines provide a robust in vitro platform to model ALS and study C9orf72-mediated disease mechanisms.
    DOI:  https://doi.org/10.1016/j.scr.2026.104085
  47. Mol Neurobiol. 2026 Aug 28. pii: 862. [Epub ahead of print]63(1):
    Quercetin as a Hypothesized Involvement of VMAT2 in Neurodegenerative Diseases-Mechanistic Insight and Therapeutic Applications.
    Kanishka Sharma, Vir Vikram, Pallavi Jamwal, Soumyadeep Bhaumik, Nitin Prasad, Rohit, Rinka Juneja.
      Neurodegenerative diseases, particularly Alzheimer's disease, Parkinson's disease and Huntington's disease are characterized by progressive neuronal loss driven by complex mechanisms such as oxidative stress, neuroinflammation, protein aggregation, neurotransmitter imbalance, and synaptic dysfunction. Among these, Alzheimer's disease remains the most prevalent and challenging disorder, lacking effective disease-modifying therapies. Quercetin, a naturally occurring flavonoid abundant in fruits and vegetables, has attracted considerable attention due to its potent antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective properties, along with its ability to cross the blood-brain barrier. This review critically examines the potential role of quercetin in modulating key pathological pathways in neurological disease, with a special focus on its interaction with the vesicular monoamine transporter 2 (VMAT2). Vesicular monoamine transporter 2 plays a crucial role in maintaining monoamine neurotransmitter homeostasis and protecting neurons from oxidative damage caused by cytosolic monoamine degradation. Increasing data indicates that VMAT2-mediated dysfunction represents one of multiple processes that lead to neurotoxicity by altering monoamine synthesis, increasing oxidative damage, and leading to synaptic damage, especially in neuronal pathways. Quercetin, as a potential monoamine oxidase inhibitor and reactive oxygen species scavenger, may indirectly preserve vesicular monoamine transporter 2 function and mitigate downstream neurotoxic events. Overall, the multitargeted actions of quercetin, combined with its potential influence on vesicular monoamine transporter 2-mediated pathways, highlight its promise as a complementary therapeutic candidate for further neurodegenerative disorders. An increasing number of studies demonstrates that quercetin may indirectly regulate VMAT2 function by eliminating reactive oxygen compounds, decreasing neuroinflammation, inhibiting monoamine oxidase activity, improving mitochondrial activity, and maintaining monoaminergic neuronal function, although there remains limited direct evidence connecting quercetin to VMAT2 regulation. The substance quercetin can reduce oxidative neuronal damage and decrease subsequent neurodegenerative events through several connected methods. Although direct experimental verification of the quercetin-VMAT2 connection is still lacking, the data that is now accessible suggests that VMAT2 may be a suitable target for further research. Therefore, the suggested quercetin-VMAT2 connection should be seen as a hypothetical and mechanistic approach.
    Keywords:  Neurodegeneration; Neuroinflammation; Oxidative stress; Quercetin; VMAT2
    DOI:  https://doi.org/10.1007/s12035-026-06164-5
  48. Pharmaceuticals (Basel). 2026 Aug 21. pii: 1319. [Epub ahead of print]19(8):
    DeepBBB: A Data-Composition-Aware Graph Screening Workflow for BBB-Focused CNS Library Construction and Prospective PAMPA-BBB Evaluation.
    Ziying Xu, Wei Xia, Haiqiang Wu, Haiping Zhang.
      Background/Objectives: Blood-brain barrier (BBB) permeability is a major practical obstacle in central nervous system (CNS) drug discovery, because only a small fraction of drug-like molecules achieve sufficient brain exposure. Methods: We present DeepBBB, a graph-based, data-composition-aware screening workflow for predicting BBB permeability and for constructing BBB-focused screening libraries from commercial chemical space. Rather than introducing a new graph-learning architecture, the workflow combines standard graph convolutional and graph-transformer models with deliberate control of training-set composition, commercial-library filtering, chemical-space profiling, and prospective experimental evaluation. Three model variants were trained on the Blood-Brain Barrier Database (B3DB): a baseline classifier/regressor pair (DeepBBB_V1_BC/RG), a variant trained with a more strongly negative-enriched configuration (DeepBBB_V2_BC), and a graph-transformer counterpart (DeepBBB_trans_BC/RG). Because the sample-level split assignments and per-compound predictions from the original runs were not recoverable, the archived summary metrics are reported descriptively in the main text and are not used to support calibration, scaffold-level validity, or generalization. Applying the workflow to the ChemDiv collection (~1.5 million compounds) and the Enamine REAL lead-like space (~1.7 billion compounds) produced three progressively more stringently filtered BBB-focused libraries (21,991; 4,808,885; and 151,790 compounds). Results: Analysis of available processed data indicated that the predicted BBB-permeable set occupies a compact, BBB-compatible property region. Physicochemical, fragment, and scaffold summaries were interpreted descriptively at the constructed-library level. In a first prospective campaign, one of 12 tested candidate compounds was PAMPA-BBB-positive (all-tested molecular-level positive fraction 8.3%; exact 95% CI 0.2-38.5%). In a second campaign, five of 35 tested candidate compounds were PAMPA-BBB-positive (14.3%; exact 95% CI 4.8-30.3%); 13 compounds were not quantifiable and were not treated as ordinary CNS-negative measurements, and the two campaigns differed in compound source, selection strategy, and assay setting, so the numerical difference is reported descriptively rather than causally. Conclusions: Together, these results support the feasibility of BBB-focused computational filtering and a PAMPA-BBB evaluation workflow for CNS-oriented discovery.
    Keywords:  BBB-focused library; CNS drug discovery; PAMPA-BBB; blood–brain barrier; class imbalance; graph neural networks; virtual screening
    DOI:  https://doi.org/10.3390/ph19081319
  49. Neurobiol Sleep Circadian Rhythms. 2026 Nov;21 100151
    The sleep-deprived blood-brain barrier: Does the Brain's gatekeeper adapt or merely fail slowly?
    Sofia K Fluke, Gabriela Hurtado-Alvarado, Christopher J Davis, Carolina Escobar, Natalí N Guerrero-Vargas, Luis Ernesto García-Páez, Rocío Ruiz-Manzano, Arturo Contis-Montes de Oca, Brieann C Satterfield.
      Chronic insufficient sleep is highly prevalent and is linked to an elevated risk of adverse health outcomes. Animal studies show that chronic sleep restriction, inducing a cumulative sleep debt, promotes blood-brain barrier (BBB) dysfunction, neuroinflammation, and can insidiously lead to neuropathology. Available studies primarily show diurnal or time-of-day variation in BBB permeability rather than direct manipulation of sleep state. Therefore, our fundamental understanding of BBB dynamics during the sleep-wake cycle remains limited. Investigating dynamic changes in the BBB induced by prolonged wakefulness is critical for understanding the heightened vulnerability of the brain to neurodegenerative diseases. In this review, we first discuss the potential role of sleep to modulate BBB dynamics. We then examine the known mechanisms driving BBB changes during sleep loss across different experimental paradigms and critically discuss the bidirectional interplay between sleep and the BBB, emphasizing how disruption of one system affects the other. This narrative-based review challenges the prevailing view of the BBB as a static, whole-brain barrier, proposing instead that it is a dynamic and adaptive interface whose regulation is tightly coupled to neuronal demands across the sleep-wake cycle.
    Keywords:  Brain clearance; Brain endothelial cells; Neural activity; Neuroinflammation; Permeability; Sleep loss
    DOI:  https://doi.org/10.1016/j.nbscr.2026.100151
  50. Alzheimers Dement. 2026 Aug;22(8): e71777
    Methodological insights and clinical outcomes in ALS and FTLD: lessons from the SPIN cohort.
    Álvaro Carbayo, Janina Turon-Sans, Daniel Alcolea, Elena Cortés-Vicente, Manuel Cabezas-Torres, Esther Alvarez-Sanchez, Laia Muñoz, Sara Rubio-Guerra, Jesús García-Castro, Judit Selma-González, Sara Bernal, Lidia Gonzalez-Quereda, Alexandre Bejanin, Mateus Rozalem Aranha, Miguel Santos-Santos, Olivia Belbin, Ana Vesperinas-Castro, Roger Collet-Vidiella, Marta Caballero-Ávila, Laura Llansó, Luis Querol, Alberto Lleó, Juan Fortea, Ellen Gelpí, Oriol Dols-Icardo, Ignacio Illán-Gala, Ricard Rojas-Garcia.
       INTRODUCTION: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) constitute a clinico-genetic-neuropathological continuum with marked heterogeneity. Reliable in vivo biomarkers of the disease are lacking. Large, multimodal cohorts are needed to advance biomarker discovery and precision medicine.
    METHODS: We describe the structure and results derived from the Sant Pau Initiative on Neurodegeneration (SPIN)-ALS-FTLD subcohort, a longitudinal, multimodal platform that integrates clinical, cognitive, genetic, biofluid, neuroimaging, and neuropathological data within a unified framework embedded in routine care.
    RESULTS: The cohort includes over 1000 participants, 800 blood, 400 CSF, and 800 DNA samples, neuroimaging in over 250 cases, and 66 neuropathological studies. Harmonized longitudinal data and biospecimen collection have enabled substantial clinical, molecular, and translational research output.
    DISCUSSION: SPIN-ALS-FTLD extends the original SPIN framework to the ALS-FTLD continuum, enabling deep phenotyping and multimodal biomarker discovery. This scalable model supports patient stratification, longitudinal monitoring, and the development of precision medicine approaches in neurodegenerative diseases.
    Keywords:  ALS–FTLD spectrum; amyotrophic lateral sclerosis; biofluids; biomarkers; cohort study; frontotemporal lobar degeneration; genetics; longitudinal registry; multimodal cohort; neurodegeneration; neuroimaging; neuropathology; precision medicine; translational research
    DOI:  https://doi.org/10.1002/alz.71777
  51. BMC Med. 2026 Aug 25. pii: 460. [Epub ahead of print]24(1):
    JP1 peptide modulates oxidative stress and autophagy via Keap1-Nrf2-ARE in ALS model mice.
    Yu Zhang, Yaxi Liu, Shiyu Shi, Qingyang Li, Yani Huo, Pan You, Mingzhu Shu, Xi Cheng, Jun Zhang, Dong Liang, Aihua Zhang, Chao Lu, Bin Shen, Jianwei Zhou, Qi Niu.
       BACKGROUND: The simultaneous modulation of oxidative stress and autophagy represents a potential therapeutic strategy for amyotrophic lateral sclerosis (ALS), yet agents capable of coordinately regulating both processes remain scarce. The Keap1‑Nrf2‑ARE pathway serves as a critical hub linking redox homeostasis and autophagic regulation, making it an attractive target for ALS intervention. JWA is a stress‑responsive protein involved in cellular protection against oxidative injury, and its neuroprotective effects have been shown to depend on activation of the MEK/ERK‑Nrf2 axis. JP1 is a functional oligopeptide derived from the JWA protein that has been engineered to cross the blood-brain barrier and specifically target integrin αVβ3. Based on the link between JWA and Nrf2 signaling, we hypothesized that JP1 activates the Keap1‑Nrf2‑ARE pathway to coordinate antioxidant defense and autophagic clearance. Here, we evaluated this hypothesis in the SOD1‑G93A mouse model, a well‑established transgenic model of familial ALS, and elucidated the underlying mechanisms.
    METHODS: We evaluated the efficacy of JP1 in the SOD1-G93A mice model using behavioral phenotyping and survival analysis. The coordinated mechanism was investigated in spinal cord tissues by profiling the Keap1-Nrf2-ARE pathway and oxidative stress, quantifying autophagic flux (by Western blotting and transmission electron microscopy) and neuronal apoptosis, and evaluating histology (by Nissl staining and immunofluorescence). Integrated transcriptomic and proteomic analyses further elucidated the global molecular landscape underlying the therapeutic effects of JP1.
    RESULTS: JP1 treatment ameliorated motor deficits and extended survival in SOD1-G93A mice without adversely affecting liver or kidney function. JP1 crossed the blood-brain barrier, targeted motor neurons expressing integrin αVβ3, and activated the ERK pathway. This promoted Keap1/Cul3 degradation and Nrf2 nuclear translocation, thereby activating the Keap1-Nrf2-ARE pathway to alleviate oxidative stress. Concurrently, JP1 restored autophagic flux, increased autophagic activity, attenuated motor neuron injury, suppressed neuronal apoptosis, and preserved neuronal structural integrity. The Nrf2 inhibitor ML385 reversed the protective effects of JP1 on survival, motor function, autophagy, oxidative stress, and neuronal apoptosis, which confirms that JP1 acts via the Nrf2 pathway.
    CONCLUSIONS: JP1 acts as a promising coordinator of antioxidant and autophagic processes by targeting the Keap1-Nrf2-ARE pathway, thus highlighting its therapeutic potential for ALS.
    Keywords:   JWA gene; Amyotrophic lateral sclerosis; Autophagy; JP1 peptide; Keap1-Nrf2-ARE pathway; Oxidative stress
    DOI:  https://doi.org/10.1186/s12916-026-05119-w
  52. J Cereb Blood Flow Metab. 2026 Aug 26. 271678X261485415
    EXPRESS: Disentangling MRI-derived blood-brain barrier leakage into vascular permeability and surface area.
    Damon Verstappen, Joost J A de Jong, Paulien H Voorter, Maud van Dinther, Robert J van Oostenbrugge, Julie Staals, Jacobus F A F A Jansen, Walter H Backes.
       BACKGROUND: In neurovascular and neurodegenerative diseases, blood-brain barrier (BBB) disruption can be subtle, diffuse, and MRI-derived measures are confounded by microvascular architecture. Therefore, we aimed to disentangle MRI-derived blood-brain barrier leakage rate (Ki) into intrinsic vascular permeability (P) and surface area (S).
    METHODS: In this cross-sectional study, 45 patients with cSVD and 26 elderly controls underwent dynamic contrast-enhanced (DCE) MRI to determine Ki and vessel architecture imaging (VAI) to estimate S. These measures were used to calculate P.
    RESULTS: Compared to normal-appearing white matter (NAWM), Ki was higher in WMH (β=0.297, p<0.001) and deep gray matter (DGM) (β=0.210, p=0.007). P was higher in WMH (β=0.410, p<0.001) and similar between NAWM and DGM. S was smaller in WMH (β=-0.467, p<0.001) and larger in DGM (β=0.540, p<0.001). Ki (β=0.289, p=0.007) and P (β=0.249, p=0.021) were only higher in patients than controls in concentric shells surrounding WMH. S was smaller in WMH of patients than controls (β=-0.085, p=0.049). With age, Ki (β=0.260, p=0.008) and P increased (β=0.273, p<0.001), while S decreased (β=-0.079, p=0.025).
    CONCLUSION: Disentangling P and S from the BBB leakage rate provides two biologically more specific and interpretable measures, which have counteracting effects on the BBB leakage in aging and disease.
    DOI:  https://doi.org/10.1177/0271678X261485415
  53. Expert Opin Ther Pat. 2026 Aug 26.
    Overcoming the blood-brain barrier for therapeutics targeting neurodegenerative diseases: a patent review (2020-present).
    Daowei Huang, Roujun Lu, Ruijing Tang, Jiarui Sun, Zhipei Sang.
       INTRODUCTION: The blood-brain barrier (BBB) restricts drug entry into the CNS, with most therapeutics showing < 1% brain penetration, limiting efficacy in neurodegenerative diseases.
    AREAS COVERED: Patents (2020-2026) were retrieved from SciFinder, Web of Science, PubMed, and Reaxys using combinations of 'blood-brain barrier,' 'brain delivery,' and neurodegenerative disease terms. Technologies were included if supported by in vitro or in vivo BBB‑penetration evidence for neurodegenerative indications; purely computational, non‑English untranslated, and non‑targeted conventional formulation patents were excluded. Eligible patents were classified into protein/antibody‑based, small molecule, nanocarrier, physical‑assisted, permeability enhancer, and emerging technology categories.
    EXPERT OPINION: Receptormedia-ted transcytosis, dual-targeting ligands, and ultrasound opening are enhancing delivery precision; emerging systems (small molecules, peptides, nanozymes) combine penetration with target inhibition, overcoming traditional bottlenecks and accelerating clinical translation.
    Keywords:  Blood-brain barrier; bioactive peptides; nanocarriers; neurodegenerative diseases; small molecule inhibitors; targeted delivery; theranostics; transcytosis; ultrasound-responsive microbubbles
    DOI:  https://doi.org/10.1080/13543776.2026.2725660
  54. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Aug 28. 1-8
    Cognitive and behavioral manifestations of the C9orf72 mutation in Amyotrophic Lateral Sclerosis: an age, education, and gender-matched cohort study.
    Seán O'Farrell, Maria Christina Holland, Colm Peelo, Russell McLaughlin, Mark Heverin, Orla Hardiman, Emmet Costello, Niall Pender.
       OBJECTIVES: The presence of a hexanucleotide expansion in the gene C9orf72 confers a higher risk of developing ALS and FTD with associated cognitive and behavioral change, although penetrance is incomplete, and many gene carriers never exhibit any clinical signs during their lifetime. To date, there have been few studies investigating additional factors such as age, years of education, gender, and their influence on cognition and behavior in people with ALS (pwALS), particularly those with a hexanucleotide expansion in the gene C9orf72.
    METHODS: We selected 104 consenting pwALS from the Irish ALS register, comprising 52 C9orf72 positive participants and 52 C9orf72 negative controls matched on age, years of education, and gender. Cognitive functioning was assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), while behavioral changes were examined using the Beaumont Behavioral Inventory (BBI).
    RESULTS: No significant differences in ECAS performance were observed across the two groups, with the exception of visuospatial performance, which was more impaired in those carrying the C9orf72 repeat expansion (p = .001). Similarly, there was no difference in behavoural scores between the 2 groups.
    CONCLUSIONS: These findings suggest that the presence of the C9orf72 repeat expansion does not presage the development of significant cognitive or behavioral impairment early in the disease stage when controlled for age, years of education, and gender. When interpreting these results, it is important to consider the relatively small sample size, and the exclusion criteria of previous clinically significant comorbidities.
    Keywords:  Amyotrophic Lateral Sclerosis; behaviour; cognition
    DOI:  https://doi.org/10.1080/21678421.2026.2721333
  55. Eur Spine J. 2026 Aug 23.
    3D U-net for volumetric segmentation of spinal cord MRI in degenerative disorders.
    P Manju Bala, S Usharani, R Rajmohan, Saran Raj Sowrirajan.
      The correct identification of spinal cord structures in magnetic resonance imaging (MRI) plays a vital role in identifying degenerative spondyloarthrosis, osteophytes, osteochondrosis, haemangioma, osteophytes and physiological lordosis malformations. Delineation, which is done physically, is time-consuming and can be varied. We will present a 3D U-Net-based deep learning model of volumetric segmentation of spinal cord MRI data in Digital Imaging and Communications in Medicine (.dcm) format in this research. The model takes advantage of three-dimensional convolutions to learn spatial dependencies in each of the axial, sagittal, and coronal planes. MRI volumes were pre-processed using normalisation, artefact removal, and volumetric resampling, resulting in a filtered dataset containing patients with multiple degenerative changes. The comparison was done with performance against expert annotations under the Dice similarity coefficient, Hausdorff distance, sensitivity, and specificity. Findings indicate that the 3D U-Net scores higher than the other models on dominant spinal cord structures. This research discusses the possibility of volumetric deep learning helping to optimise radiological processes and assist in precision medicine for spinal cord imaging.
    Keywords:  3D U Net; Deep learning; Degenerative disorders; Medical imaging; Spinal cord MRI; Volumetric segmentation
    DOI:  https://doi.org/10.1007/s00586-026-10288-6
  56. RSC Med Chem. 2026 Aug 13.
    Benzothiazole-driven molecular probes and therapeutics for neurodegenerative diseases: focus on amyloid-beta (Aβ), tau, and α-synuclein.
    Nitin Kumar, Izhar Khan, Jyoti Singh, Krishan Kumar, Virendra Kumar Kushwaha, Sunil Kumar, Smriti Ojha, Alok Kumar Dash, Gauri Shankar.
      Neurodegenerative disorders, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), represent a rapidly growing global health challenge characterized by progressive neuronal loss, irreversible cognitive decline, and the absence of effective disease-modifying therapies. A major obstacle in the clinical management of these disorders is the inability to accurately diagnose pathological changes at early stages, when therapeutic intervention is most likely to be effective. The pathological aggregation of amyloid-β (Aβ), hyperphosphorylated tau, and α-synuclein (α-syn) constitutes a central molecular hallmark of neurodegeneration and has therefore emerged as a critical target for both diagnostic imaging and therapeutic intervention. Among the numerous heterocyclic scaffolds investigated for central nervous system drug discovery, benzothiazole (BZT) has attracted exceptional attention owing to its favorable blood-brain barrier permeability, synthetic versatility, and intrinsic affinity toward β-sheet-rich protein aggregates. The clinical success of Pittsburgh compound-B (PiB) established BZT as a privileged molecular recognition motif for in vivo visualization of amyloid pathology and stimulated extensive medicinal chemistry efforts toward the development of next-generation imaging probes. More recently, advances in structure-guided design and multitarget-directed ligand (MTDL) strategies have transformed BZT from a purely diagnostic scaffold into a versatile theranostic platform capable of simultaneously recognizing and modulating neurodegenerative proteinopathies. Between 2020 and 2026, a wide range of structurally diverse BZT-based derivatives and hybrid molecules have been reported with improved affinity, selectivity, and sensitivity toward Aβ plaques, tau fibrils, and α-synuclein aggregates, while also exhibiting therapeutic activities such as inhibition of protein aggregation, fibril destabilization, cholinesterase inhibition, monoamine oxidase modulation, antioxidant activity, metal chelation, mitochondrial protection, and neuroinflammation suppression. This review provides a comprehensive overview of recent advances (2020-2026) in the design, synthesis, structure-activity relationships, molecular mechanisms, diagnostic applications, and therapeutic potential of BZT-based agents for neurodegenerative disorders. Particular emphasis is placed on the molecular basis of BZT recognition of amyloidogenic proteins, the evolution of diagnostic probes into multifunctional therapeutic hybrids, and emerging theranostic strategies targeting interconnected pathological pathways associated with AD, PD, and related proteinopathies. Furthermore, key trends in medicinal chemistry, translational challenges, and future opportunities for the development of next-generation BZT-derived diagnostics and therapeutics are critically discussed. Collectively, the evidence highlights BZT as one of the most promising privileged scaffolds for integrating early diagnosis, disease monitoring, and disease-modifying intervention within a unified molecular framework for neurodegenerative disorders.
    DOI:  https://doi.org/10.1039/d6md00462h
  57. Jpn J Radiol. 2026 Aug 26.
    Recent advances in MR neuroimaging: toward quantitative and AI-driven brain and spinal cord imaging.
    Xunyang Zhang, Akifumi Hagiwara, Masaya Takahasi, Koji Kamagata, Masaaki Hori.
      Magnetic resonance neuroimaging is undergoing a major paradigm shift from traditional qualitative anatomical mapping toward integrated, quantitative measurement systems with biological interpretability. This review systematically synthesizes nine methodological pillars driving this transformation, encompassing advances ranging from hardware innovation to artificial intelligence algorithms. We first explore the pivotal role of deep learning in image reconstruction and acceleration, followed by detailed analyses of quantitative brain oxygen metabolism assessment, standardized spinal cord imaging frameworks, and the non-invasive monitoring of the glymphatic system using diffusion MRI. Furthermore, the review delves into tractometry, susceptibility-based myelin mapping, the clinical standardization of arterial spin labeling, and the application of radiomics in extracting high-dimensional phenotypes. Finally, the importance of open science and workflow coordination in enhancing research reproducibility is highlighted. Through the deep integration of hardware, sequences, and artificial intelligence, these technologies form a synergistic ecosystem that provides unprecedented precision tools and translational potential for both basic neuroscience research and clinical precision medicine. Across these domains, AI contributes not only to acceleration and reconstruction but also to segmentation, quality control, quantitative parameter extraction, and multiparametric pattern recognition that can support diagnostic interpretation. The quantitative emphasis of this review therefore lies in measurable outputs such as image-quality metrics, metabolic and perfusion parameters, tract-specific diffusion indices, susceptibility-based components, and radiomic features.
    Keywords:  Artificial intelligence; Brain; MRI; Neuroimaging; Quantitative imaging
    DOI:  https://doi.org/10.1007/s11604-026-02037-y
  58. CNS Neurosci Ther. 2026 Aug;32(8): e71109
    Lipid Metabolism in Central Nervous System Diseases: Pathological Mechanisms and Therapeutic Advances.
    Jiayan Yuan, Shixue Huang, Kun Jiao, Shu Yang, Xuhui Ge, Wei Liu, Wei Wang, Haoming Shu, Xuhui Zhou.
       BACKGROUND: Lipids are fundamental components of the central nervous system (CNS) structure and are essential for maintaining physiological homeostasis. Dysregulation of lipid homeostasis is a critical mechanism driving the pathogenesis and progression of classic CNS diseases, including neurodegenerative disorders, traumatic injuries, and cerebrovascular diseases. These metabolic disturbances trigger pathological processes such as abnormal protein aggregation, neuroinflammation, and lipid peroxidation, creating a vicious cycle that exacerbates disease progression. While targeting lipid metabolism offers a novel therapeutic strategy, its clinical translation faces significant hurdles.
    SCOPE OF REVIEW: This review systematically summarizes the pathological roles and molecular mechanisms of lipid metabolism dysregulation across six representative CNS disorders: Alzheimer's disease (AD), Parkinson's disease (PD), spinal cord injury (SCI), traumatic brain injury (TBI), stroke, and intracerebral hemorrhage (ICH). These conditions were selected to cover a spectrum of pathologies, including protein-aggregation neurodegeneration, posttraumatic secondary injury, and cerebrovascular damage. The article outlines recent advances in therapeutic interventions targeting lipid metabolism and dissects both the shared and disease-specific regulatory mechanisms within the CNS.
    KEY CHALLENGES: Despite the therapeutic potential, several challenges impede the development of effective lipid-targeting treatments. These include the incompletely defined mechanisms underlying dynamic lipid changes across different disease stages, insufficient efficiency of drug delivery across the blood-brain barrier, and the limited efficacy of single-target interventions. This review addresses these existing hurdles and proposes potential solutions to overcome them.
    CONCLUSION: Targeting lipid metabolism represents a promising frontier for treating CNS diseases. By providing a comprehensive reference on the metabolic underpinnings of these disorders and addressing current research bottlenecks, this review aims to lay the groundwork for the development of precise, targeted therapeutic strategies in future clinical applications.
    Keywords:  lipid metabolism; neurodegeneration; therapeutic advances; traumatic CNS injuries
    DOI:  https://doi.org/10.1002/cns.71109
  59. Biomolecules. 2026 Aug 19. pii: 1208. [Epub ahead of print]16(8):
    The Prospective Regulatory Functions of lncRNAs and Their ceRNA Networks in the Development of Motor Neurons and Associated Diseases.
    Zhenzhen Wang, Yuhan Fu, Siqi Li, Yan Zhang, Tao Sun, Nan Miao.
      Motor neurons form a highly specialized network composed of α-, β-, and γ-subtypes that coordinate skeletal muscle activity. Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are characterized by the progressive degeneration of this network, resulting in motor dysfunction. Emerging evidence underscores the significant roles of long non-coding RNAs (lncRNAs) in motor neuron development and disease. However, only a few have been experimentally confirmed as true ceRNA regulators, highlighting the need to differentiate validated mechanisms from mere associations or predictions. This review summarizes the regulatory roles of lncRNA-associated ceRNA networks in motor neuron development, evaluates the evidence for their involvement in MNDs, and explores their potential impact on disease progression. It also addresses current challenges, knowledge gaps, and future research directions for understanding ceRNA-mediated mechanisms and developing therapeutic strategies for MNDs.
    Keywords:  ALS; MND; MS; SMA; ceRNA network; lncRNA
    DOI:  https://doi.org/10.3390/biom16081208
  60. J Parkinsons Dis. 2026 Aug 26. 1877718X261481663
    Low vs high frequency deep brain stimulation for Parkinson's disease-associated motor symptoms: A systematic review and meta-analysis of randomized control trials.
    Bilal Salman, Lea Aridi, Vivian Faour, Wissam Abou Ali, Bilal Al Halabi, Rima Haidar, Jihane Soueid, Feten Fekih-Romdhane, Souheil Hallit, Sami Azar, Frederic Harb.
      PurposeDeep brain stimulation (DBS) is an established treatment for motor symptoms in Parkinson's Disease (PD), but the optimal stimulation frequency remains uncertain. Previous studies have suggested that low and high frequency DBS may produce different clinical effects. This study aimed to compare the effects of low versus high frequency DBS on motor outcomes in PD.MethodsA systematic review and meta-analysis of randomized controlled trials was conducted. PubMed, Ovid, CINAHL, Clinicaltrials.gov and the Cochrane Library were searched from 2010 to November 26, 2025. Studies comparing low and high frequency DBS in patients with PD were included. Motor outcomes were pooled using a random-effects model, and subgroup analyses were performed based on age and disease duration.ResultsA total of 15 randomized controlled trials involving 416 participants were included. Overall, no significant difference in motor outcomes was observed between low and high frequency DBS. Subgroup analysis based on age showed no significant effect modification. However, subgroup analysis suggested greater improvement with high frequency DBS in patients with shorter disease duration, whereas no significant difference was observed in those with longer disease duration. Sensitivity analyses demonstrated that these findings were robust. Additionally, tremor improvement favored the use of HFDBS.ConclusionHigh and low frequency DBS appear to provide comparable overall motor benefit in PD. Stimulation frequency may have differential effects depending on disease duration, although these findings should be interpreted cautiously. Further prospective trials are needed to determine optimal programming strategies across disease stages.RegistrationThis study was registered on PROSPERO (CRD420251238009).
    Keywords:  Parkinson's disease; UPDRS-III; deep brain stimulation; meta-analysis; randomized controlled trials; stimulation frequency
    DOI:  https://doi.org/10.1177/1877718X261481663
  61. J Neurovirol. 2026 Aug 26. pii: 35. [Epub ahead of print]32(5):
    SARS-CoV-2 disrupts the integrity of a human blood-brain barrier model in the absence of infection.
    Habib Jmii, Ruth Haverty, Keith D Rochfort, Nicola F Fletcher.
      Neurological symptoms are recognized in patients with COVID-19, and include anosmia, ageusia, cognitive impairments as well as more severe complications including encephalitis and ischemic strokes. Furthermore, persistent cognitive impairment including 'brain fog' is recognised as part of the long COVID syndrome. While SARS-CoV-2 has been shown to infect cells of the central nervous system (CNS) in vitro and in vivo, it is unclear whether direct infection of the CNS or indirect mechanisms including activation of the coagulation cascade or immune activation are the key drivers of COVID-19 neuropathology. We investigated whether inactivated SARS-CoV-2, or spike protein, can disrupt the integrity of the blood-brain barrier (BBB) and characterised neuroinflammation in the absence of infection. Using an in vitro model of the BBB composed of primary human microvascular endothelial cells, astrocytes, pericytes and microglia, we observed BBB disruption following exposure of the model to SARS-CoV-2 or spike protein. Importantly, loss of BBB integrity was observed in response to luminal (mimicking 'blood side') or abluminal ('brain side') exposure to inactivated virus or spike protein. Transcriptional upregulation of a range of chemokines, inflammatory cytokines and adhesion factors, and release of inflammatory cytokines from BBB models was also observed in response to luminal or abluminal SARS-CoV-2 or spike protein exposure. These data indicate that BBB disruption and immune activation in vitro occurs in response to SARS-CoV-2 in the absence of infection, highlighting the importance of the host immune system in BBB disruption during SARS-CoV-2 infection.
    Keywords:  Immunopathology; Microvascular endothelium; Neuroinflammation; Neuropathology; Neurovascular unit
    DOI:  https://doi.org/10.1007/s13365-026-01337-3
  62. Brain. 2026 Aug 28. pii: awag293. [Epub ahead of print]
    Diagnosing multiple sclerosis: implementation and unintended effects of the 2024 McDonald criteria.
    Michael A Foster, Charles Wade, Helen L Ford, Klaus Schmierer.
      Diagnostic criteria for multiple sclerosis have evolved substantially since the Schumacher criteria were published in 1965. The most recent iteration, the 2024 McDonald diagnostic criteria, was recently released. Each revision has broadened the range of evidence that can support diagnosis while attempting to preserve specificity. The central question raised by the 2024 revision is therefore not simply whether the criteria are valid in principle, but whether they can be applied safely outside expert centres, where imaging quality, laboratory infrastructure and subspecialist interpretation vary substantially. In this review, we evaluate the 2024 criteria not only as a consensus document but as an intervention in clinical behaviour, with particular attention to misdiagnosis risk, operational feasibility and equity of implementation. In particular, we consider the role of the optic nerve and of the central vein sign and paramagnetic rim lesions in diagnosis, and how the criteria bring more diverse populations and presentations into consideration. We also review how the greater options available to achieve a diagnosis may introduce heterogeneity into diagnostic approaches, and what safeguards can be taken to minimise the risk of inappropriate application of the criteria and subsequent misdiagnosis (and inappropriate treatment). The review finishes by proposing how the changes introduced in this iteration might be refined, with more robust definitions on acquiring and interpreting the novel biomarkers.
    Keywords:  diagnostic criteria; multiple sclerosis
    DOI:  https://doi.org/10.1093/brain/awag293
  63. Brain Commun. 2026 ;8(4): fcag310
    Sex-dependent dopaminergic vulnerability may contribute to sex differences in Parkinson's disease risk.
    Tamir Eisenstein, Frederik J Lange, Michele T M Hu, Johannes C Klein.
      Men are more likely than women to develop Parkinson's disease, yet the biological basis of this sex difference in Parkinson's disease risk remains unresolved. The nigrosome-1 (NG-1), a dopaminergic subregion of the substantia nigra, is selectively vulnerable to degeneration and iron accumulation in Parkinson's disease, therefore representing a plausible locus for sex-linked vulnerability. Using iron-sensitive magnetic resonance imaging from the UK Biobank, we examined sex differences in NG-1 magnetic susceptibility across adulthood. We analysed cross-sectional data from 53 792 individuals aged 45-85 years and longitudinal follow-up in 4068 participants. Across mid-to-late adulthood, men consistently exhibited higher NG-1 magnetic susceptibility than women, suggestive of greater iron-related signal burden. In contrast, age-related trajectories and rates of within-person change were similar between sexes, with no evidence for accelerated nigrostriatal ageing in men. Sensitivity analyses showed that these sex differences were not substantially modified by genetic risk for Parkinson's disease, cardiometabolic disease or major lifestyle factors. Together, these findings suggest that sex differences in NG-1 susceptibility are expressed primarily as a stable baseline offset rather than divergent ageing dynamics. By distinguishing baseline variation from age-related changes in a selectively vulnerable dopaminergic system, this study provides population-scale evidence relevant to understanding sex differences in vulnerability to Parkinson's disease.
    Keywords:  Parkinson's disease; ageing; nigrosome-1; quantitative susceptibility imaging; substantia nigra
    DOI:  https://doi.org/10.1093/braincomms/fcag310
  64. Biomolecules. 2026 Jul 27. pii: 1098. [Epub ahead of print]16(8):
    Epilepsy-Linked Gut Microbiota and Metabolic Signatures in Acquired Epilepsy: The Focus on Short-Chain Fatty Acid and Tryptophan Metabolism.
    Teresa Ravizza, Rossella Di Sapia, Akash Bera, Claudia Fracasso, Jacopo Lucchetti, Marco Gobbi, Annamaria Vezzani.
      Epilepsy is increasingly recognized as a systemic disorder involving complex interactions between the brain and peripheral systems. Among these, the gut microbiota has emerged as a key regulator of host metabolism and immune homeostasis through the production of bioactive metabolites that mediate the communication between gut and brain. In recent years, growing evidence has linked gut dysbiosis to epilepsy, particularly in drug-resistant forms, and interventional studies targeting the gut microbiota in animal models suggest that microbiota-driven metabolic alterations may contribute to seizure generation and recurrence, as well as the associated neuropathology and cognitive deficits. In this review, we summarize current knowledge on the role of the gut microbiota-metabolome axis in acquired epilepsy, with a particular focus on short-chain fatty acids (SCFAs) and tryptophan-derived pathways. SCFAs represent major microbial products involved in energy metabolism, inflammation, blood-brain barrier integrity, neurotransmission and epigenetic mechanisms. In parallel, microbiota-dependent tryptophan metabolism represents a central hub linking intestinal microbial activity to brain function through serotonin, kynurenine, and indole pathways. Dysregulation of these pathways may influence neuronal excitability and contribute to seizures. Converging evidence supports the concept that epilepsy is associated with a coordinated alteration of gut microbial composition and host-microbiota metabolic interactions. However, further research is needed to elucidate the mutual communication between the gut and its microbiota and the metabolic flux, and their influence on brain function in neurological conditions. A better understanding of the underlying pathways and mechanisms may highlight novel therapeutic strategies and discover novel biomarkers of disease trajectory.
    Keywords:  drug-resistance; gut dysbiosis; kynurenines; short-chain fatty acids
    DOI:  https://doi.org/10.3390/biom16081098
  65. Curr Neuropharmacol. 2026 Aug 11.
    Metformin in Neurodegenerative Diseases: Mechanisms and Therapeutic Implications.
    Aveline P Langmead, Breauna A Keane, Jive A Jacob, Kota V Ramana.
      As the global burden of neurodegenerative disorders continues to rise with aging populations, there is growing interest in identifying widely available drugs that can be repurposed to target shared metabolic and inflammatory mechanisms underlying these conditions. Increasing evidence suggests that metabolic dysfunction, mitochondrial impairment, and chronic neuroinflammation play central roles in the pathogenesis of neurodegeneration, demonstrating the need for therapeutics that can modulate these interconnected pathways. Metformin has served as the gold standard for the management of type 2 diabetes for 7 decades. It offers a superior safety profile, established metabolic advantages, and affordability. Recent studies suggest that, in addition to its antihyperglycemic actions, it could also be repurposed to treat several inflammatory complications and infectious diseases. Further, recent preclinical and clinical studies suggest that, by regulating AMPK, mTOR, and mitochondrial function, metformin could also control the initiation and progression of neurodegenerative diseases. Several studies also indicate that metformin suppresses neuroinflammation by inhibiting the NF-κB signaling pathway and the NLRP3 inflammasome, thereby improving insulin signaling and metabolic homeostasis. This review integrates metabolic, inflammatory, and mitochondrial mechanisms to present a unified mechanistic framework to explain how metformin may modulate the onset and progression of neurodegeneration. Specifically, we discuss recent studies showing the therapeutic significance of metformin in Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Moreover, this review highlights metformin as a potential therapeutic candidate for future development in neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Metformin; Parkinson’s disease; diabetes; huntington’s disease; neurodegenerative disorders.
    DOI:  https://doi.org/10.2174/011570159X476604260704180015
  66. Cureus. 2026 Jul;18(7): e113424
    Bypassing the Blood-Brain Barrier: A Dual-Axis Framework for Alzheimer's Disease Utilizing Glymphatic-Lymphatic Clearance and In Situ Chaperone Synthesis.
    Huan-Wei Chen.
      Alzheimer's disease (AD) poses a dual proteotoxic challenge: extracellular amyloid-beta plaque accumulation and intracellular hyperphosphorylated tau aggregation. Conventional systemic therapies struggle to clear macromolecular waste from the brain parenchyma or to cross the blood-brain barrier (BBB) and intercept intracellular misfolding. This framework proposes active craniospinal tensioning (ACT), a single non-invasive maneuver combining dural pull-recoil with targeted suboccipital venous occlusion-rebound, hypothesized to produce two coupled therapeutic effects: macroscopic craniospinal waste clearance and localized intra-axial cytoprotection, the latter termed cerebral venous preconditioning (CVPC). Regarding the proposed macro-fluidic axis (glymphatic-lymphatic clearance), we propose that suboccipital venous occlusion transiently congests the dural sinuses and that the abrupt release of this occlusion produces a rapid antegrade venous outflow surge. Because glymphatic efflux travels through the perivenous space immediately adjacent to these vessels, we hypothesize that this hemodynamic rebound exerts a convective drag on the perivenous fluid compartment, accelerating clearance of amyloid-beta and tau complexes suspended there by the coupled dural pull-recoil mechanism. This accelerated perivenous efflux is proposed to feed the brain's established downstream clearance routes, namely, drainage into the dural venous sinuses via arachnoid granulations and into meningeal lymphatics via deep cervical lymph nodes, thereby bypassing the restriction imposed by the BBB on direct interstitial waste clearance. This fluid-dynamic mechanism is theoretical and has not yet been directly measured. Regarding the proposed micro-biochemical axis (CVPC, in situ chaperone synthesis), CVPC is conceptually modeled after ischemic preconditioning, with remote ischemic preconditioning (RIPC) as the most extensively studied form. Among RIPC's reported downstream effects, circulating heat shock protein (HSP) elevation is one well-characterized humoral mediator; however, these ~70 kDa chaperones are generally excluded from BBB crossing given the barrier's approximate small-molecule passive permeability limit of ~0.4 kDa, which constrains RIPC's central nervous system (CNS) effects largely to indirect humoral and neural signaling. We hypothesize that the same occlusion-rebound cycle instead acts locally: retrograde venous wall distension and transient mild hypoxia during occlusion at the craniospinal microvasculature, followed by shear stress during the rebound surge, may activate heat shock factor 1 (HSF-1), driving in situ synthesis of HSP 70 (HSP70) within endothelial cells, astrocytes, and neurons. We further propose that locally synthesized HSP70 could bind and stabilize early tau intermediates, limiting hyperphosphorylation and aggregation, a mechanism grounded in established HSP-tau chaperone biology but not yet demonstrated for this specific maneuver. If validated, ACT would offer a single, non-invasive strategy that combines macro-mechanical extracellular clearance with micro-biochemical intracellular cytoprotection, potentially altering the AD trajectory without the systemic liabilities associated with elevated circulating HSP levels and without dependence on BBB-crossing agents. These proposed mechanisms require preclinical and clinical validation before any therapeutic claims can be made.
    Keywords:  active craniospinal tensioning (act); alzheimer's disease; amyloid-beta pathology; blood-brain barrier (bbb); cerebral venous preconditioning (cvpc); glymphatic system; heat shock factor 1 (hsf-1); heat shock protein 70 (hsp70); tau pathology; trigeminocardiac reflex (tcr)
    DOI:  https://doi.org/10.7759/cureus.113424
  67. J Neuromuscul Dis. 2026 Aug 25. 22143602261477464
    Biallelic SIGMAR1 variants in early-onset distal hereditary motor neuropathy: A Japanese case series.
    Kento Kodama, Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Makoto Samukawa, Motomasa Suzuki, Shunsuke Ogaya, Yuka Kawata, Naoki Gamo, Shin Hisahara, Chikashi Yano, Risa Nagatomo, Takahiro Hobara, Fumikazu Kojima, Yu Hiramatsu, Satoshi Nozuma, Yusuke Sakiyama, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima.
      BackgroundDistal hereditary motor neuropathy (dHMN) is characterized by slowly progressive distal muscle weakness and amyotrophy, and it exhibits clinical overlap with Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis (ALS). Biallelic variants in SIGMAR1, encoding sigma nonopioid intracellular receptor 1, have been linked to autosomal recessive dHMN with pyramidal features. This study investigated the clinical and genetic features of patients with dHMN associated with SIGMAR1 variants in Japan.MethodsWe conducted genetic screening of Japanese patients with clinically suspected inherited peripheral neuropathies using targeted gene panels and whole-exome sequencing. SIGMAR1 variants were evaluated via segregation analysis using Sanger sequencing. Detailed clinical and electrophysiological data were systematically reviewed.ResultsBiallelic SIGMAR1 variants, including three novel variants and one previously reported variant, were identified in six patients from five unrelated families. The genotypes comprised compound heterozygous variants in four patients and homozygous variants in two patients. All patients presented with early-onset distal muscle weakness and atrophy. Enhanced tendon reflexes and pyramidal tract signs were frequently observed, whereas bulbar or respiratory involvement was absent. Nerve conduction studies consistently revealed motor-predominant axonal neuropathy with minimal sensory involvement. Disease progression was slow, and all patients remained ambulatory for years to decades after onset.ConclusionOur findings expand the clinical and genetic spectrum of SIGMAR1-associated disease and support its classification as dHMN rather than ALS. SIGMAR1 variants should be considered in the genetic evaluation of early-onset motor neuropathies, particularly in patients with dHMN accompanied by pyramidal features.
    Keywords:  CMT; IPN; SIGMAR1; dHMN; pyramidal tract
    DOI:  https://doi.org/10.1177/22143602261477464
  68. Nat Chem Biol. 2026 Aug 26.
    CA-IV-directed small-molecule shuttle enables targeted brain delivery of biologics.
    Xiaozhe Ding, Xinhong Chen, Philip Boehm, Alba Carretero-Cerdán, Seongmin Jang, Erin E Sullivan, Cynthia M Arokiaraj, Fiona Ristic, Bill C Kavvathas, Lillian J Campos, Jitendra Sharma, Shawn Kamboj, Yaping Lei, Mona Shahgholi, Danielle Mantin, Andrew S Fox, Timothy F Shay, Sarah E Reisman, Viviana Gradinaru.
      The blood-brain barrier (BBB) presents a challenge for central nervous system (CNS) therapies. Receptor-mediated transcytosis offers a solution, but existing receptor targets are ubiquitous across CNS and peripheral tissues, causing unintended exposure. We identified carbonic anhydrase IV (CA-IV) as a brain-enriched receptor enabling engineered viral capsids to cross the BBB. However, it is unclear whether CA-IV can also mediate non-viral delivery. We thus designed a reactive small-molecule shuttle, derived from an FDA-approved binder, that couples to proteins and oligonucleotides in a single step. We validated the binding of conjugated molecules to multiple mammalian CA-IV orthologs and subsequent internalization in cell-based assays. After systemic dosing, CA-IV-targeted antibody conjugates crossed the BBB in mice and neonatal macaques, preferentially accumulating in the brain and sustaining parenchymal levels for at least 7 days. This BrainCAB (Brain access through Carbonic Anhydrase-binder Bioconjugation) technology offers a compact, modular shuttle for selective and prolonged CNS delivery of large molecules.
    DOI:  https://doi.org/10.1038/s41589-026-02294-y
  69. Health Sci Rep. 2026 Sep;9(9): e73086
    Diagnostic Accuracy of Artificial Intelligence Models for Detecting Odontogenic Keratocytes on CBCT Imaging: A Systematic Review and Meta-Analysis.
    Reyhaneh Shoorgashti, Simin Lesan, Sarah Sadat Ehsani, Asma Yazdanfar.
       Background and Aims: Differentiating odontogenic keratocyst (OKC) from other radiolucent jaw lesions like ameloblastoma is clinically important but radiographically difficult. Recent advances in artificial intelligence (AI) show promise for enhancing diagnosis using cone-beam computed tomography (CBCT). This study aims to systematically evaluate and meta-analyze the diagnostic accuracy of AI models in detecting OKCs on CBCT imaging.
    Methods: A systematic review and meta-analysis was conducted according to PRISMA-DTA guidelines. Five electronic databases were searched through July 6, 2025. Studies employing AI models for OKC detection using CBCT were included. Methodological quality was assessed using QUADAS-2. Pooled estimates were computed using a random-effects model, with heterogeneity evaluated via I2 and meta-regression. The Eager test and funnel plot were employed to assess publication bias.
    Results: Twelve studies were included. AI models demonstrated high diagnostic accuracy, characterized by a pooled sensitivity of 89% (95% CI: 79%-95%) and specificity of 92% (95% CI: 81%-97%), both exceeding 85%, along with a substantial diagnostic odds ratio (87.06) and a robust discriminative ability (AUC = 0.828). Deep learning (DL) models achieved higher sensitivity (91%) than machine learning (ML) models (86%), while ML models showed slightly higher specificity. Heterogeneity was substantial (I2 = 78%-93%). Publication year explained 57.2% of the variability in sensitivity.
    Conclusions: AI-based models, particularly CNN-based DL architectures, demonstrate clinically relevant diagnostic performance with high sensitivity, specificity, and diagnostic odds ratios, supporting their potential role as adjunctive tools in CBCT-based differentiation of OKCs from other odontogenic lesions.
    Keywords:  artificial intelligence; cone‐beam computed tomography; deep learning; diagnostic accuracy; machine learning; meta‐analysis; odontogenic keratocyst; systematic review
    DOI:  https://doi.org/10.1002/hsr2.73086
  70. Curr Neurovasc Res. 2026 Aug 01.
    Current Targeted Nanoparticle Therapy for Alzheimer's Disease: Current Advances and Future Prospects.
    Ravindra Mishra, Nidhi Chauhan, Krishn Kumar Agrawal.
       BACKGROUND: The effects of Alzheimer's disease (AD) on society are profound. The blood-brain barrier selectively permits the penetration of specific forms of molecules through the blood circulation into the CNS, which can restrict the effectiveness of medications supplied systemically. The therapeutic targets are located in the CNS. However, local administration channels to the CNS are rather intrusive, which can lead to patient discomfort and limit the feasibility of repeated treatments.
    METHODOLOGY: This article has evaluated treatment methodologies for AD that use nanoparticles to target the brain and the pathological features of the illness. The material that is currently available has been categorized based on the aspect of AD that is discussed: targeted medication and neurodegeneration.
    RESULT: The use of nanoparticles in the targeted delivery of medications intended to alleviate the symptoms of AD or halt the disease's progression has yielded positive results. Because of their multivalence, nanoparticles can target the treatment site, pass through the blood-brain barrier, and be functionalized with various targeting groups. Intravenous administration, rather than more intrusive techniques, has enhanced drug bioavailability in the CNS. Furthermore, the development of vaccinations and medication formulations for intranasal delivery has utilized nanoparticles.
    DISCUSSION: This study focused on the advancement of AD treatment. Nanoparticles are designed to enhance drug bioavailability through intravenous and intranasal routes for quicker brain access with fewer side effects. Nanoparticles also aid in targeting disease features like amyloid- beta plaques and tau tangles. While results in animal models are positive, transitioning to human clinical trials requires a more profound understanding of AD mechanisms and biomarker identification.
    CONCLUSION: Research employing animal models suggests that targeted nanoparticles can enhance the effectiveness of AD treatments. A deeper understanding of AD mechanisms will lead to more successful targeted nanoparticle applications.
    Keywords:  Alzheimer's disease (AD); Blood-brain barrier; CNS; nanoparticles; neurodegenerative; targeted medicine
    DOI:  https://doi.org/10.2174/0115672026471444260724103751
  71. Mater Today Bio. 2026 Oct;40 103569
    From neuroinflammation to immune reprogramming: Nanozyme-Integrated nanoplatforms for neuroimmune modulation in Parkinson's disease.
    Shu Zhu, Zhongting Wang, Xiaoxi Shi, Shanshan Zhong, Ghulam Md Ashraf, Kailei Fu, Yugang Li.
      Parkinson's disease (PD) is a progressive neuroimmune disorder in which dysregulated neuron-glia-immune crosstalk drives chronic neuroinflammation, α-synuclein pathology, blood-brain barrier dysfunction, and mitochondrial failure, establishing interconnected neuroimmune pathways as therapeutic targets. Aberrant neuron-immune crosstalk promotes chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, blood-brain barrier (BBB) disruption, and α-synuclein pathology, thereby accelerating neurodegeneration. Understanding these interconnected mechanisms has identified multiple neuroimmune pathways as promising therapeutic targets. This review summarizes the cellular and molecular basis of physiological and pathological neuron-immune communication in PD, highlighting the roles of microglial activation, astrocyte reactivity, adaptive immune responses, inflammatory signaling networks, and neurovascular dysfunction. We further discuss emerging neuroimmune-targeted interventions aimed at restoring immune homeostasis and slowing disease progression. Particular emphasis is placed on nanozyme-integrated nanoplatforms that function simultaneously as nanozymatic catalysts and immunomodulatory adjuvants, including enzyme-mimetic nanozymes (SOD/CAT/GPx-like), single-atom catalysts, and nanozyme-integrated nanoplatforms. These platforms not only scavenge reactive oxygen species, degrade α-synuclein aggregates, and reinforce BBB integrity through localized catalytic reactions, but also reprogram innate and adaptive immune responses by modulating microglial polarization toward neuroprotective phenotypes, suppressing pro-inflammatory cytokine cascades (TNF-α, IL-1β, IL-6), and supporting regulatory T cell (Treg) responses. We examine how these nanozyme-integrated nanoplatforms can be combined with lipid-based nanoparticles, polymeric carriers, biomimetic systems, and extracellular vesicles (EVs) to achieve synergistic targeted drug delivery, gene modulation, neuroprotection, and neural repair. Finally, we address the translational challenges and prospects for merging neuroimmunology, nanocatalysis, and adjuvant engineering in PD therapy.
    Keywords:  Astrocytes; Disease modification; Microglia; Nanomedicine; Neural repair; Neuroinflammation; Neuron-immune crosstalk; Neuroprotection; Parkinson's disease; α-Synuclein
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103569
  72. Sci Adv. 2026 Aug 28. 12(35): eaee4940
    Neuron-derived SPP1 instructs microglia to limit degeneration.
    Song Li, Tatjana C Jakobs.
      Neurons actively shape immune responses that maintain central nervous system integrity. We identify SPP1 (secreted phosphoprotein 1) as a neuron-derived signal that reprograms microglia into a neuroprotective, homeostatic state after injury and during neurodegeneration. In mouse models of glaucoma and optic nerve damage, neuronal SPP1 enhances microglial autophagy, debris clearance, and anti-inflammatory activity, preserving neuronal survival and visual function. SPP1 is elevated in neurons of human and primate glaucomatous retinas, where SPP1+ cells show increased resilience. In Alzheimer's disease brain, neuronal SPP1 correlates with neuronal survival, while microglia around Aβ plaques display defective autophagy. In human iPSC co-cultures, SPP1 enhances microglial Aβ clearance and prevents neurodegeneration. Thus, SPP1 defines a protective neuron-microglia axis in glaucoma and possibly other neurodegenerative diseases.
    DOI:  https://doi.org/10.1126/sciadv.aee4940
  73. Front Pharmacol. 2026 ;17 1861778
    Microphysiological modeling of the Blood-CSF barrier for biopharmaceutical transport and sequestration: evaluation of PEG-induced accumulation and vacuolation in the choroid plexus epithelium.
    Jacquelyn Ann Brown, Monika G Judge, David K Schaffer, Dillon C Gavlock, Armando Irizarry Rovira, Steven K Engle, Thomas K Baker, John P Wikswo.
       Background: It has long been established that the central nervous system (CNS) is a highly privileged space, with the blood-brain barrier (BBB) acting as the gatekeeper that allows or denies access to the brain by nutrients, drugs, and toxins. The BBB, however, is not the only barrier at play. The barrier between blood and cerebrospinal fluid (CSF) also has a critical role in guarding and feeding the CNS, but despite its importance, the blood-CSF barrier (BCSFB) remains relatively unexplored compared to the BBB, particularly with regard to models that do not rely on animals.
    Methods: Given the lack of physiologically relevant in vitro models and the divergence between humans and animal models, we created an organ-on-chip/microphysiological system to model the human BCSFB (hBCSFB) that can act as a new approach methodology (NAM) platform for interrogating physiological functions, evaluating drug delivery technologies and xenobiotic transport, and assessing the safety, efficacy, and mechanism of action of biopharmaceuticals.
    Results: By leveraging advanced microfluidic organ chip design and gravity perfusion, we have generated a hBCSFB organ chip that recapitulates many of the physiologically relevant characteristics of this barrier, including junctional protein expression, permeability less than 1.55e-5 cm/s, transcytosis that showed dose-dependent accumulation of 10%-35%, and selective transport that was both statistically significant (p ≤ 0.05) and reproducible.
    Conclusion: Having achieved these benchmarks and validated their reproducibility, this work provides a useful in vitro system optimized for the qualitative and quantitative study of pharmacological and toxicological interactions involving the hBCSFB.
    Keywords:  blood-CSF barrier; blood-brain barrier (BBB); central nervous system (CNS); microphysiological system (MPS); polyethylene glycols (PEG)
    DOI:  https://doi.org/10.3389/fphar.2026.1861778
  74. Pharmaceuticals (Basel). 2026 Aug 20. pii: 1311. [Epub ahead of print]19(8):
    Pathogenesis-Driven Drug Repurposing with a Self-Nanoemulsifying Delivery System for Parkinson's Disease.
    Kunal Verma, Jaskiran Kaur, Mohit Kumar, Ankit Awasthi, Dinesh Kumar, Neeraj Choudhary, Emad M Abdallah.
      Background/Objectives: The aim of the present study was to investigate the mechanisms in Parkinson's disease (PD), a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, aggregation of α-synuclein, mitochondrial dysfunction, oxidative stress, neuroinflammation, gut dysbiosis, and blood-brain barrier (BBB) impairment. Although there are several approved therapies that have been developed, their aqueous solubility, oral bioavailability, first-pass metabolism, and inability to penetrate the BBB make them less effective over time. This review is intended to critically analyze the potential of self-nanoemulsifying drug delivery systems (SNEDDSs) as a pathogenesis-related approach to enhance the delivery and therapeutic activity of repurposed drugs and conventional drugs for PD. Methods: A comprehensive literature search was conducted to address the pathogenic mechanisms of PD, the deficiencies of current pharmacotherapy, recent developments in SNEDDS formulation strategies and their application in improving oral bioavailability, lymphatic transport, BBB penetration and targeted brain delivery. A special focus was dedicated to drug repurposing, functionalized SNEDDSs, PEGylation, and gut-brain axis modulation. Results: SNEDDSs significantly enhance the water solubility, stability, intestinal absorption and systemic exposure of poorly water-soluble therapeutic agents and, to a certain extent, lymphatic uptake to avoid first-pass metabolism. These systems include improved brain delivery, decreased pharmacokinetic variability, and prolonged drug levels within the therapeutic range. Moreover, SNEDDSs can be used to deliver multiple molecules that are found to be neuroprotective, antioxidant, anti-inflammatory and probiotic, all at once, which can act on multiple pathogenic mechanisms associated with PD. Functionalized and PEGylated SNEDDSs add further to formulation stability, extend systemic circulation and increase efficiency of brain targeting. Conclusions: SNEDDSs are a promising translational nanomedicine platform for enhancing the effectiveness of conventional and repurposed therapeutics in PD, which address key pharmacokinetic and biological challenges. The next generation of oral therapies with targeted surface engineering, precision drug repurposing and clinical validation will be expected to bring about a faster advancement of drugs that can alter the course of disease rather than giving only symptomatic relief.
    Keywords:  FDA-approved drug; Parkinson’s disease; blood–brain barrier; drug delivery; microbiota; neurodegenerative disorder
    DOI:  https://doi.org/10.3390/ph19081311
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