bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–10–04
forty-four papers selected by
Luca Bolliger, lxBio
  1. Potential Roles of Neuroimaging in Motor Neuron Disease.
  2. Proteostasis (in)action: the role of co-pathologies in neurodegenerative disease.
  3. Development of Antisense Oligonucleotide Gapmers for Amyotrophic Lateral Sclerosis.
  4. LRSAM1, an E3 ubiquitin ligase, modulates TDP-43 proteostasis in amyotrophic lateral sclerosis.
  5. AI-driven transcriptomics for neurodegenerative disease research: A systematic review.
  6. Insertion or deletion variants in TAF15 exon 15 are genetic factors impacting the prognosis of amyotrophic lateral sclerosis in a Japanese cohort.
  7. A genetic screen for suppressors of neuron degeneration in a C. elegans sod-1G85R model of Amyotrophic Lateral Sclerosis.
  8. Mdivi-1 regulates mitochondrial fission and function via the CaMK2/Drp1 pathway in amyotrophic lateral sclerosis.
  9. ALS-associated exitron splicing produces UBQLN2 isoforms with distinct properties.
  10. Predictive Value of the Modified Controlling Nutritional Status Score for Critical Events in Patients with Amyotrophic Lateral Sclerosis.
  11. Lipid-based Nanocarriers for Neurodegenerative Disorders: Bridging Blood-brain Barrier Biology and Translational Drug Delivery.
  12. The Versatile Roles of Exosomes in Neurodegenerative Disorders: From Pathological Mechanism and Diagnostic Biomarkers to Therapeutic Application.
  13. Polyamines across neurodegenerative proteinopathies.
  14. Motor dysfunction phenotypes in a drosophila model validate DAO as an ALS gene.
  15. Spinal cord imaging in multiple sclerosis: from diagnosis to disease progression.
  16. Associations Between Prediagnosis Plasma Neurofilament Light Polypeptide and Amyotrophic Lateral Sclerosis Risk in the Danish EPIC Cohort.
  17. Focused ultrasound blood-brain barrier opening: a review of post-procedure MRI outcomes.
  18. REM-associated nocturnal hypercapnia in amyotrophic lateral sclerosis.
  19. Amyotrophic Lateral Sclerosis.
  20. Acidic cannabinoids in brain disorders: Neurobiological mechanisms, preclinical evidence, and translational challenges.
  21. Symptomatic Rescue or Disease Modification? A Critical Review of Levodopa and Phytochemical Interventions in Caenorhabditis elegans Models of Parkinson's Disease.
  22. Permeability of the intestinal epithelial and blood-brain barriers as therapeutic targets in inflammatory depression.
  23. Bioinspired Nanomaterials for Parkinson's Disease: Engineering Membrane Interfaces to Overcome the Blood-Brain Barrier and Enable Neuron-Targeted Delivery.
  24. Explanatory limitations of CSF, plasma, and MRI biomarkers for inflammation and blood-brain barrier disruption in dementia.
  25. Neuroepigenetics of the Environmental Exposome: Molecular and Clinical Implications in Neurodegeneration.
  26. Lysosomal dysfunction in neurodegenerative disease.
  27. Acute viral infection accelerates neurodegeneration in a mouse model of ALS.
  28. Clonal CD8 T cells link peripheral and intrathecal immunity in ALS4 progression: a multiomics reference for ALS.
  29. Progressive motor impairment from intracerebral critical demyelinating lesions.
  30. Oleandrin and PBI-05204 for Neuroprotection in Alzheimer's Disease, Parkinson's Disease, and Stroke: Preclinical Mechanisms, Blood-brain Barrier Penetration, and Clinical Translation Perspectives.
  31. AZP2006 in Parkinson's disease models: A promising new neuroprotective treatment involving lysosomal homeostasis and the Progranulin/Prosaposin complex.
  32. Mapping the Intelligence: A Bibliometric Analysis of Artificial Intelligence and Machine Learning Applications in Retinal OCT for Neurodegenerative Diseases.
  33. Hybrid multimodal late fusion frameworks for bvFTD classification in imbalanced dementia datasets.
  34. The swallow tail sign: mechanisms, neuroimaging advances and future perspectives.
  35. Neuroinflammation and metabolic reprogramming in Parkinson's disease.
  36. Should MRI Replace Ultrasound as the Primary Imaging Modality in Pediatric Females With Suspected Appendicitis?
  37. Peripheral IL-17 Triggers, and anti-IL-17 Treatment Prevents, Neuroinflammation and Alterations in Neurotransmission in Hippocampus and Cognitive Impairment in Hyperammonemic Rats.
  38. Magnetic Resonance Imaging in Cerebral Small Vessel Disease-Related Depression: From Visual Scoring to Artificial Intelligence.
  39. Genetic architecture and molecular pathogenesis of Parkinson's disease: emerging mechanisms and therapeutic targets.
  40. Gut microbiota-neuroimmune crosstalk in autoimmune encephalitis: mechanistic insights and therapeutic prospects.
  41. The accessory makes the drug: ASO-delivered siRNA enters the human CNS for ALS.
  42. Development and Clinical Applications of Antisense Oligonucleotide Gapmers.
  43. Disentangling Age-Related and Disease-Specific Effects on Upper Cervical Cord Area in Patients With Multiple Sclerosis.
  44. CCL2 and CXCL2 are markers of delirium vulnerability in community dwelling older people.
  1. Curr Neurol Neurosci Rep. 2026 Sep 26. pii: 53. [Epub ahead of print]26(1):
    Potential Roles of Neuroimaging in Motor Neuron Disease.
    Jan Kassubek, Hans-Peter Müller.
       PURPOSE OF REVIEW: The review is intended to summarize and discuss the increasing roles and perspectives of neuroimaging in the clinical and scientific work-up of amyotrophic lateral sclerosis (ALS) and other motor neuron diseases (MND).
    RECENT FINDINGS: The applications of magnetic resonance imaging (MRI) and positron emission tomography (PET) identify characteristic disease-specific patterns especially for ALS including its clinical subtypes. Guided by neuroanatomical pattern stratification, these MND-associated alterations could be detected by dedicated analysis parameters from MRI, including T1-weighted structural imaging and microstructural diffusion tensor imaging, in combination with additional MR techniques, to act as diagnostic and monitoring biomarkers. Imaging in MND increasingly makes use of machine learning-based analysis methods. The conceptualization of (neuro-)imaging in ALS and other MND encompasses multiparametric technical approaches, also of regions outside the central nervous system, together with aspects of disease-specific pathophysiology which will further advance the field in future applications.
    Keywords:  Arterial spin labeling/ASL; Artificial intelligence; Biomarker; Diffusion tensor imaging/DTI; MR spectroscopy; Machine learning; Magnetic resonance imaging/MRI; Motor neuron disease; Neurodegeneration; Volumetry
    DOI:  https://doi.org/10.1007/s11910-026-01524-z
  2. Philos Trans R Soc Lond B Biol Sci. 2026 Oct 01. pii: 20250273. [Epub ahead of print]381(1960):
    Proteostasis (in)action: the role of co-pathologies in neurodegenerative disease.
    James F Morley.
      Clinically distinct neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), share in common progressive neuronal dysfunction and cell death associated with the accumulation of misfolded proteins. Central to these processes are the cellular and organismal proteostasis networks responsible for maintaining protein homeostasis through coordinated actions of molecular chaperones, the ubiquitin-proteasome system and autophagy-lysosomal pathways. As a consequence of ageing, genetic modifications and other disease-specific conditions, the proteostatic network becomes compromised, leading to the accumulation of toxic protein aggregates that disrupt neuronal function and lead to neurodegeneration. Specific misfolded proteins are associated with each neurodegenerative disease (i.e. α-synuclein in PD, amyloid-β/tau in AD and TAR DNA-binding protein 43/SOD in ALS). However, increasing evidence implicates more complex interactions of co-pathologies across these disorders, as Lewy bodies are common in AD brains and Alzheimer pathology is present in the majority of PD autopsy cases. These observations are consistent with the idea that disruption of proteostasis networks by one aggregation-prone protein could result in misfolding and aggregation of other neurodegeneration-related species. This review will examine the characteristics and consequences of co-pathologies in neurodegenerative disorders. Additionally, the review will outline emerging therapeutic strategies targeted at restoring proteostasis and mitigating the effects of co-pathological processes associated with neurodegenerative diseases. This article is part of the Theo Murphy meeting issue 'ProteostaSys: a systems view of proteostasis'.
    Keywords:  co-pathology; neurodegeneration; proteostasis
    DOI:  https://doi.org/10.1098/rstb.2025.0273
  3. Methods Mol Biol. 2026 ;3065 161-170
    Development of Antisense Oligonucleotide Gapmers for Amyotrophic Lateral Sclerosis.
    Yuriko Nakamura, Hidenori Moriyama, Toshifumi Yokota.
      Advances in genetics and RNA biology have transformed the therapeutic landscape for neurodegenerative disease. Antisense oligonucleotide (ASO) therapies-particularly RNase H-activating "gapmers"-now enable sequence-specific suppression of pathogenic transcripts in the central nervous system. In amyotrophic lateral sclerosis (ALS), tofersen, a 2'-MOE-modified phosphorothioate ASO targeting SOD1 mRNA, has entered clinical use. By promoting RNase H-mediated degradation of SOD1 transcripts after intrathecal delivery, tofersen lowers SOD1 protein in cerebrospinal fluid and plasma neurofilament light chain, demonstrating robust target engagement and neurodegeneration biomarker improvement. Although pivotal trials did not meet primary functional endpoints (ALSFRS-R) at 28 weeks, longer-term and real-world observations suggest potential clinical benefit with earlier initiation, a hypothesis now being tested in presymptomatic SOD1 variant carriers. This chapter reviews the development of gapmer ASOs for ALS with a focus on tofersen-covering chemistry and mechanism, preclinical validation, clinical efficacy and safety, biomarker readouts, and ongoing trials-while outlining key challenges (CNS delivery, adverse event monitoring, endpoint sensitivity) and future directions, including earlier intervention guided by biomarkers and extension to additional genetic forms of ALS.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Antisense oligonucleotide (ASO); Superoxide dismutase 1 (SOD1); Tofersen
    DOI:  https://doi.org/10.1007/978-1-0716-5476-7_10
  4. Brain. 2026 Sep 28. pii: awag334. [Epub ahead of print]
    LRSAM1, an E3 ubiquitin ligase, modulates TDP-43 proteostasis in amyotrophic lateral sclerosis.
    Takayuki Shirakawa, Satsuki Mikuriya, Yuki Inoue, Kota Murasaki, Florencia Salinas, Tomo Takegawa-Araki, Makoto Tamura.
      Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the cytoplasmic mislocalization, aberrant phosphorylation and pathological aggregation of TDP-43, a nuclear RNA-binding protein essential for RNA metabolism. Despite its central involvement in ALS pathogenesis, the molecular mechanisms that govern TDP-43 proteostasis remain incompletely understood. Here, we investigated the role of LRSAM1, an E3 ubiquitin ligase, in regulating TDP-43 localization and degradation. Postmortem spinal cord tissues from five patients with sporadic amyotrophic lateral sclerosis and five healthy controls were examined. Immunohistochemical analyses revealed that LRSAM1 preferentially colocalized with diffusely mislocalized cytoplasmic TDP-43 but not with dense cytoplasmic aggregates, suggesting a potential role in early-stage pathological processing. To model these effects in vitro, induced pluripotent stem cell-derived motor neurons from three patients with amyotrophic lateral sclerosis and four healthy control participants were used. Knockdown of LRSAM1 in induced pluripotent stem cell-derived motor neurons from patients with amyotrophic lateral sclerosis significantly increased cytoplasmic TDP-43 accumulation and phosphorylation, as measured by immunofluorescence imaging. Moreover, STMN2 mRNA splicing, a well-established TDP-43 functional readout, was disrupted upon LRSAM1 depletion. Conversely, overexpression of LRSAM1 ameliorated stress-induced TDP-43 mislocalization and phosphorylation in induced pluripotent stem cell-derived motor neurons from patients with amyotrophic lateral sclerosis but had minimal impact in control cells, indicating disease-specific vulnerability. Mechanistically, LRSAM1 interacted directly with the aggregation-prone C-terminal fragments of TDP-43 via the RRM2 domain of TDP-43 and promoted their proteasomal degradation. This selective interaction reduced the accumulation of toxic TDP-43 species and supported cytoplasmic proteostasis, particularly under conditions of cellular stress. In summary, our study identifies LRSAM1 as a novel modulator of cytoplasmic TDP-43 dynamics in amyotrophic lateral sclerosis. By facilitating degradation of pathogenic TDP-43 fragments, LRSAM1 preserves neuronal RNA processing and mitigates molecular hallmarks of amyotrophic lateral sclerosis. These findings enhance our understanding of post-translational control of TDP-43 and highlight LRSAM1 as a promising therapeutic target for modifying disease progression in amyotrophic lateral sclerosis.
    Keywords:  RNA-binding proteins; iPSC-derived motor neurons; motor neuron disease; proteasomal degradation; proteinopathy; ubiquitination
    DOI:  https://doi.org/10.1093/brain/awag334
  5. Comput Biol Chem. 2026 Sep 29. pii: S1476-9271(26)00575-X. [Epub ahead of print]126(Pt 1): 109448
    AI-driven transcriptomics for neurodegenerative disease research: A systematic review.
    Anushree Tripathi, Anoop Kumar Yadav, Nilesh Kumar.
       BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS), present a growing global health challenge, with traditional diagnostic and therapeutic approaches facing significant limitations in early detection and mechanistic resolution.
    OBJECTIVES: Innovations in transcriptomic technologies-spanning bulk RNA sequencing, single-cell RNA-seq (scRNA-seq), and spatially resolved transcriptomics-provide unprecedented insights into cellular heterogeneity and microenvironmental dysregulation. This systematic review synthesizes recent applications of artificial intelligence (AI), machine learning (ML), and deep learning (DL) across transcriptomic tiers to benchmark computational models for biomarker identification, disease diagnosis, patient subtyping, and drug repurposing.
    METHODS & ELIGIBILITY: Following PRISMA 2020 guidelines for qualitative systematic reviews, literature published between 2016 and 2025 was systematically searched across PubMed/MEDLINE, IEEE Xplore, Google Scholar, and bioRxiv/medRxiv. Of 1058 records identified, 19 core empirical studies met all eligibility criteria and were synthesized in depth alongside contextual reference benchmarks.
    SYNTHESIS & KEY FINDINGS: Traditional ML algorithms (SVM, RF, Elastic Net) demonstrate high diagnostic accuracy (AUC 0.72-0.98) in blood-based biomarker selection, while deep architectures (autoencoders, LSTMs, and Graph Neural Networks) excel at modeling continuous disease trajectories and resolving spatial transcriptomic niches (e.g., STAGATE, SpaGCN, cell2location). Emerging spatial deep learning models successfully localize disease-associated microglia (DAM) around amyloid plaques and trace axonal degeneration pathways.
    LIMITATIONS & CONCLUSIONS: Key translational hurdles include data scarcity in rare NDD subtypes, lack of cross-platform spatial benchmarks, and the black-box nature of deep neural networks. Integrating explainable AI (XAI) and prospective multi-modal cohorts is essential for translating computational transcriptomics into clinical diagnostics and targeted therapeutics.
    Keywords:  Artificial intelligence (AI); Bioinformatics; Biomarkers; Deep Learning; Neurodegenerative diseases (NDDs); Spatial Tran-scriptomics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.compbiolchem.2026.109448
  6. Eur J Hum Genet. 2026 Oct 01.
    Insertion or deletion variants in TAF15 exon 15 are genetic factors impacting the prognosis of amyotrophic lateral sclerosis in a Japanese cohort.
    Yuya Hatano, Tomohiko Ishihara, Mari Tada, Yutong Li, Sachiko Hirokawa, Masahiro Uemura, Shoichiro Ando, Akio Yokoseki, Akiyoshi Kakita, Osamu Onodera.
      The influence of genetic factors on the prognosis of amyotrophic lateral sclerosis (ALS) has attracted considerable attention, with numerous studies exploring this relationship in clinically diagnosed patients. The present study attempted to clarify the precise impact of genetic factors on prognosis in patients with pathologically confirmed sporadic ALS. We conducted exome analysis on 137 consecutively autopsied patients with sporadic ALS exhibiting TDP-43 pathology, screening for non-synonymous or splice-site rare variants (RVs) in ALS-related genes. The impact of these variants on ALS prognosis was subsequently assessed. The exome analysis identified 31 RVs in 27 of the 137 patients, including TAF15 exon 15 insertion/deletion mutations (TAF15-15 indels) in 9 patients. Patients harboring RVs had significantly shorter survival times (median 18.0 months) than those without RVs (28.5 months), as determined by log-rank test (p = 0.02). Notably, the 9 cases with TAF15-15 indels demonstrated a significantly poorer outcome (15.0 months, p = 3e-06). Lattice Simulation of Sticker-Spacer Interactions (LASSI) simulations revealed stronger negative sticker-sticker interactions, and a tendency toward lower saturation concentration and higher dense-phase concentration in TAF15-15 indel proteins, suggesting enhanced condensation. The present analysis of pathologically diagnosed ALS patients has yielded genetic factors that could potentially aid more accurate diagnosis and prognostication. The frequent identification of TAF15-15 indels among ALS cases, and their association with significantly poorer outcome, suggests that this type of mutation could be prognostically significant in ALS. Furthermore, the mechanism by which TAF15-15 indels influence the course of ALS could be a promising target for future treatments.
    DOI:  https://doi.org/10.1038/s41431-026-02249-w
  7. G3 (Bethesda). 2026 Oct 01. pii: jkag281. [Epub ahead of print]
    A genetic screen for suppressors of neuron degeneration in a C. elegans sod-1G85R model of Amyotrophic Lateral Sclerosis.
    Katherine S Yanagi, Alexander T Lin-Moore, Nijpawi C Gordon, Jeremy J Lins, Emma Michaela Coyne, Kathleen L Meininger, Stephanie L Moy, Loraina A Stinson, Melissa B Walsh, Mika Gallati, Animesh Mahapatra, Ruka Aderogba, Alexander Jaworski, Anne C Hart.
      Genetic variants in superoxide dismutase 1 (SOD1) cause the progressive neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). Treatments for this disease are limited, and the unique vulnerability of cholinergic and glutamatergic motor neurons to degeneration seen in ALS patients is not clearly understood. Identifying genetic modifiers of neurodegeneration can provide insight into the selective vulnerability of motor neurons in ALS and may accelerate identification of novel therapeutic targets. Here, we describe a forward genetic screen for suppressors of the stress-induced glutamatergic neuron degeneration in a single-copy C. elegans model of sod-1G85R. Used two different screening strategies, we identified 53 suppressor lines that decreased glutamatergic neuron degeneration to varying degrees. To rapidly identify suppressor genes, we sequenced suppressor lines and identified candidate suppressor genes based on frequency of de novo exonic mutations and previously published work. Two candidates were tested and excluded as suppressor genes: erh-1 and imph-1. For a subset of unidentified suppressor lines, we determined if cholinergic neurodegeneration was also suppressed; roughly one-third of suppressor lines showed no corresponding cholinergic neuron rescue, suggesting that mechanisms involved in cholinergic and glutamatergic degeneration are at least partially divergent. This study outlines the first unbiased genetic screen in a knock-in model of SOD1 neurodegeneration, describes a cohort of candidate suppressor lines with decreased SOD1-dependent neurodegeneration, excludes two candidates and discusses approaches for suppressor mutation isolation and gene identification.
    Keywords:   C elegans ; Amyotrophic Lateral Sclerosis (ALS); SOD1; forward genetic screen; suppressor screen
    DOI:  https://doi.org/10.1093/g3journal/jkag281
  8. Neuroscience. 2026 Oct 02. pii: S0306-4522(26)00663-9. [Epub ahead of print]
    Mdivi-1 regulates mitochondrial fission and function via the CaMK2/Drp1 pathway in amyotrophic lateral sclerosis.
    Yao Shai, Masood Alam, Xinyu Dong, Ying Zhang, Yujing Hu, Zhonghui He, Jinjin Feng, Yifan Chen, Zhenqi Zhou, Hongquan Jiang.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive motor neuron loss. Given the high energy reliance of motor neurons, mitochondrial dysfunction especially excessive fission critically contributes to disease pathogenesis. Mitochondrial division inhibitor-1 (Mdivi-1), an inhibitor of the fission protein Drp1, has shown neuroprotective potential, but its mechanism of action on mitochondrial quality control in ALS remains unclear. Here, we examined the effects of Mdivi-1 on mitochondrial dysfunction and cell injury in NSC34 cells expressing mutant SOD1^G93A and in SOD1^G93A transgenic mice. ALS models exhibited increased reactive oxygen species accumulation, reduced mitochondrial content, loss of mitochondrial membrane potential, enhanced apoptotic signaling, and increased phosphorylation of CaMK2 and Drp1. Mdivi-1 treatment improved cell viability, reduced oxidative stress, restored mitochondrial integrity and membrane potential, and suppressed apoptosis. In addition, Mdivi-1 decreased Drp1 phosphorylation, whereas co-treatment with the CaMK2 activator DCP-LA partially reversed these effects. Furthermore, direct inhibition of CaMK2 with KN93 reduced CaMK2 and Drp1 phosphorylation, providing additional evidence that CaMK2 regulates Drp1 activation in SOD1^G93A cells. These findings indicate that pharmacological modulation of the CaMK2/Drp1 pathway can attenuate aberrant mitochondrial fission and associated cellular dysfunction in ALS models.
    Keywords:  Amyotrophic lateral sclerosis; CaMK2; Drp1; Mitochondrial division inhibitor 1(Mdivi-1); Mitochondrial fission
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.10.002
  9. bioRxiv. 2026 Sep 10. pii: 2026.09.08.750250. [Epub ahead of print]
    ALS-associated exitron splicing produces UBQLN2 isoforms with distinct properties.
    Adenine Si-Hui Koo, Jingjing Zhou, Natasha M Méndez-Albelo, Yuchun Wei, Wei Xu, Xinyu Zhao, Colin Dewey, Randal S Tibbetts.
      X-linked amyotrophic lateral sclerosis (ALS) implicated Ubiquilin 2 (UBQLN2) is expressed from a single exon. Here, we show that human UBQLN2 mRNA is alternatively spliced by virtue of a cryptic exonic intron (exitron) spanning the 5' untranslated region and the 5' end of UBQLN2 coding sequence. Splice-out of this exitron generates a spliced UBQLN2 (UBQLN2-Sp) transcript that is translated from codon M243 to produce an N-terminally truncated UBQLN2 isoform (UBQLN2-M243) with reduced stability, diminished proteasome targeting, and altered aggregation behavior following the introduction of ALS mutations. The RNA-binding proteins SRSF1 and PTBP1 control UBQLN2 splicing through binding to splice donor-proximal motifs, while TDP-43 was implicated as an indirect splicing repressor. UBQLN2 splicing was elevated and inversely correlated with UBQLN2 gene expression in the medial motor cortex of male ALS patients. These findings suggest that alternative splicing regulates UBQLN2 gene dosage and function, which may impact UBQLN2-ALS proteinopathy.
    GRAPHICAL ABSTRACT: Created in https://BioRender.com.
    DOI:  https://doi.org/10.64898/2026.09.08.750250
  10. Clin Nutr ESPEN. 2026 Sep 30. pii: S2405-4577(26)02259-X. [Epub ahead of print] 105162
    Predictive Value of the Modified Controlling Nutritional Status Score for Critical Events in Patients with Amyotrophic Lateral Sclerosis.
    Taku Tazuma, Masahiro Nakamori, Megumi Toko, Tomoaki Watanabe, Hiroyuki Naito, Yuhei Kanaya, Dai Agari, Takeo Shishido, Eiji Imamura, Kazuki Imon, Eiichi Nomura, Tsuyoshi Torii, Takafumi Miyachi, Hiroshi Yamashita, Tomohiko Ohshita, Hirofumi Maruyama.
       BACKGROUND & AIMS: Amyotrophic lateral sclerosis (ALS) is associated with various clinical challenges and critical outcomes. Therefore, we established a regional registry and conducted the Chugoku ALS Retrospective and Prospective (CARP) study. The modified controlling nutritional status (m-CONUT) score holds the potential to comprehensively assess the condition of patients with ALS from aspects such as nutrition, metabolism, and inflammation. The present study used data from the CARP study to examine the relationship between the m-CONUT score and outcomes.
    METHODS: Patients diagnosed with possible, probable, and definite ALS according to the Awaji criteria were enrolled between 2014 and 2023. A statistical analysis of data from patients enrolled within 2 years of ALS onset and followed for at least 6 months thereafter was performed. Patients were evaluated every 3 months, and missing values were supplemented by the last observation carried forward method.
    RESULTS: This study included 36 patients. Eleven experienced critical events (ventilator placement or death), the majority of which were deaths. The m-CONUT score exhibited a worsening trend before the critical event occurred, as did the revised ALS functional rating scale score, body mass index, and forced vital capacity percentage. Critical events increased significantly with each 1-point increase in the m-CONUT score.
    CONCLUSIONS: The m-CONUT score may have potential for predicting outcomes in patients with ALS.
    Keywords:  amyotrophic lateral sclerosis; body mass index; modified controlling nutritional status score; nutrition
    DOI:  https://doi.org/10.1016/j.clnesp.2026.105162
  11. Curr Neurovasc Res. 2026 Sep 25.
    Lipid-based Nanocarriers for Neurodegenerative Disorders: Bridging Blood-brain Barrier Biology and Translational Drug Delivery.
    Ajay Pal Singh, Shatrudhan Prajapati, Shikha Yadav, Anjali Yadav.
       INTRODUCTION: Neurodegenerative disorders, including Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis, remain difficult to treat because the Blood-brain Barrier (BBB) severely restricts therapeutic access to the central nervous system. This review evaluates BBB biology and the potential of lipid-based nanocarriers to improve brain-targeted drug delivery and facilitate clinical translation.
    METHODS: A structured narrative review of peer-reviewed preclinical and clinical literature published between 2000 and 2025 was conducted using PubMed, Scopus, and Web of Science. Evidence concerning BBB structure and transport mechanisms, lipid-based nanocarrier design, physicochemical characteristics, drug-release behavior, computational modelling, therapeutic applications, and translational challenges was critically synthesized.
    RESULTS: Liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, and lipid-polymer hybrid nanoparticles demonstrated improved drug solubility, stability, controlled release, systemic circulation, and brain targeting. Preclinical evidence indicates enhanced brain bioavailability and therapeutic effects, including reductions in neuroinflammation, oxidative stress, and disease-associated pathological processes. However, clinical translation remains constrained by formulation complexity, scalability, long-term safety, and inconsistent clinical outcomes.
    DISCUSSION: Integration of BBB transport biology with surface functionalization, receptormediated targeting, formulation engineering, and computational modelling may enable more rational nanocarrier development. Nevertheless, standardized characterization, reproducible manufacturing, comprehensive safety evaluation, and stronger clinical validation are required to bridge the gap between promising preclinical findings and therapeutic implementation.
    CONCLUSION: Lipid-based nanocarriers represent promising platforms for overcoming biological and pharmacokinetic barriers in neurodegenerative disorders. Further optimization and rigorous translational validation are essential to establish their safety, reproducibility, and clinical effectiveness.
    Keywords:  Blood-brain barrier; brain-targeted drug delivery; lipid-based nanoparticles; nanostructured lipid carriers.; neurodegenerative disorders
    DOI:  https://doi.org/10.2174/0115672026478560260909100922
  12. Drug Des Devel Ther. 2026 ;20 631482
    The Versatile Roles of Exosomes in Neurodegenerative Disorders: From Pathological Mechanism and Diagnostic Biomarkers to Therapeutic Application.
    Rui Liu, Hao Yue, Xinrui Li, Weiwei Sun, Junzheng Yang.
      Neurodegenerative diseases are characterized by cognitive or motor impairments resulting from the progressive degeneration of neurons or myelin sheaths. Currently, the majority of these disorders remain incurable, leading to significant detriments in patients' quality of life and imposing substantial economic burdens. Exosomes are a type of extracellular vesicles secreted by cells into the extracellular space, typically range from 30 to 150 nanometers in diameter. These vesicles have been identified in a variety of cell types and can participate in various physiological and pathological processes, including intercellular transport of biomolecules, signal transduction, immune modulation, tissue repair, facilitation of tumor metastasis, and evasion of immune surveillance by cancer cells. In recent years, the potential applications of exosomes in neurodegenerative diseases have garnered increasing attention. Their roles encompass early diagnostic biomarker functions, vehicles for drug delivery and therapeutic agents, mediators in the propagation of pathogenic proteins, and regulators of neuroinflammatory responses. In this review, we try to aims to synthesize recent progress in exosome isolation techniques, elucidate the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), and examine the diagnostic and therapeutic applications of exosomes within these conditions. Furthermore, it addresses current limitations in exosome-based applications and explores potential strategies to overcome these challenges. The insights of this review may provide the research directions and guidance for future related researchers in these fields.
    Keywords:  diagnosis; exosomes; mechanism; neurodegenerative disease; pathogenesis; treatment
    DOI:  https://doi.org/10.2147/DDDT.S631482
  13. Neurobiol Dis. 2026 Sep 26. pii: S0969-9961(26)00375-X. [Epub ahead of print]230 107629
    Polyamines across neurodegenerative proteinopathies.
    Bedri Ranxhi, Peter A LeWitt, Wei-Ling Tsou, Sokol V Todi.
      Polyamines (PAs) are evolutionarily conserved metabolites that connect protein quality control with lysosomal, mitochondrial, and redox homeostasis. Their metabolism is situated at a critical intersection of cell-sustaining and neurodegenerative pathways. Here, we synthesize evidence across Alzheimer's disease, Parkinson's disease, polyglutamine repeat disorders, amyotrophic lateral sclerosis, and multiple system atrophy, each of which differs in vulnerability to changes in PA metabolism. Although previous reviews have investigated PAs in individual neurodegenerative disorders, few have compared their roles across the broader spectrum of neurodegenerative proteinopathies. We address this gap by synthesizing evidence across multiple diseases to examine how PAs influence disease-associated protein aggregation and clearance, and how these effects depend on PA species, concentration, cellular context, disease stage, subcellular localization, redox state, and lysosomal and mitochondrial capacity. Human tissue and biofluid studies report disease-associated changes in PA metabolites, pathway enzymes, and transporter remodeling, as a function of neurodegenerative disorders. Mechanistic studies reveal that spermidine and spermine can alter the assembly, condensation, compartmentalization, and clearance of various neurotoxic proteins, whereas the effects of putrescine are more system- and concentration-dependent. These effects engage both shared pathways and distinct mechanisms, depending on protein identity, cell type, and subcellular location. Curiously, PA manipulation may be protective in one context yet harmful in another. The framework that we propose can distinguish adaptive remodeling from pathogenic dysregulation and can guide disease-relevant therapeutic strategies.
    Keywords:  Aggregation; Alzheimer’s; Amyotrophic lateral sclerosis; Autophagy; Mitochondria; Multiple system atrophy; Oxidative stress; Parkinson’s; Polyglutamine; Proteostasis; Spermidine; Spermine; Synucleinopathies
    DOI:  https://doi.org/10.1016/j.nbd.2026.107629
  14. Hum Mol Genet. 2026 Sep 11. pii: ddag093. [Epub ahead of print]35(20):
    Motor dysfunction phenotypes in a drosophila model validate DAO as an ALS gene.
    Sylvana Tabone, Rebecca Cacciottolo, Ruben J Cauchi.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by progressive motor neuron (MN) loss. Although rare pathogenic variants in the D-amino acid oxidase (DAO) gene have been proposed to cause familial ALS, inconsistent findings across mammalian models have hindered functional validation. Here, we establish and characterise a Drosophila model of DAO loss-of-function by targeting its highly conserved orthologue, Daao1. Constitutive Daao1 knockdown caused early developmental lethality, while surviving adult escapers exhibited profound flight and climbing impairments. Contrary to expectations, Daao1 deficiency did not elevate D-serine levels in larval or adult brains, and simultaneous knockdown of serine racemase (Srr), the enzyme responsible for D-serine synthesis, failed to rescue locomotor phenotypes. Tissue-specific silencing revealed that Daao1 is essential within both MNs and muscles, but not glia, for maintaining motor performance. RNA-seq of Daao1-deficient flies uncovered widespread transcriptional dysregulation affecting metabolism, peptide transport, immune activation and developmental pathways, accompanied by alternative splicing changes in genes required for neuronal morphology and synaptic organisation. Consistent with these molecular alterations, neuromuscular junctions (NMJs) displayed reduced axonal branching and bouton numbers, indicating disrupted neuromuscular connectivity. Remarkably, ubiquitous expression of human DAO rescued lethality and motor defects, demonstrating functional conservation and supporting a role for DAO in maintaining neuromuscular health. Together, our findings reveal a previously unrecognised, D-serine-independent role for DAO in neuromuscular integrity and provide functional evidence connecting DAO dysfunction to ALS-relevant phenotypes. The DAO-ALS Drosophila model provides a powerful platform for mechanistic studies and for evaluating human DAO variants of uncertain significance in ALS.
    Keywords:  Drosophila model; amyotrophic lateral sclerosis; neurodegeneration; neurogenetics
    DOI:  https://doi.org/10.1093/hmg/ddag093
  15. J Neurol. 2026 Sep 30. pii: 634. [Epub ahead of print]273(10):
    Spinal cord imaging in multiple sclerosis: from diagnosis to disease progression.
    Tal J Koren, Jashan Dugal, Dongang Wang, Heidi Beadnall, Chenyu Tim Wang, Yael Barnett, Fernando Calamante, Xavier Montalban, Jiwon Oh, Michael H Barnett.
      Spinal cord (SC) involvement in multiple sclerosis (MS) is common and a major determinant of long-term disability in both relapsing and progressive disease phenotypes. Despite this, SC pathology remains under-assessed in both clinical practice and therapeutic trials, largely due to technical challenges inherent to spinal SC magnetic resonance imaging (MRI) conferred by the cord's small anatomical size and sensitivity to physiological motion and susceptibility artefact. This review synthesises current understanding of SC involvement in MS, integrating advances in pathophysiology, imaging, and clinical application. We describe the characteristic MRI features of MS SC lesions and their key inflammatory and non-inflammatory differentials, and examine the role of SC imaging in diagnosis, particularly in the context of the 2024 revisions to the McDonald criteria. We highlight the prognostic importance of SC lesions and atrophy, including their association with progression independent of relapse activity, and review the limited and heterogeneous evidence regarding the effects of disease-modifying therapies on SC pathology. We further evaluate current MRI acquisition strategies and consensus guidelines, and discuss emerging quantitative and advanced imaging techniques that detect microstructural and biochemical abnormalities beyond conventional imaging. Together, these developments support a more systematic integration of SC imaging into MS clinical care and trial design.
    Keywords:  Expanded disability status scale (EDSS); Magnetic resonance imaging (MRI); Multiple sclerosis; Spinal cord; Spinal cord atrophy
    DOI:  https://doi.org/10.1007/s00415-026-14122-3
  16. Ann Neurol. 2026 Oct 02.
    Associations Between Prediagnosis Plasma Neurofilament Light Polypeptide and Amyotrophic Lateral Sclerosis Risk in the Danish EPIC Cohort.
    Aline Davias, Johnni Hansen, Cezmi A Akdis, Marc G Weisskopf.
       OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a rapid time from symptoms onset to diagnosis. Elevated neurofilament light polypeptide (NfL) is well-established in symptomatic ALS and up to 5 years prediagnosis, but earlier timeframes remain understudied. We aimed to assess plasma NfL levels up to 23 years before ALS diagnosis and the relation to ALS risk.
    METHODS: We conducted a nested matched case-control study within the Danish EPIC cohort (baseline 1993-1997) including 166 ALS cases (diagnosed 1997-2017) and 332 controls matched on birth year and sex. Plasma samples collected 0.4 to 23.2 years (median 14.1 years) prediagnosis were analyzed for NfL using Olink Target 96. Odds ratios were estimated using conditional logistic regression. Discriminatory performance was evaluated using receiver operating characteristic curves.
    RESULTS: NfL levels were elevated in ALS cases relative to controls up to 14.6 years before diagnosis. Among those with blood samples collected <5, 5 to 14.6, and >14.6 years before diagnosis, the odds ratios (95% CI) for ALS per standard deviation increase in the normalized protein expression value of NfL were 3.8 (1.4-10.3), 1.7 (1.2-2.3), and 1.3 (0.9-1.7), respectively. The areas under the curve for ALS discrimination by NfL among those with blood collected <5 and 5-14.6 years before diagnosis were 0.78 and 0.63, respectively.
    INTERPRETATION: Plasma NfL elevation may occur significantly earlier than previously reported, indicating a much longer ALS prodrome. Assuming other biomarker changes may also occur earlier, this raises the possibility of identifying at-risk individuals early that could benefit epidemiologic analyses, clinical trials, and prevention efforts. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78382
  17. Expert Rev Neurother. 2026 Oct 01. 1-13
    Focused ultrasound blood-brain barrier opening: a review of post-procedure MRI outcomes.
    Suzanne LeBlang, Rashi I Mehta, Pierre-François D'haese, Augusto Grinspan, Amit Sokolov, Giulia Frazzetta.
       INTRODUCTION: Focused ultrasound (FUS) blood-brain barrier opening (BBBo) is an incisionless technique that facilitates cerebral drug delivery by temporarily increasing BBB permeability. Clinical trials have shown that FUS produces reversible BBBo and is feasible in humans. There are currently no standardized imaging protocols for assessing the safety of FUS-BBBo, although MRI is commonly performed.
    AREAS COVERED: This structured narrative review summarizes neuroimaging techniques used to assess FUS-BBBo safety in clinical trials of participants with neurological disorders that reported post-procedural MRI findings. A search of PubMed from September 2014 to April 2026 was undertaken to identify clinical trials of FUS-BBBo (13 in patients with brain tumors and 16 in neurodegenerative diseases).
    EXPERT OPINION: Localized T2* hypointense signals and T2 hyperintense signals are relatively common after FUS-BBBo. While these findings have been thought to be related to transient microhemorrhage or edema, no consistent association has been found between such findings and clinically significant adverse events. Further work incorporating standardized post-FUS-BBBo MRI safety assessments is needed to clarify the biological significance of these signal alterations, and to determine whether they indicate a potential long-term safety concern, are a harmless finding associated with the BBBo procedure, or are associated with the underlying diseases and/or concomitant drugs.
    Keywords:  Alzheimer’s disease; blood-brain barrier opening; focused ultrasound; glioblastoma; magnetic resonance imaging; neurodegenerative disease; safety
    DOI:  https://doi.org/10.1080/14737175.2026.2737272
  18. QJM. 2026 Sep 28. pii: hcag270. [Epub ahead of print]
    REM-associated nocturnal hypercapnia in amyotrophic lateral sclerosis.
    Keito Ishihara, Hiroyuki Naito, Hirofumi Maruyama.
      
    DOI:  https://doi.org/10.1093/qjmed/hcag270
  19. Continuum (Minneap Minn). 2026 Oct;32(5): 1529-1544
    Amyotrophic Lateral Sclerosis.
    Mark B Bromberg.
       OBJECTIVE: This article describes the nerve loss underlying amyotrophic lateral sclerosis, its clinical manifestations, examination findings leading to the diagnosis, the expanding role of genetics, and available treatment and patient management.
    LATEST DEVELOPMENTS: The cause of neuron death in patients with amyotrophic lateral sclerosis is not known, but many genes are strongly linked to the disease, in both patients with a family history and those with no history. A multistep pathologic process helps to explain the onset of symptoms later in life, even in patients with associated genes. Posttranslational and epigenetic changes are also important factors. Current clinical trials are based on putative pathologic mechanisms, and some newer therapies are gene-based.
    ESSENTIAL POINTS: Amyotrophic lateral sclerosis has distinctive features and can be diagnosed largely from the history and examination, and true mimics are rare. While the cause of neuronal death is not known, pathogenic and risk factor gene variations are present in a number of patients, and posttranscriptional and epigenetic changes are likely major causative factors. Environmental factors likely contribute, but specific avoidable factors have not been identified. Drugs to slow the progress of the disease are currently limited, but trials for all patients with amyotrophic lateral sclerosis continue, including a focus on genetic factors. Patient management is optimized in multidisciplinary amyotrophic lateral sclerosis clinics, and interventions for nutrition with gastric feeding tubes and respiratory insufficiency by noninvasive ventilation enhance patient comfort.
    DOI:  https://doi.org/10.1212/cont.0000000000001753
  20. Neurosci Biobehav Rev. 2026 Oct 02. pii: S0149-7634(26)00463-X. [Epub ahead of print]191 107005
    Acidic cannabinoids in brain disorders: Neurobiological mechanisms, preclinical evidence, and translational challenges.
    Alessandro Rava, Melania Di Trapano, Calvin Tse, Lawrence Ji, Hemant Kumar Bid, Viviana Trezza.
      Acidic cannabinoids, including tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and related biosynthetic precursors, represent the predominant phytocannabinoid forms naturally produced by Cannabis sativa. Long considered pharmacologically inactive intermediates, these compounds are now increasingly recognized as bioactive molecules with potential therapeutic relevance for brain disorders. Compared with their decarboxylated counterparts, acidic cannabinoids exhibit distinct physicochemical, pharmacokinetic, and pharmacodynamic properties that may confer reduced psychotropic liability together with unique neurobiological effects. Emerging preclinical evidence indicates that acidic cannabinoids modulate multiple processes implicated in neurological and psychiatric disorders, including serotonergic and endocannabinoid signaling, neuroinflammation, oxidative stress, mitochondrial dysfunction, calcium dyshomeostasis, and synaptic transmission. In this review, we critically examine current knowledge regarding acidic cannabinoids in the context of brain disorders. We first summarize their biosynthesis, chemical stability, pharmacokinetic characteristics, and pharmacological differences from neutral cannabinoids. We then examine preclinical evidence supporting their potential therapeutic effects in epilepsy, anxiety, depression, psychosis-related conditions, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We also discuss how artificial intelligence and computational approaches may support target identification, formulation optimization, pharmacokinetic modeling, and the development of personalized cannabinoid-based interventions. Finally, we highlight key methodological and translational challenges limiting the field and outline priorities for future research. Overall, acidic cannabinoids emerge as promising but still underexplored multitarget compounds with potential relevance for the treatment of brain disorders.
    Keywords:  Acidic cannabinoids; Artificial intelligence; Brain disorders; Epilepsy; Neurodegeneration; Psychiatric disorders
    DOI:  https://doi.org/10.1016/j.neubiorev.2026.107005
  21. Mol Neurobiol. 2026 Sep 26. pii: 928. [Epub ahead of print]63(1):
    Symptomatic Rescue or Disease Modification? A Critical Review of Levodopa and Phytochemical Interventions in Caenorhabditis elegans Models of Parkinson's Disease.
    Emre Aktaş, Şeyda Berk.
      Parkinson's disease (PD) is characterised by progressive dopaminergic neurodegeneration and alpha-synuclein (α-syn) aggregation, with levodopa remaining the gold-standard symptomatic therapy despite its inability to halt disease progression or prevent levodopa-induced dyskinesia (LID). Caenorhabditis elegans has emerged as a highly tractable model for mechanistic PD research owing to its conserved dopaminergic pathways, optical transparency, rapid lifecycle, and suitability for high-throughput pharmacological screening. This review critically examines the pharmacological effects of levodopa in C. elegans PD models across locomotor behaviour, α-syn aggregation, lifespan, and dyskinesia-related phenotypes, while comparing these findings with phytochemicals evaluated in analogous experimental systems. Levodopa consistently restored dopamine-dependent locomotor deficits but failed to substantially reduce α-syn aggregation or extend lifespan, recapitulating the clinical dissociation between symptomatic motor rescue and persistent neurodegeneration. In contrast, phytochemicals, including Frondoside A, hydroxytyrosol/Hidrox®, Neurogrit Gold, Mucuna pruriens extract, quercetin, and quercetin nanoemulsions, demonstrated broader mechanistic profiles involving antioxidant responses, mitophagy, proteostasis, and dopaminergic neuroprotection. The available evidence suggests that phytochemicals are best regarded not as replacements for levodopa but as candidate adjuncts that, in preclinical worm models, appear to act on upstream pathological processes; whether this translates into genuine complementarity in vivo remains a hypothesis requiring direct testing. The central argument advanced here is methodological rather than pharmacological: C. elegans is currently the only PD model in which symptomatic motor rescue and α-synuclein pathology can be quantified simultaneously in the same living animal, and this dissociation provides a measurable framework for defining what an adjunctive compound would need to achieve. On this basis, levodopa is proposed as a mandatory positive control for future C. elegans phytochemical screening. Critical translational limitations-including the absence of a blood-brain barrier in C. elegans, phytochemical bioavailability constraints, and uncertainty regarding the relationship between aggregate reduction and true neuroprotection-are also discussed.
    Keywords:   Caenorhabditis elegans ; Alpha-synuclein; Dopaminergic neurodegeneration; Levodopa; Mitophagy; Neuroprotection; Oxidative stress; Parkinson’s disease; Phytochemicals
    DOI:  https://doi.org/10.1007/s12035-026-06241-9
  22. Brain Behav Immun. 2026 Sep 26. pii: S0889-1591(26)00776-2. [Epub ahead of print] 107028
    Permeability of the intestinal epithelial and blood-brain barriers as therapeutic targets in inflammatory depression.
    Tiffany C Ho, Gabriel A Vignolle, Danny J J Wang, Arpana Church.
      Inflammation has emerged as a compelling causal contributor to depression, serving both as a biological pathway underlying specific depressive symptoms (notably anhedonia, fatigue, and cognitive difficulties) and as a defining feature in a subtype of this disorder characterized by elevated levels of circulating cytokines. Understanding when and how immune dysfunction results in depression within clinical trials is needed to advance biomarker-guided clinical research and to accelerate novels treatments for those suffering from depression. In this context, gut microbes and intestinal epithelial barrier (IEB) integrity directly influence systemic cytokine levels and peripheral immune activation-these immune signals, in turn, modulate neural circuits involved in mood, reward, and stress reactivity through several pathways. Many of these signals converge on the blood-brain barrier (BBB), the permeability of which regulates the entry of peripheral cytokines and immune cells into the central nervous system and consequently shapes neuroinflammatory responses that contribute to depressive symptoms. In this narrative review, we contend that immune-gut-brain system is critical for understanding mechanisms and potential treatments for inflammatory depression. We synthesize evidence linking inflammation to IEB and BBB permeability, summarize barrier biomarkers relevant for depression, and highlight future directions of research that focus on fortifying dual barrier dysfunction as a novel intervention target for inflammatory depression. By considering the inflammatory mechanisms that shape IEB and BBB integrity, the field will be positioned to identify upstream drivers of these sources of inflammation, refine mechanistic models of transdiagnostic symptoms relevant to inflammation (anhedonia, fatigue, executive dysfunction), and develop more targeted or personalized intervention strategies for those suffering from these conditions.
    DOI:  https://doi.org/10.1016/j.bbi.2026.107028
  23. ACS Biomater Sci Eng. 2026 Sep 30.
    Bioinspired Nanomaterials for Parkinson's Disease: Engineering Membrane Interfaces to Overcome the Blood-Brain Barrier and Enable Neuron-Targeted Delivery.
    Qucheng Huang, YuanYuan Zuo, Yining Xie, Zhenye Liu, Leiyi Wang, Hewei Xu, Miao Yu, Chang Liu.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by the selective loss of dopaminergic neurons in the substantia nigra, which gives rise to characteristic motor and non-motor behavioral impairments. Disease-modifying therapies remain elusive, largely due to the restrictive nature of the blood-brain barrier (BBB) and the lack of effective neuron-targeting strategies. Bioinspired nanomaterials-including cell membrane-derived vesicles, engineered biomimetic nanocarriers, and liposomes-have emerged as versatile platforms to address these limitations. By recapitulating key surface properties of endogenous cells, these nanocarriers facilitate BBB transport and brain accumulation, enhance neuronal recognition and preferential uptake, and enable controlled drug release, thereby potentially improving therapeutic index. In the context of PD, such targeted delivery systems offer potential not only for neuroprotection but also for ameliorating behavioral deficits. This review critically examines recent progress in bioinspired nanomaterial-based interventions for PD, with emphasis on the underlying mechanisms of BBB penetration and neuronal targeting. We further evaluate the translational promise of these platforms for modifying disease trajectories and restoring behavioral functions, and we identify remaining challenges and priority directions for future development in PD and related neurodegenerative disorders.
    Keywords:  Parkinson’s disease; bioinspired nanomaterials; biomimetic drug delivery; blood–brain barrier; neurodegeneration; neuronal targeting
    DOI:  https://doi.org/10.1021/acsbiomaterials.6c01137
  24. Front Aging. 2026 ;7 1923046
    Explanatory limitations of CSF, plasma, and MRI biomarkers for inflammation and blood-brain barrier disruption in dementia.
    Azadeh Golduzian, Erik B Erhardt, Arvind Caprihan, John C Adair, Janice E Knoefel, Jill Prestopnik, Sasha Hobson, Sephira Ryman, Andrei Vakhtin, Kiran Bhaskar, Gary A Rosenberg.
      Inflammation and blood-brain barrier (BBB) disruption are increasingly implicated in cognitive decline, but it remains unclear which fluid and imaging measures best capture these processes. Participants were drawn from two overlapping research programs, MarkVCID and UNM ADRC. We studied 149 participants with Alzheimer's disease, leukoaraiosis, mixed dementia, subcortical ischemic vascular dementia, or memory impairment. BBB permeability was assessed using the albumin index (Qalb), a global blood-to-CSF leakage ratio, and dynamic contrast-enhanced MRI permeability (Ktrans), a regional gadolinium transfer measure. Both were treated as permeability measures that inflammation may influence rather than as direct measures of inflammation. CSF and plasma biomarkers included matrix metalloproteinases, angiogenic factors, cytokines, GFAP, NfL, pTau181, and Aβ42/40; MRI measures included PSMD, mean free water, hippocampal volume, and cortical thickness. Univariate associations were screened using Spearman correlation and AIC, and multivariable models used AIC-based stepwise selection. Diagnosis-adjusted models, bootstrap selection frequencies, penalized regression, and cross-validated R2 were used as sensitivity analyses. Qalb and Ktrans were not significantly correlated (Spearman ρ = 0.14, p = 0.28), suggesting that they index different dimensions of BBB dysfunction without establishing biological independence. The multivariable CSF model for Qalb retained MMP-2, Flt-1, IL-8, GFAP, and NfL and explained approximately half the variance (R2 = 0.53), whereas the plasma model explained less variance (R2 = 0.32). For Ktrans, multivariable CSF, plasma, and MRI models explained R2 = 0.36, 0.39, and 0.14, respectively, while PSMD was the strongest FDR-robust univariate MRI correlate. CSF-plasma correlations ranged from near zero for MMP-9 (r = -0.03) to stronger associations for NfL (r = 0.74) and IL-13 (r = 0.70), indicating that plasma cannot be assumed to substitute for CSF marker-by-marker. Qalb and Ktrans should be considered complementary rather than interchangeable measures. The Qalb-CSF model showed the strongest inflammation-related signal, but these findings are exploratory and require validation in independent, longitudinal cohorts before an inflammation axis can be incorporated into an ATN(V)-based framework.
    Keywords:  ATN(V)I framework; albumin index; blood–brain barrier; dynamic contrast-enhanced MRI; mixed dementia; neuroinflammation; permeability; vascular cognitive impairment
    DOI:  https://doi.org/10.3389/fragi.2026.1923046
  25. Neurologist. 2026 Sep 28.
    Neuroepigenetics of the Environmental Exposome: Molecular and Clinical Implications in Neurodegeneration.
    Elizabeth Avendaño-Arango, Isabella Salom-Palacio, Edgard Eliud Castillo-Támara, Belkis Palacio-Villalba.
       BACKGROUND: Neuroepigenetics studies the molecular mechanisms that regulate gene expression in the nervous system without altering the DNA sequence. The environmental exposome has emerged as a key factor influencing neuronal plasticity and brain homeostasis, contributing to vulnerability to neurodegeneration.
    REVIEW SUMMARY: This narrative review analyzes the role of neuroepigenetic reprogramming as a central mechanism linking chronic environmental exposures with neurodegenerative diseases. Evidence indicates that alterations in DNA methylation, histone remodeling, and microRNA regulation contribute to mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation. These mechanisms are critically involved in the pathogenesis of Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis.
    CONCLUSIONS: Neuroepigenetics represents a central mechanistic axis in neurodegeneration by integrating environmental exposures with intrinsic biological processes. This framework offers new opportunities for the development of early biomarkers and targeted preventive and therapeutic strategies.
    Keywords:  DNA methylation; environmental exposures; exposome; neurodegeneration; neuroepigenetics
    DOI:  https://doi.org/10.1097/NRL.0000000000000694
  26. Nat Rev Neurol. 2026 Sep 29.
    Lysosomal dysfunction in neurodegenerative disease.
    Sarah M Brooker, Robert Coukos, Dimitri Krainc.
      Examination of genetic risk factors associated with neurodegenerative diseases has provided important mechanistic insights into the pathophysiology of these disorders, and it has implicated defects in lysosomal function as a key component of the neurodegenerative process. The lysosome has a primary role in mediating degradation of both intracellular contents and endocytosed material from the extracellular space. Aggregation of misfolded proteins is a pathological mechanism that is observed across neurodegenerative disorders, and aberrant lysosomal degradation of such proteins plays a pivotal part in driving neuronal dysfunction and cell loss. In addition to the crucial role of the endolysosomal system in degradation of intracellular constituents, lysosomes also serve as important nodes for intracellular signalling, participating in nutrient sensing, lipid metabolism, membrane repair and neuroinflammation. In this Review, we provide an overview of mechanisms of lysosomal dysfunction in neurodegenerative disease, with a particular focus on Parkinson disease, Alzheimer disease, frontotemporal dementia and amyotrophic lateral sclerosis.
    DOI:  https://doi.org/10.1038/s41582-026-01262-3
  27. Nat Commun. 2026 08 29. pii: 10335. [Epub ahead of print]17(1):
    Acute viral infection accelerates neurodegeneration in a mouse model of ALS.
    Art Marzok, Jonathan P Mapletoft, Imran Ahmed, Braeden Cowbrough, Daniel B Celeste, Michael R D'Agostino, Jann C Ang, Andrew T Chen, Vithushan Surendran, Yona Tugg, Hahn Li, Karena Wong, Anna Dvorkin-Gheva, Ali Zhang, Hannah D Stacey, Mannie Lam, Yasmine Kollar, Kevin R Milnes, Sam Afkhami, Matthew S Miller.
      While several viral infections have been associated with amyotrophic lateral sclerosis (ALS), the mechanism(s) through which they promote disease remains elusive. Here we investigate the impact of common, acute viral infections on ALS disease onset and progression in the SOD1G93A mouse model. A single sublethal infection prior to onset of ALS clinical signs is associated with markedly accelerated ALS disease progression characterized by rapid loss of hindlimb function. Prior infection results in gliosis in the lumbar spine and upregulation of transcriptional pathways involved in inflammatory responses, metabolic dysregulation, and muscular dysfunction. Therapeutic suppression of gliosis with an anti-inflammatory small molecule, or administration of a direct-acting antiviral, is associated with significantly improved ALS clinical signs, akin to what is observed in uninfected animals. Our study provides causal and mechanistic evidence that the immune response elicited by acute viral infections may be an important etiological factor that alters ALS disease trajectory.
    DOI:  https://doi.org/10.1038/s41467-026-77353-y
  28. Res Sq. 2026 Sep 09. pii: rs.3.rs-10810896. [Epub ahead of print]
    Clonal CD8 T cells link peripheral and intrathecal immunity in ALS4 progression: a multiomics reference for ALS.
    Laura Campisi, Marina Terekhova, Rima Melhem, Carisa Zeng, Jessie Martin, Tanya Lizbeth Joseph, Pavla Bohacova, Melina Jones, Avindra Nath, Nicole Benoit, George Harmison, Gregory Wu, Alexey Sergushichev, Maxim Artyomov, Christopher Grunseich.
      Dysregulated immune responses increasingly appear central to amyotrophic lateral sclerosis (ALS) pathology, but rapid progression and delayed diagnosis limit our understanding of how immune events evolve over the course of disease. By combining high parameter spectral flow cytometry with single cell RNA, TCR and BCR sequencing of peripheral blood and cerebrospinal fluid (CSF), we map the immune landscape in ALS4, a juvenile onset, slowly progressive ALS subtype, providing the first view of immune states spanning decades of disease progression. We identify an early emerging, progressively amplifying CD8 T cell program characterized by clonal expansion of peripheral GZMK⁺ and GZMB⁺ subsets and an abnormally high degree of TCR clonotype sharing between GZMK⁺ CSF and GZMB⁺ blood CD8 T cells. Our work defines a CD8 T cell trajectory that parallels clinical progression in ALS4 across CSF and blood and provides a reference for comparison with other ALS subtypes.
    DOI:  https://doi.org/10.21203/rs.3.rs-10810896/v1
  29. J Neurol. 2026 Sep 28. pii: 629. [Epub ahead of print]273(10):
    Progressive motor impairment from intracerebral critical demyelinating lesions.
    Purnashree Chowdhury, Eoin P Flanagan, Yong Guo, W Oliver Tobin, Bianca Albites Coen, Claudia F Lucchinetti, Brian G Weinshenker, Orhun H Kantarci, B Mark Keegan.
       BACKGROUND: Focal critical demyelinating lesions anatomically associated with progressive motor impairment are described in multiple sclerosis (MS) and restricted demyelinating diseases, typically within the spinal cord lateral column and ventral cervicomedullary junction (CMJ). This study describes such lesions within the intracerebral corticospinal tracts.
    METHODS: We retrospectively reviewed people seen at Mayo MS Clinic (2002-2025) with progressive central nervous system demyelinating disease and progressive (≥ 1 year) upper motor neuron weakness anatomically associated with a presumed demyelinating lesion of the cerebral white matter, internal capsule, or upper brainstem, excluding alternative spinal cord or CMJ lesions. Demographics, disease course, Expanded Disability Status Scale (EDSS), MS disease-modifying therapy use, brain and spinal cord magnetic resonance imaging, cerebrospinal fluid studies and neuropathology findings were reviewed.
    RESULTS: Seventeen people had an intracerebral critical demyelinating lesion: cerebral white matter in 12 (70%), internal capsule in 3 (18%) and upper brainstem in 2 (12%). Ten were female, and all were white. Progression from onset course was 13 (76%) and from relapse onset was 4 (24%). Median, interquartile range (IQR) for age at progressive motor impairment onset was 46 (IQR 38-52) years, and EDSS at last evaluation was 5.5 (IQR 4.0-5.5). Sixteen (94%) had progressive spastic hemiparesis and 1 (6%) monoparesis. Cognitive impairment occurred in 6/12 (50%) and seizures in 3/12 (25%) with cerebral white matter critical lesions. Abnormal intrathecal production of immunoglobulin G markers was consistent with MS in 10/15 (66%). Neuropathology confirmed demyelination in 4/6 biopsies.
    CONCLUSIONS: Intracerebral critical demyelinating lesions associated with progressive motor impairment can rarely occur along the corticospinal tracts of the brain.
    Keywords:  Cervicomedullary junction; Critical lesion; Demyelinating disease; Intracerebral; Motor impairment; Multiple sclerosis
    DOI:  https://doi.org/10.1007/s00415-026-14168-3
  30. Mini Rev Med Chem. 2026 Sep 28.
    Oleandrin and PBI-05204 for Neuroprotection in Alzheimer's Disease, Parkinson's Disease, and Stroke: Preclinical Mechanisms, Blood-brain Barrier Penetration, and Clinical Translation Perspectives.
    Teenu Pal, Prabhat Singh.
       INTRODUCTION: Alzheimer's disease, Parkinson's disease, and ischemic stroke are increasingly becoming one of the major health concerns across the globe due to the scarcity of effective treatments for these conditions. Natural compounds like oleandrin and PBI-05204 that are extracted from Nerium oleander have been recognised for their promising qualities in the treatment and prevention of these conditions due to their ability to provide protection to the neurons in the brain.
    METHODS: A systematic review was conducted to identify preclinical research articles related to oleandrin and PBI-05204 in the treatment of Alzheimer's disease, Parkinson's disease, and ischemic stroke. Searches were conducted on articles from January 2021 to March 2026 in Pub- Med/MEDLINE, Scopus, and Web of Science using the terms "oleandrin," "PBI-05204," "Nerium oleander," "blood-brain barrier," "neuroprotection," "Alzheimer," "Parkinson," and "stroke." Original in vitro or in vivo preclinical studies providing information on neuroprotective results, mechanistic information (BDNF, Nrf2-ARE, apoptosis, mitochondria), or information on blood-brain barrier permeability were included. Non-original articles (reviews, editorials), preclinical research not involving any neurobiological parameters, and articles in languages other than English were excluded.
    RESULTS: Preclinical studies suggest that both oleandrin and PBI-05204 can diffuse across the BBB and provide neuroprotection. These molecules were shown to increase the expression levels of BDNF, promote ARE-dependent transcription, rehabilitate mitochondrial function, and regulate apoptosis. Though these results are highly hopeful, the major translational gap is in the ability to reproduce preclinical success in the clinical environment.
    DISCUSSION: There is sufficient cellular-molecular evidence for the potential use of these compounds, namely oleandrin, as well as PBI-052040. Some challenges may arise when attempting to apply such observations as a new treatment modality at the clinical research stage. This is true for bioavailability, toxicity, and regulatory factors that need to be addressed.
    CONCLUSION: Oleandrin and PBI-05204 make for very interesting compounds to consider for their neuroprotective properties in the context of neurodegeneration. Although there is promise in the preliminary human data from these compounds, there are also significant translational hurdles that must be cleared before their final application for human benefit.
    Keywords:  Alzheimer's disease; Oleandrin; PBI-05204; Parkinson's disease; blood-brain barrier; ischemic stroke; natural products.
    DOI:  https://doi.org/10.2174/0113895575485020260907153210
  31. PLoS One. 2026 ;21(9): e0359269
    AZP2006 in Parkinson's disease models: A promising new neuroprotective treatment involving lysosomal homeostasis and the Progranulin/Prosaposin complex.
    Noelle Callizot, Georgia Culley, Grace Flower, Laura Rouvière, Véronique De Conto, Alexandre Wojcinski, Catherine Botto, Cecilia Estrella, Alexandre Henriques, Philippe Verwaerde.
      The pathohistological hallmarks of Parkinson's disease are aggregated alpha-synuclein and other aggregation-prone proteins (Lewy bodies). Recent studies show mechanistic as well as genetic connections between lysosomal dysfunction and Parkinson's disease pathology. A direct link between lysosomal function and Parkinson's disease might be the degradation of alpha-synuclein within the lysosomal system. Progranulin is necessary for maintaining lysosomal function, facilitating the activity of several lysosomal enzymes. Progranulin's exit from the endoplasmic reticulum and its lysosomal availability depend on an interaction with Prosaposin. AZP2006 (INN: Ezeprogind) is a small lysosomotropic neuroprotective molecule currently in clinical development in Progressive Supranuclear Palsy patients. Its neuroprotective effects involve the Progranulin/Prosaposin complex. In this study, we investigated the neuroprotective effects of AZP2006 in several Parkinson's-like models (vitro and vivo). We showed that AZP2006 was able to counteract a mitochondrial injury as well as the toxicity of alpha-synuclein preformed fibril spreading. We proved that Progranulin was involved in AZP2006's neuroprotective action, restoring lysosomal homeostasis and ultimately supporting the health of dopaminergic neurons. In light of this evidence, strategies with the aim of improving Progranulin and Prosaposin levels and activity offer a promising therapeutic approach in the context of proteinopathies such as Parkinson's disease.
    DOI:  https://doi.org/10.1371/journal.pone.0359269
  32. Photodiagnosis Photodyn Ther. 2026 Sep 26. pii: S1572-1000(26)00329-7. [Epub ahead of print] 105662
    Mapping the Intelligence: A Bibliometric Analysis of Artificial Intelligence and Machine Learning Applications in Retinal OCT for Neurodegenerative Diseases.
    Mohammad Danesh-Doust, Farzane Nikparast, Hoda Zare.
       BACKGROUND: Retinal optical coherence tomography (OCT) combined with artificial intelligence (AI) is increasingly proposed as a scalable window onto neurodegenerative disease, yet the intellectual architecture of this field remains unmapped.
    METHODS: Following the BIBLIO guideline, 1,036 documents (1976-2026) were retrieved from the Web of Science Core Collection and analysed with bibliometrix (v5.4.0), integrating performance analysis, collaboration and co-citation networks, and science mapping.
    RESULTS: Output grew exponentially after 2010, peaking at 139 articles in 2025. Productivity and impact concentrated in a transatlantic core (USA, Germany, UK; Charité Berlin, University College London, Johns Hopkins; Calabresi, Paul, Saidha), with a 19-journal Bradford core led by Investigative Ophthalmology & Visual Science. Thematic mapping documented a decisive post-2022 reorientation toward deep learning, optical coherence tomography angiography (OCT-A) and oculomics, with AI themes consolidating as motor themes.
    CONCLUSIONS: The field is transitioning from structural biomarker research to computational phenotyping; externally validated, globally inclusive collaborations will determine whether retinal AI fulfils its screening potential.
    Keywords:  Artificial intelligence; Deep learning; Neurodegenerative diseases; Optical coherence tomography; Retinal biomarkers
    DOI:  https://doi.org/10.1016/j.pdpdt.2026.105662
  33. Front Aging Neurosci. 2026 ;18 1892568
    Hybrid multimodal late fusion frameworks for bvFTD classification in imbalanced dementia datasets.
    Majid Ramedani, Jaya C Terli, Devesh Singh, Oliver Peters, Julian Hellmann-Regen, Josef Priller, Eike Jakob Spruth, Annika Spottke, Anne Boehlen, Patrick Weydt, Ullrich Wüllner, Elisabeth Dinter, Rene Günther, Jens Wiltfang, Björn H Schott, Emrah Düzel, Wenzel Glanz, Katharina Buerger, Daniel Janowitz, Johannes Levin, Anna Stockbauer, Mihovil Mladinov, Johannes Prudlo, Andreas Hermann, Matthis Synofzik, David Mengel, Gabor C Petzold, Anja Schneider, Falk Lüsebrink, Stefan Hetzer, Peter Dechent, Michael Ewers, Klaus Scheffler, Sophia Stöcklein, Stefan Teipel, Martin Dyrba.
       Background: Behavioral variant frontotemporal dementia (bvFTD) is an irreversible neurodegenerative disorder characterized by progressive changes in personality and behavior. Magnetic Resonance Imaging (MRI) is widely used to detect and assess structural brain alterations associated with the disease. However, due to the low prevalence of bvFTD among neurodegenerative diseases causing the dementia syndrome, conventional machine learning approaches may struggle to capture comprehensive feature representations. Therefore, this study proposes two late fusion frameworks that integrate a 3D convolutional neural network and a multilayer perceptron (MLP) for improved bvFTD diagnosis.
    Methods: A total of 5,928 participants were included, comprising 3,415 healthy controls (HC), 2,276 Alzheimer's disease (AD), and 237 bvFTD, resulting in a class imbalanced setting with bvFTD as the minority class. To address class imbalance, bvFTD data were initially augmented. A 3D-DenseNet was used to extract features from 3D T1-weighted MRI scans, while an MLP-based model was applied to regional brain volumetric measurements obtained from automated MRI-based brain segmentation. Twelve CNN models with different hyperparameter configurations were trained. Models with and without data augmentation, as well as two fusion-based approaches, were evaluated using accuracy, F1-score, and area under the curve (AUC).
    Results: Both fusion strategies improved accuracy, F1-score, and AUC compared to the baseline model without data augmentation. Notable improvement was also observed for the bvFTD class, with up to a 120% increase in F1-score. In one of the fusion frameworks, an accuracy of 0.95 ± 0.01 was achieved for bvFTD vs. HC classification. The results demonstrate the effectiveness of the fusion-based approaches compared to non-fused models, outperforming several state-of-the-art methods.
    Conclusion: The proposed frameworks demonstrate that data augmentation and fusion strategies can improve accuracy, F1-score, and AUC, with statistically significant gains. Overall, the frameworks improve diagnostic performance and support the identification of relevant biomarkers associated with bvFTD pathology.
    Keywords:  3D-CNN; bvFTD; classification; late fusion; magnetic resonance imaging
    DOI:  https://doi.org/10.3389/fnagi.2026.1892568
  34. Insights Imaging. 2026 Sep 30. pii: 240. [Epub ahead of print]17(1):
    The swallow tail sign: mechanisms, neuroimaging advances and future perspectives.
    Zhixuan Li, Haoxuan Lu, Yongqin Xiong, Caohui Duan, Xin Lou.
      Parkinson's disease (PD), the second most common neurodegenerative disorder, poses a significant challenge to elderly health. Its diagnosis currently relies primarily on clinical symptoms, which often proves inadequate for differentiating PD from other forms of parkinsonism, particularly in early disease stages. Although positron emission tomography (PET) has offered compelling evidence supporting the differential diagnosis of PD, its high cost and radiation exposure limit its widespread use. Consequently, there is a pressing need for more accessible, convenient, non-invasive, and safe diagnostic approaches. The "swallow tail sign" (STS)-an MRI-based biomarker characterized by a hyperintensity in the posterolateral substantia nigra pars compacta (SNc), surrounded by hypointense areas-has emerged as a highly promising adjunct tool. This biomarker holds potential not only to enhance diagnostic certainty in distinguishing PD from similar neurodegenerative disorders but also to improve the understanding of its pathophysiology. In this review, we outline the anatomical basis of the STS and the pathological changes in PD leading to its disappearance. We further summarize its applications across various magnetic resonance imaging (MRI) techniques and evaluate its value in identifying PD and differentiating it from other parkinsonian syndromes. With significant advancements in ultra-high-field MRI (≥ 7 T) and artificial intelligence (AI), combined with other MRI biomarkers, the value of STS will be further explored in the future. KEY POINTS: Question Despite its diagnostic potential, the biological basis, imaging interpretation, and clinical utility of the STS remain incompletely understood and warrant further investigation in parkinsonism. Findings The normal STS appears as dorsolateral nigral hyperintensity on susceptibility-sensitive MRI, while its attenuation or loss in PD supports cautious adjunctive diagnostic use. Critical Relevance Statement This review critically evaluates the biological basis, MRI interpretation, diagnostic limitations, and evolving multimodal and AI-based assessment of the STS, guiding radiologists toward its standardized and cautious adjunct use in the clinical imaging assessment of parkinsonism.
    Keywords:  Biomarkers; Magnetic resonance imaging; Parkinson disease; Pars compacta; Substantia nigra
    DOI:  https://doi.org/10.1186/s13244-026-02401-6
  35. Front Immunol. 2026 ;17 1857394
    Neuroinflammation and metabolic reprogramming in Parkinson's disease.
    Yixin Fu, Jianghao Yu, Lu Xu, Tingting Zhou, Qingshan Deng.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the pathological accumulation of Lewy bodies composed predominantly of aggregated α-synuclein (αSyn). Despite decades of progress in genetics and neuropathology, the mechanisms driving disease initiation and progression remain incompletely understood, and no disease-modifying therapy has yet demonstrated conclusive efficacy. Neuroinflammation and metabolic dysfunction have emerged as two central and mechanistically intertwined pillars of PD pathogenesis. We propose an integrative model in which these processes function not merely in parallel, but as mutually reinforcing components of a self-amplifying pathological circuit, while acknowledging that this model remains to be fully validated and that alternative causal architectures are possible. This review systematically addresses the mechanistic coupling between neuroinflammation and metabolic dysregulation in PD, covering: (1) the molecular basis of innate immune activation via DAMPs, pattern recognition receptors, and inflammasome signaling; (2) microglial metabolic reprogramming and the NLRP3/NF-κB inflammatory axis; (3) αSyn-driven innate and adaptive immune responses; (4) mitochondrial dysfunction and oxidative stress as bidirectional amplifiers; (5) the gut-brain axis as a conduit for peripheral immunometabolic disruption; (6) the AMPK/mTOR/HIF-1α molecular network integrating metabolism and inflammation; (7) sphingolipid metabolism and the GBA-lysosomal axis; and (8) translational evidence from animal models and randomized controlled trials. A concise section integrates key fluid biomarkers as clinical surrogates of the underlying mechanisms.
    Keywords:  Parkinson’s disease; metabolic reprogramming; microglia; neuroinflammation; α-synuclein
    DOI:  https://doi.org/10.3389/fimmu.2026.1857394
  36. Am Surg. 2026 Sep 29. 31348261493540
    Should MRI Replace Ultrasound as the Primary Imaging Modality in Pediatric Females With Suspected Appendicitis?
    T Hess, Rachel Nation, Thomas Presenza, Matthew Moront, Erika Lindholm.
      Limited sequence, rapid acquisition magnetic resonance imaging (MRI) is an established modality for diagnosing appendicitis, but its ability to assess gynecologic pathology remains unclear. We hypothesize that MRI alone sufficiently evaluates reproductive organs in patients with lower abdominal pain. Female patients (<18yo) undergoing MRI in the Emergency Department between January 2019 and January 2025 were reviewed. Patients were stratified into two groups: MRI alone vs pelvic ultrasound (US) and MRI. 142 patients were included with 93 receiving MRI only and 49 receiving both MRI and US. The MRI mentioned evaluation of pelvic structures in 80% of cases. Ovarian cysts were commented on in 5 patients, of which 4 also had US which added no additional information. No gynecologic pathology was missed on MRI. In this study, we found no gynecologic pathology on US that was not also noted on MRI. These findings suggest that an MRI first diagnostic pathway may be sufficient to rule out gynecologic pathology (Table 1).
    Keywords:  MRI; appendicitis; gynecology; pediatric surgery
    DOI:  https://doi.org/10.1177/00031348261493540
  37. Mol Neurobiol. 2026 Sep 26. pii: 927. [Epub ahead of print]63(1):
    Peripheral IL-17 Triggers, and anti-IL-17 Treatment Prevents, Neuroinflammation and Alterations in Neurotransmission in Hippocampus and Cognitive Impairment in Hyperammonemic Rats.
    Yaiza M Arenas, Marta Llansola, Gergana Mincheva, Carmina Montoliu, Vicente Felipo.
      Patients with liver cirrhosis who develop minimal hepatic encephalopathy (MHE) show mild cognitive impairment associated with increased peripheral inflammation, including elevated interleukin-17 (IL-17). In animal models, this inflammation promotes neuroinflammation and disrupts glutamatergic neurotransmission in the hippocampus, contributing to cognitive deficits. This study investigated whether IL-17 is directly involved in cognitive impairment in hyperammonemic rats and explored the mechanisms involved. Hyperammonemic rats received intravenous anti-IL-17 treatment at days 3-5 after induction of hyperammonemia. Cognitive assessment and blood-brain barrier integrity, neuroinflammation, and glutamatergic neurotransmission in the hippocampus were performed after four weeks. Increased peripheral IL-17 activated its receptor in endothelial cells, enhancing NADPH oxidase activity and increasing Myosin light chain kinase (MLCK) levels. This reduced the tight junction proteins occludin and ZO-1, weakening the blood-brain barrier and facilitating immune cell infiltration and IL-17 entry into the hippocampus. Consequently, microglia became activated, increasing TNFα and IL-1β levels and altering membrane expression of glutamate receptors, leading to cognitive impairment. Blocking IL-17 prevented these pathological changes and produced sustained protection against cognitive deficits. These findings support a role of IL-17 in early transmission of peripheral inflammation into the brain initiating hippocampal neuroinflammation and cognitive impairment in MHE and propose anti-IL-17 therapies for MHE.
    Keywords:  Blood–brain barrier; Cognitive impairment; Glutamatergic neurotransmission; Hepatic encephalopathy; Interleukin-17
    DOI:  https://doi.org/10.1007/s12035-026-06229-5
  38. CNS Neurosci Ther. 2026 Oct;32(10): e71188
    Magnetic Resonance Imaging in Cerebral Small Vessel Disease-Related Depression: From Visual Scoring to Artificial Intelligence.
    Chaofang Lei, Jiaxu Chen, Yilong Wang.
       BACKGROUND: Cerebral small vessel disease (CSVD) is the key pathological basis of vascular depression. The precise identification of its neuroimaging markers is of core value for early diagnosis, elucidation of its pathological mechanism, and individualized treatment. Recent advances in magnetic resonance imaging (MRI) and artificial intelligence (AI) have enabled automated, high-throughput characterization of CSVD-related brain lesions. However, the translation of these technical advances into clinical tools for depression-specific prediction and classification remains at an early stage.
    RESULTS AND CONCLUSION: This manuscript aims to summarize the application of traditional visual scoring systems in assessing the burden of CSVD and its association with depressive symptoms. Review the current status of imaging and AI research on CSVD-related depression. To provide a direction for the development of more precise and efficient imaging diagnostic tools for the future, and ultimately promote the practical application and utilization of precision medicine in the field of CSVD-related depression.
    Keywords:  artificial intelligence; cerebral small vessel disease; deep learning; depression; imaging biomarker; machine learning; magnetic resonance imaging; visual score
    DOI:  https://doi.org/10.1002/cns.71188
  39. Metab Brain Dis. 2026 Sep 28. pii: 228. [Epub ahead of print]41(1):
    Genetic architecture and molecular pathogenesis of Parkinson's disease: emerging mechanisms and therapeutic targets.
    Sumeyye Yildirim.
      According to the Global Burden of Disease Study 2023, Parkinson's disease (PD) affects an estimated 11.67 million people worldwide, a progressive neurodegenerative condition marked by the accumulation of Lewy bodies containing α-synuclein and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Over the past ten years, advances in genetic and molecular research have shown that PD pathogenesis involves interrelated mechanisms such as impaired protein homeostasis, mitochondrial dysfunction, oxidative stress, defects in lysosomal-autophagic pathways, and chronic neuroinflammation, which go beyond dopaminergic neuronal loss. This review summarizes new data about major genes associated with monogenic and polygenic forms of PD, including SNCA, LRRK2, PRKN, PINK1, DJ-1 (PARK7), GBA1, VPS35, ATP13A2, FBXO7, and the GWAS-prioritized risk genes TMEM175, SCARB2, CTSB, RIT2, DYRK1A, and BAG3, together with the molecular pathways disrupted by these genetic alterations in light of current evidence. The polygenic architecture of PD and ancestry-related variation in genetic risk are also discussed. α-synuclein aggregation and proteostasis networks, oxidative stress, autophagy and mitophagy failure, neuroinflammation, mitochondrial quality control, and epigenetic regulation are all given special attention. Apart from traditional dopaminergic treatments, new therapeutic approaches such as immunotherapies targeting α-synuclein, gene therapies mediated by adeno-associated virus (AAV), induced pluripotent stem cell (iPSC)-based methods, and genotype-guided precision medicine are critically examined. A more comprehensive understanding of the molecular mechanisms underlying PD is expected to facilitate the development of reliable biomarkers and accelerate the clinical translation of disease-modifying therapies.
    Keywords:  Autophagy; Genetic architecture; LRRK2; Mitochondrial dysfunction; Molecular pathogenesis; Neuroinflammation; Neuroprotection; Parkinson''s disease; α-synuclein
    DOI:  https://doi.org/10.1007/s11011-026-01998-3
  40. Front Microbiol. 2026 ;17 1946719
    Gut microbiota-neuroimmune crosstalk in autoimmune encephalitis: mechanistic insights and therapeutic prospects.
    Haiyan Zhang, Xue Zhou, Yugang Ma, Shoujian Zong, Xinqi Liu, Zongzhou Liu, Xingchen Wang.
      Autoimmune encephalitis (AE) comprises a heterogeneous group of inflammatory disorders of the central nervous system mediated by autoimmune responses, involving multiple pathological processes, including autoantibody production, aberrant immune-cell activation, and persistent neuroinflammation. In recent years, accumulating evidence has suggested that the gut microbiota may represent an important regulatory interface linking host metabolism, immunity, and the nervous system. Through microbial structural components, metabolites, and secreted signals, the gut microbiota may influence peripheral immune responses, blood-brain barrier integrity, and central nervous system inflammation. Conversely, neuroimmune dysregulation may reshape the intestinal microbial environment through neuroendocrine-immune regulatory networks, thereby establishing a dynamic bidirectional relationship between the gut microbiota and the neuroimmune system. However, the mechanisms underlying gut microbiota-neuroimmune interactions in AE, particularly their potential changes across the disease course, remain incompletely understood. This review summarizes current evidence regarding AE-associated alterations in the gut microbiota and disturbances of neuroimmune homeostasis, with particular emphasis on the potential molecular mechanisms through which the gut microbiota modulates neuroimmune responses and, reciprocally, the neuroimmune system reshapes the intestinal microbial environment. Within a proposed phase-based conceptual framework encompassing disease initiation, progression, and the chronic phase, we further discuss the potential dynamic changes in gut microbiota-neuroimmune crosstalk during AE. In addition, we summarize emerging therapeutic strategies, including dietary and nutritional interventions, probiotics, modulation of microbial metabolic functions, fecal microbiota transplantation, and precision microbiome engineering, and discuss their current evidence base and translational potential. Collectively, gut microbiota-neuroimmune crosstalk provides a useful conceptual framework for understanding disease heterogeneity in AE and exploring microbiota-targeted interventions. However, direct AE-specific evidence remains limited, and many proposed mechanisms are currently supported primarily by observational studies, experimental models, or evidence extrapolated from related neuroimmune disorders. Future studies integrating longitudinal clinical cohorts, multi-omics profiling, and functional validation are needed to define key microbial functions, host immune responses, and their dynamic relationships in AE, thereby providing a stronger mechanistic foundation for future precision diagnostic and therapeutic strategies.
    Keywords:  autoimmune encephalitis; gut microbiota; gut–brain axis; microbiota-based therapy; neuroimmune interactions
    DOI:  https://doi.org/10.3389/fmicb.2026.1946719
  41. Cell Stem Cell. 2026 Oct 01. pii: S1934-5909(26)00346-2. [Epub ahead of print]33(10): 1580-1581
    The accessory makes the drug: ASO-delivered siRNA enters the human CNS for ALS.
    Wenxuan Guo, Justin K Ichida.
      In a recent article in Nature Medicine, Chen et al. describe a first-in-human study using an ASO tag to deliver a SOD1 siRNA to the central nervous system (CNS), potentially achieving faster, more extensive, and better-tolerated SOD1-lowering in ALS patients.1.
    DOI:  https://doi.org/10.1016/j.stem.2026.09.004
  42. Methods Mol Biol. 2026 ;3065 19-51
    Development and Clinical Applications of Antisense Oligonucleotide Gapmers.
    Leanna Chan, Faiyza Akil Shaikh, Pusti Shah, Hidenori Moriyama, Toshifumi Yokota.
      Antisense oligonucleotides (AONs) are synthetic oligonucleotides designed to bind target RNA and have opened new treatment possibilities for genetic diseases by regulating gene expression. AONs are often used to suppress the expression of mutated genes, which may interfere with essential downstream pathways. Since AONs have been introduced for clinical use, different chemistries have been developed to further improve efficacy, potency, and safety. One such chemistry is a chimeric structure of a central block of deoxyribonucleotides flanked by sequences of modified nucleotides. Referred to as a gapmer, this chemistry produced promising results in the treatment of genetic diseases. Tofersen is an example of a recently FDA-approved antisense oligonucleotide gapmer used for the treatment of amyotrophic lateral sclerosis. Many others are being tested in clinical trials or under preclinical development. This chapter will cover advancements in gapmer treatments for various diseases, including familial hypercholesterolemia, hereditary transthyretin amyloidosis, cancer, familial chylomicronemia syndrome, familial partial lipodystrophy, familial hypertriglyceridemia, Huntington's disease, myotonic dystrophy, prion diseases, and amyotrophic lateral sclerosis.
    Keywords:  Amyotrophic lateral sclerosis; Apatorsen; Eplontersen; Familial chylomicronemia syndrome; Familial hypercholesterolemia; Familial partial lipodystrophy; Hereditary transthyretin amyloidosis; Huntington’s disease; Hypertriglyceridemia; Inotersen; Mipomersen; Myotonic dystrophy; Tofersen; Volanesorsen
    DOI:  https://doi.org/10.1007/978-1-0716-5476-7_2
  43. Neurology. 2026 Oct 27. 107(8): e218517
    Disentangling Age-Related and Disease-Specific Effects on Upper Cervical Cord Area in Patients With Multiple Sclerosis.
    Kshiteeja Jain, Loredana Storelli, Paola Valsasina, Paolo Preziosa, Alessandro Meani, Patrizia Pantano, Claudia Piervincenzi, Antonio Gallo, Alessandro D'Ambrosio, Massimo Filippi, Maria A Rocca.
       BACKGROUND AND OBJECTIVES: Cervical cord atrophy is a key predictor of disability and disease progression in multiple sclerosis (MS); however, age-related vs disease-related contributions remain unclear. Here, we investigated whether MS results in a disease-specific reduction in mean upper cervical cord area (MUCCA) beyond aging, and whether this deviation is modulated by sex and age at disease onset.
    METHODS: In this cross-sectional, multicenter study (3 Italian sites), we analyzed volumetric T1-weighted 3.0T brain MRIs and clinical data from healthy controls (HCs) and patients with MS (ages 18-70 years) without other cord pathology. Active-surface MUCCA measurements were obtained between C1 and C2/3 and normalized for head size (nMUCCA). nMUCCA lifespan trajectories were modelled in HC using polynomial regression accounting for age, age squared, sex, scanner, and interaction terms. Such model was applied to patients with MS generating nMUCCA Z-scores, capturing disease-specific atrophy beyond aging. Effects of sex and age at onset (pediatric onset <18, adult onset 18-49, and late onset ≥50 years) were evaluated, along with associations with disability, disease duration, T2 hyperintense lesion, and normalized brain volumes.
    RESULTS: In HC (n = 480, median age 41.0 years, 59% female), nMUCCA showed a nonlinear age relationship, increasing until late 30s (p ≤ 0.033) and declining after age 50 years (p ≤ 0.008). Patients with MS (n = 1,295, median age 42.0 years, 68% female) showed cord Z-scores below zero from age 30 years (p ≤ 0.039), particularly in the fifth and sixth decades, indicating reductions vs HC. Slope analysis further revealed marked early-adult decline up to late 40s, with attenuation thereafter. These patterns did not differ between men and women. Pediatric-onset MS exhibited lower Z-scores (p < 0.001) vs adult-onset and late-onset patients, but differences were not significant (p = 0.823) after disease duration adjustment. Disease-driven decline with age did not differ among onset groups (p = 0.668). Greater upper cervical cord atrophy correlated with higher disability and worse structural MRI measures (absolute ρ range = 0.196-0.392, all p < 0.001).
    DISCUSSION: In MS, upper cord atrophy exceeds age-related effects, especially in fifth-sixth decades, and attenuates later as aging effects increase. Disease-specific atrophy is independent of sex. Differences across onset groups largely reflect disease duration. Upper cord atrophy correlates with disability, supporting its role as a sensitive MS-related neurodegeneration biomarker beyond aging.
    DOI:  https://doi.org/10.1212/WNL.0000000000218517
  44. Age Ageing. 2026 09 04. pii: afag290. [Epub ahead of print]55(9):
    CCL2 and CXCL2 are markers of delirium vulnerability in community dwelling older people.
    Hannah Moorey, Hannah F Botfield, Maria Krogseth, Geir Selbaek, Daisy Wilson, Torgeir Bruun Wyller, Thomas Andrew Jackson.
       BACKGROUND: Delirium is common and age, frailty and dementia are risk-factors. The pathophysiology is complex and poorly understood, but age-related immune system changes may be key. This study aimed to measure markers of immune cell migration, accelerated immune ageing and blood-brain barrier permeability in community-dwelling, older people comparing those who developed ≥1 episode of delirium over 2 years with those that did not.
    METHODS: Baseline samples were collected from CASCADE participants who were followed up for 2 years. Delirium screening was performed weekly; positive screens or hospital admission triggered a delirium assessment. Serum was isolated, stored and analysed using a multiplex panel comparing levels between participants with and without delirium episodes.
    RESULTS: About 98 participants were included. Median age was 88 (IQR: 81.8-92.0), with 90.8% classified as frail. Forty-three participants (43.9%) experienced ≥1 delirium episodes. CCL2 (MCP-1) and CXCL2 (MIP-2α), measured in a stable state at baseline, were significantly higher in the delirium group compared to the no delirium group (13.38 (11.21-17.93) vs. 10.83 (9.03-14.64) P = .004) and (17.23 (11.80-24.22) vs. 13.49 (10.19-17.98) P = .031), respectively. When stratified by dementia status, the associations of CCL2 with delirium were maintained in both groups, but CXCL2 was only significantly higher in delirium in the subgroup without dementia.
    DISCUSSION: CCL2 and CXCL2 are chemokines involved in immune cell recruitment and markers of accelerated immune ageing. Future work should elucidate the role of immune cell recruitment and brain infiltration in delirium, to identify treatment targets. Furthermore, work should explore whether targeting immune ageing can reduce delirium risk.
    Keywords:  CCL2; CXCL2; biomarkers; chemokines; delirium; older people
    DOI:  https://doi.org/10.1093/ageing/afag290
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