bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–08–23
fifty-six papers selected by
Luca Bolliger, lxBio
  1. Spatiotemporal Dynamics and Cellular States of Neuroinflammation in Amyotrophic Lateral Sclerosis: Implications for Stage‑Specific Therapeutics.
  2. Exploring the effect of red and near-infrared light on neurodegenerative disease: A focus on amyotrophic lateral sclerosis, Charcot's devastating disease of the motor system.
  3. SOD1 Variants in Patients With Amyotrophic Lateral Sclerosis in Central Eastern Europe: From Genetic Testing to SOD1 Targeted Therapy.
  4. Exploring Genetic Therapies Targeting Amyotrophic Lateral Sclerosis in Animal Models: A Systematic Review and Meta-Analysis.
  5. Amyotrophic lateral sclerosis and degenerative cervical myelopathy: phenotype-based diagnostic pitfalls, investigative mismatch, and practical clinical reasoning.
  6. Neutralization of pathogenic PC-OxPL by AAV-delivered scFv as a therapeutic strategy for amyotrophic lateral sclerosis.
  7. Novel Compounds as TREM2 Agonists for Treating Parkinson's Disease, Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Nasu-Hakola Disease, and Stroke.
  8. Regenerative strategies for ALS: stem cells and extracellular vesicles.
  9. Short-term ambient temperature increases are associated with higher mortality in amyotrophic lateral sclerosis: a case-crossover study of weather conditions.
  10. Circulating neuron-derived cfDNA for blood-based detection of Alzheimer's and other neurodegenerative conditions.
  11. PCSK9 inhibitors in neurodegenerative disorders: mechanisms, therapeutic potential, and clinical implications.
  12. Integrated In Silico Discovery of Thymoquinone Analogs Targeting the Keap1-Nrf2 Pathway for Amyotrophic Lateral Sclerosis Therapy.
  13. Advances in the clinical application of mesenchymal stem cells for neurological disorders.
  14. Sleep-wake control with age and neurodegenerative diseases.
  15. A multi-omics characterization reveals distinct molecular signatures in the human motor cortex and lumbar spinal cord in ALS.
  16. Annexin A1 inhibits neuronal apoptosis in amyotrophic lateral sclerosis by restraining the Hippo pathway.
  17. Microglia extracellular traps (MiETs) in Neurodegeneration: Mechanisms, Evidence Gaps, and Untapped Therapeutic Promise.
  18. Auditory Biomarkers in Neurodegenerative Disorders: A Literature Review.
  19. Genetic profile of motor neuron disease in a multiregional Brazilian cohort: an 18-year real-world experience in 1,911 patients.
  20. Mitochondria-Targeted Nanotherapies in Aging Neurodegenerative Disorders: Emerging Prospects and Clinical Potential.
  21. i.c.v. delivery of AAV9-synapsin-promoted caveolin-1 attenuates neuromuscular deficits and neuromuscular degeneration in hSOD1G93A mice.
  22. A replicated astrocyte long non-coding RNA signature of Alzheimer's disease is inverted in amyotrophic lateral sclerosis.
  23. Cerebellar ataxia-onset ALS with SOD1 D91A mutation: a rare phenotype.
  24. Associations between Pre-Disease Biomarkers of Persistent Organic Pollutants and Amyotrophic Lateral Sclerosis Survival in the Danish Diet, Cancer and Health Study Cohort.
  25. Cross sectional analysis of gut microbiota of ALS patients with and without percutaneous endoscopic gastrostomy.
  26. Ultrasound-Controlled Blood-Brain Barrier (BBB) Opening in a BBB-Glioblastoma Microfluidic Chip for Drug Delivery Studies.
  27. Mitochondria-containing large extracellular vesicles target mouse motor neurons upon intramuscular injection.
  28. Gold Coast criteria for ALS diagnosis: individual participant data meta-analysis.
  29. Altered perivascular space diffusivity dynamics in motor neuron disease.
  30. ["Jiaji" (EX-B2) electroacupuncture modulates NLRP3 inflammasome activation to improve limb dysfunction in amyotrophic lateral sclerosis mice].
  31. Precision Drug Delivery Strategies for Treatment-Resistant Depression: Opportunities and Challenges of FUS-BBBO and Spatial Molecular Profiling.
  32. Qualitative and Quantitative Prediction of Blood-Brain Barrier Permeability of Chemicals via an SE(3)-Transformer-Based Model with LLM-Assisted Explanation.
  33. Microglial polarisation imbalance and receptor-targeted therapeutics in Parkinson's disease.
  34. Multidisciplinary clinic attendance and patterns of care in the U.S. National ALS Registry, 2013-2023.
  35. Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in C9ORF72 -Frontotemporal Dementia.
  36. Antisense oligonucleotide treatment following viral delivery of artificial SOD1-targeting miRNA shows improved efficacy in SOD1-G93A mice.
  37. Population-Level Nucleotide Diversity and Genetic Differentiation at SOD1 Across Global Human Populations.
  38. Dissociable Effects of Dysarthria Etiology and Severity on the Minimally Detectable Change of Speech Intelligibility.
  39. Revisiting somatosensory evoked potentials in motor neuron diseases: neurophysiological insights from a large cohort.
  40. Aquaporin-4 Mediated Glymphatic Dysfunction and Neuroinflammatory Signaling in Neurodegenerative Disorders.
  41. Portable Ultra-Low-Field MRI in Outpatient Neurology: An Examination of Clinical Performance and Patient Experience.
  42. Association of handgrip strength asymmetry with prodromal and incident Parkinson's disease: A prospective cohort study.
  43. Intracerebroventricular Administration of Gangliosides for In Vivo Functional Studies in Mice.
  44. Therapeutic targeting of G protein-coupled receptors in central nervous system disorders: from novel mechanisms to precision pharmacology.
  45. Written in the Stars: Astrocyte Biology From Evolution to Disease.
  46. Regenerative medicine for neurodegenerative diseases:History, Strategies, and Clinical Advances.
  47. Neurodegeneration as a dysregulation of neuroimmune crosstalk.
  48. Green analytical methods for quantification of a new combination therapy for amyotrophic lateral sclerosis: assessment by EPPI framework.
  49. Targeting Neurodegeneration With Naringenin: Mechanistic Perspectives and Therapeutic Implications.
  50. Impact of Neurons on Group B Streptococcus Interactions at the Blood Brain Barrier.
  51. Histone deacetylases in neurodegeneration and neuronal plasticity.
  52. Microglia-centered cellular crosstalk in neurodegeneration.
  53. Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets.
  54. Data-Driven Fatigue Trajectories in Multiple Sclerosis and Their Predictors.
  55. Structural Connectivity Alterations Within Frontal Subregions in Parkinson's Disease: Implications for Motor Dysfunction.
  56. Challenges in the Diagnosis of Multiple Sclerosis: A Case Report.
  1. ASN Neuro. 2026 ;18(1): 2715625
    Spatiotemporal Dynamics and Cellular States of Neuroinflammation in Amyotrophic Lateral Sclerosis: Implications for Stage‑Specific Therapeutics.
    Congwen Lv, Wenjia Zhu, Xinmei Wen, Yuwei Da.
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex and heterogeneous pathogenesis. Accumulating preclinical and clinical evidence indicates that neuroinflammation is an important modulator of ALS pathophysiology, involving activation of resident central nervous system immune cells, dysfunction of glial support systems, disruption of neurovascular barriers, and altered recruitment of peripheral immune cells. ALS-associated neuroinflammation is temporally dynamic and varies across anatomical compartments and cellular contexts. Multiple animal models, human neuroimaging, and post-mortem tissue suggest that relatively regulated or compensatory immune responses during early stage may progressively shift to persistent, maladaptive, and potentially neurotoxic inflammatory circuits in later stage. Although previous studies have described stage-dependent changes in individual immune cell populations, an integrated stage-dependent systematic framework that unifies dynamic alterations in both central and peripheral immune compartments remains insufficiently established. In this review, we propose a four-phase conceptual framework for ALS neuroinflammation across the progressive ALS pathogenesis, aiming to provide theoretical guidance for staging inflammatory therapeutic interventions.
    Keywords:  Amyotrophic lateral sclerosis; blood-brain barrier dysfunction; immune trajectories; metabolic reprogramming; neuroinflammation
    DOI:  https://doi.org/10.1080/17590914.2026.2715625
  2. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00015-2. [Epub ahead of print]189 205-236
    Exploring the effect of red and near-infrared light on neurodegenerative disease: A focus on amyotrophic lateral sclerosis, Charcot's devastating disease of the motor system.
    Audrey Valverde, Hélène Blasco, Philippe Corcia, Olivier Herault, Pierre Magistretti, Laurent Herault, Corrado Cali, Luca Bartesaghi, Jonathan Stone, John Mitrofanis.
      All neurodegenerative diseases, from Alzheimer's disease to amyotrophic lateral sclerosis (ALS), are characterised by a relentless and progressive degeneration of neurones. The degenerating neurones suffer from mitochondrial dysfunction, glutamate excitotoxicity, metabolic disorder and atypical protein aggregations; there is also widespread neuroinflammation and damage to the neurovascular unit across the nervous system. Unfortunately, there is no current treatment option that addresses all, if not many, of these striking abnormalities, one that stops or even slows the progression of the disease (ie neuroprotective). In this chapter, we explore the potential effectiveness of red and near infrared light (R-NIr) on ALS, one of the most devastating of all the neurodegenerative diseases. This condition impacts the motor system, from the cerebral cortex and brainstem to the spinal cord, as well as many skeletal muscles. Individuals suffer greatly and the survival period after onset of the first signs is often very short, averaging just over 2 years, as against 4-8 years in dementia. We outline two main reasons why R-NIr may have positive outcomes in ALS; (1) R-NIr has been shown to be neuroprotective in many other neurodegenerative diseases, improving cell function and survival, and; (2) unlike many other treatments attempted previously, R-NIr addresses many, if not all features of pathology associated with ALS. In summary, we suggest that R-NIr, with its multi-modal effect, could be a valuable treatment option for patients with ALS, particularly if the treatment is started early, before the development of excessive cellular damage.
    Keywords:  Amyotrophic lateral sclerosis; Near-infrared light; Neurodegenerative disease; Photobiomodulation; Red light
    DOI:  https://doi.org/10.1016/bs.irn.2026.01.013
  3. Eur J Neurol. 2026 Aug;33(8): e70717
    SOD1 Variants in Patients With Amyotrophic Lateral Sclerosis in Central Eastern Europe: From Genetic Testing to SOD1 Targeted Therapy.
    Magui Khazaal, Paula Stretavská, Magdalena Kuźma-Kozakiewicz, Krzysztof Nieporęcki, Adam Betík, Eva Vlčková, Monika Turčanová Koprušáková, Robert Petrovic, Hakan Cetin, Omar Keritam, Wolfgang Löscher, Christian Eggers, Stephan Iglseder, Radoslav Orenčák, Mária Judit Molnár, Zoltán Grosz, Tamás Szlepák, Blaž Koritnik, Magdalena Anna Koszewicz, Daniel Baumgartner, Lenka Slachtova.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is one of the most devastating fatal motor neuron diseases, characterized by progressive degeneration of motor neurons in the brain and spinal cord. A significant advance in ALS therapy was achieved with the recent European Medicines Agency approval of Tofersen, the first antisense oligonucleotide (ASO) specifically targeting SOD1 mRNA, a key genetic determinant of the disease. Yet, despite its clinical relevance, data on SOD1-ALS in Central Eastern Europe remain scarce.
    METHODS: Here, we present a multicentric study across six countries-Austria, Czechia, Poland, Hungary, Slovakia, and Slovenia-representing approximately 16% of the European Union's population. We report all pathogenic, likely pathogenic, and uncertain SOD1 variants, along with the phenotypic features, including heritability, age, site of onset, and survival. We also assessed the availability of genetic testing, counseling, and access to Tofersen therapy across the region.
    RESULTS: Out of 1200 patients with confirmed ALS, we identified 24 distinct pathogenic SOD1 variants in a total of 67 patients (median age at onset 47 [40-55] years), of whom 65.7% had familial ALS (fALS) and 34.3% had sporadic ALS (sALS). We characterized the associated phenotypes and reported that 42 patients are currently receiving Tofersen therapy.
    CONCLUSION: This study provides the first comprehensive overview of SOD1-ALS in Central Eastern Europe. Our findings underscore the importance of genetic testing and counseling, as well as equitable access to targeted therapies such as Tofersen to advance patient-specific care in this region.
    Keywords:  Central Eastern Europe; SOD1; Tofersen; amyotrophic lateral sclerosis; motor neuron disease; targeted therapy
    DOI:  https://doi.org/10.1111/ene.70717
  4. J Gene Med. 2026 Aug;28(8): e70106
    Exploring Genetic Therapies Targeting Amyotrophic Lateral Sclerosis in Animal Models: A Systematic Review and Meta-Analysis.
    Hannah E Wedgwood, Richard I Tuxworth, Zubair Ahmed.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative disease, for which there is currently no known cure. ALS primarily affects motor neurons, with rapid deterioration, meaning symptoms develop quickly, from problems with speech and muscle weakness to breathing issues and paralysis. This systematic review aimed to explore the preclinical efficacy of various genetic therapies used to target ALS using in vivo rodent models.
    METHODS: In vivo studies of genetic therapies targeting ALS and its symptoms published between January 2015 and December 2025 were included in this review. The following databases were used: Web of Science, Scopus and PubMed. The primary outcome investigated was the total number of motor neurons, with secondary outcomes of rodent survival and muscle function by observing rotarod performance also being analysed. The SYRCLE tool was used to assess risk of bias in included studies.
    RESULTS: Of the 451 studies identified by searching the databases, 53 studies were found to be eligible for this systematic review. The articles were divided into subcategories depending on the gene target of each therapy. Meta-analysis of outcomes within appropriate studies showed significant improvements for the majority of selected outcomes (p < 0.05), favouring genetic therapy intervention.
    CONCLUSIONS: Results suggest that genetic therapies in rodent models targeting ALS are effective. However, due to a high risk of bias in preclinical studies, further high-quality studies are warranted to support this conclusion and onward translation into the clinic.
    Keywords:  ALS; amyotrophic lateral sclerosis; genetic therapy; in vivo studies
    DOI:  https://doi.org/10.1002/jgm.70106
  5. Front Neurol. 2026 ;17 1901811
    Amyotrophic lateral sclerosis and degenerative cervical myelopathy: phenotype-based diagnostic pitfalls, investigative mismatch, and practical clinical reasoning.
    Dongxia Chen, Tao Shen, Hang Ren, Peng Qiu.
      Differentiating amyotrophic lateral sclerosis (ALS) from degenerative cervical myelopathy (DCM) remains difficult because the two disorders can converge clinically while diverging biologically. ALS is a progressive motor neuron disease, whereas DCM is a potentially treatable compressive myelopathy; however, both may present with upper-limb weakness, hand wasting, hyperreflexia, gait disturbance, and cervical MRI abnormalities. This narrative review examines ALS-DCM overlap through the concept of explanatory sufficiency: whether the available clinical, imaging, and electrophysiological evidence adequately explains the whole syndrome rather than a single visible abnormality. We synthesize evidence on phenotype-specific overlap, MRI-clinical mismatch, EMG/NCS distribution, somatosensory and motor evoked potentials, Gold Coast diagnostic criteria, primary lateral sclerosis, and coexistence of motor neuron disease with structural cervical pathology. The review emphasizes that MRI is indispensable but not self-interpreting, EMG/NCS is most useful when interpreted by distribution rather than positivity alone, and SEPs/MEPs can add a functional cord-conduction layer when MRI and examination are discordant. We also provide action-oriented clinical warning signs for common overlap scenarios. Rather than offering a rigid algorithm, this review proposes a clinically driven reasoning framework that helps distinguish ALS, DCM, radiculopathy, and coexistence while reducing premature diagnostic closure in neuro-spine practice.
    Keywords:  amyotrophic lateral sclerosis; degenerative cervical myelopathy; differential diagnosis; electrodiagnosis; explanatory sufficiency; magnetic resonance imaging
    DOI:  https://doi.org/10.3389/fneur.2026.1901811
  6. Mol Ther Adv. 2026 Sep 10. 34(3): 201822
    Neutralization of pathogenic PC-OxPL by AAV-delivered scFv as a therapeutic strategy for amyotrophic lateral sclerosis.
    Andreia Gomes-Duarte, Jamie K Wong, Alessandro Moro, Svetlana Pasteuning-Vuhman, Wouter Pos, Rob Haselberg, Marina Sogorb-González, Sofia Pascoal, Linda Borst, Madhurima Chatterjee, Martin Giera, Sotirios Tsimikas, Saud A Sadiq, Sander van Deventer.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder defined by progressive motor neuron loss and TDP-43 proteinopathy, yet the upstream drivers of this pathology remain unclear. Oxidized phosphatidylcholines (PC-OxPL) have emerged as potent inducers of proteinopathy in the central nervous system (CNS), but their role in ALS has not been systematically explored. We identify a distinct PC-OxPL signature in the cerebrospinal fluid (CSF) of patients with sporadic ALS (sALS) and show that apolipoprotein E (apoE)-containing particles are the primary PC-OxPL carriers in this compartment. In human iPSC-derived motor neurons, PC-OxPL exposure triggered disease-relevant transcriptional alterations and TDP-43 pathology, establishing PC-OxPL as a mediator of ALS-like neurodegeneration in vitro. To counteract this toxicity, we engineered an Adeno-Associated Virus (AAV)-delivered single-chain antibody fragment (scFv), PC-OxPL-VecTab, targeting PC-OxPL neoepitopes. PC-OxPL-VecTab neutralized PC-OxPL-induced neurotoxicity, reduced TDP-43 aggregation, and prevented motor neuron death and behavioral deficits in a sALS CSF transfer mouse model. Intrathecal delivery of PC-OxPL-VecTab in minipigs achieved broad CNS biodistribution and transgene expression, supporting the feasibility of CNS delivery. These findings position PC-OxPL as a mechanistic contributor to ALS pathogenesis and establish PC-OxPL-VecTab as a therapeutic strategy for ALS with potential broader applicability to disorders associated with PC-OxPL accumulation.
    Keywords:  TAR DNA-binding protein 43; amyotrophic lateral sclerosis; apolipoprotein E; gene therapy; oxidized phosphatidylcholines
    DOI:  https://doi.org/10.1016/j.omta.2026.201822
  7. ACS Med Chem Lett. 2026 Aug 13. 17(8): 1723-1724
    Novel Compounds as TREM2 Agonists for Treating Parkinson's Disease, Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Nasu-Hakola Disease, and Stroke.
    Ram W Sabnis, Anika R Sabnis.
      Provided herein are novel compounds as TREM2 agonists, pharmaceutical compositions, use of such compounds in treating Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Nasu-Hakola disease, and stroke, and processes for preparing such compounds.
    DOI:  https://doi.org/10.1021/acsmedchemlett.6c00372
  8. Discov Nano. 2026 Aug 17. pii: 401. [Epub ahead of print]21(1):
    Regenerative strategies for ALS: stem cells and extracellular vesicles.
    Trisha Raghunathan, Balaji Parthasarathy, Prajnya Prabhu, Preetham Mahesh, Anandh Dhanushkodi.
      Amyotrophic Lateral Sclerosis (ALS) is caused by progressive degeneration of upper and lower motor neurons. The disease is late onset, and to date, no early diagnosis is possible. Patients with ALS have a 5-year survival rate since diagnosis. Though recent studies highlighted the possible mechanisms of motor neuron degeneration in ALS, the treatment options are extremely limited. This underscores the urgent need to develop effective therapeutic strategies that can prolong patient survival and ultimately slow/halt ALS progression. Extracellular vesicles released from the degenerative milieu contribute to ALS propagation and progression by shuttling misfolded proteins, proinflammatory cytokines, and neurotoxins; thus, they could serve as a biomarker for diagnosis and prognosis. The advancement of stem cell-based therapies for neurodegenerative diseases and the evolving understanding of extracellular vesicles as potential biotherapeutics provide a ray of hope for millions of patients suffering from neurological disorders/neurodegenerative diseases like ALS.
    Keywords:  Adult stem cells; Amyotrophic lateral sclerosis; Exosomes; Neurodegeneration; Neuroprotection
    DOI:  https://doi.org/10.1186/s11671-026-04820-2
  9. Front Aging Neurosci. 2026 ;18 1868482
    Short-term ambient temperature increases are associated with higher mortality in amyotrophic lateral sclerosis: a case-crossover study of weather conditions.
    Maximilian Dimitrov, Julian Grosskreutz, Benjamin Ilse, Florian Rakers, Robert Steinbach.
       Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with vastly differing survival times. The influence of environmental exposures such as weather conditions on mortality among people living with ALS remain poorly defined. The aim of this study was to evaluate the association between short-term meteorological phenomena and the odds of death among patients with ALS.
    Methods: We conducted a retrospective case-crossover study of 298 deaths among clinically verified ALS patients that occurred within a weather-station catchment area. Daily mean data for temperature, atmospheric pressure, and relative humidity were analyzed. Associations were analyzed by comparing hazard intervals (1-3 days before death) with bidirectional control intervals in generalized linear mixed models. Results are expressed as odds ratios (OR) and 95% confidence intervals (CI).
    Results: Absolute meteorological conditions (temperature, pressure, humidity) showed no significant association with mortality, which was independently supported by seasonal/monthly death count analyses. Short-term temperature rises of 3 °C in the 24 h preceding the day before death were associated with 25% higher odds of death (OR 1.25; 95% CI 1.05-1.49). Exploratory subgroup analyses suggested that this association was most pronounced in female, ventilated, and older patients (≥65 years). Changes in relative humidity and atmospheric pressure were not significantly associated with the odds of death.
    Conclusion: Short-term temperature increases are associated with higher odds of death among people living with ALS, independent of absolute weather conditions or seasonal patterns. These findings support attention of stable ambient temperatures in end-stage care, while further studies of weather-related hazards in ALS are needed.
    Keywords:  amyotrophic lateral sclerosis; case-crossover study; end of life care; heat related mortality; mortality risk; temperature rise; thermoregulation; weather conditions
    DOI:  https://doi.org/10.3389/fnagi.2026.1868482
  10. Front Neurol. 2026 ;17 1822479
    Circulating neuron-derived cfDNA for blood-based detection of Alzheimer's and other neurodegenerative conditions.
    Chad Pollard, Ryan Miller, Isaac Stirland, Mykle Keni, Andrew Jenkins, Erin Saito, Jonathon T Hill, Tim Jenkins.
      Blood-based biomarkers for neurodegenerative diseases are improving early detection and staging, but current assays primarily reflect aggregate neuropathology or generalized neuronal injury and do not resolve the specific neuronal populations affected. Circulating cell-free DNA (cfDNA) retains stable DNA methylation patterns reflective of tissue and cellular origin, making it a promising substrate for cell-of-origin analysis. However, conventional methylation approaches are limited by bisulfite-associated DNA damage and amplification-related bias, hindering the detection of neuron-derived cfDNA, a small fraction of total circulating cfDNA. Here, we present proof-of-concept evidence that native nanopore sequencing can support both brain methylation atlas generation and downstream cfDNA cell-of-origin classifier development in neurodegenerative disease. By directly profiling endogenous DNA methylation without bisulfite conversion or PCR amplification, nanopore sequencing preserves native molecules, reduces processing-related bias, and enables flexible, genome-wide methylation profiling that can be iteratively expanded as additional reference cell types are incorporated. Using whole-genome native nanopore sequencing, we generated a methylation reference atlas from six primary human neural cell populations-cortical neurons, dopaminergic neurons, spinal motor neurons, astrocytes, Schwann cells, and microglia-and developed cell-type-informed cfDNA classifiers. Classifier performance was assessed in silico using dilution series designed to model physiologic admixture. The framework was then applied to 137 blood plasma samples from individuals with mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and healthy controls. Elevated circulating cfDNA fragments exhibited methylation patterns similar to reference profiles from selectively vulnerable neuronal populations, including cortical neuron-like signatures in AD and progressive MCI, dopaminergic neuron-like signatures in PD, and spinal motor neuron-like signatures in ALS. Multivariate integration of neuronal signatures improved the separation of diagnostic groups within this cohort (AUC > 0.85). Although the reported atlas is limited and additional validation in larger and independent cohorts will be required, these results support the feasibility of native cfDNA nanopore methylation sequencing as a flexible platform for brain-derived cfDNA analysis and more cell-type-informed investigation of neurodegeneration from peripheral blood.
    Keywords:  Alzheimer’s disease; blood biomarkers; cell-free DNA; liquid biopsy; methylation; mild cognitive impairment; neurodegeneration; precision medicine
    DOI:  https://doi.org/10.3389/fneur.2026.1822479
  11. Transl Neurodegener. 2026 Aug 18. pii: 39. [Epub ahead of print]15(1):
    PCSK9 inhibitors in neurodegenerative disorders: mechanisms, therapeutic potential, and clinical implications.
    Jia Dong James Wang, Andrea York Tiang Teo, Bin Xiao, Yinxia Chao, Zhi Dong Zhou, Brendan Jen-Wei Tan, Ling-Ling Chan, Elvira Rosalie, Eng-King Tan.
      Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in hepatic cholesterol metabolism via low density lipoprotein receptor degradation. PCSK9 inhibitors have revolutionized lipid-lowering therapy, providing robust reduction of cardiovascular risk. Large-scale randomized controlled trials and long-term extensions (e.g., FOURIER and EBBINGHAUS trials) have shown no significant adverse effects of PCSK9 inhibitors on neuropsychological testing or patient-reported cognitive outcomes, even with prolonged and intensive lowering of low-density lipoproteins. Pre-clinical studies also suggest PCSK9 as a key regulator of neurobiological processes, including synaptic plasticity, amyloid-beta clearance, neuroinflammation, and blood-brain barrier integrity. Human genetic studies revealed complex, sometimes conflicting associations between PCSK9 variants and risk of Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis. In this review, we highlight the pathophysiologic mechanisms, emerging experimental therapeutics and clinical implications of PCSK9 inhibition in neurodegenerative disorders. Long-term adequately powered trials with robust neuropsychological, biomarker, and imaging endpoints, as well as mechanistic studies in human-derived models are needed to establish the cardiovascular and neurocognitive implications of PCSK9 inhibition and guide precision medicine strategies for those at elevated risk of neurodegeneration.
    Keywords:  Alzheimer’s disease; Amyloid beta-peptides; Blood–brain barrier; Cholesterol metabolism; Cognition disorders; Neurodegenerative diseases; Neuroinflammation; PCSK9 inhibitors; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s40035-026-00568-y
  12. ChemistryOpen. 2026 Sep;15(9): e70286
    Integrated In Silico Discovery of Thymoquinone Analogs Targeting the Keap1-Nrf2 Pathway for Amyotrophic Lateral Sclerosis Therapy.
    Jabir C Nalicho, Petro E Mabeyo, Andrew S Paluch, Lucas Paul.
      Oxidative stress drives neuronal vulnerability in amyotrophic lateral sclerosis (ALS), making the Keap1-Nrf2 pathway a vital therapeutic target. While thymoquinone (TQ) modulates this axis, its efficacy is limited by low potency and poor drug-likeness. We utilized an integrated in silico workflow-including validated QSAR modeling (R2 = 0.68, Q2 ext = 0.66), ADMET profiling, docking, 200 ns molecular dynamics, and MM-PBSA analysis-to identify improved TQ-derived Keap1 inhibitors. Screening 64 analogs prioritized three leads (CHEMBL3416163, CHEMBL4636830, and CHEMBL221598) with favorable safety and blood-brain barrier permeability. Docking and dynamics confirmed these analogs form stable interactions with Kelch domain hotspots. MM-PBSA calculations revealed significantly enhanced binding free energies (-75.10 to -93.79 kJ mol-1) compared to parent TQ (-21.05 kJ mol-1), driven primarily by van der Waals and hydrophobic forces. This study identifies structurally tractable TQ analogs with improved predicted potency and establishes a robust computational framework for neuroprotective discovery. The prioritized leads are compelling candidates for in vitro and in vivo validation as redox-modulating agents in ALS.
    Keywords:  Keap1–Nrf2 signaling; QSAR modeling; amyotrophic lateral sclerosis; medicinal chemistry; molecular dynamics; molecular modeling; oxidative stress
    DOI:  https://doi.org/10.1002/open.70286
  13. Stem Cell Res Ther. 2026 Aug 18. pii: 285. [Epub ahead of print]17(1):
    Advances in the clinical application of mesenchymal stem cells for neurological disorders.
    Mohammad Chand Jamali, Alaa Shafie, Ali Jaber Alqahtani, Rithab Ibrahim Al-Samawi, Hanan Mesfer Alyami, Amal Adnan Ashour, Mohammed Fareed Felemban, Nasrin Mansuri, Faris J Tayeb, Irshad Ahmad, Mustafa Mudhafar, Salah Ahmed Sheweita.
      Therapeutic approaches employing mesenchymal stem cells (MSCs) have emerged as a promising avenue for investigating treatments for neurological disorders. This strategy aims to capitalize on the biological properties of MSCs to support the repair of damaged neural tissue and modulate pathological processes. This review provides a comprehensive overview of the current clinical evidence regarding MSC applications in major neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other pertinent disorders. Across clinical studies, MSC administration has generally demonstrated a favorable safety profile and procedural feasibility. However, therapeutic efficacy remains variable and inconsistent across trials. Importantly, differences in MSC sources, manufacturing procedures, delivery routes, dosing strategies, and patient selection contribute substantially to the heterogeneity of reported outcomes. Therefore, the current body of evidence supports the safety of MSC-based interventions, but their clinical effectiveness has not yet been consistently demonstrated. Future progress will depend largely on the standardization of cell preparation and treatment protocols, improved biomarker-driven patient stratification, and rigorously designed large-scale randomized trials.
    Keywords:  Clinical trials; MSCs; Neural regeneration; Regeneration medicine; Stem cell therapy; Translational therapy
    DOI:  https://doi.org/10.1186/s13287-026-05229-5
  14. Sleep Med Rev. 2026 Aug 14. pii: S1087-0792(26)00124-3. [Epub ahead of print]90 102352
    Sleep-wake control with age and neurodegenerative diseases.
    Wen-Xuan Tang, Chen Yang, Menghan Zhang, Clete A Kushida, Luis de Lecea, Shi-Bin Li.
      Aging causes dramatic alterations in bodily functions. Among them, sleep quality declines with age, particularly in individuals with neurodegenerative diseases. In this review, we first describe alterations in sleep-wake architecture and discuss potential mechanisms underlying sleep disorders that arise with age. We discuss evidence linking sleep disorders with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), progressive supranuclear palsy (PSP), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) syndrome. Even though the causes of AD, PD, PSP, and HD are diverse, several shared symptoms including difficulty falling asleep, fragmented sleep, and disrupted circadian rhythm collectively suggest their pathologies disrupt sleep-wake control. Hyperexcitability of implicated neurons is commonly observed prior to neurodegeneration. Upregulated neuronal excitability in the early phase of these diseases appears as a potential shared mechanism among neurodegenerative diseases. Abnormal protein accumulation and aggregation in these diseases exacerbate neuronal circuit hyperactivity by increasing neurons' intrinsic excitability or dampening inhibitory inputs to neurons controlling sleep-wake cycles. A better understanding of the mechanisms underlying sleep disorders that emerge with age may greatly benefit the development of novel preventative and therapeutic strategies for neurodegenerative diseases, and therefore improve the life quality of older adults.
    Keywords:  Aging; Circadian rhythms; Neural circuits; Neurodegenerative diseases; Neuronal excitability
    DOI:  https://doi.org/10.1016/j.smrv.2026.102352
  15. bioRxiv. 2026 Jul 28. pii: 2026.07.24.740361. [Epub ahead of print]
    A multi-omics characterization reveals distinct molecular signatures in the human motor cortex and lumbar spinal cord in ALS.
    Natalie Barretto, Benjamin T Fullerton, Aidan C Daly, Obadele Casel, Olena Kuksenko, Kristy Kang, Joana Petrescu, Maya Xia, Jacqueline Eschbach, Matthew Leung, Shruti Khiste, Brhan Gebremedhin, Colin Smith, Christopher A Jackson, Hemali Phatnani.
      Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by the loss of upper motor neurons in the motor cortex (MTC) and lower motor neurons in the spinal cord, leading to muscle atrophy and ultimately respiratory failure. While motor neurons (MNs) are the selectively vulnerable cell type, their interactions with glia contribute to the progression of ALS pathology. However, it remains unclear whether the site of ALS symptom onset influences the molecular alterations underlying MN and glial dysfunction and whether these alterations are shared between the MTC and lumbar spinal cord (LSC). To address these questions, we constructed spatially-resolved gene expression maps of the MTC and LSC by combining spatial and single-nucleus transcriptomic profiles from a cohort of non-neurological controls and ALS donors clinically stratified by site of symptom onset. In the ventral horn of the LSC, we see a decrease in genes associated with MNs and synaptic signaling in ALS donors. We also identify region-specific alterations in endothelial- and glial-related functions. Notably, the severity of these MN deficits and endothelial-related functions is influenced by the site of symptom onset, whereas alterations in glial function largely are not. In contrast to the LSC, we observe layer-specific increases in synaptic signaling in the MTC of ALS donors. Comparing the molecular and cellular changes within the LSC and MTC in ALS indicates that they are predominantly non-overlapping, and have different molecular signatures.
    DOI:  https://doi.org/10.64898/2026.07.24.740361
  16. Brain Res. 2026 Aug 17. pii: S0006-8993(26)00372-0. [Epub ahead of print]1891 150510
    Annexin A1 inhibits neuronal apoptosis in amyotrophic lateral sclerosis by restraining the Hippo pathway.
    Ying Zhang, Xinyu Dong, Yao Shai, Masood Alam, Didi Han, Yujing Hu, Zhonghui He, Zhenqi Zhou, Hongquan Jiang.
      Annexin A1 (ANXA1) is a multifunctional regulatory protein involved in neuroinflammation and cellular homeostasis, but its role in amyotrophic lateral sclerosis (ALS) remains unclear. In this study, we investigated the relationship between ANXA1 and Hippo pathway signaling in ALS. Bioinformatic analysis of transcriptomic data from iPSC-derived motor neurons showed that ANXA1 expression was reduced in ALS and associated with apoptosis and Hippo pathway-related changes. Decreased ANXA1 expression was confirmed in hSOD1^G93A transgenic mice and NSC34 motor neuron-like cells. Phosphorylation levels of MST1/2, LATS1/2, and YAP1 were elevated, indicates activation of the Hippo pathway. Functional experiments showed that ANXA1 overexpression reduced Hippo pathway activation, enhanced cell viability, and decreased apoptosis, as increased Bcl-2 expression and reduced Bax and cleaved caspase-9 levels. In contrast, ANXA1 knockdown further activated Hippo pathway and aggravated apoptotic changes. These findings identify ANXA1 as an upstream regulator associated with Hippo pathway activation in ALS and suggest that the ANXA1/Hippo axis may represent a potential therapeutic target.
    Keywords:  ANXA1; Amyotrophic lateral sclerosis; Apoptosis; HIPPO pathway
    DOI:  https://doi.org/10.1016/j.brainres.2026.150510
  17. Adv Immunol. 2026 ;pii: S0065-2776(26)00021-0. [Epub ahead of print]171 307-341
    Microglia extracellular traps (MiETs) in Neurodegeneration: Mechanisms, Evidence Gaps, and Untapped Therapeutic Promise.
    Lipika Sha, Sushmita Jha.
      Microglia are the resident myeloid cells of the central nervous system, they play essential roles in neural tissue homeostasis, including synaptic pruning, clearance of debris and protein aggregates, and regulation of neuroinflammatory processes. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, microglial activation and chronic glial-driven inflammation contribute substantially to neuronal dysfunction and loss. Beyond these well-characterised functions, recent evidence indicates that microglia can release chromatin-based extracellular traps (microglia extracellular traps, or MiETs), similar to the neutrophil extracellular traps (NETs) observed in peripheral immunity. Microglia ETs are induced by stimuli such as dopamine and microbial infection, dependent or independent of NADPH oxidase/ROS pathways and histone citrullination. This chapter provides a detailed examination of MiET formation, triggers, intracellular signalling, and structural components, as well as contribution to neurodegenerative pathology. Potential mechanisms include amplification of neuroinflammation via extracellular histones and proteases, disruption of the blood-brain barrier and extracellular matrix, synaptic damage, and possible facilitation of spread of misfolded protein aggregates. We situate MiET formation within the broader microglial functional repertoire (phagocytosis, cytokine production, synaptic stripping) and focus on how ET-dominant responses may compromise homeostatic or neuroprotective roles. The chapter reviews evidence from disease models, highlights key gaps and discusses translational implications. Targeting MiET formation or promoting the clearance of MiETs represents promising, yet unexplored, therapeutic avenues in neurodegenerative disease. By focusing on MiETs, this work expands the conceptual framework for microglial pathogenicity and invites future mechanistic and translational research.
    Keywords:  Blood–brain barrier; Histone citrullination; Microglia; Microglia extracellular traps (MiETs); Neurodegeneration; Neuroinflammation; Therapeutic targeting
    DOI:  https://doi.org/10.1016/bs.ai.2026.04.008
  18. J Otol. 2026 Jul;21(3): 160-166
    Auditory Biomarkers in Neurodegenerative Disorders: A Literature Review.
    Sreevidhya Palakkot, Arun Banik.
      The prevalence of neurodegenerative diseases is escalating globally. However, the conventional diagnostic framework fails to identify the pathology until substantial neuronal damage occurs. The evidence from the recent literature indicates that auditory dysfunction commonly precedes motor and cognitive symptoms across multiple neurodegenerative diseases. The pathophysiology involves both the peripheral and cortical auditory structures, which produce distinctive patterns reflects systemic neurodegeneration. Hence, this suggests auditory assessment as a valuable tool for early identification of neural degeneration. This review synthesises the contemporary literature on auditory dysfunctions and underlying pathophysiology in Alzheimer's disease, Parkinson's disease, Frontotemporal dementia, Amyotrophic lateral sclerosis, etc. The analysis included the temporal trajectories of auditory impairment, subjective-objective measurements, and evaluated the importance of early identification and longitudinal tracking. Objective measures of central auditory processing, including Auditory Brainstem Responses, P300, Mismatch Negativity, and speech-in-noise testing, provide objective, non-invasive diagnostic tools and its sensitivity comparable to established biomarkers. Integration of standardised auditory assessment batteries into clinical protocols could enable the early identification of pathology, differential diagnosis and the development of novel therapeutic strategies for both auditory and cognitive deficits. Current review suggests that future longitudinal studies with neurodegenerative conditions should focus on the clinical utility of auditory, cognitive, and neuroimaging biomarkers and facilitate clinical translation of these findings.
    Keywords:  auditory dysfunction; biomarkers; central auditory processing disorder; early diagnosis; electrophysiology; neurodegenerative disorder
    DOI:  https://doi.org/10.26599/JOTO.2026.9540067
  19. Front Neurol. 2026 ;17 1883977
    Genetic profile of motor neuron disease in a multiregional Brazilian cohort: an 18-year real-world experience in 1,911 patients.
    Christian Marques Couto, Elisa de Melo Queiroz, Maria Carolina da Cunha, Savana Camilla de Lima Santos, Alessandra De La Roque Ferreira, Osvaldo José Moreira Nascimento.
       Background: Genetic testing in amyotrophic lateral sclerosis (ALS) is increasingly recommended for all patients, but real-world implementation in middle-income countries remains heterogeneous. Brazilian motor neuron disease genetics has largely been characterized through protocol-based cohorts focused on the founder VAPB p.Pro56Ser variant (amyotrophic lateral sclerosis type 8, ALS8). The broader genetic landscape beyond ALS8 in Brazilian clinical populations has not been described in a large multiregional cohort. We aimed to characterize this profile.
    Methods: We retrospectively analyzed 1,911 patients with motor neuron disease followed at six SARAH Network rehabilitation hospitals across Brazil between 2007 and 2024. Genetic testing was clinically directed; ALS8 cases (n = 78) were characterized separately. We assessed characteristics of genetically tested versus untested patients, the temporal evolution of testing modalities, and the diagnostic yield by gene and by Byrne family history classification.
    Results: Of 1,833 patients without ALS8, 318 (17.3%) underwent genetic testing, with selection bias toward younger age, higher educational attainment, and positive family history of ALS or frontotemporal dementia (all p < 0.001). Testing expanded markedly after 2020, particularly C9orf72 screening and next-generation sequencing panels. Panel/exome sequencing identified pathogenic or likely pathogenic variants in 13 of 66 patients (19.7%), consistent with international literature for mixed familial-sporadic cohorts. Across all modalities, 30 patients without ALS8 carried pathogenic or likely pathogenic variants in six genes: SOD1 (n = 15), C9orf72 (n = 11; 7.0% of 157 tested), and VCP, FUS, TBK1, and SETX (n = 1 each). ATXN2 intermediate-length CAG repeats were identified in 15 of 230 patients tested (6.5%), replicating the 6.3% previously reported in a Brazilian multicenter sample. Yield by Byrne classification followed a marked gradient (Definite: 89.7%, Probable: 24.0%, Possible: 15.4%, Sporadic: 4.9%; p < 0.001). The SOD1 spectrum included recurrent variants of likely Iberian/European origin.
    Conclusion: This 18-year cohort defines a real-world genetic profile of motor neuron disease beyond ALS8, with diagnostic yield comparable to the literature and a Byrne gradient supporting universal testing. Beyond family history, socioeconomic factors appeared to shape access to testing, reinforcing the importance of equitable genetic testing for diagnostic precision, family counseling, and access to gene-targeted therapy.
    Keywords:  ATXN2; Brazilian cohort; C9orf72; SOD1; amyotrophic lateral sclerosis; genetic testing; motor neuron disease; real-world evidence
    DOI:  https://doi.org/10.3389/fneur.2026.1883977
  20. Adv Healthc Mater. 2026 Aug 19. e71594
    Mitochondria-Targeted Nanotherapies in Aging Neurodegenerative Disorders: Emerging Prospects and Clinical Potential.
    Dnyandev G Gadhave, Ashish B Jadhav, Nitin B Waghamode, Shubham Khot, Rajiya Khan, Ravi Hole, Shankar M Dhobale, Manoj Aswar, Keshav Raj Paudel.
      Aging is a significant risk factor of neurodegenerative disorders (NDs) such as Huntington's, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Although several clinical, neuroimaging, and biomarker-based diagnostic approaches are available for NDs, their limited sensitivity for early-stage detection, disease specificity, and prediction of disease progression continue to present significant clinical challenges, often resulting in delayed diagnosis and therapeutic intervention. According to previously published works, the preliminary pathological feature of such disorders is mitochondrial dysfunction. This may lead to elevated oxidative stress, impaired mitophagy, unbalanced mitochondrial function, and bioenergetic failure. This review examines how mitochondria-targeted nanotherapeutic approaches can overcome these pathological barriers and improve therapeutic outcomes in aging-associated neurodegeneration. Targeted delivery of drug-loaded nanocarriers, such as gene-delivery, lipid-based, metallic, and polymeric nanoparticles, has emerged as a potential platform to deliver medication directly to defective mitochondria. It may increase mitochondrial biogenesis, maintain redox balance, and protect against neuronal degeneration. This work incorporates disease-specific mitochondrial pathology with current progress in targeted nanotherapeutics, age-associated delivery barriers, clinical revolution, and emerging artificial intelligence (AI)-enabled precision therapeutic approaches. Mitochondria-targeted nanotherapeutics depict a potential disease-modifying strategy for aging-related NDs. However, further advancements in targeting efficacy, scalable production, long-term safety, and clinical validation can facilitate a successful clinical revolution.
    Keywords:  blood–brain barrier; clinical insights; mechanistic insights; mitochondrial dysfunction; nanotechnology; neurodegenerative disorders
    DOI:  https://doi.org/10.1002/adhm.71594
  21. Mol Ther Adv. 2026 Sep 10. 34(3): 201820
    i.c.v. delivery of AAV9-synapsin-promoted caveolin-1 attenuates neuromuscular deficits and neuromuscular degeneration in hSOD1G93A mice.
    Noriyuki Watanabe, Yumi Kawahori, Vinh Ta, Dongsheng Wang, Kenneth A Ohgi, Hongxia Wang, Natalia Kleschevnikova, Eiichi Ishikawa, Brian P Head.
      Practical and broad biodistributable gene delivery interventions are essential for advancing therapeutic strategies targeting neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously demonstrated that subpial delivery of AAV9-synapsin-promoted caveolin-1 (SynCav1) afforded significant neuroprotective effects in mutant superoxide dismutase (SOD)-1-induced ALS pathology. However, subpial delivery is regionally restricted, technically challenging, and highly invasive. This study evaluated whether the intracerebroventricular (i.c.v.) route of administration (ROA), an alternative CNS delivery strategy less invasive than direct spinal cord injections, could achieve broader CNS biodistribution and produce functional or histological benefits in hSOD1G93A mice. i.c.v. administration of AAV9-SynCav1 achieved widespread Cav-1 overexpression in the motor cortex and spinal cord. SynCav1-treated male mice exhibited improved running wheel (RW) performance and better motor-evoked potentials. Immunofluorescence revealed attenuated degeneration of cholinergic motor neurons (MNs) in the cervical and lumbar ventral horn, as well as preserved diaphragm neuromuscular junction (NMJ) innervation in SynCav1-treated mice. These findings serve as preclinical proof of concept that i.c.v. delivery of AAV9-SynCav1 can achieve CNS target engagement and produce selective functional and anatomical benefits in hSOD1G93A mice.
    Keywords:  AAV9-SynCav1; amyotrophic lateral sclerosis; caveolin-1; intracerebroventricular administration; motor neuron; neuroprotection
    DOI:  https://doi.org/10.1016/j.omta.2026.201820
  22. Brain Res. 2026 Aug 21. pii: S0006-8993(26)00375-6. [Epub ahead of print] 150513
    A replicated astrocyte long non-coding RNA signature of Alzheimer's disease is inverted in amyotrophic lateral sclerosis.
    Hidenori Tani.
      Reactive astrocyte transitions are central to neurological disease, yet their long non-coding RNA (lncRNA) regulators remain poorly defined, and single-nucleus studies frequently treat nuclei rather than donors as replicates. This study analyses publicly available human single-nucleus RNA sequencing from four disorders using donors as the unit of inference throughout: Alzheimer's disease (AD; middle temporal gyrus, 88 donors), C9orf72-associated amyotrophic lateral sclerosis and ALS/frontotemporal dementia (ALS; frontal cortex), multiple sclerosis (MS; cortex and white matter), and major depressive disorder (MDD; amygdala). The public MDD release pools nuclei by condition, so that arm cannot support donor-level inference and is exploratory only. Covariate-adjusted pseudobulk analysis of 70,009 CE astrocytes, controlling for sex, age at death and assay chemistry, identified 1,019 down-regulated autosomal lncRNAs after sex-chromosome transcripts were removed. This signature was not attributable to astrocyte subtype composition, which did not differ between groups, and 99.9% of members remained down-regulated within the dominant homeostatic subtype alone. The signature replicated in an independent AD cohort (32 of 41 testable members concordant; resampling P < 0.0001). Testing it outside AD gave a directional result: it was concordant in the MS discovery cohort (P < 0.0001) but inconclusive in an independent MS cohort in which the transcripts lay near the detection floor, and it was reproducibly inverted in ALS, in the C9orf72 discovery cohort and in an independent motor-cortex cohort not restricted to C9orf72 carriers. The inversion survived negative controls for global normalisation and expression level. These astrocyte lncRNA changes are therefore disorder-specific rather than pan-neuroinflammatory.
    Keywords:  Disorder specificity; Donor-levelpseudobulk inference; Independent replication; Long non-coding RNA; Reactive astrocyte; Single-nucleus RNA sequencing
    DOI:  https://doi.org/10.1016/j.brainres.2026.150513
  23. Front Neurol. 2026 ;17 1889931
    Cerebellar ataxia-onset ALS with SOD1 D91A mutation: a rare phenotype.
    Denis V Shevchuk, Evgeny P Nuzhnyi, Ekaterina Yu Fedotova, Margarita V Ershova, Ivan V Minaev, Georgy A Anikin, Arina R Protsenko, Natalia Yu Abramycheva, Maria N Zakharova, Sergey N Illarioshkin.
       Background: Amyotrophic lateral sclerosis (ALS) associated with mutations in the superoxide dismutase 1 (SOD1) gene is recognized for phenotypic variability, yet cerebellar ataxia as a presenting feature has been reported only in isolated cases.
    Methods: We describe four unrelated patients: three men and one woman, aged 35 to 49 years at symptom onset, who carried the SOD1 D91A (p.Asp91Ala) mutation. Two patients were heterozygous and two homozygous for the D91A variant. Clinical, neuroimaging, electrophysiological and genetic data were reviewed.
    Results: All patients presented with progressive gait ataxia as their initial and predominant symptom, with upper and lower motor neuron signs emerging months to years later and ultimately meeting criteria for ALS. Diagnostic latencies from ataxia onset to recognition of ALS ranged from 3 to 9 years. Cerebellar signs included gait and limb ataxia, dysmetria, intention tremor, and oculomotor abnormalities; neuroimaging revealed mild cerebellar atrophy only in one case, and electrophysiological evidence of lower motor neuron involvement was often limited at initial assessment. To our knowledge, this is the largest reported case series of patients homogeneous for a single SOD1 mutation and a shared cerebellar ataxia-onset ALS phenotype.
    Conclusion: The findings expand the clinical spectrum of SOD1-associated ALS and underscore the importance of SOD1 genetic testing in patients with progressive adult-onset ataxia of undetermined origin, particularly given the emerging availability of SOD1-targeted therapies.
    Keywords:  Asp91Ala; D91A; SOD1; amyotrophic lateral sclerosis; cerebellar ataxia; genotype–phenotype correlation; motor neuron disease
    DOI:  https://doi.org/10.3389/fneur.2026.1889931
  24. Ann Neurol. 2026 Aug 19.
    Associations between Pre-Disease Biomarkers of Persistent Organic Pollutants and Amyotrophic Lateral Sclerosis Survival in the Danish Diet, Cancer and Health Study Cohort.
    Aline Davias, Paul Knekt, Panu Rantakokko, Johnni Hansen, Marc G Weisskopf.
       OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord. Most patients survive 3 to 5 years after diagnosis, although some live 10 years or more. Prognostic factors are incompletely understood, but previous case-control studies suggest that exposure to persistent organic pollutants (POPs) may be associated with ALS survival, but this has not been explored within prospective analysis of POP biomarkers. In this study, we aimed to prospectively investigate the relationship between exposure to POPs-assessed in pre-disease plasma samples-and survival with ALS in the Danish Diet, Cancer, and Health study cohort.
    METHODS: We identified 166 incident ALS cases using the Danish National Patient Register via International Classification of Diseases (ICD) codes. We measured concentrations of 13 polychlorinated biphenyls (PCBs), 9 organochlorine pesticides, and 3 polybrominated diphenyl ethers in plasma samples collected at inclusion in the study (baseline). To assess the relationship between POP exposures and ALS survival, we used separate Cox models for each POP group adjusting for diagnosis age, sex, smoking status, body mass index, and marital status. We selected the most relevant POP groups for ALS survival using an elastic net penalized Cox proportional hazards regression model and then ran a model using a summary environmental risk score (ERS).
    RESULTS: Single-pollutant Cox models showed that exposure to non-dioxin like PCBs, hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), and chlordane compounds were associated with shorter survival. Elastic net penalized Cox proportional hazards regression selected HCB and chlordane compounds as the most relevant POPs for survival. The ERS Cox model showed a significant association with shorter survival (hazard ratio [HR]: 1.4, 95% confidence interval [CI]: 1.1-1.7). A 1 standard deviation (SD) higher ERS score was associated with an HR for death of 1.4 (95% CI: 1.1-1.7). Predicted median survival for those with an ERS score 1 SD higher than the mean was 12 months shorter (26 vs 38 months).
    INTERPRETATION: Our study suggests that pre-disease exposure to some POPs such as HCB and chlordane compounds could negatively influence ALS survival. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78334
  25. Front Microbiol. 2026 ;17 1842792
    Cross sectional analysis of gut microbiota of ALS patients with and without percutaneous endoscopic gastrostomy.
    Jose Enrique de la Rubia Ortí, Guillermo Bargues-Navarro, Sandra Sancho-Castillo, Jesús Privado, María Benlloch García, Claudia Emmanuela Sanchis Sanchis, Laura Garcia Martinez, María Cuerda-Ballester, Palmira Martínez Bolós, Francisco Jose Roig.
       Introduction: This cross-sectional study investigated the differences in gut microbiota in patients with Amyotrophic Lateral Sclerosis (ALS) with and without percutaneous endoscopic gastrostomy (PEG), exploring their cross-sectional associations with nutritional intake.
    Methods: Use of shotgun metagenomics and dietary assessments.
    Results: We identified significant taxonomic shifts and changes in diversity across groups. PEG patients exhibited reduced abundance of short-chain fatty acids (SCFAs)- producing genera, such as Faecalibacterium and Lachnospira, suggesting a dysbiotic profile; the Firmicutes/Bacteroidetes ratio was also lower in PEG patients but is reported as a descriptive indicator only. Correlations between specific bacterial taxa and nutrient intake, highlight the potential role of the gut microbiota in ALS pathophysiology. These findings describe cross-sectional differences in microbial composition associated with nutritional status and feeding route.
    Discussion: Our results provide a foundation for microbiome-targeted interventions in the management of ALS, although findings related to PEG should be interpreted as exploratory given the limited sample size. Furthermore, all comparisons involving the external control group (BioProject PRJNA961076) must be interpreted with caution due to potential batch effects from differences in sample collection, DNA extraction kits, and sequencing platforms.
    Keywords:  amyotrophic lateral sclerosis; bacterial diversity; gut microbiota; metagenomics; nutritional assessment; percutaneous endoscopic gastrostomy
    DOI:  https://doi.org/10.3389/fmicb.2026.1842792
  26. J Vis Exp. 2026 Aug 18.
    Ultrasound-Controlled Blood-Brain Barrier (BBB) Opening in a BBB-Glioblastoma Microfluidic Chip for Drug Delivery Studies.
    Yihong Li, Liyang Wu, Huadong Fan.
      The blood-brain barrier (BBB) is a major obstacle to treating glioblastoma (GBM) by restricting the entry of most therapeutic molecules into the brain. Interspecies differences in BBB structure and function complicate the clinical translation of animal models, highlighting the need for human-relevant in vitro BBB platforms for assessing drug permeability in GBM therapy. Here, a protocol is described for constructing a microfluidic BBB-GBM chip model. This model establishes a tri-culture system comprising human cerebral microvascular endothelial cells (HCMECs), primary astrocytes (ACs), and U87-MG cells within a Matrigel-embedded microfluidic platform. BBB integrity is verified through continuous zonula occludens-1 (ZO-1) immunostaining and FITC-dextran permeability assay. Low-intensity ultrasound (US) (1 MHz, 1 W/cm2, 30 s) is then employed to induce transient and largely reversible BBB opening, allowing tumor-targeting nanomicelles (SFN@RB@SPMs) to efficiently traverse the barrier and accumulate in GBM cells. A key feature of this protocol is the integration of real-time BBB permeability and drug delivery measurements within a single ultrasound-responsive chip, providing a powerful platform to dissect the mechanisms of ultrasound-augmented drug delivery in GBM.
    DOI:  https://doi.org/10.3791/72041
  27. Extracell Vesicle. 2026 Jun;pii: 100100. [Epub ahead of print]7
    Mitochondria-containing large extracellular vesicles target mouse motor neurons upon intramuscular injection.
    Paromita Paul Pinky, Zhong-Min Wang, Purva Khare, Jhanvi R Jhaveri, Abigail Sullivan, Vivek Basudkar, Krithika S Rao, Audrey Lawrence, Adithri Pingali, Kandarp M Dave, Donna B Stolz, Ming Sun, Si-Yang Zheng, Sruti S Shiva, Carol Milligan, Osvaldo Delbono, Devika S Manickam.
      Amyotrophic Lateral Sclerosis (ALS) is a neurological disorder that causes progressive degeneration of motor neurons. Mitochondrial dysfunction accelerates neurodegeneration, aggravating the severity of ALS. We hypothesized that increasing the mitochondrial function of motor neurons may promote neuronal survival. Therefore, we investigated the potential of neuron-derived mitochondria containing extracellular vehicles (EVs) as a novel therapeutic approach for ALS using differentiated NSC-34 cells as a surrogate for neurons. Neuron derived-large EVs (lEVs) but not small EVs (sEVs) contained mitochondria. However, we observed increased cell viability and oxygen consumption rates in heat-stressed neurons treated with both sEVs and lEVs suggesting improved mitochondrial function in recipient neurons. The increased oxygen consumption rates in sEV-treated heat-stressed neurons was accompanied by a greater proton leak compared to lEV treatment. The greater proton leak observed with sEVs likely suggests a lower efficiency of oxidative phosphorylation compared to that achieved by cells treated with mitochondria-containing lEVs. These findings suggest that mitochondrial components present in sEVs, such as proteins and mitochondrial DNA, may too contribute to improving cellular respiration. Furthermore, we have demonstrated that lEV mitochondria are transported into the lumbar spinal cord motor neurons following intramuscular injection in C57BL/6 mice in an EV dose-dependent manner. Collectively, for the first time, we have demonstrated the therapeutic effects of neuronal EVs in recipient heat-stressed neurons and the delivery of lEV mitochondria to spinal cord motor neurons in vivo without any EV surface modifications for neuronal targeting. Further studies will determine the therapeutic efficacy of mitochondria-containing EVs in the SOD1G93A transgenic mouse model of ALS.
    Keywords:  ALS; EVs; extracellular vesicles; large EVs; mitochondria; motor neurons; small EVs; spinal cord
    DOI:  https://doi.org/10.1016/j.vesic.2025.100100
  28. J Neurol. 2026 Aug 19. pii: 532. [Epub ahead of print]273(9):
    Gold Coast criteria for ALS diagnosis: individual participant data meta-analysis.
    Nipun Shrestha, Zachary Munn, Aicee Calma, Nathan Pavey, Yukiko Tsuji, Parvathi Menon, Alessandro Padovani, Barbara Risi, Lucia Ferullo, Massimiliano Filosto, Gordon Jewett, Kazumoto Shibuya, Ryo Otani, Toshio Shimizu, Satoshi Kuwabara, Yu-Ichi Noto, Takamasa Kitaoji, Birger Johnsen, Dongchao Shen, Liying Cui, Leonard H van den Berg, Ruben P A van Eijk, Philip van Damme, Matthew C Kiernan, Lynne Giles, Steve Vucic.
       BACKGROUND: To evaluate the diagnostic accuracy of the Gold Coast criteria (GCC) and compare their performance with the revised El Escorial (rEEC) and Awaji criteria in patients with suspected amyotrophic lateral sclerosis (ALS).
    METHODS: Embase, MEDLINE, and Scopus were searched for English-language studies published between January 1, 2020, and August 11, 2025. Eligible studies assessed the diagnostic accuracy of GCC compared with rEEC and Awaji criteria in suspected ALS. Authors were invited to contribute individual participant data. Data were checked, harmonised, and recoded. A one-stage individual-participant data meta-analysis, adjusted for age and sex, was performed. Diagnostic performance was assessed using pooled sensitivity, specificity, and area under the receiver operating characteristic curve. Risk of bias was assessed using QUADAS-2 and QUADAS-C, and certainty of evidence using GRADE for diagnostic test accuracy. The study was registered with PROSPERO, CRD420251123597.
    RESULTS: Individual participant data were available for 3007 participants from five international studies. GCC demonstrated higher sensitivity than rEEC and Awaji criteria: 0.96 (95% confidence interval [CI] 0.93-0.98) versus 0.87 (95% CI 0.78-0.92) and 0.87 (95% CI 0.78-0.93), respectively. Certainty of evidence for sensitivity was moderate at pre-test probabilities of 50% and 75%, and low at 25%. Specificity was numerically lower for GCC at 0.68 (95% CI 0.53-0.81) compared with rEEC at 0.73 (95% CI 0.59-0.83) and the Awaji criteria at 0.72 (95% CI 0.57-0.83). The certainty of evidence for specificity was rated as very low across all assessed pre-test probabilities (25%, 50%, and 75%).
    CONCLUSIONS: GCC provide a sensitive framework for suspected ALS and may support earlier diagnosis in specialist settings. Specificity was imprecise and heterogeneous, supporting use with mimic exclusion and longitudinal reassessment.
    Keywords:  Amyotrophic lateral sclerosis; Awaji and revised El Escorila criteria; Gold Coast criteria
    DOI:  https://doi.org/10.1007/s00415-026-14046-y
  29. Brain Commun. 2026 ;8(4): fcag307
    Altered perivascular space diffusivity dynamics in motor neuron disease.
    Ilaria Bottale, Edoardo G Spinelli, Silvia Basaia, Alma Ghirelli, Andrea Gardoni, Tommaso Russo, Elisa Canu, Veronica Castelnovo, Paride Schito, Yuri Falzone, Massimo Filippi, Federica Agosta.
      Converging evidence supports a key pathogenic role of the glymphatic system in the accumulation of pathological aggregates in several central nervous system proteinopathies, including amyotrophic lateral sclerosis and other motor neuron diseases. This study aimed to investigate potential glymphatic impairment using diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) across motor neuron disease phenotypes, to examine its clinical correlates, and to assess its relationship with white matter damage. Fifty-seven patients with motor neuron disease and 32 age- and sex-matched healthy controls underwent a 3 Tesla brain MRI scan, including diffusion tensor imaging sequences. We obtained the DTI-ALPS index from each individual, evaluating its relationship with measures of motor and cognitive disability, site of symptom onset, cognitive status, genetic status and fractional anisotropy of white matter tracts. Comparisons between groups were evaluated using analysis of covariance adjusting for age, sex, local fractional anisotropy and white matter hyperintensity burden. Partial correlations with clinical and cognitive measures were also tested. Patients with motor neuron disease exhibited significantly lower DTI-ALPS index values relative to healthy controls (P = 0.05). Patients with bulbar onset had lower DTI-ALPS values than those with spinal onset (P = 0.017). Comparable DTI-ALPS values were found across patients with classical amyotrophic lateral sclerosis clinical presentation and predominant upper or lower motor neuron clinical presentations, with no effect of cognitive diagnosis or genetic status. DTI-ALPS exhibited a significant correlation with disease duration (r = -0.38, P = 0.01). Motor neuron disease patients presenting insomnia had significantly lower DTI-ALPS values compared to those without sleep disturbances (P = 0.002). Significant positive correlations were found between ALPS index and fractional anisotropy values across major white matter tracts, including the internal and external capsules, superior longitudinal fasciculi, anterior, posterior and superior corona radiata, posterior thalamic radiation, fornix and the genu and body of the corpus callosum. This study confirms the presence of altered interstitial fluid diffusivity dynamics across motor neuron disease phenotypes, with greater impairment observed in bulbar-onset cases, patients with longer disease duration, and those experiencing more pronounced sleep disturbances. These findings may support a potential pathogenic role of glymphatic failure in the accumulation of TAR DNA-binding protein 43 proteinopathy and widespread microstructural axonal damage in motor neuron diseases.
    Keywords:  DTI-ALPS; MRI; amyotrophic lateral sclerosis; glymphatic system; motor neuron disease
    DOI:  https://doi.org/10.1093/braincomms/fcag307
  30. Zhen Ci Yan Jiu. 2026 Aug 25. pii: 1000-0607(2026)08-1044-09. [Epub ahead of print]51(8): 1044-1052
    ["Jiaji" (EX-B2) electroacupuncture modulates NLRP3 inflammasome activation to improve limb dysfunction in amyotrophic lateral sclerosis mice].
    Shi-Lin Wang, Long He, Jing Yang, Na Zhang, Yuan-Zheng Sun, Guan-Ping Liu.
       OBJECTIVES: To investigate the regulatory effect of "Jiaji" (EX-B2) electroacupuncture (EA) on the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome in the lumbar spinal cord and to explore its mechanism in improving limb dysfunction in amyotrophic lateral sclerosis (ALS) mice.
    METHODS: Fifty-four mice carrying the human superoxide dismutase 1 G93A (hSOD1G93A) gene were randomly divided into model, Jiaji EA, and inhibitor groups, with 18 mice per group. Eighteen mice not carrying the hSOD1G93A gene served as wild group. At 60 d of age, the Jiaji EA group was given EA at L1-L2 and L5-L6 EX-B2 points with continuous wave, 1 mA, 2 Hz. The needles retained for 20 min, twice every week. The inhibitor group received intraperitoneal injection of the NLRP3 inhibitor (10 mg/kg, twice every week). All treatments were administered for 4 consecutive weeks. The survival period of mice in each group was observed to assess disease progression；the rotarod test was conducted to evaluate motor coordination and limb motor function；HE staining was used to observe pathological changes in the gastrocnemius, and muscle atrophy was assessed by measuring the cross-sectional area of the gastrocnemius fiber；Nissl staining was performed to evaluate the number of motor neurons in the lumbar spinal cord anterior horns；the protein expressions of NLRP3, Caspase-1, apoptosis-associated speck-like protein (ASC), interleukin-1β (IL-1β), interleukin-18 (IL-18), and tumor necrosis factor-α (TNF-α) in the lumbar spinal cord were detected by Western blot；the mRNA expressions of NLRP3, Caspase-1, ASC, IL-1β, IL-18, and TNF-α were detected by real-time quantitative PCR.
    RESULTS: Compared with the wild group, mice in the model group exhibited shortened survival time (P<0.01)；reduced time spent on the rotating rod starting from the 13th week of age (P<0.05)；significantly shorter and rounded gastrocnemius fibers with enlarged inter-fiber spaces, nuclear translocation and leakage. The cross-sectional area of the gastrocnemius fibers was reduced (P<0.01)；the number of motor neurons in the spinal anterior horns was decreased (P<0.01)；protein and mRNA expressions of NLRP3, Caspase-1, ASC, IL-1β, IL-18, and TNF-α were increased in the lumbar spinal cord (P<0.01). Compared with the model group, survival time was prolonged in the Jiaji EA and inhibitor groups (P<0.01)；rotarod time was prolonged starting from the 13th week of age (P<0.05)；gastrocnemius fibers exhibited more regular margins and larger morphology, with reduced inter-fiber spaces, and reduced number of rounded fibers and improvement in nuclear translocation and leakage；cross-sectional areas of gastrocnemius fiber were increased (P<0.01)；the numbers of motor neurons in the spinal anterior horns were increased (P<0.01)；protein and mRNA expressions of NLRP3, Caspase-1, ASC, IL-1β, IL-18, and TNF-α decreased in the lumbar spinal cord (P<0.05, P<0.01). Compared with the inhibitor group, mice in the Jiaji EA group exhibited prolonged rotarod time from the 17th week of age (P<0.05)；the cross-sectional area of the gastrocnemius fiber increased (P<0.05)；protein and mRNA expressions of NLRP3, Caspase-1 and IL-18 in the lumbar spinal cord were higher (P<0.05, P<0.01), while protein and mRNA expressions of TNF-α were lower (P<0.05, P<0.01).
    CONCLUSIONS: EX-B2 EA improves limb function and prolongs survival in ALS mice, with its underlying mechanism potentially involving the alleviation of neuroinflammation through inhibition of NLRP3 inflammasome activation.
    Keywords:  Amyotrophic lateral sclerosis; Gastrocnemius; Jiaji electroacupuncture; NLRP3 inflammasome; Neuroinflammation
    DOI:  https://doi.org/10.13702/j.1000-0607.20251237
  31. Drug Des Devel Ther. 2026 ;20 628676
    Precision Drug Delivery Strategies for Treatment-Resistant Depression: Opportunities and Challenges of FUS-BBBO and Spatial Molecular Profiling.
    Chungang Zhang, Deyu Fang, Lin Zhang.
      In this review, treatment-resistant depression (TRD),a clinically defined subtype of major depressive disorder, is characterized by substantial disease burden and heterogeneous pathophysiology, with many patients showing inadequate or transient responses to currently available pharmacological therapies. Emerging evidence indicates that some treatment failures may reflect limitations in central nervous system (CNS) drug delivery in addition to disease heterogeneity and pharmacological factors. TRD treatment failure from a drug-delivery perspective is reviewed here, and barriers such as the problem of crossing the blood-brain barrier, mismatch in drug distribution, and insufficient local PK/PD or target binding are listed. Focused ultrasound-mediated blood-brain barrier opening (FUS-BBBO) is expected to be a method for targeted drug delivery to a specific area in the brain at a particular time, and it is not a standalone treatment for depression. FUS-BBBO has shown some preliminary clinical feasibility and safety in several CNS disorders, including neuro-oncology and neurodegenerative diseases, and is expected to be used as a new type of CNS drug delivery system. However, its application in TRD is still in the theoretical stage and requires disease-specific validation. To address target heterogeneity, spatial transcriptomics and single-nucleus multi-omics have been proposed in the review as necessary ways to optimise target selection. The above ways can increase the precision of the target Area by providing cell-type and molecular-level information that is unavailable in traditional imaging-based localisation methods, thereby improving the precision of therapeutic targeting. The medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), hippocampus, and amygdala are potential target areas. Each connected to specific disease mechanisms and necessitating unique therapeutic agents. Finally, the review proposes a three-step translational framework-patient stratification, target constraint, and cargo matching-and delineates five interlinked clinical development barriers: long-term safety of repeated BBB opening, technical standardization and reproducibility, quantifiable intracerebral PK, biological hit verification, and mechanism-enriched trial design. We propose that the translational potential of FUS-BBBO in TRD may be realized through a closed-loop precision-therapy framework. This framework integrates patient stratification, region-specific delivery, pharmacodynamic verification, and mechanism-matched cargo selection.
    Keywords:  focused ultrasound–mediated blood–brain barrier opening; pharmacokinetic/pharmacodynamic stratification; precision central delivery; spatial transcriptomics; treatment-resistant depression
    DOI:  https://doi.org/10.2147/DDDT.S628676
  32. Environ Sci Technol. 2026 Aug 18. 60(32): 22653-22664
    Qualitative and Quantitative Prediction of Blood-Brain Barrier Permeability of Chemicals via an SE(3)-Transformer-Based Model with LLM-Assisted Explanation.
    Lilai Shen, Ziyu Chen, Weiwei Huan, Yizhou Huang, Peirong Wu, Hou Guo, Chunlong Zhang, Shulin Zhuang.
      The blood-brain barrier (BBB) regulates the entry of chemicals into the central nervous system, and contaminants with high permeability can accumulate in the brain, posing neurotoxicity risks. Given the urgent need for high-throughput neurotoxicity assessment, this study proposes a multifeature fusion framework for identifying and quantifying the BBB permeability to neurotoxic chemicals. BBBProfiler leverages an SE(3)-Transformer to encode the three-dimensional molecular geometry and a deep neural network to encode collision cross-section (CCS) and fingerprint, followed by adaptive integration of modality representations through gating weights. Under the scaffold-split evaluation, BBBProfiler achieves high performance with an area under the receiver operating characteristic curve (AUC) of 93.72% and a recall of 89.19% for classification, and a coefficient of determination (R2) of 0.72 for regression. Its predictive performance was validated using a BBB bioassay (11 chemicals) and an external data set (2023 chemicals), in which the model achieved 94.42% AUC. Substructure mask explanation analysis revealed CCS as an influential feature that correlated well with BBB permeability to chemicals (R2 = 0.84). Model predictions were supplemented with natural-language explanations generated from a large language model. BBBProfiler is deployed on a publicly accessible platform (https://www.ai4environ.cn/BBBProfiler) to facilitate the development of new approach methodologies for neurotoxicity evaluation.
    Keywords:  Blood−brain barrier; Deep learning; Health risk assessment; Large language model; Permeability
    DOI:  https://doi.org/10.1021/acs.est.6c06459
  33. Adv Immunol. 2026 ;pii: S0065-2776(24)00075-0. [Epub ahead of print]171 343-369
    Microglial polarisation imbalance and receptor-targeted therapeutics in Parkinson's disease.
    Riddhi Upadhyay, Murugan Sevanan.
      Parkinson's Disease (PD) is a progressive neurodegenerative disease, which is mainly characterised by the selective depletion of dopaminergic neurons in the substantia nigra and deposition of misfolded aggregates of α-synuclein. It is increasingly being observed that neuroinflammation, mitochondrial dysfunction, and lost neurotrophic support are interacting factors that drive disease progression. The aggregated 1-synuclein triggers an anti-inflammatory phenotype and pro-inflammatory phenotypes in activated microglia, which produce cytokines and reactive oxygen species, aggravating stress in neurons. At the same time, mitochondrial dynamic dysfunction increases oxidative injury, which makes neurons sensitive to degeneration. The low concentration of neurotrophic factors, especially the brain-derived neurotrophic factor (BDNF), impairs the innate ability of the brain to repair itself and maintain its synapses. These pathological processes gradually create a loop of self-feeding, which results in prolonged inflammation, loss of proteostasis, and gradual loss of dopaminergic neurons. This network is interconnected, and understanding it is crucial in the creation of therapies that attempt to restore proteostasis, inhibit inflammation, and increase neurotrophic signalling to delay or prevent PD progression.
    Keywords:  M1/M2 Phenotype modulation; Microglial polarisation; Neuroinflammation; Parkinson’s disease therapeutics; α-Synuclein aggregation
    DOI:  https://doi.org/10.1016/bs.ai.2024.10.003
  34. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Aug 19. 1-9
    Multidisciplinary clinic attendance and patterns of care in the U.S. National ALS Registry, 2013-2023.
    D Kevin Horton, Jaime Raymond, Theodore Larson, Stephen A Goutman, Paul Mehta.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) multidisciplinary clinics (MDCs) are the standard model of care, but national-level data on utilization and outcomes in the United States are lacking.
    OBJECTIVE: To compare baseline characteristics and symptoms, clinical interventions and specialized care processes, and healthcare utilization among U.S. National ALS Registry (Registry) participants by MDC attendance.
    METHODS: Registry data from 2013 to 2023 were analyzed for participants completing demographic and clinical surveys, stratified by MDC attendance (attendance vs. no attendance by survey completion).
    RESULTS: Among 4764 participants, 77.0% reported attending an MDC. Baseline characteristics were similar between groups, including sex, age at diagnosis, and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. MDC attendees reported lower prevalence of dysphagia (23.6% vs. 27.5%, p = 0.007) and bowel/bladder issues (10.7% vs. 14.3%, p = 0.001). Attendees were more likely to use evidence-based interventions, including wheelchairs/scooters, noninvasive ventilation, percutaneous endoscopic gastrostomy (PEG), communication devices, and ALS disease-modifying therapies, specifically riluzole (72.7% vs. 48.1%) and edaravone (10.5% vs. 2.6%) (all p < 0.001). MDC attendees also demonstrated higher rates of specialized care processes, including advance directive completion, genetic testing, and prior research participation (all p < 0.001). For healthcare utilization, MDC attendance was associated with fewer emergency department visits among those with any use (RR 0.90, 95% confidence interval (CI) 0.82-0.99) and shorter hospital stays (β = -2.67 days, 95% CI -4.56 to -0.78).
    CONCLUSION: MDC attendance was associated with greater uptake of evidence-based interventions, higher rates of specialized care processes, and reduced healthcare utilization intensity, consistent with previously reported multidisciplinary ALS care outcomes.
    Keywords:  Amyotrophic lateral sclerosis; National ALS Registry; clinical interventions; healthcare utilization; multidisciplinary care
    DOI:  https://doi.org/10.1080/21678421.2026.2717968
  35. bioRxiv. 2026 Jul 27. pii: 2026.07.26.740405. [Epub ahead of print]
    Integrative synaptosome multi-omics reveals disrupted synapse organization and localized cryptic transcripts in C9ORF72 -Frontotemporal Dementia.
    Ashton M Spillman, Eric B Alsop, Lauren M Gittings, Krystine Garcia-Mansfield, Ignazio Piras, Anna Bonfitto, Melissa N Martinez, Ritin Sharma, Kim R Preller, Matthew Huentelman, Patrick Pirrotte, Kendall Van Keuren-Jensen, Rita Sattler.
      Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are linked neurodegenerative diseases characterized by both synaptic dysfunction and TDP-43 pathology. A hexanucleotide repeat expansion (HRE) in the C9ORF72 (C9) gene represents the most common genetic cause of FTD and ALS, yet the synapse-specific mechanisms underlying disease pathogenesis remain poorly understood. Here, we performed integrated multi-omic profiling of synaptosomes enriched from postmortem frontal cortex and patient-derived induced pluripotent stem cell (iPSC)-derived cortical neurons to define molecular alterations associated with C9-FTD-mediated synaptic dysfunction. Proteomic profiling of frontal cortex-derived synaptosomes identified 1,324 differentially abundant proteins (p<0.05) enriched in pathways regulating synaptic vesicle transport and synapse organization, while synaptosomal RNA sequencing revealed 2,835 differentially expressed protein-coding genes. C9-FTD iPSC-cortical neurons exhibited reductions in excitatory and inhibitory postsynaptic markers, accompanied by progressive impairment of neuronal network activity, supporting both structural and functional deficits. iPSC-derived synaptosomes recapitulated key molecular pathways observed in patient brain, revealing convergent dysregulation of synaptic signaling pathways. Comparative analyses revealed divergence between protein and RNA alterations, consistent with the disruption of regulatory processes that link RNA and protein abundance diseased synapses. Consistent with TDP-43 loss-of-function pathology we identified cryptic exon (CE)-containing transcripts within C9-FTD frontal cortex-derived synaptosomes, including KALRN and STMN2, providing evidence that aberrantly spliced RNAs localize to synaptic compartments. Together, these findings define convergent molecular pathways underlying synapse vulnerability in both C9-FTD model systems and identify synaptic localization of CE-containing transcripts as a previously unrecognized feature of TDP-43 proteinopathy.
    DOI:  https://doi.org/10.64898/2026.07.26.740405
  36. Mol Ther Adv. 2026 Sep 10. 34(3): 201818
    Antisense oligonucleotide treatment following viral delivery of artificial SOD1-targeting miRNA shows improved efficacy in SOD1-G93A mice.
    Zachary C E Hawley, Amanda J Guise, Ingrid D Pardo, Twinkle Chowdhury, Sam Hana, Maria I Zavodszky, Linda Engle, Kelly Wiltberger, Dan Bartlett, Denitza Raitcheva, Santhosh Bommegowda, Wan-Hung Lee, Shukkwan K Chen, Adam Sheehy, Rachelle Driscoll, Michael Peterson, Jennifer Sebalusky, Stefan Hamann, Galina Marsh, Jessica Doherty, Kay-Ellen Chicoine, Paige Cundiff, Sean Dwyer, Pete Clarner, Weike Zeng, Daniel Ferretti, Taras Tuczkewycz, Isabel Isaza, Melissa Patrovanie, Collin Mcgladrigan, Jenhwa Chu, James P Morrison, H Moore Arnold, Shen Shen, Jessica A Hurt, Patrick Trapa, Danielle L Graham, Edward D Plowey, Shih-Ching Lo.
      Adeno-associated virus (AAV) artificial microRNAs (amiRNAs) targeting superoxide dismutase 1 (SOD1) have been proposed as a therapeutic strategy for people living with amyotrophic lateral sclerosis (ALS) who harbor toxic gain-of-function variants in the SOD1 gene. Clinical efforts have primarily focused on AAV delivery via the cerebrospinal fluid (CSF), as blood-brain-barrier-crossing capsids are still being developed preclinically. However, intra-CSF delivery has been shown to be highly variable and increases the risk for AAV-related adverse events such as dorsal root ganglion (DRG) toxicity. Here, we show that immunosuppressants (IMS) following intra-CSF delivery of AAV9-amiR-SOD1 in non-human primates (NHPs) prevented AAV-related DRG toxicity, and this benefit was maintained for over 300 days even after immunotherapy stopped at 90 days post-AAV treatment. In line with prior literature, we found intra-CSF delivery of AAV9-amiR-SOD1 to be highly variable in adult mice and NHPs, requiring higher doses of virus to achieve efficacious endpoints. To address this concern, we developed a proof-of-principle study showing that AAV9-amiR-SOD1, in combination with a SOD1-targeting antisense oligonucleotide, provided an additive therapeutic benefit in SOD1-G93A mice compared with AAV9-amiR-SOD1 alone. This combinatorial approach lowered the viral load needed to reach efficacious endpoints, which could mitigate AAV-related adverse events alongside IMS.
    Keywords:  AAV; ALS; SOD1; adeno-associated virus; antisense oligonucleotides; artificial miRNAs; gene therapy
    DOI:  https://doi.org/10.1016/j.omta.2026.201818
  37. Ann Hum Genet. 2026 Aug 17.
    Population-Level Nucleotide Diversity and Genetic Differentiation at SOD1 Across Global Human Populations.
    Sergio V Flores, Patricia Lillo, Jorge Briceño-Moya.
       BACKGROUND: The SOD1 gene encodes superoxide dismutase 1, an antioxidant enzyme in which pathogenic variants cause a subset of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although the clinical and molecular consequences of SOD1 variants are well established, its locus-wide population genetic architecture has not been systematically characterized across global populations.
    OBJECTIVE: To characterize patterns of genetic diversity, population differentiation, and evolutionary constraint across the SOD1 locus in worldwide human populations.
    METHODS: We analyzed genomic variation spanning the SOD1 region in the five continental populations of the 1000 Genomes Project. Nucleotide diversity (π), fixation index (FST), and allele frequency distributions were estimated using sliding-window analyses. Bootstrap resampling was used to compare diversity within and outside the coding region. Recent positive selection was assessed using XP-nSL, and codon-based evolutionary analyses were performed using primate SOD1 orthologs.
    RESULTS: The coding region consistently exhibited a twofold to threefold reduction in nucleotide diversity relative to adjacent genomic sequences across all populations. Bootstrap analyses confirmed significantly lower diversity within the locus than in flanking regions (p < 0.05 in all populations). Population differentiation was low (mean FST ≈ 0.03) and showed no pronounced peaks within the coding interval, whereas allele frequency distributions were broadly similar across continental populations. XP-nSL analyses detected no evidence of population-specific recent selective sweeps. Codon-based analyses identified only 31 variable codons among 155 analyzed positions, six codons under negative selection, and no evidence of positive selection.
    CONCLUSION: The SOD1 locus exhibits reduced standing genetic variation, limited continental differentiation, and strong evolutionary conservation, consistent with sustained functional constraint. These findings provide a comprehensive population genetic framework for interpreting genetic variation at this medically important locus.
    Keywords:  FST; SOD1; allele frequency; amyotrophic lateral sclerosis; nucleotide diversity; population genetics
    DOI:  https://doi.org/10.1111/ahg.70052
  38. J Speech Lang Hear Res. 2026 Aug 18. 1-13
    Dissociable Effects of Dysarthria Etiology and Severity on the Minimally Detectable Change of Speech Intelligibility.
    Kelly E Zdrowak, Antje S Mefferd, Kaila L Stipancic.
       PURPOSE: The minimally detectable change (MDC) provides a threshold for interpreting changes in outcome measures that are outside of measurement error. There is emerging evidence that dysarthria etiology and speech severity impact the MDC of speech intelligibility; however, an investigation of these factors is needed to determine the unique effects of dysarthria etiology and speech severity. The purpose of the current study was to calculate and compare MDCs of speech intelligibility across five dysarthria etiology groups and four severity levels.
    METHOD: Speech Intelligibility Test recordings from 200 speakers were used as stimuli, including recordings from healthy controls (n = 40) and individuals with neurodegenerative diseases such as amyotrophic lateral sclerosis (n = 16), Huntington's disease (n = 44), multiple sclerosis (n = 60), and Parkinson's disease (n = 40). Thirty inexperienced listeners provided orthographic transcriptions of 20 speakers each. MDCs were calculated, and speech severity levels were categorized based on empirically defined speech severity levels reported in Stipancic et al. (2021). Statistical analyses, including multiple linear regression, assessed the effects of etiology and severity on MDCs.
    RESULTS: Speech severity was a significant predictor of MDCs, with greater impairments to speech intelligibility resulting in higher MDCs. Dysarthria etiology was not a significant predictor of MDCs.
    CONCLUSION: The impact of speech severity on MDCs of intelligibility in dysarthria underscores the need to calculate and provide MDCs across severity ranges to enhance the interpretation of patient outcomes.
    DOI:  https://doi.org/10.1044/2026_JSLHR-25-00740
  39. Clin Neurophysiol. 2026 Aug 14. pii: S1388-2457(26)00872-2. [Epub ahead of print]191 2112372
    Revisiting somatosensory evoked potentials in motor neuron diseases: neurophysiological insights from a large cohort.
    Virginia Iacobelli, Maria Vizziello, Letizia Clementi, Paola Anversa, Daniele Cazzato, Amedeo De Grado, Annamaria Gallone, Mikael Gian Andrea Izzo, Paola Lanteri, Susanna Usai, Giuseppe Lauria, Davide Rossi Sebastiano, Eleonora Dalla Bella.
       OBJECTIVE: To systematically investigate Somatosensory Evoked Potential (SEP) abnormalities in a large cohort of patients with Motor Neuron Disease (MND), and to explore their relationship with Motor Evoked Potentials (MEPs) and clinical phenotypes.
    METHODS: We retrospectively analyzed 267 patients with confirmed MND who underwent standardized SEPs and transcranial magnetic stimulation. Patients were divided into pure/predominant Upper Motor Neuron (UMN) and pure/predominant Lower Motor Neuron/Amyotrophic Lateral Sclerosis (LMN/ALS) groups. SEP abnormalities were assessed using internal normative data, including prolonged latencies, reduced amplitudes, and increased N20-P25 amplitudes. MEPs were classified semi-quantitatively as normal or abnormal by independent raters.
    RESULTS: At least one SEP abnormality was detected in 75 % of patients, with no significant differences between the UMN and LMN/ALS groups. Increased N20-P25 amplitudes were observed in both phenotypes, suggesting widespread sensory cortical hyperexcitability across the MND spectrum. In contrast, abnormal MEPs were significantly more frequent in UMN patients (p < 0.001). No significant association was found between SEP abnormalities and MEP findings. Upper- and lower-limb SEP latencies were strongly correlated (all p < 0.001), whereas increased SEP amplitudes did not correlate with latency abnormalities.
    CONCLUSIONS: SEP abnormalities are highly prevalent in MND and appear largely independent from corticospinal dysfunction. Increased SEP amplitudes likely reflect primary cortical sensory hyperexcitability rather than impaired sensory conduction.
    SIGNIFICANCE: These findings support the concept of MND as a multisystem network disorder that involves sensory cortical circuits and highlight the role of SEPs in the diagnostic workup.
    Keywords:  Amyotrophic lateral sclerosis; Cortical hyperexcitability; Motor neuron disease; Somatosensory evoked potentials; Transcranial magnetic stimulation
    DOI:  https://doi.org/10.1016/j.clinph.2026.2112372
  40. Int J Neurosci. 2026 Aug 17. 1-29
    Aquaporin-4 Mediated Glymphatic Dysfunction and Neuroinflammatory Signaling in Neurodegenerative Disorders.
    Balbir Singh, Shareen Singh, Souvik Banerjee, Shrey Bhargava, Vetriselvan Subramaniyan, Thakur Gurjeet Singh.
      Aquaporin channels are the predominant fluid regulating channel found in the central nervous system (CNS) and plays a pivotal role in maintaining fluid and ion homeostasis, as well as regulating neuroinflammation, neurodegeneration, and blood-brain barrier (BBB) disruption. This protein is primarily located at astrocytes endfeet within the blood cerebral barrier and other central nervous system (CNS) junctions, facilitating the movement of water in both directions, buffering potassium levels, and aiding in the clearance of interstitial solutes, along with toxic metabolites such as amyloid-β, via the glymphatic system. Changes in the expression or polarization of AQPs are implicated in neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, epilepsy, and ischemic stroke. Impaired functionality of AQPs is involved in a number of pathological processes including heightened oxidative stress, disruption of the blood-brain barrier, and neuroinflammation. Such pathways are targeted by transcription factors, including nuclear factor κB (NFκB), and signaling pathways, including p38 MAPK, that increase AQPs expression following the action of stressors. Furthermore, impairment of AQPs polarity suppresses glymphatic clearance and promotes toxic protein accumulation, one of the key features of Alzheimer 's disease. AQPs structural features, including its six transmembrane helices and conserved NPA motifs, are critical for function, positioning it as a putative therapeutic target. Preclinical data support the notion that modulation of AQPs activity may offer neuroprotection through restoration of homeostasis and reduction of inflammation in neurodegenerative disease. This review describes the mechanistic links between AQPs dysfunction and neurodegenerative disease, highlighting its potential and limitations as a therapeutic target for the prevention of CNS disorders.
    Keywords:  Aquaporins; Glymphatic system; Molecular mechanisms; Neuroinflammation; Neuroprotection; neurodegeneration
    DOI:  https://doi.org/10.1080/00207454.2026.2719591
  41. J Neuroimaging. 2026 Jul-Aug;36(4):36(4): e70143
    Portable Ultra-Low-Field MRI in Outpatient Neurology: An Examination of Clinical Performance and Patient Experience.
    Laszlo Mechtler, Sameer Ahmad Ansari, Jamal Derakhshan, Edmond Knopp, Nandor Pinter, Mohamad Asaad Nasri, Gincy Samuel.
       BACKGROUND AND PURPOSE: Brain magnetic resonance imaging (MRI) is an essential component for outpatient neurological evaluation, though access to timely imaging at the point of care is not feasible for most outpatient neurology practices. Portable ultra-low-field MRI systems offer a potential solution, but studies describing their clinical performance in routine outpatient neurology practice remain limited. This study evaluated clinical concordance and patient experience of portable MRI (pMRI) compared to standard-of-care MRI (sMRI) in independent neurology practices.
    METHODS: In this prospective, multicenter study, adults presenting to outpatient neurology clinics and requiring clinically indicated brain MRI completed imaging with both pMRI (0.064 T) and sMRI (91% 3 T, 9% 1.5 T) in the neurology clinic. All examinations were independently reviewed by board-certified neuroradiologists in a blinded, randomized fashion without access to clinical history. The primary endpoint was patient-level concordance between modalities for the presence or absence of abnormal findings. Discordant cases underwent post hoc unblinded paired review with clinical history to assess clinical significance. Secondary endpoints included patient-reported experience, assessed using a structured questionnaire evaluating noise, comfort, claustrophobia, anxiety, and overall experience on 10-point Likert scales, as well as modality preference.
    RESULTS: Among 125 participants imaged for common outpatient indications, including headache (40%), cognitive impairment or dementia (16%), multiple sclerosis follow-up (16%), and tumor surveillance (16%), portable and sMRI demonstrated 92% concordance on blinded review. Following clinically informed post hoc review, concordance increased to 98%. pMRI was rated more favorably across all patient experience domains (p < 0.001), and participants preferred pMRI (61%) over sMRI (14%) by a 4:1 ratio.
    CONCLUSIONS: In outpatient neurology practices, pMRI images demonstrated high clinical concordance with sMRI for identifying the presence or absence of structural brain abnormalities and were strongly preferred by patients. These findings support the use of pMRI as a practical point-of-care imaging tool for neurology patients, enabling timely access to structural neuroimaging during the clinical encounter.
    Keywords:  access to care; diagnostic concordance; outpatient neurology; patient preference; point of care; portable MRI; ultra‐low‐field MRI
    DOI:  https://doi.org/10.1111/jon.70143
  42. J Parkinsons Dis. 2026 Aug 20. 1877718X261479507
    Association of handgrip strength asymmetry with prodromal and incident Parkinson's disease: A prospective cohort study.
    Min Cai, Xiao Chen, Sheng Zhuang, Yaqi Li, Fan Chen, Xiang Gao.
      BackgroundAsymmetry symptoms are well recognized in Parkinson's disease (PD). However, whether handgrip strength (HGS) asymmetry can prospectively predict incident PD remains unknown.ObjectivesTo prospectively examine the association between HGS asymmetry and subsequent risk of incident PD.MethodsIncluded were 497,100 participants without PD at baseline from the UK Biobank. HGS asymmetry index was calculated by dividing the absolute inter-hand difference in HGS by the average HGS of the two hands. The primary outcome was incident PD identified through hospital admissions, death registries, and self-reported data. As secondary outcome, prodromal PD was defined as the presence of ≥3 out of 8 prodromal PD features assessed through self-reported data, hospital admission records and primary care data. The associations were evaluated using Cox regression models. Several lag analyses were conducted to examine how many years in advance could HGS asymmetry predict incident PD.ResultsDuring a median follow-up of over 13 years, 2868 participants developed PD. HGS asymmetry (highest vs. lowest quartile) was associated with higher risk of developing PD (HR = 1.23; 95% CI: 1.10, 1.37) (P-trend < 0.001). Lag analysis suggested that HGS asymmetry could even predict incident PD in 8 years. Significant association between HGS asymmetry and prodromal PD risk was also observed. The significant associations between HGS asymmetry and PD risk persisted when further excluding those with low HGS or prodromal PD.ConclusionsHigher HGS asymmetry was associated with a higher risk of incident PD, suggesting the potential of HGS asymmetry as an early indicator for PD.
    Keywords:  Parkinson's disease; asymmetry; handgrip strength; prodromal Parkinson's disease
    DOI:  https://doi.org/10.1177/1877718X261479507
  43. Methods Mol Biol. 2026 ;3035 455-472
    Intracerebroventricular Administration of Gangliosides for In Vivo Functional Studies in Mice.
    John Monyror, Melanie Horkey, Asifa K Zaidi, Simonetta Sipione.
      Levels of gangliosides are reduced in several neurological conditions, and their restoration has shown therapeutic potential in animal models of Huntington's disease and Parkinson's disease. However, the full range of functions of gangliosides in the brain, along with their molecular targets and mechanisms of action following exogenous administration, remains ill-defined. Due to their poor blood-brain barrier (BBB) permeability, gangliosides face significant challenges when delivered through non-invasive routes. Direct intracerebroventricular (ICV) infusion circumvents this issue by bypassing the BBB, ensuring a more precise delivery to brain structures and eliminating uncertainties related to brain penetration. Here, we describe a protocol for ICV infusion of gangliosides in mice that enables in vivo pre-clinical studies of their effects, while eliminating uncertainties about the extent of drug delivery to the brain through the BBB.
    Keywords:  GM1; Huntington’s disease; Neurodegeneration; Osmotic minipumps; Stereotaxic surgery
    DOI:  https://doi.org/10.1007/978-1-0716-5288-6_31
  44. Eur J Pharmacol. 2026 Aug 20. pii: S0014-2999(26)00757-0. [Epub ahead of print]1033 179275
    Therapeutic targeting of G protein-coupled receptors in central nervous system disorders: from novel mechanisms to precision pharmacology.
    Chicheng Zhou, Chunting Zhu, Xueying Wang, Yang Yang, Jinhuan Wei.
      G protein-coupled receptors (GPCRs) are major therapeutic targets for central nervous system disorders, with more than 500 approved drugs targeting this receptor family worldwide. This review comprehensively examines the pathophysiological roles and therapeutic potential of GPCRs in major neurological and psychiatric disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and depression. We highlight how dysregulated signaling through specific GPCRs, including dopamine and adenosine A2A receptors in PD, the mGlu5 receptor and muscarinic acetylcholine receptors in AD, S1P and GPR17 receptors in MS, and 5-HT1A and GPR39 receptors in depression, contributes to disease pathogenesis. Beyond canonical monomeric activation, this review emphasizes emerging concepts in GPCR heterodimerization (e.g., the 5-HT1A/orexin 1 receptor complex activating Gαs pathways), biased signaling, and allosteric modulation, which provide opportunities to develop therapeutics with greater specificity and fewer adverse effects. We also evaluate the therapeutic potential of targeting these mechanisms using specific pharmacological agents, including synthetic compounds and structurally defined natural product-derived molecules. The chemical structures of key natural products-including paeoniflorin, rosmarinic acid, and ergothioneine-are presented, with their GPCR interactions and critical pharmacophores highlighted. Finally, we discuss future directions involving advanced technologies, including cryo-electron microscopy, induced pluripotent stem cell-derived brain organoids, structural biology, and artificial intelligence, to improve understanding of complex GPCR signaling. The development of biased ligands, stage-specific interventions, and GPCR-based biomarkers represents a critical step toward personalized and more effective treatments for neurological disorders.
    Keywords:  Alzheimer's disease; Depression; G protein-coupled receptors; Multiple sclerosis; Natural products; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.ejphar.2026.179275
  45. Acta Physiol (Oxf). 2026 Sep;242(9): e70289
    Written in the Stars: Astrocyte Biology From Evolution to Disease.
    Carmen Falcone, Lutgarde Arckens, Monica Baiula, Andrea Bedini, Riccardo Bocchi, Matthew J Broadhead, Marco Caprini, Fabio Cavaliere, Fabrizia Cesca, Helena H Chowdhury, Katarzyna Ciuba, Laura Civiero, Carole Escartin, Stefano Ferroni, Francesco Formaggio, Angelisa Frasca, Rossella Gratton, Matthew Holt, Nunzio Iraci, Marko Kreft, Loredana Leggio, Annamaria Lia, Anna R Malik, Rogier Min, Franziska E Müller, Cahuê Murat, Maria João Pereira, Aleksandra Pekowska, Francesco Petrelli, Paula Ramos-Gonzalez, Maria V Sanchez-Mico, Zala Smole, Dimitra Sokolova, Maite Solas, Alessia Soldano, Lukasz Mateusz Szewczyk, Carola Torazza, Francesco Paolo Ulloa Severino, Nerea Urrestizala-Arenaza, Andre Zeug, Jiafeng Zhou, Micaela Zonta, Robert Zorec, Alexei Verkhratsky, Nilhan Gunhanlar.
      In the 21st century, neuroglial research has entered a period of Renaissance, extending the views of prominent neuroanatomists and neurologists of the 19th and early 20th centuries, who assigned to glial cells numerous physiological functions and highlighted their fundamental role in the pathophysiology of nervous system diseases. Astrocytes are highly diversified in structure and function; they control brain homeostasis, support synaptic connectivity, and enable information processing in neural networks. Evolutionary diversification of astrocytes, initially emerging as supportive cells of primitive sensory organs, drove a continuous expansion of astroglial complexity and functional versatility, ultimately making them indispensable neuroprotectors and homeostatic regulators. The large, morphologically elaborate astrocytes of the human brain arguably reflect an evolutionary response to increased neuronal homeostatic demands. Astrocytes are indispensable for synaptic function, serving as the principal regulators of neurotransmitter turnover and neuronal excitability. Astrocytes also govern brain energy metabolism, mitochondrial dynamics, and calcium signaling, thereby actively shaping cortical plasticity and circuits. Astrocytes are fundamental elements of the pathophysiology of neurological, neuropsychiatric, and neurodegenerative diseases, including Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, Rett syndrome, genetic astrocytopathies, and neurotrauma, where they demonstrate complex reactive changes directed at tissue preservation and regeneration, but which can also contribute to disease progression. Advances in single-cell transcriptomics, calcium imaging, chemogenetics, and iPSC-based models have transformed our understanding of astrocyte diversity and disease-specific dysfunction, opening new avenues of investigation. Given that no CNS disorder is known to occur without astrocyte involvement, multiple astrocyte-specific molecules represent compelling targets for cell-directed therapeutic strategies.
    Keywords:  Alzheimer's disease; Parkinson's disease; Rett syndrome; amyotrophic lateral sclerosis; astrocytes; evolution; neurodegeneration; neuropathology; synaptic transmission
    DOI:  https://doi.org/10.1111/apha.70289
  46. Transl Res. 2026 Aug 18. pii: S1931-5244(26)00171-4. [Epub ahead of print]
    Regenerative medicine for neurodegenerative diseases:History, Strategies, and Clinical Advances.
    Jia Li, Hongmei Duan, Peng Hao, Wen Zhao, Yudan Gao, Zhaoyang Yang, Xiaoguang Li.
      In the context of global ageing, the prevalence of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is rapidly increasing. However, current symptomatic treatments have achieved limited benefits in clinical settings and fundamentally fail to reverse the progressive loss of specific neuronal populations. Halting neurodegeneration and restoring impaired cognitive, motor or visual functions through nerve regeneration and circuit reconstruction represent the clinically meaningful goals for treatments of NDDs. Regenerative medicine has emerged as a promising paradigm to address this unmet need. In this review, we trace the historical evolution of regenerative therapies for NDDs - from early exploratory cell transplantation to modern approaches involving pluripotent stem cells (PSCs) and in vivo direct reprogramming. Furthermore, we elucidate the core strategies of regenerative medicine within an integrated framework encompassing "Replacement", "Regeneration", and "Rejuvenation". Finally, we highlight recent advances in clinical research, particularly milestone trials in cell replacement therapy for PD, as well as the application of mesenchymal stem cells (MSCs) in AD and ALS.
    Keywords:  Regenerative medicine; cell therapy; neurodegenerative diseases; reprogramming
    DOI:  https://doi.org/10.1016/j.trsl.2026.08.005
  47. Cell. 2026 Aug 20. pii: S0092-8674(26)00813-5. [Epub ahead of print]189(17): 5156-5173
    Neurodegeneration as a dysregulation of neuroimmune crosstalk.
    F Chris Bennett, Soyon Hong, Ning Jiang, Ivan Marazzi.
      Neurodegeneration is increasingly recognized not only as a disorder of neurons but also as a breakdown of dialogue between the nervous and immune systems. Recent discoveries reveal that immune cells and inflammatory signals are deeply interwoven with brain function across the lifespan. Far from passive responders, immune cells act as sentinels and shapers of neuronal resilience, vulnerability, and repair. Together, robust data support a model in which neurodegeneration emerges from complex interactions between neural and immune networks, positioning the immune system as both a sensor and driver of brain health. This perspective synthesizes a growing body of work arguing that neurodegenerative diseases are a failure of neuroimmune crosstalk-where protective signals are lost, and maladaptive responses take hold. By restoring immune homeostasis, fine-tuning inflammatory responses, or targeting epigenetic regulators of the immune state, it may be possible not only to slow degeneration but also to promote recovery. We outline the key challenges and opportunities for this paradigm shift and highlight how a deeper integration of neuroscience and immunology could transform the future of treating neurodegenerative diseases. Lastly, we describe critical focus areas to improve our understanding of neurodegeneration and highlight the development of immune-based therapeutics for neurodegeneration.
    DOI:  https://doi.org/10.1016/j.cell.2026.07.015
  48. Sci Rep. 2026 Aug 20. pii: 26178. [Epub ahead of print]16(1):
    Green analytical methods for quantification of a new combination therapy for amyotrophic lateral sclerosis: assessment by EPPI framework.
    Faten M Aboukhalil, Essam F Khamis, Mahmoud A El-Sayed, Rasha M Youssef, Amira F El-Yazbi.
      Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to progressive muscle weakness, paralysis, and respiratory failure. The recently proposed combination therapy consisting of celecoxib and ciprofloxacin hydrochloride has emerged as a potential treatment for amyotrophic lateral sclerosis and other neurodegenerative disorders. The present study aimed to develop and validate simple, sensitive, environmentally friendly, and cost-effective analytical methods for the simultaneous determination of celecoxib and ciprofloxacin hydrochloride in bulk powders, laboratory-prepared tablets and plasma. Two ultraviolet spectrophotometric methods were established. The first method relies on direct absorbance measurements of ciprofloxacin hydrochloride at 318 nm and celecoxib at the isosbestic point at 266 nm, while the second one employs first-derivative ratio spectrophotometry for the selective determination of ciprofloxacin hydrochloride and celecoxib at 280 nm and 254 nm, respectively. Moreover, a reversed-phase high-performance liquid chromatographic method was developed using a C18 stationary phase, an optimized mobile phase composition and both diode array and fluorescence detectors, achieving efficient separation and accurate quantification of both analytes. The developed procedures were successfully applied to laboratory-prepared tablets and plasma following optimization of the sample preparation protocol to minimize matrix interference and to improve analytes recovery. Validation results showed excellent linearity over the investigated concentration ranges together with satisfactory accuracy, precision, selectivity, and sensitivity, confirming the reliability of the proposed methods for routine quality control and bioanalytical applications. The overall analytical performance and environmental sustainability of the developed methods were further assessed using the environmental performance and practicality Index framework, demonstrating their suitability as reliable and sustainable analytical approaches for the determination of celecoxib and ciprofloxacin hydrochloride.
    Keywords:  Celecoxib; Ciprofloxacin; EPPI framework; Plasma; RP-HPLC; Spectrophotometry; Sustainability and Amyotrophic lateral sclerosis
    DOI:  https://doi.org/10.1038/s41598-026-66936-w
  49. Mol Nutr Food Res. 2026 Aug;70(16): e70584
    Targeting Neurodegeneration With Naringenin: Mechanistic Perspectives and Therapeutic Implications.
    Nista Gurung, Ganesh Bohara, Nikesh Rimal, Dong-Young Choi.
      Neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, retinal neurodegeneration, and spinal cord injury represent a growing global health burden with limited therapeutic options. Natural compounds, particularly flavonoids, have emerged as promising neuroprotective agents. Naringenin (NAR), a citrus-derived flavanone, exhibits potent antioxidant, anti-inflammatory, and neuroprotective properties. Recent studies revealed that NAR modulates multiple cellular pathways, including oxidative stress reduction, mitochondrial protection, autophagy induction, inhibition of microglial activation, and suppression of neuroinflammatory signaling such as NF-κB and NLRP3 inflammasome. Furthermore, NAR has demonstrated the ability to reduce amyloid-β plaque deposition, inhibit α-synuclein aggregation, preserve dopaminergic neurons, modulate immune responses in multiple sclerosis, and improve functional recovery after spinal cord injury. This review comprehensively summarizes the mechanistic insights and therapeutic potential of NAR across various neurodegenerative diseases, highlighting its promise as a multifunctional neuroprotective agent and the need for further translational research.
    Keywords:  Alzheimer's disease; Huntington's disease; Naringenin; Neurodegeneration; Neuroprotective
    DOI:  https://doi.org/10.1002/mnfr.70584
  50. bioRxiv. 2026 Jul 31. pii: 2026.07.31.741976. [Epub ahead of print]
    Impact of Neurons on Group B Streptococcus Interactions at the Blood Brain Barrier.
    Lena M Seyfarth, Natalie G Alexander, Alyssa S Arnett, Kathryn N Seely, Benjamin T Klemp, Taryn E Keyzer, Nadine Vollmuth, Caylah Griffin, Michael D Burton, Erica L Sanchez, Brandon J Kim.
      Streptococcus agalactiae (Group B Streptococcus , GBS) is a Gram-positive opportunistic pathogen and the leading cause of neonatal bacterial meningitis, a life-threatening infection of the central nervous system (CNS) that occurs when bacteria cross the blood-brain barrier (BBB). GBS commonly colonizes the maternal genital tract and is a major cause of invasive neonatal disease, including bacteremia and meningitis. Despite treatment advances, GBS meningitis remains associated with substantial mortality and long-term neurological sequelae. The BBB is a highly specialized barrier formed by brain endothelial cells (BECs) that restrict microbial entry into the CNS through tightly regulated intercellular junctions. The BBB exists within the neurovascular unit, where neurons and other CNS cell types actively regulate endothelial barrier properties through intercellular signaling. However, the contribution of neuronal-endothelial interactions to BBB function during neonatal meningitis remains poorly understood. To investigate the mechanisms by which GBS disrupts and penetrates the BBB, we utilized induced pluripotent stem cell (iPSC)-derived brain-like endothelial cells. EZ-Sphere-derived neurons generated from the same iPSC source were incorporated into an isogenic BBB model to determine whether neuronal-endothelial communication influences GBS interaction with BECs. Neuronal co-culture significantly reduced GBS adherence to and invasion of BECs while preserving tight junction integrity during infection. Application of neuron-conditioned medium similarly decreased bacterial adherence and invasion, suggesting that neuron-derived soluble factors enhance barrier integrity during GBS infection. Together, these findings demonstrate that neuronal signaling enhances BBB resistance to GBS and highlight a previously underappreciated role for neurovascular crosstalk in limiting bacterial pathogenesis.
    Importance: Group B Streptococcus (GBS) is the leading cause of bacterial meningitis in newborns. GBS interacts with and crosses the blood-brain barrier (BBB) contributing to a potentially fatal infection without treatment. Understanding how the BBB interacts with bacterial pathogens is critical for developing new strategies to protect vulnerable infants. In this study, we used human stem cell-derived models to recapitulate the BBB and examine how communication between brain endothelial cells and neurons influence host response to bacterial infection. These findings identify neuronal-endothelial communication as a potential contributor to BBB protection and provide a foundation for future studies aimed at preventing GBS invasion of the central nervous system.
    DOI:  https://doi.org/10.64898/2026.07.31.741976
  51. Methods Enzymol. 2026 ;pii: S0076-6879(26)00239-9. [Epub ahead of print]733 321-366
    Histone deacetylases in neurodegeneration and neuronal plasticity.
    Bhupesh Mehta, Sinjitha Nambiar, Omkar Shirke, Satyarth Pandita, Yogananda S Markandeya.
      This chapter pulls together current research on how HDAC shuttling between the nucleus and cytoplasm affects neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's, and epilepsy. It takes a close look at why these shifts in HDAC localization matter so much in brain disease and its implications for new treatments. Histone deacetylases (HDACs) are a big deal when it comes to gene regulation in the brain. They play key roles in both neurodegeneration and the brain's ability to adapt, working inside the nucleus and out in the cytoplasm. This chapter unpacks the molecular mechanisms behind HDAC trafficking-how they move around-highlights the different roles of HDAC isoforms, and compares localization-specific effects. It digs into how HDACs impact protein aggregation and synaptopathies. Some findings stand out: HDAC4 and HDAC1 are tightly controlled by phosphorylation signals, which change their cellular localization and influence neuronal mortality. For example, HDAC6 is majorly involved in cellular trafficking and clearing protein aggregates, whereas HDAC4 aggregation in the nucleus is responsible for driving neuronal toxicity. If HDAC1 undergoes nuclear export, it interacts with motor proteins to impact mitochondrial transport. Drugs that block HDAC6 look promising in preclinical models-they help restore neuronal transport systems and clear protein aggregation. Moving HDAC4 out of the nucleus seems to support better synaptic function and motor skills. As a general rule, HDAC accumulation in the nucleus shuts down genes that keep neurons alive, but keeping them in the cytoplasm helps preserve connections between neurons. You'll also find thorough, practical advice on how to study HDACs in brain research-covering everything from enzyme assays and cell experiments to live animal models, plasticity tracking, drug testing, and data analysis. A major innovation featured here is using CRISPR-based tricks to control exactly where HDACs go inside cells: forced targeting using dCas9 fusions, editing natural localization signals, and even using optogenetics for precise on-demand control. In short, the chapter is a hands-on guide for anyone trying to unravel HDAC mechanisms in diseases like Alzheimer's, Parkinson's, Huntington's, or in studies of brain plasticity. Some standout methods include tracking HDAC localization in the cells, measuring how phosphorylation affects their shuttling, and using HDAC2 inhibitors for cognitive boosts. It also covers isoform-specific approaches in Huntington's models, manipulating HDAC location with CRISPR for deeper insights, and combining live-cell imaging with biochemical and chromatin studies for robust validation. This chapter sheds light on the latest advances, with a strong focus on precision, quantitative results, and translating these findings into real-world applications.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; CRISPR; HDAC; Huntington’s disease; Parkinson’s disease
    DOI:  https://doi.org/10.1016/bs.mie.2026.06.025
  52. Adv Immunol. 2026 ;pii: S0065-2776(26)00032-5. [Epub ahead of print]171 437-462
    Microglia-centered cellular crosstalk in neurodegeneration.
    Hao Huang, Elvira Mass.
      Neuroinflammation shaped by aberrant cellular interactions represents a hallmark of neurodegenerative diseases of the central nervous system (CNS). Microglia are specialized tissue-resident macrophages that reside in the CNS parenchyma and have emerged as central regulators of this aberrant cellular crosstalk. They integrate local signals and orchestrate the cellular interaction networks that underlie disease progression. Recent advances in single-cell and single-nucleus omics, in combination with spatially resolved approaches, have substantially advanced our understanding of microglial dynamics in neurodegeneration. These technological and conceptual advances have revealed an unexpected diversity of disease-associated microglial states and highlighted microglia as central organizers of multicellular interaction networks within diseased CNS tissue. In this chapter, we discuss how these advances have reshaped our understanding of microglia-centered cellular crosstalk in neurodegeneration. We focus on the diversification of neurodegenerative CNS microglial states, the interaction of microglia with neurons, glial cells, adaptive immune cells, and the vasculature. We further discuss how this framework provides a basis for therapeutic strategies aimed at modulating, replacing, or reprogramming microglia in neurodegenerative disease.
    Keywords:  Disease-associated microglia (DAM); Microglia; Microglia-adaptive immune cell crosstalk; Microglia-neuron interactions; Microglial heterogeneity; Neurodegeneration; Neuroinflammation; Single-cell transcriptomics; Synaptic pruning
    DOI:  https://doi.org/10.1016/bs.ai.2026.06.001
  53. MedComm (2020). 2026 Sep;7(9): e70915
    Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets.
    Tianjiao Li, Qian Zhang, Yichen Wu, Ruixue Huang.
      Neurodegenerative diseases (NDs) are marked by selective neuronal vulnerability and progressive failure of neural circuits. Increasing evidence indicates that neuronal loss is not driven by a single terminal event, but emerges from interacting regulated cell death (RCD) programs. These programs are closely coupled to mitochondrial injury, proteostatic collapse, lysosomal stress, metabolic imbalance, glial state transitions, and chronic neuroinflammation. Yet, how distinct death pathways are organized across cell types, disease stages, and disease-specific microenvironments remains unresolved. This review examines RCD as an integrated pathogenic network in major NDs. Caspase and B-cell lymphoma 2 (BCL2) family signaling, receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein activation, NOD-like receptor family pyrin domain containing 3 and gasdermin signaling, GPX4-linked lipid peroxidation control, and autophagy lysosomal failure are discussed as convergent stress response modules rather than isolated pathways. Across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, these modules shape neuronal fate through disease-specific interactions with mitochondrial dysfunction, iron dyshomeostasis, inflammasome activation, and microglial metabolic remodeling. We further evaluate emerging therapeutic strategies that target cell death crosstalk, restore autophagy lysosomal competence, or improve delivery to the central nervous system, highlighting the importance of molecular selectivity, cellular context, disease stage, and translational feasibility.
    Keywords:  apoptosis; cell death; ferroptosis; necroptosis; neurodegenerative diseases
    DOI:  https://doi.org/10.1002/mco2.70915
  54. Neurol Neuroimmunol Neuroinflamm. 2026 Sep;13(5): e200643
    Data-Driven Fatigue Trajectories in Multiple Sclerosis and Their Predictors.
    Alessandro Cruciani, Emanuele Olivieri, Ronja Christensen, Sarmad Al-Araji, Samih Fourali, Weaam Hamed, Anna He, Baris Kanber, Davide Maccarrone, Suraya Mohamud, Riccardo Nistri, Anestis Passalis, Valeria Pozzilli, Ferran Prados, Charmaine Yam, Marios C Yiannakas, Alan J Thompson, Frederik Barkhof, Ahmed T Toosy, Olga Ciccarelli.
       BACKGROUND AND OBJECTIVES: Fatigue is one of the most disabling symptoms of multiple sclerosis (MS), yet its longitudinal trajectories and determinants remain poorly characterized. We aimed to identify trajectories of cognitive and physical fatigue in relapsing-remitting MS (RRMS) and to determine baseline clinical and MRI predictors of worsening fatigue.
    METHODS: We conducted a prospective, single-center cohort study embedded in the Predicting Optimal INdividualised Treatment response in MS (POINT-MS) program at the Queen Square MS Centre (London, United Kingdom). Adults with RRMS initiating a new disease-modifying therapy within 3 months of baseline were enrolled and underwent clinical and MRI assessments at baseline, 6 months, and 18 months. Key inclusion criteria were a diagnosis of RRMS, availability of baseline brain and cervical spinal cord MRI, and completion of at least 3 Modified Fatigue Impact Scale (MFIS) assessments. The primary outcome was the longitudinal change in MFIS cognitive and physical subscale scores. Fatigue trajectories were identified using growth mixture modeling. Baseline predictors included demographic factors, disability, cognitive performance, depression diagnosis, proportion of disease duration on disease-modifying treatments (DMTs), and MRI-derived measures of cervical spinal cord cross-sectional area (C-CSA) and regional brain volumes standardized to healthy-control norms. Predictor importance was assessed with conditional random forests, followed by multivariable modeling.
    RESULTS: We enrolled 225 participants. Three distinct fatigue trajectories emerged for both cognitive and physical MFIS subscales, including improving, stable/mild-worsening, and worsening classes. Worsening trajectories showed annualized increases of +3.32 points/year (cognitive) and +3.37 points/year (physical). Smaller baseline C-CSA was the strongest MRI predictor of worsening trajectories. Clinically, the proportion of disease duration spent on DMTs was the most influential predictor.
    DISCUSSION: Fatigue in RRMS follows heterogeneous trajectories over short-term follow-up. Smaller cervical spinal cord area was the strongest MRI predictor of worsening fatigue. Damage to ascending somatosensory axons within the cervical cord may reduce afferent input to the thalamus and diminish thalamocortical drive, contributing to both the motor and the cognitive-arousal dimensions of fatigue. These findings support incorporating cervical cord MRI into prognostic models and future fatigue research.
    DOI:  https://doi.org/10.1212/NXI.0000000000200643
  55. Acad Radiol. 2026 Aug 19. pii: S1076-6332(26)00580-5. [Epub ahead of print]
    Structural Connectivity Alterations Within Frontal Subregions in Parkinson's Disease: Implications for Motor Dysfunction.
    Yue Yuan, Xue Chen, Yande Ren, Mengjie Li, Wanyi Liu, Yanjiang Wang, Marcus Kaiser.
       RATIONALE AND OBJECTIVES: Parkinson's disease (PD) is characterized by disrupted basal ganglia-thalamo-cortical connectivity, yet how frontal network topology relates to motor phenotype heterogeneity remains unclear. Conventional atlas-based approaches average out microscale organization within heterogeneous cortical areas. This study aimed to characterize fine-grained frontal subregional connectivity alterations in PD using high-resolution structural network analysis.
    MATERIALS AND METHODS: Twenty-three patients with PD and 22 age- and sex-matched controls underwent diffusion tensor imaging and T1-weighted magnetic resonance imaging. Individual high-resolution frontal networks were constructed, and graph-theoretical metrics were computed for each frontal subregion to quantify connectivity patterns. Consensus Louvain clustering assessed modularity, and machine learning with SHapley Additive exPlanations interpretation performed individual classification.
    RESULTS: Patients with PD exhibited heterogeneous topological alterations across multiple frontal subregions (corrected p < 0.05). The left rostral middle frontal gyrus (RMF.L) showed increased density and degree, whereas the lateral and medial orbitofrontal cortices showed decreases. RMF.L further exhibited a greater number of modules together with an altered modular organization. These topological alterations were significantly correlated with UPDRS-III motor scores. Topological features achieved a diagnostic accuracy of 91.69% for PD diagnosis and 91.90% for subtype differentiation, exceeding the performance of connectivity-based features.
    CONCLUSION: Intraregional topological reorganization within the frontal lobe, most prominently in RMF.L, was associated with motor impairment in PD and may reflect maladaptive network remodeling. High-resolution network analysis may provide a sensitive framework for characterizing intraregional structural reorganization in PD and warrants further validation as an adjunctive imaging marker for disease stratification.
    Keywords:  Diffusion tensor imaging; Frontal lobe; Network topology; Parkinson's disease; Subregional connectivity
    DOI:  https://doi.org/10.1016/j.acra.2026.07.073
  56. Acta Med Litu. 2026 ;33(1): 222-231
    Challenges in the Diagnosis of Multiple Sclerosis: A Case Report.
    Kristina Galinytė, Gintarė Butenytė, Gintarė Žemgulytė, Jurgita Makštienė, Renata Balnytė.
       Introduction: : Multiple sclerosis (MS) may present as a tumor-like, or tumefactive demyelinating lesion, that is indistinguishable clinically and radiologically from a brain tumor. This poses a diagnostic challenge.
    Case presentation: We present a case report of a 23-year-old woman who was hospitalized in the Neurosurgery Department for biopsy of a brain mass. She had been diagnosed with Hodgkin's lymphoma at the age of 12, underwent surgery and chemotherapy, and had been in remission ever since. During her annual follow-up a magnetic resonance imaging (MRI) of the brain was performed that revealed a lesion in the right temporal lobe. It was interpreted as central nervous system (CNS) lymphoma. Before arranged neurosurgical intervention, a follow-up MRI scan revealed multiple new small lesions in both hemispheres. Biopsy was not performed, and the patient was referred to the Neurology Department for clarification of the diagnosis. No abnormalities were detected in the tests performed. Cerebrospinal fluid (CSF) was not tested due to the patient's refusal to repeat the unsuccessful procedure. The patient was discharged from the hospital. Three months later, she arrived at the Emergency Department abroad with impaired coordination and hypoesthesia on the right side of the body. Two MRI scans revealed a new lesion in the left posterior periventricular area. CNS lymphoma was suspected again. The patient received treatment with levetiracetam and dexamethasone. Upon her return, an MRI scan was repeated, which revealed an enlargement of the lesion. CSF testing showed indistinct oligoclonal bands. As CNS lymphoma could not be excluded, a lesion biopsy was performed after discontinuation of the steroids therapy. Histological examination excluded malignancy. Later, an MRI scan was repeated; it showed two new contrast-enhancing lesions. Relapsing-remitting multiple sclerosis (RRMS) diagnosis was confirmed, and treatment with disease-modifying therapies (DMTs) was planned.
    Conclusions: Open-ring enhancement with little or no mass effect on MRI suggests a tumefactive demyelinating lesion (TDL). Moreover, TDLs tend to have a lower relative cerebral blood volume, and higher minimum and average apparent diffusion coefficient values compared to CNS lymphomas. Flow cytometry shows a monotypic B lymphoid population in cases of CNS lymphoma, not in MS.
    Keywords:  CNS lymphoma; differential diagnosis; tumor-like multiple sclerosis
    DOI:  https://doi.org/10.15388/Amed.2026.33.1.20
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