bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–08–09
fifty-two papers selected by
Luca Bolliger, lxBio
  1. Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.
  2. Targeting TDP-43 in sporadic amyotrophic lateral sclerosis.
  3. Evidence-based physiotherapy recommendations for the management of motor aspects in amyotrophic lateral sclerosis.
  4. Genetically inferred effects of brain structure and gene expression on neurodegenerative diseases: a Mendelian randomization study.
  5. Targeting Ubiquitinated Protein Aggregates in Neurodegenerative Diseases: current Status and Future Directions.
  6. Targeting mitochondria for the treatment of neurodegenerative diseases.
  7. Inhibition of Glutamate Decarboxylase in the Spinal Cord Induces Motor Deficits and Motor Neuron Degeneration.
  8. Sensory Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis Involves a Broad Hand Representation Within the Primary Somatosensory Cortex.
  9. Long-term trajectories of physical, psychological, and psychosocial experiences among people living with amyotrophic lateral sclerosis using tracheostomy invasive ventilation: An 18-year longitudinal study.
  10. Quantitative Assessment of Tongue Atrophy in Amyotrophic Lateral Sclerosis Using Transoral Tongue Ultrasonography (TOTU): A Retrospective Single-Center Study.
  11. Interleukin-6 trans-signalling as a selectively targetable driver of neurodegeneration.
  12. Neuropsychological Sub-Phenotypes in Amyotrophic Lateral Sclerosis.
  13. ALSUntangled #84 - ivermectin.
  14. Rheological and Technological Design of Texture-Modified Food Systems for Dysphagia Management in Amyotrophic Lateral Sclerosis.
  15. In-Vitro Evaluation of HIV/SARS-CoV-2 Co-Infection Mediated Proteomic Changes in Astrocytes and Pericytes Reveals Altered Signaling Pathways Associated With Neurodegenerative Disorders.
  16. A plug-and-play multi-organ-on-chip for studying interaction between central nervous system and peripheral monocytes following neuroinjury from radiation and Parkinson's disease.
  17. Intron retention in health and amyotrophic lateral sclerosis.
  18. Oxidative stress as a driver of organelle cascade damage in neurological diseases.
  19. Response to "Palpebral ptosis as the initial symptom of amyotrophic lateral sclerosis": the potential usefulness of cortical excitability and motor band sign as biomarkers of upper motor neuron degeneration.
  20. The Effectiveness Based on Optimal Dose and Administration Route, and Safety Profiles of Stem Cells and Derived Products in the Treatment of Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.
  21. Quantitative susceptibility mapping in neurodegenerative diseases: An umbrella review of iron-related biomarkers and mechanisms.
  22. Neural stem cell-derived small extracellular vesicles ameliorate disease progression in the SOD1 G93A murine model of amyotrophic lateral sclerosis.
  23. Mechanisms, Biomarkers and Therapeutic Implications of Neuroinflammation in Alzheimer's Disease.
  24. Early and Divergent Lipid Mediator Remodelling in Fast Versus Slow Skeletal Muscles of Female hSOD1G93A Mice.
  25. A phosphorylation‑independent monoclonal antibody improves detection of TDP‑43 pathology across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and limbic predominant age related TDP‑43 encephalopathy neuropathological change.
  26. The Oral-Brain Axis: Mechanistic Insights Linking Periodontitis With Alzheimer's and Parkinson's Diseases.
  27. Depressive symptoms in amyotrophic lateral sclerosis: associations with quality of life, disease progression and perceived social support-a German multicenter study.
  28. Application of Low-Intensity Focused Ultrasound in Parkinson's Disease.
  29. Clinical genome sequencing in neurodegenerative diseases-outcome in the first 500 patients.
  30. Distinct competitive and allosteric binding modes of nanobodies targeting EphA4.
  31. From neural development to regenerative medicine: A research journey in stem cell biology, spinal cord repair, and iPSC-based drug discovery.
  32. Temporal order of clinical, imaging, and biomarker changes in frontotemporal lobar degeneration-associated syndromes.
  33. Clinical features of older MS patients with and without Alzheimer disease biomarkers.
  34. Investigating changes in the blood-brain barrier in schizophrenia spectrum disorders: design and methodology of a longitudinal dynamic contrast-enhanced MRI study.
  35. Senescence Associated With Neurodegeneration: Simultaneous Assessment of β-gal Activity And Nissl Stain In Histological Sections of Rodent Brain.
  36. Glial cell toxicity in a Drosophila C9orf72 neurodegeneration model.
  37. Locus Coeruleus as a Master Regulator of Diverse Functions in the Central Nervous System: Its Relevance in Ageing and Neurodegenerative Disorders.
  38. Zafirlukast Exacerbates Behavioral Seizure Activity and Blood-Brain Barrier Disruption Despite Modestly Reducing Neuronal Injury Markers in a PTZ-Induced Early Epileptogenesis Mouse Model.
  39. Frontotemporal dementia with right temporal predominance: a clinical comparison with left-predominant FTD.
  40. Steroids for Drug-Resistant Seizures and Prolonged Stroke-Like Episode in a Patient With Sturge-Weber Syndrome: A Case Report.
  41. Mitochondrial Permeability Transition Regulators As Emerging Therapeutic Targets in Aging and Neurodegeneration: Recent Insights.
  42. Lineage-Driven Understanding of Human Pericyte Heterogeneity in Vascular Modeling and Regeneration.
  43. Wild-type C9orf72 drives proteasomal dysfunction and mutant aggregates via a Stat1-Isg15 axis in Huntington's disease.
  44. Mitochondrial homeostasis dysregulation: Potential mechanisms of Alzheimer's disease mediated by TDP-43.
  45. Psychomotor retardation and risk of Parkinson's disease in unipolar depression: A retrospective cohort study.
  46. Association of therapeutic plasma exchange with functional outcomes in selected neurological disorders: a retrospective cohort study from a single tertiary center in Saudi Arabia.
  47. Toward the prevention of clinically manifest Parkinson's disease.
  48. GBA1 variants and mortality in Parkinson's disease: A systematic review and meta-analysis.
  49. Gut-derived signals regulating glial activation and secondary neuroinflammation after spinal cord injury: an evidence mapping and mechanistic framework.
  50. Antigen presentation at the blood-brain barrier amplifies neuroinflammation.
  51. Chronic neurological diseases with acute respiratory failure in a real-life cohort: insights into ICU and long-term survival-A retrospective study.
  52. Diagnostic Accuracy of MRI-Based Artificial Intelligence Models for Distinguishing Alzheimer's Disease and Mild Cognitive Impairment From Cognitively Normal Controls: A Systematic Review and Meta-Analysis.
  1. Mol Neurobiol. 2026 Aug 01. pii: 800. [Epub ahead of print]63(1):
    Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.
    Mengqi Chu, Miaomiao Tan, Xulin Gan, Shumao Cui, Liyun Shi.
      Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose an urgent global health challenge. Growing evidence establishes microglia-driven neuroinflammation as a key driver of disease onset and progression, with mitochondrial dysfunction emerging as an early trigger of microglial activation. This review comprehensively summarizes current progress on how mitochondrial alterations regulate microglial activation across AD, PD, and ALS. We identify conserved mechanisms including metabolic reprogramming, impaired mitophagy, and inflammatory signaling, though Aβ, α-synuclein, and TDP-43 engage these pathways through disease-specific molecular routes. Therapeutic strategies targeting microglial mitochondria, including cGAS-STING and NLRP3 inhibitors, TREM2 agonists, and mitochondrial transplantation, remain largely preclinical. Emerging targets such as OLFML3 and GPNMB require functional validation in microglia. Collectively, this review underscores that preserving microglial mitochondrial health represents a promising therapeutic frontier and identifies key priorities for translating these strategies toward clinical application.
    Keywords:  Microglia; Mitochondria; Neurodegenerative diseases
    DOI:  https://doi.org/10.1007/s12035-026-06091-5
  2. J Neurol. 2026 Aug 01. pii: 498. [Epub ahead of print]273(8):
    Targeting TDP-43 in sporadic amyotrophic lateral sclerosis.
    Carlos Estevez-Fraga, Rodrigo Alvarez-Velasco, Tariq Afroz, Marcos R Costa, Ana Jovičić, Felix L Yeh, Peter McColgan, Andrea Malaspina, Alexander McCampbell.
      Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder characterized by motor neuron degeneration leading to early mortality. Despite advances in understanding genetic and molecular contributors, effective disease-modifying therapies for sporadic ALS are of limited utility. The identification of the accumulation of TAR DNA-binding protein 43 (TDP-43) in 97% of total ALS cases represents a critical pathogenic hallmark. This review examines key biological mechanisms underlying TDP-43 pathology, emerging therapeutic strategies, and evolving approaches to clinical trial design and biomarker development. TDP-43 loss of nuclear function, leading to widespread RNA missplicing, and inclusion of cryptic exons, represents an early and critical event in ALS pathogenesis causing downstream dysregulation of key neuronal genes such as STMN2 and UNC13A contributing to axonal degeneration and synaptic dysfunction. Therapeutic strategies targeting these pathways are currently under investigation. Additional approaches aim to ameliorate TDP-43 gain-of-function through cytoplasmic TDP-43 aggregation or modulating processes such as stress responses and RNA metabolism, although clinical translation has been challenging. Advances in biomarkers, including neurofilament light chain and cryptic exon-derived peptides, provide tools for developing efficient clinical trials. However, heterogeneity in disease progression and limitations of available clinical endpoints complicate trial design. Integration of biological insights with biomarker-driven patient stratification and optimized trial methodologies is essential to improve clinical trial outcomes. Emerging biomarkers may enable earlier diagnosis, monitoring of therapeutic response, and personalized treatment approaches. Continued alignment of biological discovery with innovative clinical trial design holds promise for advancing effective therapies and transforming the future of ALS.
    Keywords:  Amyotrophic lateral sclerosis; Clinical trials; STMN2; TDP-43; UNC13A
    DOI:  https://doi.org/10.1007/s00415-026-14023-5
  3. Neurodegener Dis Manag. 2026 Aug 05. 1-11
    Evidence-based physiotherapy recommendations for the management of motor aspects in amyotrophic lateral sclerosis.
    Stephano Tomaz da Silva, Aline Alves de Souza, Luciana Protásio de Melo, Roberta de Oliveira Cacho, Ledycnarf Januário de Holanda, Leila Denise Neto Ortiz, Mário Emílio Teixeira Dourado Júnior, Igor Braga Farias, Filipe Gonçalves, Danilo Alves Pinto Nagem, Ricardo Alexsandro de Medeiros Valentim, Ana Raquel Rodrigues Lindquist, Tatiana Souza Ribeiro.
       AIM: To provide evidence-based recommendations for the physiotherapy management of Amyotrophic Lateral Sclerosis (ALS).
    MATERIALS AND METHODS: Evidence-based recommendations were developed by a multidisciplinary team, including PhDs and master's-level researchers, physicians, and experienced physiotherapists specializing in neurological rehabilitation.
    RESULTS: After the selection process, 23 studies were included. Eighteen recommendations addressing motor aspects in ALS were formulated.
    CONCLUSIONS: Therapeutic exercise should be considered to improve or maintain ALSFRS-R scores in people with ALS. However, the effects of other interventions examined in this study remain uncertain with respect to motor aspects.
    Keywords:  Amyotrophic lateral sclerosis; evidence synthesis; evidence-based practice; exercise therapy; physical therapy modalities
    DOI:  https://doi.org/10.1080/17582024.2026.2713034
  4. Arch Med Sci. 2026 ;22(3): 1663-1677
    Genetically inferred effects of brain structure and gene expression on neurodegenerative diseases: a Mendelian randomization study.
    Sen Wang, Yiqun Lin, Yujie Che, Jiahang Zhao, Linyu Xu, Wen He, Wei Zhang.
       Introduction: Against the backdrop of accelerating population aging, the risk of neurodegenerative diseases (NDDs) has risen significantly. While brain structure plays a critical role in NDDs, the interplay between them remains unclear. This study employed Mendelian randomization (MR) to investigate potential causal relationships between brain structure, region-specific gene expression, and four NDDs - Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) - providing new directions and genetically informed hypotheses for disease research.
    Material and methods: MR analyses were conducted using inverse-variance weighted (IVW), MR-Egger, weighted median, weighted mode, and Wald ratio methods. Summary-data-based MR (SMR) was applied to identify brain genes influencing NDDs. We calculated F-statistics, 95% confidence intervals (CIs), odds ratios, and p-values. Sensitivity analyses included the heterogeneity I2 statistic, Cochran's Q test, Egger intercept test, MR-PRESSO, and leave-one-out validation.
    Results: Data from 512 unsupervised deep-learning imaging phenotypes (UDIPs) were analyzed. Thirty-four UDIPs showed associations consistent with a potential causal role in AD, 56 in PD, 22 in ALS, and 92 in MS. After false discovery rate (FDR) correction, 4 remained significant for AD and PD, 3 for ALS, and 28 for MS (p < 0.05). Brain regions (excluding the cervical spinal cord C-1) exhibited shared causal genetic features across all four NDDs, primarily involving HLA-class genes.
    Conclusions: This study provides genetic evidence suggestive of potential causal associations between UDIPs, brain gene expression, and NDDs. These findings offer genetically predicted evidence that may generate hypotheses and inform future mechanistic research into NDD pathogenesis.
    Keywords:  Mendelian randomization; aging; brain regions; brain structure; gene expression; neurodegenerative diseases
    DOI:  https://doi.org/10.5114/aoms/219499
  5. Mol Cell Biol. 2026 Aug 04. 1-19
    Targeting Ubiquitinated Protein Aggregates in Neurodegenerative Diseases: current Status and Future Directions.
    Masahiko Takahashi, Takayuki Abe, Masahiro Fujii.
      Various cellular stressors inhibit translation initiation and promote ribosome disassembly, thereby transiently inducing stress granules (SGs), dynamic ribonucleoprotein condensates that contain mRNAs and RNA-binding proteins. Although SG assembly is usually reversible, dysregulated SG dynamics can trigger the formation of persistent ubiquitin-positive protein inclusions. There is increasing evidence that this conversion of SGs into insoluble aggregates represents a central pathogenic mechanism in neurodegenerative proteinopathies, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). TAR DNA-binding protein 43 (TDP-43) and Tau are causative factors in ALS and AD, respectively, and both localize to SGs under stress conditions. During disease progression, TDP-43 or Tau within SGs undergoes pathological changes that promote the formation of neurotoxic inclusions, which propagate neuronal dysfunction and death. This review summarizes recent advances in understanding the molecular factors that regulate SG assembly and disassembly, as well as the pathological processes that drive the conversion of SGs into aggregates associated with neurodegenerative diseases. Particular emphasis is placed on the role of the ubiquitin-specific protease 10 (USP10), which modulates SG dynamics and has been mechanistically implicated in both ALS and AD. Finally, we discuss the therapeutic potential of targeting these pathways to mitigate neurodegenerative disease progression.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; stress granule; ubiquitin-specific protease 10
    DOI:  https://doi.org/10.1080/10985549.2026.2705871
  6. Front Neurosci. 2026 ;20 1835506
    Targeting mitochondria for the treatment of neurodegenerative diseases.
    Qian Li, Ming You.
      Mitochondria are central regulators of cellular metabolism, redox balance, calcium signaling, and cell survival, making them essential for neuronal function. Because neurons rely heavily on mitochondrial oxidative phosphorylation to meet their high energetic demands, mitochondrial dysfunction has emerged as a key pathogenic driver in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Defects in mitochondrial bioenergetics, excessive reactive oxygen species production, impaired mitochondrial dynamics, disrupted mitophagy, and dysregulated calcium handling collectively contribute to neuronal damage, synaptic dysfunction, and neuroinflammation. These insights have prompted growing interest in therapeutic strategies that directly target mitochondria to restore organelle homeostasis. Recent advances in chemical biology and nanomedicine have enabled the development of mitochondria-targeted ligands, peptide-based targeting systems, and carrier or nanotechnology-enabled delivery platforms designed to overcome biological barriers and selectively deliver therapeutic cargos to mitochondria within the central nervous system. In this Review, we summarize mitochondrial pathological mechanisms in neurodegenerative diseases and discuss emerging mitochondria-targeted therapeutic strategies, highlighting delivery technologies, therapeutic modalities, and translational challenges. Although most strategies remain at the preclinical or proof-of-principle stage, these advances are beginning to shape a conceptual framework for precision mitochondrial medicine, with the longer-term goal of developing disease-modifying interventions for neurodegenerative disorders.
    Keywords:  blood–brain Barrie; mitochondrial dysfunction; mitochondrial targeting; nanocarrier delivery system; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnins.2026.1835506
  7. Neurotox Res. 2026 Aug 05. pii: 40. [Epub ahead of print]44(4):
    Inhibition of Glutamate Decarboxylase in the Spinal Cord Induces Motor Deficits and Motor Neuron Degeneration.
    Elizabeth Colín-Martínez, Uri Nimrod Ramírez-Jarquín, Ricardo Tapia, Clorinda Arias.
      Motor neuron (MN) diseases such as amyotrophic lateral sclerosis (ALS) are characterized by the loss of cortical and spinal MNs. Although the precise mechanisms of MN degeneration are still unknown, downregulation of GABAergic circuits has been identified in both ALS patients and transgenic models of the disease. GABA synthesis depends on the activity of the enzyme glutamate decarboxylase (GAD), of which two isoforms are known: GAD65 and GAD67. To study the effects of decreased GABA synthesis on spinal cord motor function, we analyzed the effects of administering three selective inhibitors of GAD: 3-mercaptopropionic acid (MPA), a competitive inhibitor of GAD, thiosemicarbazide (TSC), and pyridoxal phosphate γ-glutamyl hydrazone (PLPGH), two GAD cofactor blockers. A single dose of any of these inhibitors did not affect motor behavior or MN morphology. However, subchronic (3 days) and chronic (10 days) administration of MPA, TSC or PLPGH in rats caused motor alterations and cellular changes, including episodic myoclonus-like movements, flaccidity in the ipsilateral phalanges, loss of 35-50% of MNs, reactive astrogliosis and decreased GAD activity. These findings suggest that chronic inhibition of GAD can lead to MN degeneration and further suggest that GABA metabolism in the spinal cord may participate in the mechanisms that cause MN death in patients with neurodegenerative diseases such as ALS.
    Keywords:  ALS; GABA metabolism; GAD inhibitors; GAD isoforms; Motor neuron degeneration; Rat spinal cord
    DOI:  https://doi.org/10.1007/s12640-026-00815-0
  8. Muscle Nerve. 2026 Aug 03.
    Sensory Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis Involves a Broad Hand Representation Within the Primary Somatosensory Cortex.
    Yoshiyuki Matsuki, Kota Bokuda, Ryo Morishima, Tomoya Kawazoe, Hideki Kimura, Kazushi Takahashi, Yuki Nakayama, Toshio Shimizu.
       INTRODUCTION/AIMS: Sensory cortical hyperexcitability, reflected by enlarged median nerve somatosensory evoked potentials (SEPs), has been reported in amyotrophic lateral sclerosis (ALS) and is associated with shorter survival. This study investigated whether similar changes involve the ulnar nerve representation within the hand area of the primary somatosensory cortex and examined their relationship with survival.
    METHODS: Ninety-nine patients with sporadic ALS and 42 healthy controls were retrospectively studied. Sensory nerve action potentials (SNAPs) and SEPs were recorded following median and ulnar nerve stimulation. SNAP amplitudes and the peak-to-peak amplitudes between N20 and P25 (N20p-P25p) were compared between groups. Patients were followed until death or tracheostomy, and associations between SEP amplitudes and survival were analyzed using Kaplan-Meier and Cox proportional hazards analyses.
    RESULTS: SNAP amplitudes did not differ between patients and controls. In contrast, patients with ALS showed larger N20p-P25p amplitudes for both median and ulnar nerve SEPs. N20p-P25p amplitudes were positively correlated between the two nerves, and the ulnar-to-median amplitude ratio did not differ from controls. Patients with ulnar N20p-P25p ≥ 4.89 μV had significantly shorter survival than those with lower amplitude (log-rank test, p = 0.035). Multivariate Cox analysis identified increased N20p-P25p amplitude as an independent predictor of shorter survival for both nerves.
    DISCUSSION: Sensory cortical hyperexcitability in ALS extends beyond the median nerve to the ulnar nerve hand area of the somatosensory cortex. Its association with survival supports the notion that sensory cortical dysfunction represents a fundamental pathophysiological feature of ALS and a potential electrophysiological prognostic marker.
    Keywords:  amyotrophic lateral sclerosis; sensory cortex; somatosensory evoked potential: ulnar nerve; survival
    DOI:  https://doi.org/10.1002/mus.70371
  9. J Health Psychol. 2026 Aug 01. 13591053261474390
    Long-term trajectories of physical, psychological, and psychosocial experiences among people living with amyotrophic lateral sclerosis using tracheostomy invasive ventilation: An 18-year longitudinal study.
    Yuko Hirano.
      Advances in respiratory care have enabled people living with amyotrophic lateral sclerosis (PALS) using tracheostomy invasive ventilation (TIV) to live for many years with the disease. However, longitudinal evidence describing their psychosocial trajectories remains limited. This study explored the long-term trajectories of three PALS using TIV through repeated face-to-face assessments over an approximately 18 year period. Psychological state, subjective physical symptoms, and hope followed similar patterns across participants, worsening after illness onset and reaching their lowest levels between diagnosis and TIV initiation before improving and becoming increasingly individual over time. Perceived psychological support and sources of joy peaked after TIV initiation before fluctuating, whereas perceived financial status remained relatively stable. These findings demonstrate a shared pattern of early adaptation followed by increasingly individual long-term trajectories, providing a foundation for trajectory-informed holistic care.
    Keywords:  amyotrophic lateral sclerosis; holistic care; longitudinal trajectories; psychosocial adaptation; tracheostomy invasive ventilation
    DOI:  https://doi.org/10.1177/13591053261474390
  10. Muscle Nerve. 2026 Aug 04.
    Quantitative Assessment of Tongue Atrophy in Amyotrophic Lateral Sclerosis Using Transoral Tongue Ultrasonography (TOTU): A Retrospective Single-Center Study.
    Naoki Iijima, Yuta Hagiwara, Seiya Ishii, Wataru Kaneko, Takashi Araga, Yoshihisa Yamano.
       INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease accompanied by bulbar dysfunction, in which tongue atrophy contributes to dysarthria and dysphagia. Conventional tongue assessments rely on inspection, palpation, or electrophysiological testing but are limited by subjectivity and invasiveness. A rapid, objective, and repeatable imaging-based method for evaluating tongue size would be valuable. We quantified tongue atrophy in ALS using a standardized protocol for transoral tongue ultrasonography (TOTU) and assessed discrimination.
    METHODS: This retrospective, cross-sectional study included 15 patients with ALS and 15 controls who underwent TOTU. Using standardized mid-sagittal images, tongue cross-sectional area (cm2) and tongue thickness (mm) were measured three times per subject and averaged. Associations with age, body mass index (BMI), disease duration, and ALS Functional Rating Scale-Revised (ALSFRS-R) scores were explored. Discrimination was evaluated using receiver operating characteristic (ROC) analyses.
    RESULTS: Both tongue cross-sectional area (6.26 ± 1.37 vs. 9.44 ± 1.02 cm2) and tongue thickness (31.47 ± 3.0 vs. 39.44 ± 1.39 mm) were significantly lower in the ALS group than in controls (both p < 0.001). These indices showed no significant associations with age, BMI, disease duration, or ALSFRS-R scores. ROC analyses showed high discriminative ability, with an area under the curve of 0.982 for tongue cross-sectional area and 1.000 for tongue thickness.
    DISCUSSION: Standardized TOTU enables rapid, quantitative, noninvasive assessment of tongue size and reliably detects tongue atrophy in ALS, supporting bedside evaluation of bulbar involvement.
    Keywords:  amyotrophic lateral sclerosis; tongue atrophy; tongue cross‐sectional area; tongue thickness; transoral ultrasonography
    DOI:  https://doi.org/10.1002/mus.70370
  11. Trends Neurosci. 2026 Aug 07. pii: S0166-2236(26)00140-2. [Epub ahead of print]
    Interleukin-6 trans-signalling as a selectively targetable driver of neurodegeneration.
    Grace Risby-Jones, John D Lee, Jenny N Fung.
      Interleukin-6 (IL-6) exerts protective and pathogenic effects in the central nervous system through distinct receptor-signalling modes. Classical signalling via membrane-bound IL-6 receptor (IL-6R) is often associated with homeostatic and reparative functions, whereas trans-signalling, mediated by soluble IL-6R, expands IL-6 responsiveness to gp130-expressing cells and may promote chronic inflammation. Emerging evidence implicates dysregulated IL-6 trans-signalling in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Here, we review mechanisms linking IL-6 trans-signalling to immune, glial, neuronal, and vascular dysfunction in neurodegeneration. We highlight key knowledge gaps and discuss whether selective targeting of trans-signalling can limit inflammatory pathology while preserving beneficial classical IL-6 functions.
    Keywords:  astrocytes; biomarker stratification; blood–brain barrier; cytokine signalling; microglia; neuroinflammation
    DOI:  https://doi.org/10.1016/j.tins.2026.07.002
  12. Eur J Neurol. 2026 Aug;33(8): e70706
    Neuropsychological Sub-Phenotypes in Amyotrophic Lateral Sclerosis.
    Barbara Poletti, Edoardo Nicolò Aiello, Monica Consonni, Barbara Iazzolino, Silvia Torre, Veronica Faltracco, Alessandra Telesca, Francesca Palumbo, Beatrice Curti, Giulia De Luca, Arianna Moreschi, Francesca Frisco, Eleonora Dalla Bella, Enrica Bersano, Nilo Riva, Federico Verde, Stefano Messina, Alberto Doretti, Alessio Maranzano, Claudia Morelli, Stefano Francesco Cappa, Andrea Calvo, Michael J Strong, Vincenzo Silani, Giuseppe Lauria, Adriano Chiò, Nicola Ticozzi.
       BACKGROUND: This study aimed at identifying neuropsychological sub-phenotypes in amyotrophic lateral sclerosis (ALS) within the mild cognitive impairment (MCI) and mild behavioral impairment (MBI) frameworks.
    METHODS: We used individual task-/item-level data from the cognitive and behavioral sections of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) from 901 non-demented ALS to derive neuropsychological sub-phenotypes pursuant to classical MCI and MBI frameworks and in accordance with an expanded version of Strong's criteria, which also addressed memory and visuo-spatial measures.
    RESULTS: The prevalence of MCI and MBI was 39% and 37%, respectively in this retrospective review. The following MCI sub-phenotypes were identified: dysexecutive MCI-single- and multiple-domain (dMCI-sd: 63%; dMCI-md: 24%, respectively); non-dysexecutive MCI-single- and multiple-domain (ndMCI-sd: 12%; ndMCI-md: 1%, respectively). MBI was classified as follows: apathetic MBI-single- and multiple-domain (aMBI-sd: 40%; aMBI-md: 20%, respectively); apathetic-disinihibited/perseverative MBI-multiple domain (ad/pMBI-md: 21%); disinihibited/perseverative MBI-multiple domain (d/pMBI-md: 7%); psychotic MBI-single- and multiple-domain (psyMBI-sd: 2%; psyMBI-md: 3%, respectively); unclassifiable MBI-multiple domain (uMBI-md: 1%). 143 (16%) of patients exhibited mild cognitive and behavioral impairment (MCBI).
    CONCLUSIONS: This study delivers a provisional, ECAS-based classification for the neuropsychological sub-phenotyping of non-demented ALS patients, which, with further validation, might be useful for both research and clinical purposes.
    Keywords:  amyotrophic lateral sclerosis; edinburgh cognitive and behavioral ALS screen; frontotemporal‐spectrum disorder; neuropsychology; phenotype; research criteria
    DOI:  https://doi.org/10.1111/ene.70706
  13. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Aug 06. 1-6
    ALSUntangled #84 - ivermectin.
    Benjamin Helmold, Carmel Armon, Michael Benatar, Tulio Bertorini, Mark Bromberg, Andrew Brown, Javier Mascias Cadavid, Olimpia Carbunar, Gregory T Carter, Jesse Crayle, Eva Feldman, Juliette Foucher, Jonathan Glass, Ethan Greenstein, Sartaj Jhooty, Nan Jiang, Noah Nathan Kochen, Christopher McDermott, Natasha Olby, Gary Pattee, Devon Porter, Alan Premasari, Anusha Rao, Dylan Ratner, Kim Staats, Elia Tito, Fernando Vieira, Paul Wicks, Richard Bedlack.
      ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). In this review, we explore the possibility of using ivermectin to slow ALS progression. Ivermectin's ability to modulate neuroinflammation and excitotoxicity give it plausible mechanisms for treating ALS, though it does not get into the brain very well. One preclinical study demonstrated that ivermectin lengthened lifespan within a mouse model of mSOD1 genetic ALS. This finding has not been replicated. The 2 PALS we found who had data comparing ALSFRS-R progression on and off ivermectin appeared to have no benefit from it. We found no trials of ivermectin in PALS. Ivermectin is low cost and generally well tolerated with most adverse effects being mild and transient, but serious side effects can rarely occur, and it has not been carefully studied in PALS. We cannot at present endorse ivermectin as an ALS treatment.
    Keywords:  Ivermectin; alternative therapy; off-label use
    DOI:  https://doi.org/10.1080/21678421.2026.2714724
  14. J Texture Stud. 2026 Aug;57(4): e70105
    Rheological and Technological Design of Texture-Modified Food Systems for Dysphagia Management in Amyotrophic Lateral Sclerosis.
    Zulfiya Konarbayeva.
      Amyotrophic lateral sclerosis (ALS) is frequently accompanied by progressive dysphagia, weight loss, and hypermetabolism, which complicate the maintenance of adequate nutritional status. For these patients, food systems must not only provide sufficient energy and protein within a limited volume but also exhibit textural and rheological properties that support safe swallowing. This review analyzes technological and rheological approaches to the design of texture-modified food systems for nutritional support in ALS. Particular attention is given to apparent viscosity, shear-thinning behavior, yield stress, structural homogeneity, and storage stability as parameters affecting bolus formation, swallowing safety, and product performance. The relevance of the International Dysphagia Diet Standardization Initiative framework for classifying food textures and liquid consistencies is also considered. The review further examines the functional and technological roles of animal- and plant-based raw materials, including regional raw materials, in the formulation of energy-dense and structurally stable foods. Proteins, lipids, hydrocolloids, starch gels, and polysaccharide networks are discussed as key components for controlling texture, viscosity, gelation, emulsion stability, and nutritional density. Technological strategies such as homogenization, emulsification, protein-based structuring, hydrocolloid thickening, high-pressure homogenization, and 3D food printing are considered in relation to their potential for developing safe, acceptable, and locally adaptable products for patients with ALS-related dysphagia. The findings highlight the need to integrate food texture science, rheological control, nutritional adequacy, sensory acceptability, and regional availability in the development of clinically relevant texture-modified foods.
    Keywords:  IDDSI; amyotrophic lateral sclerosis; clinical nutrition; dysphagia; food design; rheological properties; swallowing safety; texture‐modified foods
    DOI:  https://doi.org/10.1111/jtxs.70105
  15. J Med Virol. 2026 Aug;98(8): e71086
    In-Vitro Evaluation of HIV/SARS-CoV-2 Co-Infection Mediated Proteomic Changes in Astrocytes and Pericytes Reveals Altered Signaling Pathways Associated With Neurodegenerative Disorders.
    Arpan Acharya, Michellie Thurman, Debapriya Sutar, Oluwatayo Israel Olasunkanmi, Johid R Malik, Shetty Ravi Dyavar, Ákos Végvári, Siddappa N Byrareddy.
      Coronavirus disease 2019 (COVID-19) survivors frequently experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Importantly, complications arising from microvascular dysfunction, blood-brain barrier (BBB) disruption, and chronic neuroinflammation have been implicated in driving PASC within the central nervous system (CNS), known as neuro-PASC. Notably, people with HIV (PWH), who suffer from chronic neuroinflammation, BBB impairment, and glial cell dysfunction, collectively known as neuro-HIV, are generally at higher risk of neuro-PASC. The overlap between neuro-PASC and neuro-HIV raises concerns that HIV and SARS-CoV-2 co-infection may exacerbate neurological dysfunctions among PWH. In this study, using an in-vitro cell culture model, we examine the effects of HIV and SARS-CoV-2 mono- and co-infection in microglia, astrocytes, and pericytes. Our results demonstrated that majority of brain cell types support SARS-CoV-2 replication, in the presence and absence of HIV infection. Furthermore, in both mono- and co-infected cells, there were varying degree of up- and downregulation of SARS-CoV-2 host cell entry factors, such as ACE2, TMPRSS2, NRP1, and TRIM28, and inflammatory cytokines including IL-6, TNF-α, and IL-1β. Moreover, conditioned media collected from HIV, SARS-CoV-2, and HIV/SARS-CoV-2 co-infected astrocytes and pericytes were shown to be neurotoxic. Additionally, proteomic analysis has revealed a unique set of proteins significantly up/down regulated in HIV/SARS-CoV-2 co-infected astrocytes and pericytes. The gene set enrichment analysis of these proteins indicates dysregulation of lipid, energy, and immune metabolism pathways linked to neurodegenerative disorders like Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis. These in-vitro findings indicate that astrocytes and pericytes from HIV/SARS-CoV-2 co-infection exhibit altered protein expression profiles, implicating dysregulated signaling pathways associated with neurodegenerative dysfunction.
    Keywords:  ACE‐2; COVID‐19; HIV; PASC; SARS‐CoV‐2; and pericytes; astrocytes; co‐infection; long‐covid; microglia; neuroHIV
    DOI:  https://doi.org/10.1002/jmv.71086
  16. RSC Adv. 2026 Jul 31.
    A plug-and-play multi-organ-on-chip for studying interaction between central nervous system and peripheral monocytes following neuroinjury from radiation and Parkinson's disease.
    Yu Chen, Zhirong Wan, Beiqin Liu, Hong Ma, Shuyue Wang, Yaoyuan Cui, Yulin Deng, Jichen Du.
      Following neuroinjury (e.g., from radiation or Parkinson's disease), peripheral monocytes infiltrate the CNS, promoting neuroinflammation and cognitive decline. However, studying this is challenging due to a lack of suitable in vitro models. Multi-organ-on-a-chips (MOCs) address this gap with interactable in vitro models. We developed a plug-and-play multi-organ-chip (PPMOC) to mimic CNS-monocyte interactions. The PPMOC features two chambers, each with an insert for CNS or monocyte models, interconnected by a channel. A PDMS-based fabrication method using laser cutting of polymethyl methacrylate was developed for its fabrication. Finally, the PPMOC was employed to investigate CNS-monocyte interactions in radiation-induced neuroinjury and Parkinson's disease (PD). Results show that radiation caused neuroinjury, manifesting as decreased viability and morphological damage in nerve cells, and increased permeability of the blood-brain barrier (BBB). Further analysis revealed that radiation-induced neuroinjury inhibits the proliferation of THP-1 cells and promotes their activation and differentiation. Similarly, in PD, increased BBB permeability and activation of THP-1 cells were observed. Analysis of exosomes from the medium revealed upregulation of miR-151a-5p and miR-423-3p. Both models showed upregulated expression of inflammatory proteins and cytokines (e.g., CD14, TLR-2, IL-6, TNF-α, CCL-20), indicating monocyte activation. To sum up, PPMOC, a user-friendly and flexible multi-organ-on-a-chip, will become an important tool for studying CNS-monocyte interactions.
    DOI:  https://doi.org/10.1039/d6ra01858k
  17. Brain. 2026 Aug 03. pii: awag142. [Epub ahead of print]
    Intron retention in health and amyotrophic lateral sclerosis.
    Chloe Y Wang, Stephanie Taylor, Virenkumar A Pandya, Benjamin E Clarke, Koustav Pal, Tatyana A Shelkovnikova, Yiran Wang, Raphaëlle Luisier, Rickie Patani.
      Intron retention (IR) is the molecular phenomenon by which introns, historically thought to represent non-coding 'junk', remain unspliced within pre-mRNA transcripts, resulting in their incorporation into the mature mRNA molecule. While the role of IR is well established in species of plant, fungi, insects and viruses, it remains relatively understudied in mammalian biology. It was previously assumed that IR only played a limited role in downregulating a transcript's translation potential through downstream initiation of nuclear detention or nonsense mediated decay (NMD). However, recent studies highlight IR's significantly more complex and dynamic contribution to cellular physiology and disease. In particular, a role for IR is emerging in both health and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a rapidly progressive and invariably fatal disease that renders patients paralysed and unable to eat, speak or breathe. Significant technological advances now permit a comprehensive interrogation of previously unrecognized aspects of RNA metabolism in clinically relevant human cell types. In this review, we focus on the differential role(s) of nuclear and cytoplasmic intron retaining transcripts (nIRTs and cIRTs, respectively), as well as how IRTs may influence subcellular localization of ribonucleoprotein (RNP) complexes, loss of function of bound RNA binding proteins (RBPs) and liquid-liquid phase separation (LLPS) in physiology and disease. Additionally, we discuss the potential of IRTs as independent regulatory elements beyond their protein-coding functions and highlight how artificial intelligence is poised to accelerate discoveries in this area. In the context of IR's increasing appreciation, we also highlight its potential as a therapeutic target and explore current and future challenges in this burgeoning field.
    Keywords:  RNA binding protein; amyotrophic lateral sclerosis; gene expression regulation; intron retention; phase separation; splicing
    DOI:  https://doi.org/10.1093/brain/awag142
  18. Front Aging Neurosci. 2026 ;18 1892923
    Oxidative stress as a driver of organelle cascade damage in neurological diseases.
    Shiwang Li, Taijian Cao, Qiang Zhang.
      As a core driver in the pathological progression of neurological diseases, oxidative stress contributes to the onset and development of multiple disorders, including traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), by inducing interconnected and bidirectional damage among mitochondria, endoplasmic reticulum, lysosomes, and the nucleus. This review systematically summarizes the oxidative stress-mediated inter-organelle crosstalk network: Mitochondria act as one of the earliest and central hubs, and their dysfunction (e.g., reactive oxygen species burst, calcium overload, and respiratory chain impairment) induces endoplasmic reticulum stress via ROS diffusion and calcium signaling disturbance. The disruption of endoplasmic reticulum calcium homeostasis further exacerbates mitochondrial damage, forming a vicious cycle. Lysosomes exhibit reduced membrane stability and impaired autophagic flux under oxidative stress, failing to clear damaged organelles and aggravating oxidative stress accumulation. Ultimately, oxidative stress signals are transmitted to the nucleus, resulting in DNA damage, aberrant epigenetic modifications, and activation of pro-inflammatory/pro-apoptotic genes, thereby accelerating disease progression. Notably, this organelle injury transmission is not a rigid unidirectional linear cascade; primary lysosomal or MAM defects can independently initiate the full organelle damage loop without preceding mitochondrial dysfunction. This review integrates current studies, clarifies context-dependent and disease-specific characteristics of organelle interactions, and discusses potential therapeutic strategies with critical consideration of translational challenges and limitations, providing a theoretical foundation for mechanistic research and clinical intervention of neurological diseases.
    Keywords:  inflammatory response; mitochondria; neurological diseases; organelles; oxidative stress
    DOI:  https://doi.org/10.3389/fnagi.2026.1892923
  19. Neurol Sci. 2026 Aug 06. pii: 685. [Epub ahead of print]47(9):
    Response to "Palpebral ptosis as the initial symptom of amyotrophic lateral sclerosis": the potential usefulness of cortical excitability and motor band sign as biomarkers of upper motor neuron degeneration.
    Moisés León-Ruiz, Carlos Castañeda-Cabrero, Julián Benito-León.
      
    DOI:  https://doi.org/10.1007/s10072-026-09303-x
  20. Stem Cells Int. 2026 ;2026 4122493
    The Effectiveness Based on Optimal Dose and Administration Route, and Safety Profiles of Stem Cells and Derived Products in the Treatment of Patients With Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.
    Mahdieh Pourasghari, Soraya Babaie, Raha Markazi-Movaghar, Saba Salehpour, Bina Eftekharsadat, Azizeh Farshbaf-Khalili.
       Background: This systematic review and meta-analysis aimed to evaluate the effectiveness of stem cell therapies for patients with amyotrophic lateral sclerosis (ALS) based on optimal dosing and administration routes, as well as the safety profiles of stem cells and their derived products.
    Methods: The review followed PRISMA guidelines and involved a comprehensive literature search up to October 2025, receiving ethical approval from Tabriz University of Medical Sciences and registration in PROSPERO. It utilized international databases, including PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, ClinicalTrials.gov, and Science Direct. The included studies comprised randomized controlled trials (RCTs), quasi-experimental studies, and other interventional designs involving ALS patients treated with stem cell therapies. In total, 31 studies were analyzed, featuring 7 controlled trials with 370 participants and 24 non-controlled pre-post studies with 460 participants. Heterogeneity was evaluated using I 2 statistics, and subgroup analyses were conducted based on treatment duration and dosing.
    Results: A pooled analysis (treatment group: n = 93; control group: n = 90) demonstrated a significant attenuation in the progression of disease severity, as measured by the ALS Functional Rating Scale (ALSFRS), in stem cell groups versus controls (weighted mean difference [WMD]: 8.89 95% CI: 4.12-13.67; p = 0.0003), which was beneficial for both the ≥10 × 106 and <10 × 106 dose sub-groups. However, a meta-analysis of single-arm studies in two control (pre-intervention) and intervention phases (n = 88) demonstrated no significant difference in progression of ALSFRS between study phases by time: month 3 (WMD: -1.27 (-3.01 to 0.47); p = 0.15), month 6 (WMD: -2.69 (-5.62 to 0.25); p = 0.07), month 9 (WMD: -1.55 (-3.49 to 0.39); p = 0.12), and month 12 (WMD: -7.59 (-13.95 to -1.26); p = 0.02). An accelerated decline in forced vital capacity (FVC) was observed during the intervention phase, with statistically significant reductions at month 3 (WMD: -10.91; 95% CI: -16.39 to -5.43; p < 0.0001) and month 6 (WMD: -15.97; 95% CI: -28.60 to -3.33; p = 0.01) compared with the pre-intervention control phase. Nevertheless, sensitivity analyses excluding studies involving high-dose mesenchymal stem cell (MSC) therapies demonstrated that these differences were no longer statistically significant. Moreover, no significant change in progression rate was observed at month 9 (WMD: -8.10 (-18.25 to 2.06); p = 0.12). The route of MSCs administration (intrathecal [IT], intramuscular [IM], and intravenous [IV]) had no effect on the results of ALSFRS and FVC, reinforced by sensitivity analyses. Adverse events were mostly mild, with headaches most frequent in high-dose groups.
    Conclusion: Stem cell therapy for ALS appears to be safe, with preliminary evidence suggesting potential therapeutic benefit in slowing disease progression in selected patients. Nevertheless, the existing evidence base remains exploratory, and definitive conclusions regarding clinical effectiveness cannot yet be drawn. Future research should prioritize large-scale and multicenter RCTs with standardized cell manufacturing protocols and longer follow-up periods.
    Keywords:  amyotrophic lateral sclerosis; exosomes; motor neuron disease; neuromuscular disorders; secretome; stem cells; systematic review
    DOI:  https://doi.org/10.1155/sci/4122493
  21. Magn Reson Imaging. 2026 Aug 03. pii: S0730-725X(26)00158-X. [Epub ahead of print] 110765
    Quantitative susceptibility mapping in neurodegenerative diseases: An umbrella review of iron-related biomarkers and mechanisms.
    Sadegh Ghaderi, Sana Mohammadi, Yasser Iturria-Medina.
      Pathological iron accumulation is a common pathophysiological hallmark across multiple neurodegenerative diseases (NDDs), motivating the need for accurate, non-invasive quantification methods. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique that enables in vivo measurement of tissue magnetic susceptibility (χ), providing a sensitive proxy for iron content. This umbrella review systematically evaluates the diagnostic accuracy, clinical correlations, and distinct iron distribution patterns of QSM in major NDDs, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and atypical Parkinsonism. We included 15 (13/15 were rated Low or Critically Low on AMSTAR 2) systematic reviews and meta-analyses (through July 15, 2026); however, the findings should be interpreted cautiously because of heterogeneity and the low methodological quality. A Corrected Covered Area (CCA) analysis demonstrated only slight overlap of primary studies across the included reviews (CCA = 5.42%). Collectively, the evidence indicates that QSM provides comparable or higher diagnostic sensitivity and reliability than conventional R2* and SWI techniques, particularly for deep gray matter structures. The findings support significant iron overload in the substantia nigra, particularly in the pars compacta, as a robust biomarker for PD that correlates with motor severity and disease duration. Furthermore, regional iron profiling in the basal ganglia is critical for differential diagnosis; specifically, elevated χ in the putamen and globus pallidus effectively distinguishes multiple system atrophy and progressive supranuclear palsy from idiopathic PD. Distinctively, AD and ALS exhibit specific χ alterations in the thalamus, motor cortex, and hippocampus, reflecting divergent iron-related pathophysiological mechanisms, which correlate with cognitive impairment and upper motor neuron signs. Overall, QSM shows diagnostic promise and offers mechanistic insights into iron-related neurodegenerative processes.
    Keywords:  Iron accumulation; Magnetic susceptibility; Neurodegenerative diseases; Neuroimaging; Quantitative susceptibility mapping
    DOI:  https://doi.org/10.1016/j.mri.2026.110765
  22. J Neuropathol Exp Neurol. 2026 Aug 06. pii: nlag013. [Epub ahead of print]
    Neural stem cell-derived small extracellular vesicles ameliorate disease progression in the SOD1 G93A murine model of amyotrophic lateral sclerosis.
    Yalan Wan, Chao Gao, Jieyu Li, Mingyue Luan, Yuxuan Lu, Jiaxin Wang, Biyu Yang, Jie Zheng, Yun Yuan, Jun Wei, Zhaoxia Wang, Jianwen Deng.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects motor neurons leading to muscle weakness, paralysis, and ultimately, respiratory failure. Extracellular vesicles (EVs) facilitate intercellular communication by mimicking the functions of their parent cells. In this study, we found that repeated administration of neural stem cell-derived extracellular vesicles (NSC-derived EVs) improved motor performance and provided protection to lumbar motor neurons, the neuromuscular junctions, and muscle morphology in the SOD1 G93A transgenic mouse model of ALS. Furthermore, by analyzing the RNA-sequencing of muscle specimens from ALS-SOD1 patients, we demonstrated that the rescue effects of NSC-derived EVs might be linked to the p53 pathway. Compared to the PBS control treatment group, both TP53 and the p53 upregulated modulator of apoptosis (PUMA) were downregulated in the spinal cord of mice treated with NSC-derived EVs. These data provide additional knowledge for the promising use of NSC-derived EVs as a potential therapy for ALS.
    Keywords:  SOD1; amyotrophic lateral sclerosis; extracellular vesicles; neural stem cells; therapy
    DOI:  https://doi.org/10.1093/jnen/nlag013
  23. Int J Dev Neurosci. 2026 Aug;86(5): e70168
    Mechanisms, Biomarkers and Therapeutic Implications of Neuroinflammation in Alzheimer's Disease.
    Shaunt Papelian.
      Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide, affecting millions of individuals and imposing substantial socioeconomic burdens. While traditional research has focused on amyloid-β (Aβ) plaques and neurofibrillary tangles as primary pathological hallmarks, mounting evidence implicates neuroinflammation as a critical third pillar in AD pathogenesis. This review critically evaluates current understanding of neuroinflammatory mechanisms in AD, examining the complex interplay between cellular mediators, molecular pathways and environmental triggers across a temporal disease-stage framework. We explore the dual and stage-dependent roles of microglia and astrocytes, expand discussion of blood-brain barrier (BBB) dysfunction and peripheral immune infiltration as underappreciated pathogenic contributors, and integrate emerging evidence linking neuroinflammation specifically to tau pathology and its stereotyped propagation through the brain. Diagnostic biomarkers, including translocator protein-positron emission tomography (TSPO-PET) and plasma glial fibrillary acidic protein (GFAP), are evaluated with explicit attention to clinical utility, technical limitations, and their relationship to established AD biomarkers. Therapeutic strategies are critically assessed with careful distinction between preclinical proof-of-concept data and available clinical evidence, and key translational challenges are highlighted throughout. The review emphasizes the need for stage-appropriate intervention windows, patient stratification by neuroinflammatory endotype, and biologically rational combination strategies. Understanding neuroinflammation's temporal and spatial dynamics offers promising but as yet insufficiently realized avenues for early intervention and disease modification in AD.
    Keywords:  Alzheimers disease; TREM2; astrocytes; biomarkers; blood–brain barrier; disease stages; immunotherapy; microglia; neuroinflammation; tau pathology
    DOI:  https://doi.org/10.1002/jdn.70168
  24. J Cachexia Sarcopenia Muscle. 2026 Aug;17(4): e70357
    Early and Divergent Lipid Mediator Remodelling in Fast Versus Slow Skeletal Muscles of Female hSOD1G93A Mice.
    Sebastiaan Dalle, Kaat Vanderbeke, Thibaut Burg, Moniek Schouten, Wout Lauriks, Nicole Hersmus, Ludo Van Den Bosch, Katrien Koppo.
       BACKGROUND: Skeletal muscle atrophy in amyotrophic lateral sclerosis (ALS) drives loss of muscle strength, function and quality of life in ALS patients. The endocannabinoid system (ECS) regulates muscle homeostasis via regenerative and metabolic processes, and although ECS alterations have been reported in ALS neural tissues, ECS remodelling within ALS skeletal muscle has never been studied. This study investigated temporal and muscle type-specific ECS changes in ALS.
    METHODS: Female hSOD1G93A transgenic mice and nontransgenic littermates were studied at presymptomatic and symptomatic ages (56-138 days of age; n = 7-8/group). Endocannabinoids, N-acyl-ethanolamine congeners and inflammatory lipid mediators were quantified using targeted LC-MS/MS in the tibialis anterior (TA) and soleus (SOL) muscles. ECS-related enzymes and receptors were assessed by immunoblotting and integrated with transcriptomic analyses of skeletal muscle biopsies from ALS patients (n = 5/group; ~63 years). To evaluate therapeutic relevance, ALS mice were treated with the fatty acid amide hydrolase (FAAH) inhibitor URB937 or vehicle (n = 10-11/group), and survival, body weight, welfare and motor function were assessed longitudinally.
    RESULTS: ALS caused severe atrophy in the predominantly fast-twitch TA muscle (-76.5%; p < 0.01), while the slow-twitch soleus was largely preserved (-14.4%; p < 0.01). Accordingly, the lipid perturbation due to ALS was more pronounced in the TA, reflected by extensive alterations in unsaturated fatty acids, hydroxy- and epoxy-fatty acids (TA: 63% and SOL: 22% of lipid mediators different between ALS vs. NTG) and marked ECS remodelling, including elevated anandamide (+37.3%; p = 0.03) and multiple N-acyl-ethanolamine congeners (+76-102%; p < 0.05), reduced 2-arachidonoylglycerol (-28%; p = 0.06), increased CB1 receptor expression (+93%; p < 0.01) and dynamic, age-dependent regulation of FAAH (presymptomatic: -68%; p = 0.04, symptomatic: +21%; p = 0.02). In contrast, the SOL showed modest or opposite changes, consistent with its relative resistance to atrophy. Notably, ECS remodelling in the TA was already evident at presymptomatic age (e.g., CB1: +76%; p = 0.01) and the same ECS enzymes were affected in human ALS skeletal muscle transcriptomes (e.g., twofold decrease in FAAH; pFDR = 0.010). Despite evidence for a therapeutic potential, chronic peripheral FAAH inhibition with URB937 did not improve weight loss, motor functions and survival of ALS mice (all p > 0.05).
    CONCLUSIONS: Muscle type-specific endocannabinoid system remodelling in ALS precedes overt neurological decline and might relate to degenerative features such as metabolic disturbance and inflammation. Although peripheral FAAH inhibition alone was insufficient to modify disease outcomes, these findings identify the endocannabinoid system as an integral component of ALS muscle pathology and support skeletal muscle lipid signalling as a potentially relevant early target for adjunctive therapeutic strategies.
    Keywords:  ALS; FAAH; SOD1; cannabinoid receptor; endocannabinoid system; neurodegeneration
    DOI:  https://doi.org/10.1002/jcsm.70357
  25. J Neuropathol Exp Neurol. 2026 Aug 06. pii: nlag085. [Epub ahead of print]
    A phosphorylation‑independent monoclonal antibody improves detection of TDP‑43 pathology across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and limbic predominant age related TDP‑43 encephalopathy neuropathological change.
    Xiaojing Zheng, Ning Zhang, Lixia Wang, Hongjuan Zhao, ChengGang Liu, Jiayu Wang, Wanli Zhao, Junli Zhao, Peiyan Yang, Lorraina Robinson, Lindsay Hunt, Alex Lokken, Leo Lin, Peter T Nelson, Julia Kofler, Hehuang Xie, Haibin Xia, Qinwen Mao.
      TDP-43 proteinopathies encompass frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), amyotrophic lateral sclerosis (ALS-TDP), and limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC). These proteinopathies exhibit subtype-specific aggregate architectures that may constrain epitope accessibility in situ. We compared a phosphorylation-independent monoclonal antibody targeting a C-terminal epitope (MAb No. 9) with the phospho-specific pSer409/410 antibody to determine whether its signal relates to regional neurodegeneration in a multicenter autopsy cohort spanning FTLD-TDP types A-C, ALS-TDP, and Alzheimer disease neuropathologic change (ADNC) with or without LATE-NC. Immunolabeling with MAb No. 9 detected pathological TDP-43 across all diagnostic groups with enhanced labeling of dystrophic neurites and thread/dot-like pathology in FTLD-TDP types A/B and in ALS-TDP. MAb No. 9 performance was equivalent to p409/410 in FTLD-TDP type C. In ADNC with stage 3 LATE-NC, MAb No. 9 revealed a greater limbic burden and labeled both α type and β type inclusions. Dual label immunofluorescence demonstrated strong spatial overlap with p409/410 but additionally highlighted fine punctate pathology. MAb No. 9 burden in FTLD-TDP type A correlated strongly with cortical neurodegeneration but showed weaker and variable associations, particularly in severely atrophic cortex. These findings indicate that filament architecture governs C-terminal epitope accessibility and that MAb No. 9 may be a complementary tool for subtype refinement, clinicopathologic correlation and translational biomarker development in TDP-43 proteinopathies.
    Keywords:  Alzheimer disease neuropathologic change; TDP-43; frontotemporal lobar degeneration; limbic-predominant age-related TDP-43 encephalopathy neuropathological change; phosphorylation-dependent antibody; phosphorylation-independent antibody; proteinopathy
    DOI:  https://doi.org/10.1093/jnen/nlag085
  26. Cureus. 2026 Jun;18(6): e111856
    The Oral-Brain Axis: Mechanistic Insights Linking Periodontitis With Alzheimer's and Parkinson's Diseases.
    Roopse Singh, Shilpi Asthana, Anveksha Arya, Mayur Kaushik, Mehvish Khan.
      Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are major causes of disability and mortality worldwide. Emerging evidence suggests that chronic peripheral inflammation and microbial dysbiosis may contribute to neurodegenerative processes. The oral-brain axis has recently gained attention as a biological framework linking oral microbial communities, systemic inflammatory responses, immune regulation, and central nervous system function. Within this context, periodontitis, a prevalent chronic inflammatory disease driven by oral dysbiosis, has been proposed as a potential modifiable risk factor for neurodegeneration. This narrative review examines current evidence supporting the oral-brain axis and its role in the relationship between periodontitis and neurodegenerative disorders. Key mechanisms include systemic dissemination of periodontal pathogens and their virulence factors, persistent inflammatory signaling, blood-brain barrier dysfunction, neuroimmune activation, oxidative stress, and protein aggregation. Particular attention is given to the contribution of Porphyromonas gingivalis and associated virulence factors to neuroinflammation, amyloidogenesis, and neuronal injury. Epidemiological, clinical, and experimental studies linking periodontal disease with cognitive decline, Alzheimer's disease, and Parkinson's disease are also discussed. Current evidence supports a biologically plausible association between periodontal disease and neurodegeneration through interconnected microbial, inflammatory, and vascular pathways. Although causality remains to be established, the oral-brain axis provides valuable insight into potential mechanisms underlying this relationship. Improved understanding of these interactions may facilitate the development of preventive and therapeutic strategies that integrate oral healthcare with approaches aimed at preserving neurological health and reducing the burden of neurodegenerative diseases.
    Keywords:  alzheimer’s disease; blood-brain barrier; neurodegenerative diseases; neuroinflammation; oral microbiome; oral-brain axis; parkinson’s disease; periodontal disease (pd); periodontitis
    DOI:  https://doi.org/10.7759/cureus.111856
  27. BMC Psychol. 2026 Aug 04. pii: 1132. [Epub ahead of print]14(1):
    Depressive symptoms in amyotrophic lateral sclerosis: associations with quality of life, disease progression and perceived social support-a German multicenter study.
    Nina Domke, Kristina Geue, Ina Schlichte, Markus Ullsperger, Thomas Meyer, Susanne Petri, Stefanie Schreiber, Stefan Vielhaber, Florian Junne, Susanne Vogt.
       BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disease. Patients with ALS are at increased risk of developing depressive symptoms. A clearer understanding of the associations between depressive symptoms, disease progression, health-related quality of life and perceived social support is needed to advance intervention-oriented research and improve psychosocial care in ALS.
    METHODS: In a multicenter cross-sectional study, patients with ALS were asked to complete patient-reported outcomes (PROs) to evaluate depressive symptoms (ALS-Depression-Inventory, ADI-12), health-related quality of life (ALS-Assessment-Questionnaire, ALSAQ-5/ALSAQ-40), physical functioning (ALS-Functional Rating Scale-Extension, ALSFRS-EX) and perceived social support (Multidimensional Scale of Perceived Social Support, MSPSS). To evaluate associations between demographic/clinical variables and PROs, we performed Pearson's, Spearman's, and partial correlation analyses. In addition, a multiple regression was run to identify predictors of depressive symptoms. Comparisons of patient groups were performed with chi-squared tests for categorical variables and Student t-tests or one-way analysis of variance (ANOVA) for continuous variables, followed by post-hoc tests.
    RESULTS: Out of the 150 patients examined, 60% reported depressive symptoms, with half of them exhibiting clinically relevant depressive symptoms. Depressive symptoms were significantly associated with disease progression (r = .466, p < .001), various aspects of health-related quality of life (mobility: r = .394, activities of daily living: r = .268 and emotional well-being: r = .793, all p < .001), the MSPSS sum score (partial r = -.234, p  = .007), and the ALSFRS-EX sum score (r = -.352, p < .001). Patients with depressive symptoms reported significantly more physical impairments (p = .002) and less perceived social support by their families (p = .016) and friends (p < .001) compared to patients without depressive symptoms.
    CONCLUSIONS: Depressive symptoms are prevalent in patients with ALS and are closely associated with faster disease progression, reduced physical functioning, poorer health-related quality of life, and lower perceived social support. Further studies, particularly using qualitative methods, are needed to elucidate protective factors, clarify psychosocial mechanisms, and support the conceptualization of specialized and integrated psychosocial care for patients with ALS in Germany.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Depressive symptoms; Disease progression; Emotional well-being; Health-related quality of life; Perceived social support
    DOI:  https://doi.org/10.1186/s40359-026-05273-z
  28. Ultrasound Med Biol. 2026 Aug 03. pii: S0301-5629(26)00264-4. [Epub ahead of print]
    Application of Low-Intensity Focused Ultrasound in Parkinson's Disease.
    Yunyi Dai, Jiayi Mao, Tianhua Yang, Jialei Luo, Xinyi Yan, Gaoyi Yang.
      Parkinson's disease (PD) is characterized by dopaminergic neuronal loss and α-synuclein aggregation, while current therapies remain symptomatic and limited. Low-intensity focused ultrasound (LIFU) has emerged as a non-invasive neuromodulation modality enabling precise targeting of deep brain structures. This review summarizes its applications in PD from mechanistic and translational perspectives. LIFU acts via two major pathways: direct modulation of cortico-basal ganglia circuits and blood-brain barrier opening for targeted drug delivery. It regulates key pathological processes, including α-synuclein aggregation, neuroinflammation and neurotrophic signaling. Despite promising pre-clinical and early clinical results, challenges remain in parameter optimization, variability and long-term safety, warranting further investigation for clinical translation.
    Keywords:  Blood–brain barrier; Drug delivery; Low-intensity focused ultrasound; Neuroinflammation; Neuromodulation; Parkinson’s disease; α-Synuclein
    DOI:  https://doi.org/10.1016/j.ultrasmedbio.2026.07.003
  29. Hum Mol Genet. 2026 Jul 28. pii: ddag072. [Epub ahead of print]35(16):
    Clinical genome sequencing in neurodegenerative diseases-outcome in the first 500 patients.
    Emma Ehn, Håkan Thonberg, Inger Nennesmo, Anna Lindstrand, Malin Kvarnung, Caroline Graff.
      Neurodegenerative diseases (NDDs) are clinically and genetically heterogeneous, requiring neuropathology or molecular testing for a definitive diagnosis. Clinical whole genome sequencing (WGS) enables comprehensive variant calling across flexible gene lists that can be tailored to the clinical presentation. By allowing simultaneous detection of single-nucleotide variants, copy-number variants, structural variants, and repeat expansions, WGS has the potential to improve diagnostic yield, facilitate genetic counseling and support clinical trial inclusion. This study assesses the diagnostic performance of WGS in individuals with NDD. WGS in 500 individuals representing a wide spectrum of NDDs identified a disease-causing variant in 61 cases, resulting in a diagnostic yield of 12%. These variants were found in 16 different genes, with C9orf72 being the most prevalent. Repeat expansions represented the largest variant class, accounting for 35 of 61 LP/P cases (57%); most of which were C9orf72 expansions (31/35). In the largest phenotype groups, frontotemporal dementia (FTD) had the highest diagnostic yield (19%) followed by amyotrophic lateral sclerosis (ALS, 13%), whereas an underlying monogenic cause was expectedly low in Alzheimer disease (AD, 4%). A positive family history was present in the majority (74%) of FTD, ALS, combined ALS-FTD and AD cases with an LP/P finding. Clinical WGS provides a clear diagnostic advantage in NDDs marked by substantial clinical and genetic overlap. WGS enables comprehensive variant detection and mapping of genotype-phenotype relationships across the disease continuum. In FTD and ALS, these results support universal access to genetic testing independent of age at onset or family history.
    Keywords:  Neurogenetics; neurodegeneration; rare variants; whole genome sequencing
    DOI:  https://doi.org/10.1093/hmg/ddag072
  30. J Biol Chem. 2026 Aug 05. pii: S0021-9258(26)02266-0. [Epub ahead of print] 113394
    Distinct competitive and allosteric binding modes of nanobodies targeting EphA4.
    He Jiang, Lulu Ding, Chenlu Yang, Guankai Guo, Chao Zhong, Zhiqiang Ma, Haoran Zhu, Jiahua Zhang, Yang Luo, Zhen Liu, Rui Liu, Yu Ding.
      EphA4 signaling is a key negative regulator of axonal regeneration and a genetic modifier of amyotrophic lateral sclerosis (ALS), making EphA4 an attractive but mechanistically underexplored therapeutic target. Although EphA4-targeting nanobodies have shown inhibitory potential, the structural principles governing their binding and inhibitory mechanisms remain largely unknown. Here, we report high-resolution crystal structures of the EphA4 ligand-binding domain (LBD) in complex with four nanobodies (Nb50, Nb53, Nb57, and Nb60), resolved at 1.34-2.21 Å. Nb50, Nb53, and Nb57 competitively engage the canonical ephrin-binding pocket through deep CDR3 insertion, directly mimicking ephrin recognition. In contrast, Nb60 adopts a previously unrecognized binding mode, contacting two EphA4 molecules at noncanonical sites in the crystal structure through framework-dominated interactions and supporting a structural model for steric and allosteric restriction of ephrin access. Integrated biophysical analyses reveal distinct thermodynamic and kinetic signatures underlying these binding mechanisms. Together, our findings uncover unexpected structural diversity in nanobody-mediated EphA4 recognition and provide a framework for rational development of EphA4-targeted modulators for ALS and related neurodegenerative conditions.
    Keywords:  Amyotrophic Lateral Sclerosis (ALS); Antibody; EphA4; Nanobody; Structure
    DOI:  https://doi.org/10.1016/j.jbc.2026.113394
  31. Regen Ther. 2026 Dec;33 101157
    From neural development to regenerative medicine: A research journey in stem cell biology, spinal cord repair, and iPSC-based drug discovery.
    Hideyuki Okano.
      This commemorative article reflects on a research journey spanning neural development, stem cell biology, regenerative medicine, and iPSC-based drug discovery. My early work focused on RNA-mediated regulation in the nervous system, including studies on myelin basic protein gene regulation and the identification and functional characterization of the RNA-binding protein Musashi. These studies contributed to the conceptual foundation of neural stem cell biology and helped establish methods for identifying and isolating neural stem/progenitor cells, including those present in the adult human brain. Building on this foundation, my colleagues and I pursued translational research in spinal cord injury, ranging from analyses of injury pathophysiology and molecular interventions to preclinical studies using rodent and non-human primate models. These efforts ultimately led to the first-in-human clinical study of induced pluripotent stem cell-derived neural stem/progenitor cell transplantation for subacute spinal cord injury. In parallel, we developed patient-derived iPSC platforms for neurological disease modeling and drug discovery, particularly for amyotrophic lateral sclerosis, where iPSC-based screening identified Ropinirole as a therapeutic candidate and enabled reverse translational research linking cellular phenotypes with clinical responses. Looking ahead, I argue that the future of regenerative therapy will depend on the continued integration of developmental biology, stem cell science, disease modeling, rehabilitation, and clinical translation to address unmet medical needs in disorders of the central nervous system.
    Keywords:  Amyotrophic lateral sclerosis; Induced pluripotent stem cells; Neural stem cells; Regenerative medicine; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.reth.2026.101157
  32. Alzheimers Dement. 2026 Aug;22(8): e71722
    Temporal order of clinical, imaging, and biomarker changes in frontotemporal lobar degeneration-associated syndromes.
    Alberto Benussi, Valeria Bracca, Enrico Premi, Valentina Cantoni, Federica Palacino, Aurora Saccavini, Maria Sofia Cotelli, Giuliano Binetti, Rosa Manenti, Antonella Alberici, Roberto Gasparotti, Nicholas J Ashton, Henrik Zetterberg, Kaj Blennow, Roberta Ghidoni, Barbara Borroni.
       BACKGROUND: The temporal sequence of clinical, imaging, and biological changes in sporadic frontotemporal lobar degeneration (FTLD)-associated syndromes remains poorly characterized, and a comprehensive biomarker cascade model is lacking.
    METHODS: We developed a data-driven biomarker cascade model in 489 patients across the FTLD spectrum (211 behaviorial variant frontotemporal dementia [bvFTD], 129 primary progressive aphasia [PPA], 71 corticobasal syndrome [CBS], 66 progressive supranuclear palsy [PSP], and 12 FTD associated with amyotrophic lateral sclerosis [FTD-ALS]; 1904 patient-visit observations). Plasma, magnetic resonance imaging (MRI), and clinical biomarkers were modeled using sigmoid trajectories fitted to covariate-adjusted longitudinal data.
    RESULTS: Plasma glial fibrillary acidic protein departed from normality earliest, followed by Trail Making Test Part B (TMT-B), white matter lesion volume, and neurofilament light chain. Insular atrophy showed the steepest transition among MRI measures; clinical dementia rating dementia staging instrument plus National Alzheimer's Coordinating Center behavior and language domains sum of boxes declined most steeply overall. TMT-B inflected earliest in bvFTD, whereas insula atrophy dominated in PPA.
    CONCLUSIONS: This first data-driven temporal cascade of multimodal biomarkers in sporadic FTLD-associated syndromes offers a framework for disease staging and stage-specific clinical trial design.
    Keywords:  biomarker cascade; brain atrophy; clinical trial design; disease progression; frontotemporal dementia; frontotemporal lobar degeneration; neurofilament light chain; neuropsychological assessment; plasma GFAP; white matter hyperintensities
    DOI:  https://doi.org/10.1002/alz.71722
  33. Mult Scler Relat Disord. 2026 Jul 24. pii: S2211-0348(26)00441-4. [Epub ahead of print]114 107406
    Clinical features of older MS patients with and without Alzheimer disease biomarkers.
    Apollo Rodriguez, Bradley Judge, Nicole Shelley, Vivek Mehta, Karl Friedrichsen, Jeremy Strain, Tammie Ls Benzinger, Suzanne E Schindler, David M Holtzman, Anne H Cross, Matthew R Brier.
      Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammatory demyelination and axonal injury. Magnetic resonance imaging (MRI) plays a central role in MS diagnosis. Recent work suggests that biomarkers indicative of Alzheimer's disease (AD) are markedly reduced in people with MS. Whether differences in AD biomarkers are related to different features of MS, including MRI characteristics or treatment history, is unclear. In this study, 100 MS patients from Washington University in St. Louis underwent review of their most recent MRI as well as their prior and present MS disease-modifying treatment (DMT) exposures. We then ascertained the relation of MRI features and DMT to plasma AD biomarker measurements, with only a small subset (N=7) demonstrating APS2+ biomarker evidence of AD. Lesion distribution across MS topographies and total white matter lesion (WML) burden were both similar across MS patients with and without biomarker evidence of AD. Central vein sign (CVS), a recently integrated imaging biomarker of MS, was highly prevalent across the MS cohort and did not differ by AD biomarker status or MS clinical typicality at diagnosis, supporting the MS diagnoses even for people with atypical initial presentations. DMT exposure history showed associations with AD biomarkers: longer exposure to B cell-depleting anti-CD20 monoclonal antibody therapies (BCDT) corresponded to lower levels of amyloid pathology as measured by plasma biomarkers, and longer exposure to interferon-beta corresponded to a less pathological Aβ42/40 ratio. These findings indicate that structural MRI features do not explain differences in AD biomarker profiles in MS, whereas treatment-related immunologic effects may contribute to variation in AD pathology risk in MS patients.
    Keywords:  Alzheimer's Disease; B-cell depleting therapy; Central vein sign; Multiple sclerosis; disease-modifying therapy
    DOI:  https://doi.org/10.1016/j.msard.2026.107406
  34. Eur Arch Psychiatry Clin Neurosci. 2026 Aug 04.
    Investigating changes in the blood-brain barrier in schizophrenia spectrum disorders: design and methodology of a longitudinal dynamic contrast-enhanced MRI study.
    Anne Wendl, Amelie Zöllinger, Daniel Lukas, Isabel Lutz, Michelle Schamberger, Constanze Lobinger, Isabel Maurus, Alkomiet Hasan, Elias Wagner, Peter Falkai, Andrea Schmitt, Florian J Raabe, Kolja Schiltz, Klaus Seelos, Sophia Stöcklein, Emanuel Boudriot, Vladislav Yakimov, Lukas Roell, Daniel Keeser, Joanna Moussiopoulou.
      Schizophrenia spectrum disorders (SSDs) are clinically and biologically heterogeneous and lack reliable biomarkers for stratification, treatment response and course prediction. Evidence from postmortem, fluid biomarker, and neuroimaging studies suggests that changes in the blood-brain barrier (BBB) may contribute to pathophysiology in a biologically defined subgroup. However, findings in this context are inconsistent and often based on cross-sectional or indirect measures. This study is a longitudinal, multimodal investigation designed to quantify BBB permeability across disease phases using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and to integrate these measures with deep clinical phenotyping. We recruit inpatients with SSDs and healthy controls (HC). Participants undergo multimodal MRI including DCE-MRI at three time points: acute psychosis (baseline; V1), early treatment (4-6 weeks; V2), and long-term follow-up (2.5 years; V3). Clinical characterization includes standardized measures of psychopathology, functioning and cognition. Blood samples are collected at each visit, while CSF is obtained at V1. DCE-MRI-derived voxel-wise permeability metrics are then analyzed. Primary objectives are to compare BBB leakage cross-sectionally between SSD and HC. Secondary objectives include (i) characterizing spatial and temporal leakage profiles across illness phases, (ii) analyzing associations with psychopathology and biological (e.g., inflammatory) signatures, as well as exploratory identification of subgroups. By providing a longitudinal, BBB-specific neuroimaging framework embedded in a deep phenotyping infrastructure, the IMPACT study aims to elucidate BBB alterations in SSDs and to support stratification approaches in precision psychiatry.
    Keywords:  Blood–brain barrier; Deep phenotyping; Dynamic contrast-enhanced MRI; Inflammation; Schizophrenia spectrum disorders
    DOI:  https://doi.org/10.1007/s00406-026-02316-9
  35. J Vis Exp. 2026 Jul 17.
    Senescence Associated With Neurodegeneration: Simultaneous Assessment of β-gal Activity And Nissl Stain In Histological Sections of Rodent Brain.
    Verónica Salas-Venegas, Ricardo J Ramírez-Carreto, Anahí Chavarría.
      Cellular senescence is a physiological process characterized by irreversible cell cycle arrest that impairs tissue regeneration and function. This phenomenon has emerged as a key driver of neurodegeneration, fueled by the accumulation of senescent cells within the central nervous system (CNS). Senescent cells acquire a pro-inflammatory senescence-associated secretory phenotype (SASP) that sustains chronic neuroinflammation and disrupts the neuronal microenvironment. Consequently, essential processes such as neurogenesis, synaptic plasticity, and neuronal survival are compromised. An extensive body of literature associates cellular senescence with several neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, or multiple sclerosis, and acute neuronal-related damage, such as cerebral ischemia or traumatic brain injury. The combined assessment of senescence-associated β-galactosidase (SA-β-gal) activity and Nissl staining in histological sections provides a comprehensive approach to evaluate cellular senescence and neuronal integrity simultaneously within the same tissue context. This strategy enables precise spatial correlation between the accumulation of senescent cells in specific vulnerable regions (e.g., the hippocampus or cortex) and neuronal loss or tissue damage. By integrating a functional marker of senescence with a classical indicator of neuronal morphology and density, this approach strengthens the interpretative robustness of the analysis. Moreover, it enables a more accurate characterization of the relationship between senescent burden and neurodegenerative changes, maximizing the information yield from limited tissue samples. Moreover, this protocol can determine how senescent cell accumulation occurs in response to interventions (pharmacological, genetic manipulation, etc.) in rodent models of neurodegenerative diseases, thereby providing a powerful tool to analyze this contribution to their pathophysiology.
    DOI:  https://doi.org/10.3791/70676
  36. PLoS Genet. 2026 Aug 05. 22(8): e1011909
    Glial cell toxicity in a Drosophila C9orf72 neurodegeneration model.
    Isabel Hubbard, Josh Dubnau.
      The most common genetic cause of both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G4C2 repeat in the first intron of the gene C9orf72. The C9orf72 repeat expansion is bidirectionally transcribed into sense and anti-sense RNA foci, and also produces dipeptide repeats (DPRs) via a non-canonical translation mechanism known as repeat-associated (RAN) translation. Each of these components of the G4C2 repeat expansion cause neurodegenerative effects in animal models when expressed in neurons, but impacts from glial expression are more poorly understood. Here, we use glial cell type-specific expression of individual DPRs, of RNA repeat-only, or of the G4C2 repeat, that produces both DPRs and RNA repeats, to systematically investigate glial toxicity of each component. We find that as with neurons, the GR and G4C2 transgenes produce the highest degree of toxicity when expressed in glia. Each of these transgenes are capable to produce the GR DPR, which also is the most toxic factor in neurons. We demonstrate that both the GR and G4C2 transgenes cause activation of mdg4, an endogenous retrovirus (ERV). Such ERV expression is a hallmark of TDP-43 dysfunction that is commonly observed in C9orf72 patients. We find that glial expression of either the GR or the G4C2 transgene is toxic to glial cells, but such expression does not cause loss nearby neurons. However, blocking apoptotic signaling within glia that express either GR or G4C2 via expression of the p35 caspase inhibitor further exacerbates effects on lifespan and ablating such glia via expression of the proapoptotic reaper gene partially ameliorates these effects. Together, these results indicate that expression of toxic C9orf72 components in glia produces deleterious effects on lifespan, though potentially through different mechanisms than seen in TDP-43 models of ALS/FTD.
    DOI:  https://doi.org/10.1371/journal.pgen.1011909
  37. Ann Neurosci. 2026 Aug 04. 09727531261462296
    Locus Coeruleus as a Master Regulator of Diverse Functions in the Central Nervous System: Its Relevance in Ageing and Neurodegenerative Disorders.
    Ahana Bhattacharya, Ravi Manjithaya, Yasha Chickabasaviah, Phalguni Anand Alladi.
       Background: The brainstem nucleus locus coeruleus (LC) is a rod-shaped, cylindrical, deeply pigmented neuromelanin (NM)-rich cluster of noradrenergic cells placed bilaterally in the dorsolateral tegmentum of the pons. The main neurotransmitter synthesised by these neurons is norepinephrine (NE), which polymerises to NM. Collectively, it regulates a plethora of activities, including vigilance, synaptic plasticity, memory processing, pain, stress responses, selective attention, cognition, sleep, emotion, capillary wall permeability and cerebral blood flow, thereby holding a 'master key' to several processes. Despite being small in dimensions, it is of enormous significance in diverse functions. Degeneration of the LC occurs early and progressively in both Alzheimer's disease (AD) and Parkinson's disease (PD), with diverse impacts, and is linked to neuropsychiatric entities such as depression, anxiety, cognitive impairment, schizophrenia and rapid eye movement sleep disorders, thereby raising considerable interest in normal physiology as well as in disease.
    Summary: This review is to better understand the neuroanatomical connections of human LC (master regulator of the central nervous system), pigmentation, cellular types, neurotransmitters/co-transmitters, and its role in ageing and neurodegenerative diseases. Recent and relevant classical research and review articles were referred to from PubMed to prepare a short review of the structure of LC, its projections, NM pigment and neuroprotection. We further examined the details of its cell types, neurotransmitters, co-transmitter functions and its effects in ageing, AD and PD, with emphasis on human studies.
    Key Message: LC is a vital region that offers neuroprotection, assists in the maintenance of cognitive reserve and enhances resilience and neuronal survival, despite the presence of AD and PD pathology for several decades. Further, it synthesises NE and co-transmitters that regulate attention, sleep-wake cycle, mood, cognition and so on. Maintaining its integrity and function promises potential scope to promote its health with normal ageing and improve clinical strategies in patients with neurodegeneration.
    Keywords:  Alzheimer’s disease; Human locus coeruleus; Parkinson’s disease; anatomical connections; neuropeptides
    DOI:  https://doi.org/10.1177/09727531261462296
  38. Mol Neurobiol. 2026 Aug 05. pii: 812. [Epub ahead of print]63(1):
    Zafirlukast Exacerbates Behavioral Seizure Activity and Blood-Brain Barrier Disruption Despite Modestly Reducing Neuronal Injury Markers in a PTZ-Induced Early Epileptogenesis Mouse Model.
    Volkan Gorgulu, Cansin Sirin Tomruk, Pelin Ergun, Berrin Ozdil, Ebru Sanci, Aylin Buhur, Eser Y Sozmen, Timur Kose, Nefise Ulku Karabay Yavasoglu, Altug Yavasoglu.
      Epilepsy is one of the most prevalent neurological disorders worldwide, and approximately 25% of patients remain refractory to pharmacological treatment. Blood-brain barrier (BBB) disruption and reactive gliosis are key mechanisms implicated in early epileptogenesis. This study investigated the effects of zafirlukast, a leukotriene receptor antagonist, on BBB permeability, reactive gliosis, and behavioral seizure activity in a pentylenetetrazol (PTZ)-induced early epileptogenesis model in C57BL/6 mice. Zafirlukast was administered twice daily at a dose of 10 mg/kg. Seizure activity was evaluated by behavioral observation in terms of seizure severity, latency, duration, and frequency. BBB permeability was assessed using the Evans Blue assay, and brain tissues were analyzed by biochemical and immunohistochemical methods. The PTZ + ZAFIR group exhibited more severe seizures, characterized by increased seizure frequency and duration, shorter latency, and a higher kindling rate (80% vs. 27%). BBB permeability was also increased, whereas MMP-9 levels remained, suggesting disruption may be linked to direct mechanical effects of recurrent seizures rather than inflammation. Clues suggest that zafirlukast may exert paradoxical effects on two prominent cell types involved in reactive gliosis. While increased GFAP and TGF-β1 expression may reflect enhanced astrocyte activation, changes in IL-1β and Iba1 expression suggest suppression of microglial activation. Notably, pro-inflammatory and oxidative stress markers remained unchanged despite the increase in seizure severity. The observed reduction in neurodegeneration may be attributable to the suppressive effects of zafirlukast on microglial activation and the subsequent reduction in pro-inflammatory cytokine release. These findings indicate a complex role for leukotriene signaling during early epileptogenesis. Further studies using different doses, vehicles, and experimental models are warranted to clarify the effects of zafirlukast on the mechanisms underlying early epileptogenesis.
    Keywords:  Astrocytes; Blood–brain barrier; Epilepsy; Gliosis; Seizures; Zafirlukast
    DOI:  https://doi.org/10.1007/s12035-026-06110-5
  39. J Neurol. 2026 Aug 07. pii: 519. [Epub ahead of print]273(9):
    Frontotemporal dementia with right temporal predominance: a clinical comparison with left-predominant FTD.
    Jennifer C Thompson, Christopher Kobylecki, Matthew Jones, Jessica Haigh, Matthew Larbey, Tobias C Langheinrich, Rachel Thomasson, Anna M T Richardson, Julie S Snowden.
       BACKGROUND: The right-temporal variant of frontotemporal dementia (FTD) is well characterised. Whether it should be considered a distinct clinical entity, separate from other syndromes of FTD, remains an open question. The study addressed the issue through a retrospective comparison of clinical characteristics of patients with predominant atrophy in right or left anterior temporal lobe (R-ATL vs. L-ATL).
    METHODS: Patients were identified from a clinical database, diagnosed with FTD, and reported to show temporal lobe atrophy on imaging. Fifty-one patients were selected in whom independent ratings of atrophy were greatest in right or left anterior temporal lobe. Presenting symptoms, cognitive and behavioural characteristics, neuropsychological findings, and diagnostic classification were recorded.
    RESULTS: Difficulty recognising people, impaired decision-making, perseverative preoccupations, disinhibition, and loss of empathy characterised the R-ATL group, in keeping with the previous reports. There was, however, overlap in cognitive and behavioural symptomatology in R-ATL and L-ATL, and sensitivity and specificity values were modest. Group differences diminished with disease progression. The most common clinical classification at first assessment in both groups was semantic dementia (SD), with other patients being classified as behavioural-variant FTD (bvFTD), FTD with amyotrophic lateral sclerosis or mixed FTD/SD. Not all patients with L-ATL met criteria for semantic variant primary progressive aphasia (svPPA).
    CONCLUSIONS: The data question the notion that R-ATL and L-ATL presentations are separate entities. We argue that a common diagnostic framework for the two is warranted, with classification being based on cognitive/behavioural characteristics rather than neuroradiological grounds.
    Keywords:  Frontotemporal dementia; Primary progressive aphasia; Right-temporal variant frontotemporal dementia; Semantic dementia; Semantic variant PPA
    DOI:  https://doi.org/10.1007/s00415-026-14042-2
  40. Ann Child Neurol Soc. 2026 Jun;4(2): 159-166
    Steroids for Drug-Resistant Seizures and Prolonged Stroke-Like Episode in a Patient With Sturge-Weber Syndrome: A Case Report.
    Brenna N Keam, Fabiola A Morales-Vias, Siddharth S Gupta, Doris D Lin, Anne M Comi.
       Introduction: Sturge-Weber syndrome (SWS) brain involvement has been associated with impairments in the blood-brain barrier (BBB) and microglial activation within involved cortical regions. Acute neurological crises, including seizures, stroke-like episodes, and/or significant headaches, are common in these patients. This report describes in detail an adolescent with SWS and acute drug-resistant status epilepticus, headache, and stroke-like episode who improved clinically when treated with high-dose steroids. Review of medical records identified two other patients previously treated with steroids for acute neurological symptoms.
    Case Presentation: A 13-year-old boy with SWS brain involvement presented with fever, headache, seizures, and right-sided weakness. Brain magnetic resonance imaging (MRI) revealed characteristic findings of SWS. The patient was placed on continuous electroencephalogram that showed findings consistent with electrographic status epilepticus. Seizures were refractory to multiple anti-seizure medications as well as to an intravenous midazolam drip. A repeat MRI of the brain documented a significant increase in leptomeningeal enhancement with associated gyral edema and sulcal effacement. Steroid therapy with methylprednisolone and prednisone improved his status epilepticus and stroke-like symptoms, including resolution of seizures and marked improvement in his hemiparesis.
    Conclusion: This patient suggests a potential role for inflammation-targeted therapies in individuals with SWS brain involvement who present with prolonged neurological crises. Two other patients with SWS brain involvement who were treated with high-dose steroids in the context of acute neurological episodes also support the need for future clinical and preclinical research to validate this approach.
    Keywords:  Sturge–Weber syndrome; hemiparesis/stroke‐like episode; status epilepticus; steroids
    DOI:  https://doi.org/10.1002/cns3.70068
  41. J Mol Neurosci. 2026 Aug 05. pii: 124. [Epub ahead of print]76(3):
    Mitochondrial Permeability Transition Regulators As Emerging Therapeutic Targets in Aging and Neurodegeneration: Recent Insights.
    Lishu Guo.
      Aging is characterized by increased reactive oxygen species (ROS) and leads to mitochondrial dysfunction. This age-related decline in mitochondrial function is a major factor in the development of neurodegenerative diseases. Mitochondrial permeability transition pore (PTP) is a multi-protein complex that forms a non-specific channel across the inner mitochondrial membrane, and its opening is tightly linked to mitochondrial function and cell death. Dysregulation of PTP opening is now recognized as a central pathogenic mechanism in both normal aging and age-associated neurodegenerative diseases. This review integrates current understanding of mitochondrial permeability transition with emerging evidence implicating three novel regulatory components: F-ATP synthase inhibitory factor 1 (IF1), subunit j of F-ATP synthase, and mitochondrial carrier homolog 2 (MTCH2), expanding the therapeutic landscape for treating aging and neurodegeneration through targeting the PTP.
    Keywords:  Aging; Mitochondria; Mitochondrial permeability transition; Neurodegeneration; The permeability transition pore
    DOI:  https://doi.org/10.1007/s12031-026-02583-0
  42. Int J Stem Cells. 2026 Aug 04.
    Lineage-Driven Understanding of Human Pericyte Heterogeneity in Vascular Modeling and Regeneration.
    Seungyeon Lee, Chan Mi Baek, Somin Lee, Min Gi Jo, Yong Jun Kim.
      Pericytes are mural cells embedded within the microvascular wall that regulate endothelial stabilization, angiogenesis, and vascular permeability. Once regarded as a relatively uniform vascular support population, pericytes are now recognized as quantitatively and functionally heterogeneous across organs. Neural barrier beds such as brain and retina exhibit high pericyte density and near-continuous mural coverage, whereas peripheral tissues including skeletal muscle display sparse investment. These anatomical differences parallel functional specialization, with central nervous system pericytes exerting strong control over blood-brain barrier (BBB) integrity and transcytosis, while peripheral pericytes participate prominently in vascular remodeling and repair. A critical yet under-integrated dimension of this heterogeneity is developmental origin. Trunk and visceral pericytes arise predominantly from mesodermal progenitors, whereas cranial and forebrain-associated pericytes derive largely from neural crest lineage. This spatial segregation of embryonic origin aligns with vascular specialization, suggesting that lineage contributes to mural regulatory architecture. Stem cell-based comparisons further demonstrate that neural crest-derived pericyte-like cells induce BBB phenotypes more effectively than mesoderm-derived counterparts under identical endothelial conditions, supporting a lineage-linked functional bias. This review integrates anatomical distribution, quantitative investment patterns, molecular signaling mechanisms, and embryonic lineage into a unified framework of pericyte heterogeneity. We propose that developmental origin establishes a regulatory foundation upon which vascular niche signals act, and should therefore be treated as a primary experimental and translational design variable in vascular modeling and regenerative strategies.
    Keywords:  Blood-brain barrier; Cell lineage; Neural crest; Pericytes; Vascular remodeling
    DOI:  https://doi.org/10.15283/ijsc26028
  43. Neurotherapeutics. 2026 Aug 05. pii: S1878-7479(26)00140-6. [Epub ahead of print] e00970
    Wild-type C9orf72 drives proteasomal dysfunction and mutant aggregates via a Stat1-Isg15 axis in Huntington's disease.
    Siew Chin Chan, Chih-Wei Tung, Chih-Yi Chang, Ching-Chun Su, Yi-Ching Chen, Po-Ming Wu, Chia-Yu Tung, Shih-Feng Chen, Hsiao-Ying Kuo, Pei-Hsun Cheng, Chuan-Mu Chen, Shang-Hsun Yang.
      Mutant C9orf72 has been extensively studied as a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, and is also known to generate Huntington's disease (HD)-like phenocopies. However, despite this strong disease association, the role of wild-type C9orf72 (wt-C9orf72) in neurodegeneration remains largely unexplored. HD is a neurodegenerative disease, and characterized by the accumulation of misfolded mutant Huntingtin (mHTT) and impaired proteostasis, yet the upstream mechanisms driving ubiquitin-proteasome system (UPS) dysfunction are not fully understood. Here, we identify a previously unrecognized modulatory role of wt-C9orf72 in regulating mHTT aggregation in experimental HD models. Analysis of public transcriptomic datasets reveal context-dependent C9ORF72 expression changes across HD-related human datasets, while C9orf72 levels are increased in R6/2 mouse brain lysates. Functional analyses reveal that overexpression of wt-C9orf72 increases mHTT aggregation and is accompanied by increased apoptotic signaling and reduced cell viability. Unbiased proteomic profiling identifies Stat1 as a key downstream effector. Mechanistically, wt-C9orf72 promotes Stat1 activation and nuclear translocation, leading to transcriptional upregulation of Isg15, a ubiquitin-like modifier. Elevated Isg15 disrupts UPS function, resulting in accumulation of polyubiquitinated proteins and impaired proteasomal degradation. Importantly, genetic suppression of Stat1 or Isg15 significantly attenuates C9orf72-associated mHTT aggregation, supporting a functional C9orf72-Stat1-Isg15 axis. Consistent with these cell-based findings, Stat1, phosphorylated Stat1 and Isg15 levels are elevated in the cortex and striatum of R6/2 HD mouse brains. Collectively, our findings identify a novel wt-C9orf72-Stat1-Isg15 axis that promotes proteasomal dysfunction and mHTT aggregation, providing new insights into wt-C9orf72-associated protein homeostasis.
    Keywords:  Huntington’s disease; Isg15; Stat1; Ubiquitin-proteasome system; Wild-type C9orf72
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00970
  44. Ageing Res Rev. 2026 Aug 05. pii: S1568-1637(26)00282-5. [Epub ahead of print] 103290
    Mitochondrial homeostasis dysregulation: Potential mechanisms of Alzheimer's disease mediated by TDP-43.
    Wendi Huang, Juan Huang, Nanyu Kuang, Jingjing Wu, Fei Feng, Yong Luo, Nanqu Huang.
      Alzheimer's disease (AD) exhibits substantial clinical and pathological heterogeneity that is not fully explained by amyloid-β and tau pathology alone. TAR DNA-binding protein 43 (TDP-43) is increasingly recognized as a frequent copathology in AD, particularly in limbic regions, where its presence is associated with accelerated cognitive decline. Disruption of mitochondrial homeostasis is also an early and consistent feature of AD and contributes to neuronal vulnerability. In this review, we summarize current evidence linking TDP-43 pathology to impaired mitochondrial homeostasis in AD. We outline key features of mitochondrial homeostasis in neurons, review neuropathological and clinical data supporting the relevance of TDP-43 in AD, and synthesize emerging mechanisms by which TDP-43 may perturb mitochondrial homeostasis, including effects on expression, aggregation and localization, quality control, organelle dynamics, and endoplasmic reticulum-mitochondria communication.
    Keywords:  Alzheimer's Disease; Mitochondrial fission; Mitochondrial fusion; Mitochondrial homeostasis; Mitophagy; TDP-43
    DOI:  https://doi.org/10.1016/j.arr.2026.103290
  45. J Affect Disord. 2026 Aug 07. pii: S0165-0327(26)01192-4. [Epub ahead of print] 122339
    Psychomotor retardation and risk of Parkinson's disease in unipolar depression: A retrospective cohort study.
    Hamilton Morrin, James B Badenoch, Ella Burchill, Aurore Fayosse, Archana Singh-Manoux, Paul Shotbolt, Michael S Zandi, Anthony S David, Glyn Lewis, Jonathan P Rogers.
       BACKGROUND: Depression is associated with an increased risk of subsequent Parkinson's disease. Neuroimaging studies suggest a neurobiological overlap in mechanisms underlying Parkinson's disease and psychomotor retardation in depression. Our aim was to investigate whether, among individuals with depression, the presence of psychomotor retardation was associated with the development of subsequent Parkinson's disease.
    METHODS: In a retrospective cohort study, electronic healthcare records from individuals diagnosed with depression at age 40 or over in a large mental health service in London, UK were examined for the presence of psychomotor retardation. Linkage to general hospital records was used to ascertain diagnoses of Parkinson's disease between 2007 and 2023. A mixed-effects Cox model, incorporating a participant-level random intercept and psychomotor status as a fixed-effects exposure was used to compare the hazard of Parkinson's disease in depression with and without psychomotor retardation.
    RESULTS: Among 6326 patients with depression, there were 17,998 psychomotor observation intervals and 138 incident Parkinson's disease cases. PMR-positive status was associated with a higher subsequent hazard of Parkinson's disease in the adjusted mixed-effects Cox model (hazard ratio 1.57, 95% CI 1.11-2.22; p = 0.011). Secondary analyses demonstrated a significant difference in psychomotor retardation probability at up to 2.5 years before Parkinson's diagnosis.
    CONCLUSIONS: Psychomotor retardation in later-life depression is associated with increased risk of subsequent Parkinson's diagnosis over an extended period of time, suggesting that the relationship cannot solely be explained by misdiagnosis. Psychomotor retardation might therefore serve as a marker of prodromal Parkinson's disease.
    Keywords:  Cohort study; Depression; Electronic health records; Parkinson's disease; Psychomotor retardation; Survival analysis
    DOI:  https://doi.org/10.1016/j.jad.2026.122339
  46. Front Neurol. 2026 ;17 1876331
    Association of therapeutic plasma exchange with functional outcomes in selected neurological disorders: a retrospective cohort study from a single tertiary center in Saudi Arabia.
    Fatemah I Ammar, Esraa Aljahdali, Amal Alshrif, Asmaa Alshareef, Dania Faidah, Mohammed Almohammadi, Seraj Makkawi.
       Background: Neurological disorders are associated with considerable morbidity and healthcare impact. Therapeutic plasma exchange (TPE) is an intervention that removes pathogenic antibodies, immune complexes, and other plasma constituents from circulation. Previous studies have suggested that TPE could be associated with improved outcomes in selected neurological disorders.
    Objectives: To evaluate functional outcomes following therapeutic plasma exchange in patients with selected neurological disorders at National Guard Health Affairs (NGHA) in Jeddah, Saudi Arabia.
    Methods: This retrospective cohort study analyzes 133 patients diagnosed with various neurological disorders who received TPE between August 2015 and December 2022 at NGHA. Diagnoses included multiple sclerosis (MS), myasthenia gravis (MG), Guillain-Barré syndrome (GBS), neuromyelitis optica spectrum disorder (NMOSD), chronic inflammatory demyelinating polyneuropathy (CIDP), autoimmune encephalitis (AE), and other neurological conditions including amyotrophic lateral sclerosis (ALS), transverse myelitis, cerebellar ataxia, paraneoplastic neurologic syndrome, polymyositis, and central nervous system (CNS) infections. The effectiveness of TPE was assessed using the Modified Rankin Scale (mRS) before and 90 days following the final TPE session. Statistical analysis included Wilcoxon signed-rank tests and Mann-Whitney U test, with significance set at (p < 0.05).
    Results: Significant improvements in mRS scores were observed following TPE for MS, MG, and GBS (all p < 0.001), as well as for NMOSD (p = 0.008), CIDP (p = 0.007), and AE (p = 0.018), but not in other neurological disorders (p = 0.234). Overall mortality was 6.8%, with no TPE-related deaths. Comorbidities among deceased patients included hypertension, diabetes mellitus, malignancy, chronic kidney disease, and cardiovascular disease.
    Conclusion: TPE was associated with improved functional outcomes in selected neurological disorders. Comorbidities were common among patients with poorer outcomes. Due to the retrospective design and potential confounding factors, causal inferences cannot be established. Further prospective studies are warranted to evaluate the role of TPE and optimize patient selection.
    Keywords:  Guillain-Barré syndrome; autoimmune encephalitis; chronic inflammatory demyelinating polyneuropathy; multiple sclerosis; myasthenia gravis; neuromyelitis optica spectrum disorder; therapeutic plasma exchange
    DOI:  https://doi.org/10.3389/fneur.2026.1876331
  47. J Neural Transm (Vienna). 2026 Aug 04.
    Toward the prevention of clinically manifest Parkinson's disease.
    Günter Höglinger, Franziska Hopfner.
      Parkinson's disease (PD) is the fastest growing neurological disorder worldwide and is projected to affect unprecedented numbers of individuals by 2050. At the same time, PD research is undergoing a profound conceptual transformation. Advances in molecular neuropathology, genetics, biomarker science, artificial intelligence, multimodal imaging, digital medicine, and precision therapeutics are reshaping PD from a clinically defined syndrome into a biologically measurable and potentially preventable process. This Perspective is not a report of new empirical findings and should not be read as an evidence-based forecast of what will most likely occur by 2050. Rather, it deliberately formulates a normative strategic vision: clinically manifest PD should become a preventable public-health burden. In this context, "eradication" does not imply elimination of all α-synuclein pathology, genetic susceptibility, or neurodegenerative biology. It refers to the long-term objective of preventing or substantially eliminating the transition to disabling, clinically manifest PD before irreversible symptomatic neurodegeneration occurs. We outline the prerequisites for such a future, including validated biological staging, risk stratification, longitudinal biomarker trajectories, trial enrichment, preventive endpoints, regulatory qualification, scalable implementation, and equitable global access. The analogy to poliomyelitis is used as a model of strategic goal-setting and international coordination, not as a biological equivalence between an infectious disease and a heterogeneous neurodegenerative disorder. Several enabling technologies already exist in early or research form, including α-synuclein seed amplification assays, genetic and prodromal risk models, digital monitoring, multimodal imaging, and mechanism-based therapeutic development. Other components remain aspirational and will require major scientific, regulatory, ethical, and societal advances. The central purpose of this article is therefore not to predict the future from the current trajectory, but to define a desired destination around which the field can organize scientific innovation.
    Keywords:  Artificial intelligence; Biomarkers; Digital twins; Parkinson’s disease; Precision neurology; Prevention; Public health; α-synuclein
    DOI:  https://doi.org/10.1007/s00702-026-03240-x
  48. J Parkinsons Dis. 2026 Aug 07. 1877718X261470604
    GBA1 variants and mortality in Parkinson's disease: A systematic review and meta-analysis.
    Nathan Chan, Anthony Raphael, Justin Kim, Amy Haryanto, Saman Heshmat, Tien K Khoo.
      BackgroundVariants in the GBA1 gene are a common genetic risk factor for Parkinson's disease (PD). While GBA1-PD is associated with more rapid motor and cognitive decline, evidence regarding impact on survival remains debatable.ObjectivesThis systematic review and meta-analysis synthesizes longitudinal evidence of GBA1 variants as a prognostic factor for all-cause mortality in PD.MethodsWe searched MEDLINE, Embase, Cochrane (CENTRAL), ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform for studies comparing mortality in GBA1-PD versus non-carriers from inception to September 2025. Risk of bias was assessed using the Quality in Prognosis Studies tool. Hazard Ratios were pooled using a random-effects meta-analysis. Subgroup analysis was stratified by variant severity.ResultsEight studies (N = 13,690) were included. The primary meta-analysis (n = 4947) revealed GBA1 variants were associated with significantly increased all-cause mortality risk versus non-carriers (HR 1.53, 95% CI 1.24-1.87; I2 = 0.7%). A subgroup analysis suggested a possible severity-dependent effect, with severe variants showing higher point estimates (HR 1.87; 95% CI 1.24-2.82) than mild variants (HR 1.38; 95% CI 1.03-1.83), although the test for subgroup differences was not statistically significant.ConclusionsGBA1 variants are a significant prognostic marker for reduced survival in PD. This risk may increase with variant severity and persist after adjustment for dementia in the studies that examined this, although the available data is limited. Limitations include heterogeneous screening methods and predominance of European ancestry in study populations. GBA1 status should be considered a significant prognostic factor for stratification in clinical trials and management.
    Keywords:  biomarkers; epidemiology; genetics; neurodegeneration; pathophysiology
    DOI:  https://doi.org/10.1177/1877718X261470604
  49. Front Cell Neurosci. 2026 ;20 1897379
    Gut-derived signals regulating glial activation and secondary neuroinflammation after spinal cord injury: an evidence mapping and mechanistic framework.
    Baoxiu Yi, Wenguang Chen, Zhenhai Chi, Qiangjian Mao, Xiaoqin Li, Yuelai Chen.
      Secondary neuroinflammation after spinal cord injury (SCI) is a key pathological process that affects neuronal survival, axonal regeneration, and functional recovery. Increasing evidence suggests that dysbiosis of the gut microbiota, disruption of the intestinal barrier, and abnormal microbial inflammatory and metabolic signals may promote the progression of secondary injury after SCI. However, direct, continuous, and cell-type-specific evidence explaining how gut-derived signals influence glial and neurovascular unit responses within the injured spinal cord through peripheral immune imbalance, blood-spinal cord barrier (BSCB) disruption, and local molecular pathways remains limited. In this narrative review, we organize the existing literature into an evidence map and propose a mechanistic hypothesis: After SCI, autonomic dysfunction, impaired gut motility, and neurogenic bowel dysfunction may disrupt the homeostasis of gut microbiota and barrier, leading to lipopolysaccharide (LPS) overflow, reduced short-chain fatty acids (SCFAs), altered tryptophan metabolism, and increased trimethylamine N-oxide (TMAO). These signals may modulate the responses of microglia/infiltrating macrophages, astrocytes, and the neurovascular unit via peripheral immunity, BSCB, and pathways, including TLR4/NF-κB, NLRP3, and AhR. We also distinguish direct SCI evidence, single-study support, and extrapolated evidence, and specifically avoid presenting the tryptophan metabolite-AhR axis or TMAO-NLRP3 axis as established SCI pathways. Overall, the gut-spinal cord axis may provide a useful framework for understanding and targeting secondary neuroinflammation after SCI. Still, its causal chain, temporal characteristics, and cell-specific effects require further validation.
    Keywords:  NLRP3 inflammasome; glial cells; gut-derived signals; gut–spinal cord axis; secondary neuroinflammation; spinal cord injury
    DOI:  https://doi.org/10.3389/fncel.2026.1897379
  50. Trends Immunol. 2026 Aug 07. pii: S1471-4906(26)00185-7. [Epub ahead of print]
    Antigen presentation at the blood-brain barrier amplifies neuroinflammation.
    Sidar Aydin, Javier Pareja, Roland Liblau, Britta Engelhardt.
      Immune surveillance of the central nervous system (CNS) is regulated by the brain barriers. Antigen presentation at the blood-brain barrier (BBB) has been proposed to promote antigen-specific T-cell entry into the CNS, largely based on in vitro studies. Recent in vivo and transcriptomic studies call for a reassessment of this concept. In healthy mouse and human CNS endothelium, major histocompatibility complex (MHC) class I expression is low, and MHC class II is minimal to absent. During neuroinflammation, brain microvascular endothelial cells (BMECs) can acquire antigen-presenting features, predominantly in the context of strong or prolonged inflammation. We propose that BMEC antigen presentation amplifies vascular pathology rather than initiating CNS T-cell entry during immune surveillance or disease.
    Keywords:  T-cell migration; antigen presentation; brain barriers; central nervous system
    DOI:  https://doi.org/10.1016/j.it.2026.07.006
  51. J Clin Neurosci. 2026 Aug 05. pii: S0967-5868(26)00379-6. [Epub ahead of print]153 112228
    Chronic neurological diseases with acute respiratory failure in a real-life cohort: insights into ICU and long-term survival-A retrospective study.
    Ülgen Yalaz Tekan, Emine Aksoy, Feyza Kargın, Rabia Sarı Küçük, Cüneyt Saltürk, Fulya Çiyiltepe, Dilek Yavuz, Gökay Güngör, Nalan Adıgüzel, Zühal Karakurt.
       BACKGROUND: Patients with chronic neurological diseases (CND) are at increased risk of pulmonary complications that often require ICU admission. This study aimed to identify clinical factors associated with ICU mortality and long-term survival in patients with CND who developed acute respiratory failure (ARF).
    METHODS: This retrospective cohort study was conducted in a level III respiratory ICU. Patients with pre-existing CND admitted to the ICU with ARF were included. ICU mortality was analyzed using multivariable logistic regression. Long-term survival after ICU discharge was evaluated using Kaplan-Meier survival analysis and Cox proportional hazards models. Mortality timing was further characterized using hazard function analysis.
    RESULTS: A total of 220 patients were included; the most common neurological diagnoses were dementia (37.3%), stroke (22.7%), and amyotrophic lateral sclerosis (14.1%). ICU mortality was 33.6%. Higher APACHE II scores were independently associated with increased ICU mortality (OR 1.076 per point increase; 95% CI 1.029-1.126; p < 0.001). Long-term survival differed significantly by post-discharge respiratory support strategy, with Kaplan-Meier analysis demonstrating more favorable survival patterns among patients receiving home non-invasive mechanical ventilation (NIMV) (p = 0.003). In Cox regression analysis, age, home NIMV, and feeding modality at discharge were independently associated with long-term outcomes. Survival analyses revealed an early clustering of deaths within the first months after ICU discharge, particularly among patients with dementia.
    CONCLUSIONS: In patients with CND, acute physiological severity was the main determinant of ICU mortality, whereas long-term survival after ICU discharge was poor, with deaths clustering within the first months thereafter. Post-discharge respiratory support and nutritional management should be individualized according to the expected clinical trajectory and patient values.
    Keywords:  Amyotrophic lateral sclerosis; Dementia; Enteral nutrition; Mechanical ventilation; Neurologic diseases; Tracheostomy; İntensive care units
    DOI:  https://doi.org/10.1016/j.jocn.2026.112228
  52. Dement Neurocogn Disord. 2026 Jul;25(3): 141-151
    Diagnostic Accuracy of MRI-Based Artificial Intelligence Models for Distinguishing Alzheimer's Disease and Mild Cognitive Impairment From Cognitively Normal Controls: A Systematic Review and Meta-Analysis.
    Sara Mahmoud Ibrahim Allaham.
      Magnetic resonance imaging (MRI)-based artificial intelligence (AI) models are increasingly applied to brain MRI for diagnosing Alzheimer's disease (AD) and mild cognitive impairment (MCI), but their overall diagnostic performance remains unclear. We systematically searched PubMed/MEDLINE, Embase, Web of Science, Scopus, and IEEE Xplore until February 15, 2026, for diagnostic accuracy studies of machine-learning or deep-learning models using structural brain MRI to distinguish AD vs. cognitively normal (CN) controls and MCI or late mild cognitive impairment (LMCI) vs. CN controls. Seven studies met inclusion criteria, contributing five AD vs. CN and two MCI/LMCI vs. CN tasks, predominantly using deep-learning architectures applied to Alzheimer's Disease Neuroimaging Initiative cohorts. For AD vs. CN (five studies), pooled sensitivity was 0.96 (95% confidence interval [CI], 0.93-0.97) and pooled specificity was 0.95 (95% CI, 0.92-0.97), indicating excellent discrimination. For MCI/LMCI vs. CN (two studies), sensitivity was consistently high (0.91-0.93), whereas specificity varied widely (0.54-0.98), limiting the interpretability of pooled estimates. MRI-based AI models therefore show strong performance for established AD but heterogeneous specificity for MCI, underscoring the need for larger, externally validated studies in diverse populations.
    Keywords:  Alzheimer Disease; Artificial Intelligence; Deep Learning; Dementia; Magnetic Resonance Imaging; Mild Cognitive Impairment
    DOI:  https://doi.org/10.12779/dnd.2026.25.3.141
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