bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–07–26
58 papers selected by
Luca Bolliger, lxBio
  1. Psychiatric disorders in amyotrophic lateral sclerosis: a short note.
  2. Relationship Between miRNA and Neurodegenerative Diseases Such as Alzheimer's disease, Parkinson's, Huntington's disease, Amyotrophic Lateral Sclerosis.
  3. SOD1-lowering therapy for patients with wildtype SOD1-ALS: a case report.
  4. Site-targeted proximal complement C3 inhibition, but not C5 blockade, attenuates neurodegeneration in a mouse model of amyotrophic lateral sclerosis: Implications for failed clinical trials.
  5. Troponin T and Neurofilament Light Chain Levels as Complementary Biomarkers of Disease Accumulation and Aggressiveness in Amyotrophic Lateral Sclerosis.
  6. The Anterior Belly of the Digastric Muscle as a Novel Target for Needle Electromyography in Amyotrophic Lateral Sclerosis.
  7. Rapid Eye Movement Sleep Suppressing Antidepressant Prescription is Associated with Improved Survival in Amyotrophic Lateral Sclerosis.
  8. The centrosome-cilium-centriolar satellite axis in neurodegenerative diseases.
  9. An investigation of factors associated with speech intelligibility in patients with amyotrophic lateral sclerosis: Integrating acoustic and lingual motor measures.
  10. A Blood-Derived Factor Rescues ALS: Platelet Factor 4 Activates OPTN-Dependent Autophagy to Clear SOD1 Aggregates Independently of PINK1.
  11. Cellular and signalling mechanisms that regulate the blood-brain barrier.
  12. Sustainable next-generation prebiotics for brain health: microbiota-gut-brain axis in neurodegenerative and demyelinating diseases.
  13. Exploring shared genetic pathways and gene interplay in major neurodegenerative diseases: a comprehensive review.
  14. Sex-associated differences in routine inflammatory markers and neuromuscular ultrasound measurements in amyotrophic lateral sclerosis: a retrospective cross-sectional study.
  15. BiGranMolNet: A deep learning method for predicting blood-brain barrier permeability based on Bi-Granularity Molecular Graphs.
  16. Strenuous physical activity is associated with a younger age of amyotrophic lateral sclerosis onset in two independent cohorts.
  17. Macrophage responses to and elevated antibody levels against Chlorovirus ATCV-1 in ALS patients.
  18. Use of blood-based neurofilament light chain as an endpoint in clinical trials of neurodegenerative conditions: a scoping review.
  19. Unraveling the role of lipid metabolism in ALS risk: a Mendelian randomization analysis using GWAS data.
  20. Neurotransmitter-Defined Degeneration Patterns in Sporadic and C9orf72-Associated Amyotrophic Lateral Sclerosis: Predilection to GABAergic, Serotonergic, Opioid, Glutamatergic, Endocannabinoid, and Microglial Systems-Implications for Therapy Development.
  21. Protein Lactylation in Central Nervous System Diseases: Molecular Mechanisms and Targeted Therapeutic Strategies.
  22. Insights into the blood-brain barrier in mental health disorders: from experimental models to clinical findings.
  23. Neurodegenerative Diseases and Sleep Disorders: The Bidirectional Relationship.
  24. Development and characterization of a novel TDP-43 positron emission tomography tracer: [18F]JNJ-TDP43-1.
  25. F waves as a measure of enhanced spinal motoneuron excitability in primary lateral sclerosis.
  26. Histone lactylation-mediated glycolysis-ferroptosis axis in neurological diseases.
  27. Exosomes in Neurodegenerative Disorders: Isolation Strategies, Therapeutic Potential, and Clinical Trials.
  28. Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System.
  29. Neuroinflammation as a failure of allostatic integrity: a hierarchical-circular model of biological memory for pathogenesis in neurodegenerative and neuropsychiatric diseases.
  30. Micronutrient-Assisted Biomaterial Strategies as Neuropharmacological Modulators of Neuroinflammation and Oxidative Stress in Neurodegenerative Diseases.
  31. Autoimmune signatures in neurodegenerative dementias: from peripheral immune activation to CNS pathology.
  32. Home mechanical ventilation for amyotrophic lateral sclerosis-a national study of survival and treatment trends across 27 years.
  33. Human blood-brain barrier spheroid models for the evaluation of drugs targeting brain vascular inflammation.
  34. In Silico Modeling of Nanoparticle Transport across the Blood-Brain Barrier: A Systematic Review.
  35. Bioactive compounds from traditional Chinese medicine for mitochondrial dysfunction-oriented nanodelivery in neurodegenerative diseases.
  36. Neurovascular unit senescence as a driver of blood-brain barrier dysfunction in Alzheimer's disease：Mechanisms, consequences, and therapeutic implications.
  37. Modeling Alzheimer's disease with brain organoids: mechanisms, applications, and future directions.
  38. Asymptomatic spinal cord lesions in Multiple Sclerosis: A systematic review and meta-analysis of subclinical disease activity.
  39. From synaptic development to degeneration: a narrative review of small molecule strategies targeting alpha-synuclein in Parkinson's disease.
  40. Serum miR-423-5p discriminates patients with Parkinson's disease from healthy individuals and is associated with severity and the risk of cognitive dysfunction.
  41. Integrative multicohort analysis reveals consistent sex differences in gut microbiota of multiple sclerosis patients.
  42. The New Spine of Access to the Brain's Secrets: Extracellular Vesicles from Cerebrospinal Fluid Liquid Biopsies in CNS Diseases and Blood-Brain Barrier Research.
  43. Multilevel Assessment of a Carbosilane Dendrimer-siRNA Nanoplatform: Cellular Compatibility, Blood-Brain Barrier Model Integrity, and Murine Model Biodistribution.
  44. Application of the Allen Human Brain Atlas in Alzheimer's disease and Parkinson's disease.
  45. Niacin alleviates cerebral microvascular endothelial cell apoptosis induced by hypervirulent Klebsiella Pneumoniae by reducing the accumulation of reactive oxygen species.
  46. When algorithms speak first: The public health risk of consumer AI in ALS diagnosis.
  47. Weaker Hydrophobic Collapse in Peptide Amphiphile Supramolecular Assemblies Enhances Permeation Across a Blood-Brain Barrier Model.
  48. Greater burden of Alzheimer's Co-pathology in women with Parkinson's disease dementia.
  49. E326K GBA polymorphism is associated with clinical and pathological features of synucleinopathy in the absence of overt Parkinson's disease or Lewy body dementia.
  50. JAK/STAT signaling pathway inhibitors in neurodegenerative diseases: current status and future perspectives.
  51. Associations of viral infections and antiviral vaccinations with anti-NMDAR and other forms of autoimmune encephalitis.
  52. Phytochemicals with potential NMDAR-inhibitory activities: a review of neuroprotective mechanisms against excitotoxicity.
  53. The Neurology of Menopause.
  54. Chemically Programmed Prodrug Nanoparticles for Precise Oral Dopamine Delivery to Deep Brain Regions in Parkinson's Disease.
  55. Targeting progressive multiple sclerosis: Toward mechanism-informed precision medicine.
  56. Real-world application of the conventional components of the 2024 McDonald diagnostic criteria for multiple sclerosis in China: a comparative study with the 2017 criteria.
  57. Differential effects of hormone therapy formulations on Parkinson's disease risk: a systematic review and meta-analysis.
  58. PatientSpace: A multimodal graph-based latent representation framework for modeling neurodegenerative disease heterogeneity.
  1. J Neural Transm (Vienna). 2026 Jul 23.
    Psychiatric disorders in amyotrophic lateral sclerosis: a short note.
    Kurt A Jellinger.
      Traditionally, amyotrophic lateral sclerosis (ALS) has been defined as a rapidly progressive neurodegenerative disorder that affects the large motor neurons of the brain and spinal cord. The assumption that ALS is a pure motor disorder has been increasingly challenged by accumulating evidence about an association between ALS and psychiatric disorders. They often precede the onset of motor symptoms or psychoses; hallucinations and schizophrenia may occur as concomitant changes. These non-motor disorders have a close relationship with disease onset or may be related to a larger framework of neuronal network disruptions in motor neuron disorders. The link between ALS and schizophrenia was supported by substantial genetic correlations associating the C9orf72 gene expansion with psychiatric disorders. The genetic correlation between ALS and schizophrenia was estimated to be 14.3% with frequent polygenic risk scores. Increased psychotic symptoms in C9orf72 carriers correlate with atrophy in a distributed cortical and subcortical network that includes multiple cerebral regions. ALS kindreds often present higher rates of psychiatric illnesses, and early schizophrenia is significantly associated with the development of ALS. Further studies should attempt to delineate the risk of psychiatric disorders in C9orf72 kindreds to aid in clinical decision making and genetic counseling, through collaborations between neurology and psychiatry.
    Keywords:   C9orf72 expansions; ALS; Functional connectivity; Hallucinations; Psychosis; Schizophrenia
    DOI:  https://doi.org/10.1007/s00702-026-03231-y
  2. Mini Rev Med Chem. 2026 Jul 16.
    Relationship Between miRNA and Neurodegenerative Diseases Such as Alzheimer's disease, Parkinson's, Huntington's disease, Amyotrophic Lateral Sclerosis.
    Aysenur Keskin, Rasim Mogulkoc, Abdulkerim Kasim Baltaci.
      The regulatory roles of miRNAs on CNS homeostasis, neuronal differentiation, and synaptic plasticity make these molecules indispensable for healthy brain functions. miRNA dysregulation, by triggering abnormal neurodevelopment, has a critical impact on the etiology and progression of neurodegenerative diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding ribonucleic acid (RNA) molecules, 18 to 24 nucleotides long. They play a role in posttranscriptional gene regulation by binding to complementary sequences on messenger RNA (mRNA), thereby promoting mRNA degradation or preventing translation into protein. MiRNAs are essential regulators of the genome because they bind targets and alter gene expression. MiRNA biogenesis and functions are tightly regulated, and their dysregulation is associated with various diseases, including cancer, cardiovascular diseases, and neurodegenerative disorders. In particular, disruption of the Blood-Brain Barrier in neurodegenerative diseases allows molecules to leak into the bloodstream, enabling the detection of miRNAs in other body fluids and making these fluids potential biomarker sources. In this context, miRNAs can be measured in blood, cerebrospinal fluid, and other biological samples. It has significant potential for early diagnosis, disease progression monitoring, and evaluation of treatment efficacy. In this review, the relationship between MiRNAs and neuronal degeneration diseases was evaluated. In this review, prepared in light of the current literature scanned through the PubMed database, we examined data from the last 5 years (2021-2026) on neurodegenerative diseases associated with miRNA dysregulation, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease (HD).
    Keywords:  alzheimer's disease; amyotrophic lateral sclerosis; huntington's disease; miRNA; neuronal degeneration; parkinson's disease
    DOI:  https://doi.org/10.2174/0113895575484348260702044851
  3. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jul 22. 1-3
    SOD1-lowering therapy for patients with wildtype SOD1-ALS: a case report.
    Nathan Carberry, Joanne Wuu, Michael Benatar.
      Background and Objectives: To describe clinical and biomarker experience using an SOD1 antisense oligonucleotide (ASO) in a patient with non-SOD1 amyotrophic lateral sclerosis (ALS). Methods: Case report. Results: In a 72-year-old male with non-SOD1 ALS, rapid decline on the ALS functional rating scale revised (ALSFRS-R) and a rise in serum neurofilament light chain (NfL) concentration were observed following 3 loading doses of an SOD1 ASO before the patient succumbed to disease. The time from symptom onset to death was 9 months. Discussion: While treatment was initiated relatively late (∼7 months) after symptom onset and follow-up duration was short, the observed increase (as opposed to a reduction) in serum NfL and accompanying rapid functional decline, suggest the lack of a therapeutic effect in someone with fast progressing non-SOD1 ALS.
    Keywords:  ALS; NfL; Qalsody; amyotrophic lateral sclerosis; biomarker; neurofilament light chain; tofersen
    DOI:  https://doi.org/10.1080/21678421.2026.2705142
  4. Neurotherapeutics. 2026 Jul 23. pii: S1878-7479(26)00139-X. [Epub ahead of print]23(5): e00969
    Site-targeted proximal complement C3 inhibition, but not C5 blockade, attenuates neurodegeneration in a mouse model of amyotrophic lateral sclerosis: Implications for failed clinical trials.
    Moumita Majumder, Davis M Borucki, Nityananda Chowdhury, Khalil Mallah, Stephen Tomlinson.
      Complement activation contributes to amyotrophic lateral sclerosis (ALS) neuropathology, but whether motor neuron degeneration is driven by proximal or terminal activation products remains unresolved. Failed trials of C5 inhibition - ravulizumab (CHAMPION-ALS) and zilucoplan (ATHLEET/HEALEY ALS Trial), and of systemic C3 inhibition (pegcetacoplan, MERIDIAN) underscore this mechanistic gap. We compared two pharmacologically distinct inhibitors in hSOD1G93A mice. CR2Crry blocks complement at C3 and localizes to sites of active deposition. BB5.1, functionally equivalent to ravulizumab, selectively blocks C5a generation and membrane attack complex (MAC) assembly. Treatment began at symptom onset and continued to humane endpoint. Both agents achieved robust target engagement across spinal cord, sciatic nerve, and neuromuscular junction (NMJ). Only CR2Crry extended survival, preserved motor function, and attenuated weight loss. CR2Crry reduced microglial activation and C3 opsonization in the ventral horn, diminished macrophage infiltration, preserved sciatic nerve axonal integrity, and maintained NMJ innervation. BB5.1 failed to modify any functional or neurodegenerative pathology despite confirmed MAC suppression. Proximal C3 activation products, not C5a or MAC, are the dominant drivers of complement-mediated neurodegeneration in the hSOD1G93A model of ALS. Site-targeted C3 inhibition may address the mechanistic limitation underlying recent clinical trial failures and represents a translationally justified therapeutic strategy.
    Keywords:  ALS; C3; Neuroinflammation; Site-targeted complement inhibition; hSOD1(G93A)
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00969
  5. Ann Clin Transl Neurol. 2026 Jul 23.
    Troponin T and Neurofilament Light Chain Levels as Complementary Biomarkers of Disease Accumulation and Aggressiveness in Amyotrophic Lateral Sclerosis.
    Julia Sellin, Sofia Waldorf, Janina von der Gablentz, Torsten Grehl, Huelya Nazlican, Thomas Meyer, Julian Grosskreutz, Patrick Weydt, Sarah Bernsen.
       OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease requiring reliable biomarkers to improve patient stratification and trial design. While serum neurofilament light chain (sNfL) reflects neuroaxonal stress and disease aggressiveness, troponin T (TnT) may capture complementary aspects of neuromuscular involvement. We assessed the associations of TnT and sNfL with D50-derived measures of disease aggressiveness (D50) and disease accumulation (rD50) in ALS.
    METHODS: In this retrospective observation, TnT and sNfL levels from ALS patients in two independent German cohorts were analyzed using the D50 disease progression model; discovery cohort (Essen, n = 433) and an independent replication cohort (Bonn, n = 185).
    RESULTS: TnT levels were strongly associated with rD50-defined disease phases in the discovery cohort (p < 0.001). While not all subgroup-specific associations were replicated, the overall relationship between TnT and disease accumulation was supported in the independent replication cohort. In contrast, sNfL showed no consistent relationship with rD50-derived disease phases. sNfL concentrations demonstrated a significant inverse association with D50, supporting a relationship with disease aggressiveness across both cohorts (p < 0.001). Associations between TnT levels and D50-defined disease aggressiveness were generally weaker and less consistent.
    INTERPRETATION: TnT was associated with measures of disease accumulation (rD50), whereas sNfL was more closely associated with disease aggressiveness (D50). Our results suggest that TnT and sNfL capture different dimensions of disease status within the D50 framework. Further longitudinal studies are needed to determine whether combining these biomarkers improves disease stratification or prognostic assessment in clinical practice and therapeutic trials.
    Keywords:  D50; amyotrophic lateral sclerosis; biomarker; neurofilament light chain; troponin T
    DOI:  https://doi.org/10.1002/acn3.70499
  6. Muscle Nerve. 2026 Jul 21.
    The Anterior Belly of the Digastric Muscle as a Novel Target for Needle Electromyography in Amyotrophic Lateral Sclerosis.
    Tatsuya Fukumoto, Yusuke Osaki, Kenta Hanada, Koji Fujita, Ryuji Kaji, Yuishin Izumi.
       INTRODUCTION/AIMS: Needle electromyography (EMG) in the bulbar region aids in the diagnosis of amyotrophic lateral sclerosis (ALS) but remains technically challenging. The genioglossus muscle (GM) is commonly examined; however, pain and poor relaxation may limit its evaluation. The trapezius is an alternative target but is innervated by the spinal accessory nerve. We investigated the utility of the anterior belly of the digastric muscle (ABDM), innervated by the trigeminal nerve, for bulbar EMG evaluation.
    METHODS: In this unblinded, prospective observational study, consecutive patients with suspected ALS underwent needle EMG of the ABDM, GM, masseter muscle (MM), and trapezius. Relaxation levels, EMG abnormalities, and pain (100-mm visual analog scale [VAS]) were assessed.
    RESULTS: Twenty-seven clinically diagnosed ALS patients were analyzed. Relaxation was better in the ABDM than in the GM (p < 0.001) and comparable to that in the MM and trapezius. Fasciculation potentials were detected more often in the ABDM (52%) than in the GM (0%) and MM (22%; p = 0.039) and were comparable to the trapezius (59%). Chronic denervation occurred at similar frequencies across muscles (33%-59%). The combination of abnormal spontaneous activity and chronic denervation was most frequent in the ABDM (37%). Pain was lower with the ABDM (median VAS score of 21) than with the GM (28; p = 0.0052) and MM (32; p < 0.001) and was similar to the trapezius (23).
    DISCUSSION: The ABDM may be a practical additional target for bulbar EMG in ALS, with favorable relaxation, lower pain, and potentially improved electrodiagnostic yield.
    Keywords:  amyotrophic lateral sclerosis; bulbar‐onset ALS; diagnosis; digastric muscle; needle electromyography
    DOI:  https://doi.org/10.1002/mus.70354
  7. Neurol Sci. 2026 Jun 21. pii: 646. [Epub ahead of print]47(8):
    Rapid Eye Movement Sleep Suppressing Antidepressant Prescription is Associated with Improved Survival in Amyotrophic Lateral Sclerosis.
    Cosmo Fowler, David C Kaelber, Donald L Bliwise, Meredith K Greer.
       INTRODUCTION: Rapid eye movement (REM) sleep is a period of physiological vulnerability for patients with neuromuscular disease, owing to a generalized loss of muscle tone that spares only the diaphragm. Several antidepressants have been observed to reduce REM sleep fraction on polysomnography. We investigated whether prescription of REM-suppressing antidepressants (RSAs) versus non-REM-suppressing antidepressants (NRSAs) is associated with differential survival in patients with amyotrophic lateral sclerosis (ALS).
    METHODS: Using the U.S. Collaborative Network of the TriNetX Analytics platform, we compared 1-year mortality in ALS patients prescribed RSAs or NRSAs within 3 months of diagnosis, identified by ICD-10-CM-coded encounter diagnoses with riluzole prescription between May 2014 and May 2024. We used Cox proportional hazards models, Kaplan-Meier analysis, and risk difference analysis, with and without propensity score matching (PSM).
    RESULTS: Among 14,441 patients with ALS and riluzole prescription, 5,057 were prescribed either RSAs (N = 4,177) or NRSAs (N = 880). The NRSA cohort had a higher risk of death (HR 1.28, 95% CI 1.11 - 1.46), with 1-year survival of 60.73% versus 68.61% for RSAs (log-rank p<0.001). After PSM, the difference narrowed and was borderline by log-rank test (60.97% vs 65.92%, p=0.035), while the risk-difference analysis was no longer significant (RR 1.07, 95% CI 0.92 - 1.25), indicating an attenuated and statistically fragile association.
    CONCLUSIONS: RSA prescription was associated with modestly better survival, but this association weakened markedly after matching and cannot establish causation; residual confounding, particularly by indication, cannot be excluded. These findings are hypothesis-generating, and prospective studies incorporating polysomnography and ALS-specific prognostic factors are needed.
    Keywords:  Amyotrophic lateral sclerosis; Antidepressants; Hypoventilation; Neuromuscular disease; Rapid eye movement sleep; Respiratory failure
    DOI:  https://doi.org/10.1007/s10072-026-09202-1
  8. EMBO Rep. 2026 Jul 21.
    The centrosome-cilium-centriolar satellite axis in neurodegenerative diseases.
    Umut Sahin, Elif Nur Firat-Karalar.
      Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and hereditary ataxias, remain major global health challenges with limited therapeutic options. Although clinically and genetically diverse, these diseases share extensively studied cellular and molecular hallmarks, including protein aggregation, impaired proteostasis, cytoskeletal abnormalities, altered energy metabolism, nucleic acid damage, and chronic inflammation. Emerging evidence indicates that dysfunction of the centrosome-cilium-satellite axis intersects with these established pathways in disease- and cell type-specific contexts. This axis, composed of centrosomes, primary cilia, and centriolar satellites, coordinates cytoskeletal organization, ciliary signaling, trafficking, proteostasis, and stress responses and acquires specialized functions in neurons that support polarity, connectivity, and long-term maintenance. In this review, we outline the structure, function, and neuronal specializations of the centrosome-cilium-satellite axis, then examine how its dysfunction has been reported in neurodegenerative disease models. We also discuss centriolar satellites as regulators of centrosome and cilium biology whose disease-specific roles in classical NDDs remain comparatively underexplored, with insights from Huntington's disease and schizophrenia. Finally, we discuss therapeutic strategies aimed at restoring axis structure and dynamics, modulating ciliary signaling, and correcting disease-linked genetic or transcript-level defects, emphasizing mechanism-based approaches that require validation in disease-relevant models. Together, the centrosome-cilium-satellite axis provides an emerging framework for understanding context-dependent organelle dysfunction in neuronal vulnerability and neurodegeneration.
    DOI:  https://doi.org/10.1038/s44319-026-00877-3
  9. Clin Linguist Phon. 2026 Jul 22. 1-20
    An investigation of factors associated with speech intelligibility in patients with amyotrophic lateral sclerosis: Integrating acoustic and lingual motor measures.
    Yohei Tsujisawa, Ikuko Takahashi-Iwata, Ichiro Yabe, Masahiko Mukaino, Isamu Shibamoto.
      Speech intelligibility in amyotrophic lateral sclerosis (ALS) progressively declines, but contributing clinical factors may vary according to disease presentation and extent of bulbar involvement. This study examined factors associated with intelligibility in three ALS groups: spinal-onset, spinal-onset with bulbar involvement (spinal + bulbar), and bulbar-onset. Speech intelligibility (visual analogue scale), hypernasality, maximum tongue pressure, respiratory function (%VC and FEV1/FVC), and second formant (F2) transition measures (transition duration and excursion) were evaluated. Exploratory two- and three-dimensional visualisations were used to examine interrelationships among variables, and regression analyses were conducted in groups with sufficient sample size. In spinal-onset ALS, only hypernasality was associated with intelligibility. In bulbar-onset ALS, both tongue pressure and hypernasality were significantly associated with intelligibility, while preserved F2 excursion showed an additional trend towards better intelligibility. In the spinal + bulbar group, descriptive findings suggested that reduced tongue pressure and increased hypernasality were associated with lower intelligibility. These findings suggest that speech intelligibility in ALS is influenced by different combinations of bulbar-related impairments depending on clinical presentation and extent of bulbar involvement. In particular, tongue strength, velopharyngeal function, and residual tongue mobility may be relevant to intelligibility outcomes with bulbar involvement. Combined evaluation of these measures may help inform individualised clinical assessment and management.
    Keywords:  Amyotrophic lateral sclerosis; F2 transition; bulbar involvement; maximum tongue pressure; speech intelligibility
    DOI:  https://doi.org/10.1080/02699206.2026.2704600
  10. Adv Sci (Weinh). 2026 Jul 23. e76778
    A Blood-Derived Factor Rescues ALS: Platelet Factor 4 Activates OPTN-Dependent Autophagy to Clear SOD1 Aggregates Independently of PINK1.
    Qingjian Xie, Yanbo Zhu, Wenhua Jiang, Haobo Xie, Yaojia Li, Mengjie Hu, Kezheng Li, Huan Yu, Yixuan Pan, Chaoyi Jiang, Xueqin Song, Dongsheng Fan, Binbin Deng.
      Peripheral factors that systemically regulate amyotrophic lateral sclerosis (ALS) have remained elusive-until now. Here, by integrating population-scale epidemiology with mechanistic dissection, we identify platelet factor 4 (PF4) as the central driver of a circulating neuroprotective axis that restores proteostasis and rescues ALS. In a prospective cohort of >500 000 UK Biobank participants, platelet indices were strongly associated with ALS risk, and serum PF4 levels were significantly reduced in ALS patients. Systemic administration of recombinant PF4 in hSOD1G93A mice produced dramatic therapeutic effects: extended survival, preserved motor function, attenuated neuroinflammation, and reduced neuromuscular junction denervation. Remarkably, this efficacy appears pathology-selective-robust in SOD1-driven models but shows no observable effect in TDP-43 or C9orf72 ALS models. Mechanistically, PF4 achieves what few molecules can: it engages the cell surface receptor LRP1 to activate the TBK1-OPTN signaling axis, restoring impaired autophagic flux through a PINK1/Parkin-independent pathway requiring ATG7, establishing a previously unrecognized peripheral platelet-autophagy-neuron axis that facilitates the co-clearance of pathological SOD1 aggregates and damaged mitochondria. This study unveils PF4 as a first-in-class circulating autophagy regulator with therapeutic potential in ALS. Beyond identifying a candidate biomarker and drug lead, it reveals that systemic factors can directly engage central proteostatic machinery-opening a new frontier for ALS therapy.
    Keywords:  OPTN; PF4; SOD1; amyotrophic lateral sclerosis; mitophagy; proteostasis
    DOI:  https://doi.org/10.1002/advs.76778
  11. Nat Rev Mol Cell Biol. 2026 Jul 20.
    Cellular and signalling mechanisms that regulate the blood-brain barrier.
    Joseph Amick, Ludmila Gordon, Chenghua Gu.
      The blood-brain barrier (BBB) is a unique specialization of central nervous system (CNS) capillary endothelial cells that controls molecular traffic between the blood and the brain. In doing so, the BBB maintains a safe and homeostatic environment for proper neuronal function. The BBB restricts drug delivery to the CNS, while BBB defects contribute to neurodevelopmental and neurodegenerative disorders. In this Review, we discuss the distinct features of CNS capillary endothelial cells that form the BBB. Meanwhile, interactions between capillary endothelial cells and surrounding pericytes, astrocytes and with the extracellular matrix of the basement membrane, are crucial for BBB formation and maintenance. We examine how molecular regulators of capillary endothelial cells and signalling pathways that control cell-cell interactions render the BBB a dynamic and selective interface. We highlight emerging areas of BBB research, including heterogeneity of brain vascular permeability and technology development. Finally, we discuss how insights from BBB biology are shaping therapeutic strategies targeting the BBB.
    DOI:  https://doi.org/10.1038/s41580-026-01000-z
  12. Crit Rev Food Sci Nutr. 2026 Jul 18. 1-22
    Sustainable next-generation prebiotics for brain health: microbiota-gut-brain axis in neurodegenerative and demyelinating diseases.
    Luna Barrera-Chamorro, Teresa Gonzalez-de la Rosa, Joaquin Arzalluz-Luque, Maria Torrecillas-Lopez, Elvira Marquez-Paradas, Carmen M Claro-Cala, Maria D Navarro-Hortal, Sara Eichau, Maria I Garcia-Sanchez, Sergio Montserrat-de la Paz.
      Neurodegenerative and neuroinflammatory diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are increasingly associated with disruption of the microbiota-gut-brain axis. Common alterations include reduced beneficial microbial taxa, impaired short-chain fatty acid production, intestinal and blood-brain barrier dysfunction, and sustained inflammatory responses. These findings support the development of microbiota-targeted dietary interventions. This review summarizes current evidence on polyphenols, bioactive peptides, and pectin-derived oligosaccharides (POS) as prebiotic or prebiotic-like compounds with potential activity through the microbiota-gut-brain axis. Particular attention is given to structure-function relationships, host-microbe interactions, and the sustainable recovery of these compounds from food by-products. Preclinical studies suggest that these bioactives may reduce microglial activation, improve mitochondrial function, strengthen intestinal and blood-brain barrier integrity, and enhance cognitive or motor performance. Early clinical studies also indicate possible benefits on mood, selected cognitive outcomes, metabolic regulation, and inflammatory biomarkers, although evidence remains limited. Microbiota-derived metabolites from polyphenols, such as urolithins, together with glycomacropeptide and POS, appear to be key mediators. However, clinical validation in major neurodegenerative diseases remains fragmented. Standardized formulations, mechanistic trials, harmonized endpoints, and precision-nutrition strategies are required to confirm their therapeutic potential.
    Keywords:  Bioactive peptides; microbiota-gut-brain axis; multiple sclerosis; pectin; polyphenols
    DOI:  https://doi.org/10.1080/10408398.2026.2703335
  13. Gene. 2026 Jul 20. pii: S0378-1119(26)00328-8. [Epub ahead of print]1010 150318
    Exploring shared genetic pathways and gene interplay in major neurodegenerative diseases: a comprehensive review.
    Priyanka Priyadarshini Pattnaik, Shakti Ketan Prusty, Sanghamitra Pati, Kiran Anjum Jew, Anirban Kumar Bora, Jyotirmaya Sahoo, Pratap Kumar Sahu.
      Neurodegenerative diseases are progressive disorders that involve the loss and dysfunction of neurons. Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, Frontotemporal dementia are examples of diseases. While different clinically, these disorders have a common genetic, molecular and cellular basis. This review examines the common genetic pathways, along with the interactions between genes of major neurodegenerative diseases, with a focus on the key genes, such as APOE, SNCA, MAPT, TARDBP, LRRK2 and HTT. The common pathogenic mechanisms considered to play a major role in disease progression include protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, neuroinflammation, diminished autophagy, and impaired lysosomal function, as well as synaptic degeneration. The review also emphasizes the role of systems biology strategies, such as genome-wide association studies, transcriptomics, proteomics, metabolomics, interactome analysis, and multi-omics integration, to unveiling complex molecular networks in neurodegeneration. Furthermore, the emerging biomarker strategies and therapeutic strategies targeting convergence signaling pathways including NF-κB, PI3K-Akt-mTOR, MAPK and Wnt/β-catenin are summarized. The common genetic basis and the cross-connecting molecular mechanisms of the various neurodegenerative diseases could help in the discovery of new biomarkers and pan-therapeutic targets. Further advances in molecular genetics, computational biology and precision medicine are needed to enhance early detection and the creation of effective disease-modifying treatments.
    Keywords:  Biomarkers; Gene interplay; Multi-omics; Neurodegeneration; Neuroinflammation; Precision medicine; Protein aggregation
    DOI:  https://doi.org/10.1016/j.gene.2026.150318
  14. Ann Med. 2026 Dec;58(1): 2703317
    Sex-associated differences in routine inflammatory markers and neuromuscular ultrasound measurements in amyotrophic lateral sclerosis: a retrospective cross-sectional study.
    Jun Wang, Ying Wang, Tianhua Yang, Xinyi Yan, Jialei Luo, Shenghai Wu, Jiahui Tong, Min Zhao, Gaoyi Yang.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with substantial clinical heterogeneity. Systemic inflammatory markers and neuromuscular ultrasound measurements have both been studied in ALS, but their sex-associated differences within ALS cohorts remain incompletely characterized.
    OBJECTIVE: To examine sex-associated differences in routine inflammatory markers and neuromuscular ultrasound measurements in patients with ALS, and to determine whether these differences persisted after adjustment for available clinical and anthropometric variables.
    METHODS: In this retrospective cross-sectional study, 135 patients with ALS were included. Routine inflammatory markers, including neutrophils, monocytes, lymphocytes, platelets, and erythrocyte sedimentation rate (ESR), were analyzed alongside quantitative neuromuscular ultrasound measurements. Between-sex comparisons were performed, and false discovery rate correction was applied to account for multiple testing. Multivariable linear regression analyses were performed with adjustment for age, disease duration, body mass index (BMI), ALSFRS-R total score, FVC% predicted, smoking status, hypertension, and diabetes.
    RESULTS: Female patients showed lower ALSFRS-R total scores and higher estimated progression rates in unadjusted comparisons, whereas pulmonary function variables did not differ significantly between sexes. After FDR correction, estimated progression rate, neutrophil count, monocyte count, ESR, and masseter muscle thickness remained significantly different between sexes, while the ALSFRS-R difference was borderline significant. In fully adjusted models, female sex was associated with lower neutrophil count, monocyte count, and median nerve cross-sectional area; biceps brachii thickness showed a less stable association after sensitivity analysis. An exploratory secondary analysis showed lower rectus femoris cross-sectional area during thigh-lift in female patients after full adjustment. In the spline sensitivity analysis, this association remained statistically significant but was interpreted cautiously because it was not present in the earlier adjustment models.
    CONCLUSIONS: Selected routine inflammatory markers and neuromuscular ultrasound measurements differed between male and female patients within this ALS cohort. These findings support consideration of sex and anthropometric context, including body size, when interpreting inflammatory markers and ultrasound-based structural measurements. In the absence of healthy controls, the observed ultrasound differences cannot be attributed specifically to ALS-related biology. Studies with healthy controls, longitudinal functional outcomes, body-composition assessment, and independent multicenter cohorts are needed to clarify the disease-specific and prognostic relevance of these observations.
    Keywords:  Amyotrophic lateral sclerosis; cross-sectional study; neuromuscular ultrasound; routine inflammatory markers; sex-associated differences
    DOI:  https://doi.org/10.1080/07853890.2026.2703317
  15. J Biomed Inform. 2026 Jul 18. pii: S1532-0464(26)00103-6. [Epub ahead of print]181 105079
    BiGranMolNet: A deep learning method for predicting blood-brain barrier permeability based on Bi-Granularity Molecular Graphs.
    Yidan Wang, Yizhuo Wang, Yang Wang, Jiajun Wang.
       OBJECTIVE: The selective permeability of the blood-brain barrier (BBB) hinders the delivery of central nervous system (CNS) drugs to brain targets. It is therefore crucial to determine BBB permeability during CNS drug development.
    METHODS: We propose BiGranMolNet (Bi-Granularity Molecular Graph Network), a BBB permeability prediction model based on graph convolutional networks. We integrated datasets from multiple sources to construct comprehensive benchmarks containing 2148 regression samples and 16,904 classification samples. Molecular graphs were constructed at two granularities (atom-level and motif-level), and graph convolutional networks were used to learn representations for each granularity. A cross-attention mechanism fused the dual-granularity features, and a weighted loss function was introduced to mitigate class imbalance.
    RESULTS: In 5-fold cross-validation and structure-aware evaluations, BiGranMolNet achieved stable and competitive performance on both regression and classification tasks.
    CONCLUSIONS: By integrating molecular structural information at atomic and motif levels, BiGranMolNet provides a reliable computational tool for BBB permeability prediction. The proposed framework can support early-stage CNS drug screening by prioritizing compounds with favorable brain exposure potential and by offering structure-aware clues for molecular optimization.
    Keywords:  Blood–brain barrier permeability; Cross-attention; Drug discovery; Graph neural networks
    DOI:  https://doi.org/10.1016/j.jbi.2026.105079
  16. Brain Commun. 2026 ;8(4): fcag272
    Strenuous physical activity is associated with a younger age of amyotrophic lateral sclerosis onset in two independent cohorts.
    Jaimee Kennedy, Ahmad Al Khleifat, Andrew King, Safa Al-Sarraj, Ammar Al-Chalabi, Jacqueline C Mitchell, Claire Troakes.
      Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease characterized predominantly by degeneration of both upper and lower motor neurons, thought to occur due to an interplay between genetics and environmental factors. Physical activity has been suggested as a potential risk factor for ALS; however, the exact role of exercise in the onset and progression of the disease is still unclear. We assessed lifetime physical activity in two independent ALS cohorts: post-mortem brain donors from the London Neurodegenerative Diseases Brain Bank (n = 139) and patients from the Motor Neurone Disease (MND) Register of England, Wales and Northern Ireland (n = 166 cases, 196 controls). In both cohorts, highly active individuals developed ALS symptoms at a significantly younger age, 54.2 years (mean, standard deviation = 7.5) in the post-mortem cohort and 58.0 years (median, interquartile range = 15) in the MND Register, compared with 63.9 years (mean, standard deviation = 11.5) and 63.0 years (median, interquartile range = 17.5) in inactive individuals, respectively [one-way analysis of variance (ANOVA), F(2, 136) = 6.10, P = 0.003, η2 = 0.08, 95% confidence interval (CI) 0.02-1.00 and Kruskal-Wallis, H(2) = 7.39, P = 0.02, η2 = 0.03, 95% CI 0.003-0.12]. Cox regression showed a higher hazard of earlier onset in highly active patients [post-mortem: hazard ratio (HR) 2.84, 95% CI 1.55-5.26, P = 0.0008; MND Register: HR 2.34, 95% CI 1.30-4.23, P = 0.005]. Our findings suggest that strenuous physical activity may be associated with a significantly younger age of ALS onset, replicated in both the post-mortem and MND Register cohorts, but not with an increased risk of developing ALS. Logistic regression analysis confirmed that neither highly active [odds ratio (OR) 1.43, 95% CI 0.69-2.99, P = 0.333] nor being active (OR 1.30, 95% CI 0.72-2.37, P = 0.386) was significantly associated with ALS risk, whereas a history of head injury was (OR 1.72, 95% CI 1.03-2.88, P = 0.038). These results suggest that strenuous exercise may accelerate disease onset in predisposed individuals, while the role of head injury requires further study and the findings may in fact indicate reverse causality.
    Keywords:  age onset; amyotrophic lateral sclerosis; exercise; motor neuron disease; physical activity
    DOI:  https://doi.org/10.1093/braincomms/fcag272
  17. Antiviral Res. 2026 Jul 21. pii: S0166-3542(26)00150-6. [Epub ahead of print]253 106491
    Macrophage responses to and elevated antibody levels against Chlorovirus ATCV-1 in ALS patients.
    Thomas M Petro, Gary L Pattee, Ahmed Esmael, Irina V Agarkova, David D Dunigan, Fabrizio Chiodo, Cristina De Castro, James L Van Etten.
      Acanthocystis turfacea chlorella virus 1 (ATCV-1) is a giant virus that is part of the human oral microvirome. Previously we showed that ATCV-1 infects mouse macrophages, stimulates production of inflammatory cytokines, and accelerates motor neuron disease in the Amyotrophic Lateral Sclerosis (ALS) model SOD1-G93A transgenic mice. This, coupled with significantly elevated levels of serum IgG1 antibody to ATCV-1 in ALS patients compared with healthy controls, suggests involvement of ATCV-1 in ALS. Herein, using serum and CSF from a different ALS cohort we again show elevated antibodies to ATCV-1 in ALS patients compared with healthy controls. To assess ATCV-1 in human macrophages, we challenged immature (IMM), M0, M1, and M2 human THP-1 macrophage cells containing an Interferon Stimulated Response Element (ISRE) promoter-reporter with ATCV-1 or its Major Capsid protein (MCP) glycans. ATCV-1 infected M1 THP-1 to a greater degree than IMM, M0, or M2 THP-1. The initial high ISRE-promoter activity of M1 THP-1 was suppressed by the MCP-Glycans of ATCV-1. M0, but not IMM or M2 THP-1 produced IL-6 in response to ATCV-1 or its MCP-glycan, while high levels of IL-6 from unchallenged M1 THP-1 increased further by ATCV-1 or its MCP glycan. In contrast, ATCV-1 or its MCP-Glycan significantly reduced the high levels of IL-10 produced by M2 THP-1. Thus, antibody to ATCV-1 in ALS patients and the susceptibility of human M1 macrophages to ATCV-1 infection with boosted inflammatory cytokine and diminished anti-inflammatory cytokine production suggest that ATCV-1 may contribute to ALS motor neuron disease.
    Keywords:  Amyotrophic lateral sclerosis; Antibodies; Cerebral spinal fluid; Chlorovirus ATCV-1; Inflammatory cytokines; Serum; THP-1 macrophage polarization
    DOI:  https://doi.org/10.1016/j.antiviral.2026.106491
  18. J Neurol. 2026 Jul 20. pii: 476. [Epub ahead of print]273(8):
    Use of blood-based neurofilament light chain as an endpoint in clinical trials of neurodegenerative conditions: a scoping review.
    Yuming Zheng, Oneil G Bhalala, Kai Sin Chin, Rosie Watson, Nawaf Yassi.
       INTRODUCTION: Neurofilament light chain (NfL) is a structural axonal protein measurable in CSF and blood, increasingly investigated as a biomarker of neuroaxonal injury in clinical and research contexts. This review aims to explore the use of blood-based NfL as an endpoint in clinical trials of neurodegenerative conditions.
    METHOD: A database search of MEDLINE and EMBASE was conducted to identify interventional clinical trials and/or related post hoc analyses for neurodegenerative diseases, published between 2013 and 2024 that reported the use of serum or plasma NfL as an endpoint. Additional studies from reference lists of included trials were manually considered for inclusion where relevant. Data were charted descriptively by disease type and summarised.
    RESULTS: 49 studies were included, 29 in multiple sclerosis (MS), eight in amyotrophic lateral sclerosis (ALS), six in Alzheimer's disease (AD), and six in other diseases. Across studies, reductions in NfL often paralleled improvements in primary efficacy outcomes, supporting its use as a biomarker of disease activity and treatment response. However, several studies demonstrated a lack of concordance between change in NfL and in clinical outcomes, some of which may be related to the non-disease-modifying mechanisms of the interventions studied. This necessitates careful consideration when applying blood-based NfL as a biomarker endpoint for studies involving such interventions.
    CONCLUSION: Blood NfL is a promising biomarker with potential utility as a surrogate endpoint in neurological clinical trials, particularly for diseases with active axonal injury. Further validation, particularly around disease- and intervention-specific interpretation, is needed before blood NfL can be incorporated more routinely as a clinical endpoint.
    Keywords:  Blood biomarkers; Clinical trials; Neurodegenerative diseases; Neurofilament light; NfL; Plasma biomarkers; Serum biomarkers
    DOI:  https://doi.org/10.1007/s00415-026-14007-5
  19. Orphanet J Rare Dis. 2026 Jul 20.
    Unraveling the role of lipid metabolism in ALS risk: a Mendelian randomization analysis using GWAS data.
    Houwen Zhang, Chunrong Li, Jialin Yu, Yu Liang, You Wu, Fangzheng Cao.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Lipid metabolism is closely related to neuronal function and energy homeostasis, but the genetic association between specific lipid species and ALS risk remains unclear.
    OBJECTIVE: This study aimed to investigate the potential causal associations between genetically predicted lipid species and ALS risk using a two-sample Mendelian randomization (MR) approach.
    METHODS: Summary-level GWAS data for 179 lipid species were obtained from 7,174 Finnish participants in the GeneRISK cohort. ALS GWAS data included 29,612 ALS cases and 122,656 controls. The inverse variance weighted (IVW) method was used as the primary MR approach, supplemented by MR-Egger, weighted median, weighted mode, and simple mode analyses. False discovery rate (FDR) correction was applied across all lipid traits based on IVW P values. Sensitivity analyses were conducted to assess heterogeneity, horizontal pleiotropy, and robustness.
    RESULTS: After FDR correction, genetically predicted higher levels of diacylglycerol (DAG) (18:1_18:1), phosphatidylcholine (PC) (16:1_18:1), PC (18:0_18:1), phosphatidylethanolamine (PE) (O-16:1_18:2), and several triacylglycerol (TAG) species were associated with increased ALS risk. Phosphatidylinositol (PI) (16:0_18:1) showed only a nominal protective association and did not remain significant after FDR correction. Sensitivity analyses did not indicate substantial heterogeneity or horizontal pleiotropy.
    CONCLUSION: This MR study provides genetic evidence supporting potential associations between specific lipid species and ALS risk. These findings highlight lipid metabolism as a relevant pathway in ALS susceptibility.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Diacylglycerol; Lipid traits; Mendelian randomization (MR); Triacylglycerol
    DOI:  https://doi.org/10.1186/s13023-026-04503-2
  20. Ann Neurol. 2026 Jul 21.
    Neurotransmitter-Defined Degeneration Patterns in Sporadic and C9orf72-Associated Amyotrophic Lateral Sclerosis: Predilection to GABAergic, Serotonergic, Opioid, Glutamatergic, Endocannabinoid, and Microglial Systems-Implications for Therapy Development.
    Marlene Tahedl, We Fong Siah, Jasmin Lope, Jennifer C Hengeveld, Mark A Doherty, Russell L McLaughlin, Orla Hardiman, Ee Ling Tan, Alison Toomey, Jana Kleinerova, Peter Bede.
       OBJECTIVE: Amyotrophic lateral sclerosis (ALS) has a markedly distinctive clinical and neuroradiological signature, with the preferential involvement of specific brain networks and the apparent sparing of others. The molecular underpinnings of the strikingly selective anatomical vulnerability have not been fully elucidated to date despite the potential therapeutic relevance of characterizing neurotransmitter receptor-defined susceptibility to degeneration.
    METHODS: A large neuroimaging study was undertaken with 258 participants to systematically evaluate topological associations between neurodegeneration and neurotransmitter expression distributions. Patients were stratified based on their genetic profile into sporadic and C90rf72 hexanucleotide repeat expansion carriers. Anatomical associations were evaluated between patterns of atrophy and topological neurotransmitter receptor distributions. Cross-sectional and longitudinal trends were comprehensively evaluated over 4 consecutive timepoints.
    RESULTS: Our analyses reveal topological associations between neurodegeneration in sporadic ALS and GABA-A receptor α5-selective component (GABAa5), serotonin 1a receptor, and kappa opioid receptor expression maps. In addition to these networks, neuronal loss in patients with GGGGCC hexanucleotide repeat expansions exhibit predilection to glutamatergic, endocannabinoid, and microglial systems. Our multi-timepoint longitudinal analyses reveal dynamic temporal associations between focal volume loss and neurotransmitter expression with increasing spatial associations with noradrenaline transporter and GABAa5, but high attrition rates preclude definite longitudinal inferences.
    INTERPRETATION: Our data suggest the preferential vulnerability of GABAergic, serotonergic, kappa opioid mediated networks in sporadic ALS. In C9orf72-assocaited ALS, glutamatergic, endocannabinoid circuits are also susceptible and microglia-mediated neuroinflammation is also implicated. The comprehensive evaluation of neurotransmitter-receptor associations not only offer academic insights regarding pathophysiological processes in ALS, but may inform targeted therapy development strategies. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78316
  21. Int J Nanomedicine. 2026 ;21 621038
    Protein Lactylation in Central Nervous System Diseases: Molecular Mechanisms and Targeted Therapeutic Strategies.
    Ziyan Cheng, Guangxin Ou, Guilong Zhang, Waqas Ahmed, Yongquan Han, Dongshan Zhang, Tianran Chai, Meng Hu, Qiankun Zhang, Jiaxin Lei, Lanjie Lei, Zhihan Zhu.
      Lactate, once considered merely a metabolic byproduct, is now recognized as a cornerstone of central nervous system (CNS) homeostasis, serving as both a vital energy substrate and signaling molecule. The identification of lysine lactylation (Kla) has established this modification as a key epigenetic link between cellular metabolism and genomic regulation. This review examines the molecular mechanisms underlying protein lactylation, including enzymatic regulation by writers, erasers, and readers as well as non-enzymatic mechanisms. The multifaceted roles of Kla are explored in the context of CNS disorders, ranging from malignancies, acute injuries, and neurodegenerative diseases. The review further examines Kla's role in neuroinflammation, metabolic reprogramming, and neuroplasticity, highlighting its potential as a sensitive biomarker. Potential therapeutic strategies are also considered, including metabolic inhibitors and nanocarriers capable of crossing the blood-brain barrier (BBB) to restore metabolic and epigenetic balance.
    Keywords:  central nervous system diseases; epigenetic regulation; lactate; lactylation; therapeutic strategies
    DOI:  https://doi.org/10.2147/IJN.S621038
  22. Rev Neurosci. 2026 Jul 27.
    Insights into the blood-brain barrier in mental health disorders: from experimental models to clinical findings.
    Maria Grazia Ferraro, Adrien Stanley, Pellegrino Lippiello, Silvia Pascarella, Luisa Speranza, Mariateresa Ricci, Floriana Volpicelli, Sergio Chieffi, Maria Concetta Miniaci.
      The blood-brain barrier (BBB) is recognized as a protective interface that maintains neural homeostasis. Specifically, it blocks the entrance of potentially harmful agents and controls the molecular traffic between the circulatory system and the central nervous system. Emerging evidence from preclinical models and clinical studies indicates that alterations in the BBB's permeability and transport processes contribute to the pathophysiology of several mental illnesses, including depression, anxiety, bipolar disorder, and schizophrenia. Specifically, we examine whether BBB disruption contributes to the onset and progression of psychiatric conditions, whether psychiatric pathology itself promotes barrier dysfunction, or whether these processes interact in a self-perpetuating cycle. By providing a translational perspective that bridges experimental models and clinical observations, this review provides a comprehensive and dynamic perspective on its role in mental health. Understanding these mechanisms may open new avenues for therapeutic strategies focused on preserving or restoring barrier integrity as a means of preventing or mitigating psychiatric disorders.
    Keywords:  blood–brain barrier; neuroinflammation; neurovascular unit; psychiatric disorders; tight junctions
    DOI:  https://doi.org/10.1515/revneuro-2026-0085
  23. Med Clin North Am. 2026 Sep;pii: S0025-7125(25)00179-8. [Epub ahead of print]110(5): 889-905
    Neurodegenerative Diseases and Sleep Disorders: The Bidirectional Relationship.
    Karan M Desai, Mayur D Thakkar, Tanvee S Somaiya, Davis C Thomas.
      Neurodegeneration is mostly irreversible and progressive. Neurodegenerative diseases (NDDs) represent a large group of disorders that have varied clinical and pathologic representations. These include Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis, among others. A common factor in all these NDDs is sleep disorders (SDs). NDDs and SDs are bidirectional. Screening for SDs should be an integral part of a workup of NDDs. Management of one can improve the prognosis of the other.
    Keywords:  Alzheimer’s disease; Dementia; Neurodegeneration; Neurodegenerative disease; Neurodegenerative disorders; Parkinsonian syndromes; Parkinson’s disease; Sleep disorders
    DOI:  https://doi.org/10.1016/j.mcna.2025.12.001
  24. Alzheimers Dement. 2026 Jul;22(7): e71675
    Development and characterization of a novel TDP-43 positron emission tomography tracer: [18F]JNJ-TDP43-1.
    Chunfang A Xia, Mani Salarian, Christopher J Gartshore, Antonella Scaglione, Thomas Hayes, Shuanglong Liu, Hsiu-Ming Tsai, Javier Echavarren, Jose Maria Cid, Alessandra Matzeu, A Katrin Szardenings.
       INTRODUCTION: Neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and Alzheimer's disease (AD) are associated with TAR DNA-binding protein 43 (TDP-43) pathology. A positron emission tomography (PET) tracer targeting TDP-43 aggregates could improve early diagnosis and guide treatment development for TDP-43-related conditions.
    METHODS: Specific binding was evaluated using fluorescent labeling of compound, surface plasmon resonance (SPR), and autoradiography (ARG). Brain PET imaging in rats, nonhuman primate (NHP), and a disease mouse model was performed to characterize tracer pharmacokinetics and in vivo target binding.
    RESULTS: JNJ-TDP43-1 exhibited high binding affinity for pathological TDP-43 (Kd = 7.1 nM) and remarkable selectivity over other proteinopathies. PET imaging demonstrated robust brain uptake and rapid washout in rodents and NHP. In vivo target engagement was confirmed in an AAV-hTDP43 disease model.
    DISCUSSION: [18F]JNJ-TDP43-1 is a promising PET ligand for early diagnosis and evaluating therapies in TDP-43-related diseases.
    Keywords:  TDP‐43; [18F]JNJ‐TDP43‐1; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; limbic‐predominant age‐related TDP‐43 encephalopathy; neurodegenerative disorders; positron emission tomography
    DOI:  https://doi.org/10.1002/alz.71675
  25. Clin Neurophysiol. 2026 Jul 18. pii: S1388-2457(26)00839-4. [Epub ahead of print] 2112339
    F waves as a measure of enhanced spinal motoneuron excitability in primary lateral sclerosis.
    David Burke.
      
    DOI:  https://doi.org/10.1016/j.clinph.2026.2112339
  26. Front Mol Neurosci. 2026 ;19 1820758
    Histone lactylation-mediated glycolysis-ferroptosis axis in neurological diseases.
    Zengrong Wei, Lu Bai, Xueting Liu, Yanling Zhou, Lei Zheng, Baiwen Zhang, Long Wang, Wei Zou.
      Histone lactylation is an emerging epigenetic modification that covalently links the glycolytic metabolite lactate to histones, thereby establishing a direct link between cellular metabolic status and gene transcription programs. Recent studies have shown that this modification plays a key role in regulating cellular sensitivity to ferroptosis, forming a novel regulatory axis of "glycolysis-lactylation-ferroptosis." This article systematically reviews the biological functions of histone lactylation in the nervous system, with a focus on elucidating how it participates in the pathological processes of various neurological diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), cerebral stroke, and amyotrophic lateral sclerosis (ALS), by regulating the expression of ferroptosis-related genes. The article integrates the latest research on molecular mechanisms, explores the value of this regulatory axis as a potential biomarker for disease diagnosis and a therapeutic target, and provides an outlook on future research directions in this field.
    Keywords:  epigenetics; ferroptosis; glycolysis; histone lactylation; neurological diseases
    DOI:  https://doi.org/10.3389/fnmol.2026.1820758
  27. CNS Neurol Disord Drug Targets. 2026 Jul 14.
    Exosomes in Neurodegenerative Disorders: Isolation Strategies, Therapeutic Potential, and Clinical Trials.
    Sourin Bhukta, Narahari N Palei, Vishakha Jaiswal, Anuradha Mishra, Prathap M.
      Exosomes represent a promising class of naturally produced nanoparticles that exist at the nanoscale and carry a negative surface charge under physiological conditions. These tiny membranebound vesicles are released by cells throughout the body and function as biological messengers, transporting various molecular cargos between cells and facilitating critical cell-to-cell communication pathways. Existing therapies for neurodegenerative disorders face two critical barriers: they cannot precisely target the affected brain areas, and the blood-brain barrier blocks most potential treatments from entering the brain. Exosomes offer a promising solution to these challenges. Unlike most synthetic drug delivery systems that struggle to penetrate the brain's protective barrier, these naturally derived nanocarriers exhibit an inherent capacity to traverse the blood-brain barrier. This unique property, combined with their capacity for efficient intracellular delivery of therapeutic payloads, positions exosomes as an exciting platform for transporting pharmaceutical agents to the affected neural tissues. Through strategic engineering and modification, these vesicles can be transformed into highly precise delivery vehicles capable of targeting specific organs, tissues, or even individual cell types. This review explores the therapeutic potential and drug delivery applications of exosomes in the management of major neurodegenerative disorders. This review provides an in-depth examination of exosome biogenesis, current isolation methodologies, and surface engineering strategies, while critically evaluating the strengths and limitations of each approach. In addition, this review summarizes the current preclinical models and provides an overview of ongoing clinical trials investigating exosome-based therapies for neurological disorders.
    Keywords:  Exosome; clinical study; isolation; nanocarriers; neurodegenerative disorder; preclinical
    DOI:  https://doi.org/10.2174/0118715273459760260626154255
  28. Ann Neurol. 2026 Jul 19.
    Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System.
    Rama Krishna Koppisetti, Nicolas R Barthélemy, Kanta Horie, Cindy V Ly, Kaleigh F Roberts, Srinivas Koutarapu, Richard J Perrin, Erin E Franklin, Chiara Pedicone, Joshua Orrick, Justin Melendez, Timothy M Miller, Chihiro Sato, Nupur Ghoshal, Alison M Goate, Celeste M Karch, Randall J Bateman, Soumya Mukherjee.
       OBJECTIVE: Tau is widely studied in neurodegeneration, yet most work has focused on canonical brain tau isoforms. A longer isoform, "big tau," produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and central nervous system (CNS) regions. We sought to characterize big tau composition, anatomic distribution, and disease relevance.
    METHODS: Mass spectrometry (MS) was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord and peripheral nerves. Big and canonical ("small") tau isoforms were also quantified in cerebrospinal fluid (CSF) from controls and participants stratified by amyloid status and cognitive impairment.
    RESULTS: Human big tau results from insertion of either 355 or 251 amino acids encoded by exon 4a-long and exon 4a-short, respectively. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms. Total tau levels were approximately 1,000-fold higher in the brain than in the PNS; however, the relative abundance of big tau increased from the CNS to the PNS, comprising 50% of the total tau in the periphery and approximately 1% in the brain, primarily localized to the cerebellum. In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD pathology.
    INTERPRETATION: Big tau represents a distinct tau population enriched in the PNS and uncoupled from disease-associated changes in brain-derived tau, suggesting that distinguishing big tau from canonical tau may improve interpretation of tau biomarkers and help differentiate CNS neurodegeneration from peripheral nerve pathology. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78300
  29. Front Syst Neurosci. 2026 ;20 1888548
    Neuroinflammation as a failure of allostatic integrity: a hierarchical-circular model of biological memory for pathogenesis in neurodegenerative and neuropsychiatric diseases.
    Samuel Ruesga Mundo.
       Introduction: Chronic neuroinflammation is a hallmark of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease) and neuropsychiatric disorders (major depression, schizophrenia). However, current models fail to explain why some individuals develop persistent neuroinflammation while others maintain homeostasis, nor why similar inflammatory pathology produces such diverse clinical phenotypes.
    Hypothesis: We propose that pathological neuroinflammation emerges from a failure of allostatic integrity-the capacity of the organism to maintain adaptive circular information flow across five interconnected levels: (1) genetic architecture and morphogenetic programming, (2) epigenetic molecular memory, (3) allostatic load and systemic physiological adaptation, (4) the psychoneuroimmuneendocrine (PINE) network, and (5) interoceptive-neuronal integration. When this circular flow is disrupted, maladaptive stable states become entrenched, perpetuating chronic inflammation.
    Development of the hypothesis: Synthesizing evidence from longitudinal and mechanistic studies (with foundational older works cited where necessary), we discuss how: (a) early-life stress epigenetically programs inflammatory reactivity; (b) elevated allostatic load predicts chronic neuroinflammation; (c) PINE network dysregulation perpetuates pro-inflammatory signaling; and (d) interoceptive dysfunction may prevent the downregulation of inflammation. Allostatic integrity is introduced as a dynamic systems-level property hypothesized to moderate the relationship between inflammatory pathology and clinical expression.
    Testable predictions: The framework generates falsifiable predictions: (1) composite indices of allostatic integrity will outperform single biomarkers in predicting transition to chronic neuroinflammation; (2) multidomain interventions targeting multiple levels will produce multiplicative (synergistic) effects; (3) patients with similar inflammatory profiles but contrasting allostatic integrity will show markedly different clinical trajectories; and (4) improvements in allostatic integrity will correlate with reduced neuroinflammation independent of direct anti-inflammatory therapies.
    Conclusion: The Hierarchical-Circular Model reframes chronic neuroinflammation not as a linear cascade but as a potential systemic failure of biological memory and allostatic integrity. Pending empirical validation, this framework may offer a conceptual basis for biomarker development, multidomain prevention, and personalized treatment strategies.
    Keywords:  PINE system; allostasis; allostatic integrity; biological memory; hierarchical-circular model; neurodegeneration; neuroinflammation; neuropsychiatry
    DOI:  https://doi.org/10.3389/fnsys.2026.1888548
  30. Curr Neuropharmacol. 2026 Jul 15.
    Micronutrient-Assisted Biomaterial Strategies as Neuropharmacological Modulators of Neuroinflammation and Oxidative Stress in Neurodegenerative Diseases.
    Riya Sarkar, Koyel Banerjee, Sangita Das, Ishani Sadhukahn, Bhumika Bose, Rachayita Biswas, Sneha Pan, Krishnendu Adhikary, Rajkumar Maiti.
      Neurodegeneration results from the convergence of several molecular processes, including inflammation in the brain (i.e., neuroinflammation), elevated levels of free radicals that damage cells, mitochondrial dysfunction, and the inability to remove damaged proteins from the brain. Even though many agents provide neuroprotection in research models, their clinical use is limited because they cannot effectively cross the blood-brain barrier to reach the areas of the brain where they are needed. Limitations include the inability to cross the blood-brain barrier, poor bioavailability, rapid metabolism and clearance, non-specific targeting, efflux by transport proteins, toxicity, and low solubility and stability. The classification of micronutrients (e.g., vitamins, polyphenols, minerals), which are naturally present antioxidants and anti-inflammatory substances, plays a role in modulating the most important signaling pathways in the body, including those mediating the inflammatory response (i.e., NF-κB and NLRP3) and the process that causes glial cell death (i.e., JAK/STAT). Micronutrients have a significant drawback for therapeutic use because they are rapidly metabolized and cannot cross the blood-brain barrier. Developments in synthetic biomaterials and nanotechnology offer a potential avenue for addressing the challenges of delivering micronutrients to the brain by targeting them to specific areas and releasing them over a sustained period. This study presents current information on the mechanisms by which micronutrients modulate molecular pathways and their potential application in emerging biomaterials to develop a new class of neuroprotective therapeutic agents that may ultimately be used to treat patients with degenerative diseases (e.g., Alzheimer's, Parkinson's, and Huntington's). Additionally, clinical challenges are addressed to translate these products from the laboratory to the clinic. The idea presented in this review connects molecular neuromodulation via micronutrients and bioactive nutraceuticals with a new strategy for pharmacological delivery using biomaterials. Instead of considering nutrition and those biomaterials as separate therapeutic areas, an integrated mechanistic model is presented that shows how micronutrients can act as endogenous pathway regulators and how biomaterials can enhance pharmacokinetics and targeting.
    Keywords:  Alzheimer's disease; Neurodegeneration; Parkinson's disease; micronutrients; neuroinflammation; tau protein.
    DOI:  https://doi.org/10.2174/011570159X485083260630050618
  31. Front Immunol. 2026 ;17 1893167
    Autoimmune signatures in neurodegenerative dementias: from peripheral immune activation to CNS pathology.
    Xin Zhao, Guifeng Zhang, Zheng Wang, Dazheng Zhang, Zhangyong Xia, Chengju Huo.
      Neurodegenerative dementias, including Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, and related tauopathies, are traditionally defined by protein aggregation, neuronal dysfunction, synaptic loss, and glial-mediated neuroinflammation. However, emerging evidence indicates that adaptive immunity may also contribute to disease heterogeneity and progression. These disorders should not be considered classical autoimmune diseases, but they may display autoimmune-like signatures, including neural antigen-specific T cell responses, clonal expansion of T cells in blood or cerebrospinal fluid, CNS infiltration of adaptive immune cells, and brain-targeting autoantibodies. Recent studies have linked α-synuclein-specific T cell reactivity to early Parkinson's disease, identified clonally expanded CD8+ T cells in Alzheimer's disease cerebrospinal fluid, and provided direct evidence of adaptive immune involvement in Lewy body dementia, including altered peripheral immunophenotypes and CD4+ T cell-associated neurodegenerative mechanisms. Experimental tauopathy models further show that microglia-mediated T cell infiltration can drive neurodegeneration. Humoral autoreactivity and progression-associated immune changes further suggest that adaptive immune profiles may help define biologically distinct dementia subgroups. In this mini review, we summarize evidence connecting peripheral immune activation, intrathecal adaptive immune remodeling, and CNS pathology in neurodegenerative dementias. We also discuss how longitudinal blood-CSF profiling, single-cell/TCR/BCR sequencing, autoantibody profiling, and mechanistic validation may clarify whether these immune signatures are pathogenic, compensatory, or bystander responses.
    Keywords:  T cells; adaptive immunity; autoantibodies; autoimmunity; neurodegenerative dementia
    DOI:  https://doi.org/10.3389/fimmu.2026.1893167
  32. Ann Am Thorac Soc. 2026 Jul 24. pii: aaoag219. [Epub ahead of print]
    Home mechanical ventilation for amyotrophic lateral sclerosis-a national study of survival and treatment trends across 27 years.
    Andreas Palm, Magnus Ekström, Jonas Einarsson, Karin Ersson, Caroline Ingre, Ulf Kläppe, Eva Lindberg, Mirjam Ljunggren, Ingela Nygren, Josefin Sundh, Ludger Grote.
       RATIONALE: Home mechanical ventilation (HMV) improves survival in Amyotrophic lateral sclerosis (ALS) and may be provided non-invasively (NIV) or invasively (IV). While NIV is guideline-recommended, the role of IV remains controversial, and data on long-term outcomes and NIV-to-IV transitions are limited.
    OBJECTIVES: To examine survival across HMV strategies in people with ALS (pwALS) in Sweden over 27 years, factors associated with IV initiation, temporal trends in IV use and survival, and regional variation in IV utilisation.
    METHODS: A longitudinal cohort study of pwALS in the Swedish National Registry of Ventilatory Failure (Swedevox) 1996-2022, cross-linked with national registries. Factors associated with mortality and treatment patterns were assessed using multivariable regression models.
    RESULTS: Among 1,360 pwALS, initial NIV was most common (92%), followed by IV (5%) and NIV-to-IV transitions (3%). Most IV initiations were non-elective (77% vs. 18% NIV, p < 0.001). NIV-to-IV transitions occurred mainly in metropolitan areas (OR 5.11; 95% CI 2.30-11.4). Median survival differed across observed treatment pathways (p < 0.001): 1.7 years with NIV, 4.9 years with IV, and 6.5 years with NIV-to-IV. Mortality was associated with higher age (aHR 1.33 per decade; 95% CI 1.26-1.41), female sex (aHR 1.15; 95% CI 1.02-1.29), and acute initiation (aHR 1.26; 95% CI 1.08-1.47). Longer time from diagnosis to NIV initiation was associated with reduced mortality risk (aHR 0.58 per year; 95% CI 0.55-0.62). Over time, patients initiated HMV at older age with better lung function and lower PaCO2 values among those with available measurements, whereas overall survival remained unchanged.
    CONCLUSION: Patients receiving IV had longer observed survival, likely reflecting the benefits of a secured airway as well as patient selection and underlying disease trajectory. Most IV initiations were unplanned. Over three decades, HMV was initiated in older patients at an earlier stage of respiratory decline, but overall survival remained unchanged. IV use increased with marked regional variation.
    Keywords:  HMV; NIV; Non-invasive ventilation; Sweden; invasive ventilation; mortality; regional differences; respiratory failure; tracheostomy; tracheotomy; transition
    DOI:  https://doi.org/10.1093/annalsats/aaoag219
  33. J Pharmacol Sci. 2026 Sep;pii: S1347-8613(26)00034-4. [Epub ahead of print]162(1): 40-49
    Human blood-brain barrier spheroid models for the evaluation of drugs targeting brain vascular inflammation.
    Ayuka Ebisawa, Hanae Morio, Asuka Minasato, Hiromu Watanabe, Furano Kunitomo, Aleksandra Rutkowska, Tomomi Furihata.
      The blood-brain barrier (BBB), primarily formed by brain microvascular endothelial cells (BMECs), restricts substance entry into the brain. BBB inflammation, involving barrier dysfunction and immune cell recruitment, contributes to neurological diseases and represents a therapeutic target. In this study, we characterized human immortalized cell-based multicellular spheroidal BBB (hiMCS-BBB) models as a tool for evaluating effects of BBB inflammation-targeted drugs. First, we examined the responses of the hiMCS-BBB models to the pro-inflammatory cytokine (TNF-α and IFN-γ) exposure. The cytokine treatment reduced claudin-5 protein expression levels at the BBB, accompanied by a 1.4 ± 0.1-fold increase in lucifer yellow permeability. Consistently, E-selectin protein expression was upregulated, accompanied by a 22.1-fold increase in THP-1 cell adhesion to the BBB. Then, we tested whether natalizumab (a monoclonal antibody used for multiple sclerosis treatment) and JPH203 (an inhibitor of L-type amino acid transporter 1) could modulate the immune cell adhesion. Both agents remarkably suppressed the cytokine-induced THP-1 cell adhesion to 0.2-fold relative to the respective controls. To summarize, our results demonstrate that the hiMCS-BBB models exhibit key features of BBB inflammation in response to inflammation stimuli and recapitulate clinically relevant responses to anti-inflammatory drugs, highlighting their potential to accelerate BBB-targeting drug development.
    Keywords:  Blood-brain barrier; Drug evaluation; Inflammation; Microphysiological systems; Spheroid models
    DOI:  https://doi.org/10.1016/j.jphs.2026.06.005
  34. Comput Struct Biotechnol J. 2026 ;35(3): 0020
    In Silico Modeling of Nanoparticle Transport across the Blood-Brain Barrier: A Systematic Review.
    Qianqian Xia, S H B Herath Mudiyanselage, Sébastien Lafond, Hergys Rexha.
      Reliable prediction of nanoparticle (NP) transport across the blood-brain barrier (BBB) is essential for designing effective central nervous system-targeted drug delivery systems. The BBB protects the brain but severely restricts the entry of therapeutic compounds, and fewer than 5% of candidate drugs reach the brain in pharmacologically meaningful amounts. NP-based delivery systems have emerged as a promising approach to overcome this limitation by enhancing drug stability, circulation, and BBB penetration. Experimental in vivo animal models and in vitro BBB assays provide valuable mechanistic insights but are costly, time-consuming, and limited in translational efficiency. In silico methodologies offer a complementary strategy by enabling efficient screening of NP designs, supporting interpretation of experimental data, and reducing dependence on animal models. This paper presents a systematic review of 56 peer-reviewed publications that applied computational methods to study NP transport across the BBB. The included works fall into 5 main categories: (a) molecular simulations, (b) quantitative structure-activity/property relationship models, (c) machine learning and deep learning approaches, (d) pharmacokinetic and pharmacodynamic modeling, and (e) nanoinformatics frameworks. These approaches address key stages of NP transport, including protein corona formation, interactions with endothelial membranes, and translocation across the barrier. By comparing these diverse methods, this review highlights their complementary strengths and integration potential for improving permeability prediction. Together, they demonstrate how multiscale computational modeling enhances understanding of NP behavior at the BBB, supports more ethical and nonanimal research, and paves the way for artificial intelligence-guided design of brain-targeted nanomedicines.
    DOI:  https://doi.org/10.34133/csbj.0020
  35. Phytomedicine. 2026 Jul 14. pii: S0944-7113(26)00821-4. [Epub ahead of print]159 158590
    Bioactive compounds from traditional Chinese medicine for mitochondrial dysfunction-oriented nanodelivery in neurodegenerative diseases.
    Ting Cheng, Wenjie Hao, Mingwei Li, Yulong Yang, Zhihong Rao, Wenming Yang.
       BACKGROUND: Bioactive compounds from traditional Chinese medicine (TCM) have shown therapeutic potential in neurodegenerative diseases (NDDs), particularly through the regulation of mitochondrial function. Recent studies indicate that encapsulating these TCM bioactive compounds in nanodelivery systems significantly enhances their bioavailability, improves their ability to target the central nervous system, and offers more precise drug delivery.
    PURPOSE: This review aims to synthesize current evidence on how TCM bioactive compounds modulate mitochondria-related pathological nodes in NDDs and discuss how nanodelivery systems can be rationally engineered for blood-brain barrier (BBB) traversal, neuronal uptake, and mitochondrial or mitochondrial dysfunction-responsive delivery.
    METHODS: This is a structured narrative review. Relevant literature on TCM bioactive compounds, mitochondrial dysfunction, and nanodelivery systems for NDDs was retrieved from PubMed, Web of Science, and Scopus through April 2026. After applying predefined inclusion criteria, studies published between 2014 and 2025 were selected for analysis. The emphasis was placed on mechanistic studies, representative nanoformulations, and recent translational evidence.
    RESULTS: Current evidence indicates that bioactive compounds from traditional Chinese medicine, particularly polyphenols, alkaloids, flavonoids, saponins, and terpenoids, converge on several shared mitochondrial pathological nodes in neurodegenerative diseases, including oxidative stress, impaired bioenergetics, disrupted mitochondrial dynamics, defective mitophagy, and mitochondria-mediated apoptosis. Nanodelivery systems consistently improve the physicochemical properties, pharmacokinetic stability, blood-brain barrier transport, and intracellular exposure of these compounds, thereby enhancing their therapeutic potential. Mechanistically, rational integration of disease-responsive nanocarriers with mitochondria-regulating compounds enables spatiotemporal modulation of mitochondrial function rather than merely increasing drug accumulation. However, current evidence remains predominantly preclinical, with most formulations achieving brain targeting rather than verified mitochondrial subcellular targeting. Standardized evaluation of multistage BBB-neuron-mitochondria delivery efficiency, long-term safety, and translational performance is still lacking.
    CONCLUSION: Mitochondrial dysfunction-oriented nanodelivery of TCM bioactive compounds represents a promising strategy for NDD intervention. Future progress depends on more rigorous quality control from the herbal materials to the final nanoformulations, improved pharmacokinetic and safety evaluations, better disease-relevant animal models, and regulatory science frameworks tailored for botanical nanomedicines.
    Keywords:  Bioactive compounds; Mitochondrial dysfunction; Nanodelivery neurodegenerative diseases; TCM
    DOI:  https://doi.org/10.1016/j.phymed.2026.158590
  36. Ageing Res Rev. 2026 Jul 18. pii: S1568-1637(26)00252-7. [Epub ahead of print]121 103260
    Neurovascular unit senescence as a driver of blood-brain barrier dysfunction in Alzheimer's disease：Mechanisms, consequences, and therapeutic implications.
    Mingyuan Yao, Annan Liu, Liping Xing, Jing Song, Yu Yang, Xiaokai Yue, Honglin Li.
      Alzheimer's disease (AD) is a common age-related neurodegenerative disorder (NDD), with ageing as its primary risk factor. Cellular senescence, characterized by permanent cell-cycle arrest, apoptosis resistance and acquisition of the senescence-associated secretory phenotype (SASP), is the cellular hallmark of ageing. Recent evidence indicates that blood-brain barrier (BBB) dysfunction precedes cognitive decline and pathological protein deposition, representing an early event in AD, with the neurovascular unit (NVU) providing the structural and functional basis of the BBB. Mounting evidence shows that the core NVU cells-brain microvascular endothelial cells (BMECs), pericytes and astrocytes-enter senescence under AD-related conditions. SASP factors released by these cells disrupt BBB junction proteins and trans-BBB transport systems, and propagate senescence within the NVU via paracrine signaling. Peripheral inflammatory mediators and immune cells then traverse the compromised BBB, aggravating AD pathology, while accumulating Aβ, tau and reactive oxygen species (ROS) reciprocally accelerate NVU senescence, constituting a proposed vicious cycle. At the molecular level, the cGAS-STING pathway concurrently drives senescence maintenance, SASP induction and type I interferon (IFN-I)-mediated downregulation of BBB junction proteins, serving as a key convergence point linking NVU senescence to BBB injury. From the NVU perspective, this review systematically examines how cellular senescence drives BBB dysfunction and AD progression, clarifies the role of cGAS-STING as a molecular node, and discusses therapeutic strategies targeting NVU senescence to preserve BBB integrity, aiming to offer new insights into AD mechanisms and treatment.
    Keywords:  Alzheimer’s disease (AD); Blood-brain barrier (BBB); CGAS-STING; Cellular senescence; Neurovascular unit (NVU); Therapeutic strategy
    DOI:  https://doi.org/10.1016/j.arr.2026.103260
  37. Front Cell Dev Biol. 2026 ;14 1791272
    Modeling Alzheimer's disease with brain organoids: mechanisms, applications, and future directions.
    Qing Zhao, Songtao Li, Yanxiu Ju, Xiangyi Kong, Xilin Liu.
      Human pluripotent stem cell-derived brain organoids have emerged as a transformative platform for modeling Alzheimer's disease (AD), thus addressing long-standing translational obstacles posed by the disease's complex etiology and interspecies differences. This review systematically examines methodological advances in brain organoid technology, from basic fabrication and brain-region-specific organoids to multicellular assembloids that incorporate microglia and vascular components, with an emphasis on strategies for overcoming fetal-like phenotypes. We surveyed literature published between 2018 and April 2026 that focused on human iPSC-derived organoid models that recapitulate core AD pathologies, including Aβ plaques, tau tangles, neuroinflammation, and blood-brain barrier dysfunction. Key findings demonstrate that organoids effectively capture genotype-phenotype relationships for major AD genes (APP, PSEN1, PSEN2, and APOEε4), enable the dissection of signaling pathway dysregulation (Wnt/β-catenin), and when combined with CRISPR editing and single-cell multi-omics, reveal cell-type-specific disease mechanisms. Organoids have also been successfully applied to patient-specific "avatar" models and high-throughput drug screening, thus advancing precision medicine approaches. However, current technological bottlenecks-including a lack of functional vascularization, batch-to-batch variability, and insufficient standardization-limit the full recapitulation of chronic, age-dependent AD pathology. This review critically evaluates these limitations, addresses ethical considerations surrounding neural organoids, and looks forward to future integration with artificial intelligence, spatial omics, and multi-organ systems to accelerate the translation of organoid-based discoveries into clinical applications.
    Keywords:  3D cell culture; Alzheimer’s disease; brain organoids; disease modeling; drug screening; induced pluripotent stem cells; neurodegenerative diseases; precision medicine
    DOI:  https://doi.org/10.3389/fcell.2026.1791272
  38. Mult Scler Relat Disord. 2026 Jul 24. pii: S2211-0348(26)00436-0. [Epub ahead of print]113 107401
    Asymptomatic spinal cord lesions in Multiple Sclerosis: A systematic review and meta-analysis of subclinical disease activity.
    Mario Rotolo, Rocco Capuano, Sara Scannapieco, Annalisa Rienzo, Roberto Erro, Marianna Amboni, Maria Teresa Pellecchia, Paolo Barone, Maria Di Gregorio.
       BACKGROUND: Spinal cord lesions are common in Multiple Sclerosis (MS) and contribute to disability, but the frequency of new asymptomatic lesions during follow-up is uncertain.
    OBJECTIVE: To review new asymptomatic spinal cord lesions (aSCLe), estimate the patient-level proportion developing at least one lesion, and assess isolated spinal cord activity without concomitant brain Magnetic Resonance Imaging (MRI) activity.
    METHODS: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. PubMed, Scopus, and Web of Science were searched through May 1st, 2026 for studies reporting new aSCLe on follow-up MRI in clinically stable patients with MS (pwMS). According to the criteria used in original papers, MS stability was clinically defined most commonly as the absence of relapses, new neurological symptoms, and/or disability progression during the interval assessed; however, operational definitions varied across studies. The primary outcome was the patient-level proportion developing at least one new lesion. Comparable studies were pooled using a random-effects generalized linear mixed model (GLMM).
    RESULTS: Nine studies were included in the qualitative synthesis and three in the meta-analysis (1637 patients). The pooled proportion developing at least one new asymptomatic spinal cord lesion was 13.0% (95% confidence interval 6.2-25.1; I² = 96.5%). In relapsing-remitting multiple sclerosis, the pooled estimate was 19.1% (95% confidence interval 13.2-26.7; I² = 79.1%). Isolated spinal cord activity was reported across studies but could not be pooled because of heterogeneous definitions and analytic units.
    CONCLUSIONS: Available evidence suggests that new asymptomatic spinal cord lesions may occur during clinically stable follow-up in a meaningful proportion of pwMS. Clinicians should recognize that spinal cord activity may be missed when surveillance relies on brain MRI alone. Standardized whole-cord protocols and patient-level reporting are needed to determine prognostic value and implications for treatment escalation.
    Keywords:  Asymptomatic lesions; Magnetic resonance imaging; Multiple sclerosis; Spinal cord; Systematic review
    DOI:  https://doi.org/10.1016/j.msard.2026.107401
  39. Metab Brain Dis. 2026 Jul 23. pii: 174. [Epub ahead of print]41(1):
    From synaptic development to degeneration: a narrative review of small molecule strategies targeting alpha-synuclein in Parkinson's disease.
    Leanne Khoo, Khuen Yen Ng, Cien Leong Chye, Yi Ko, Jia Yee Lee, Yian Koh, Min Tze Tsen, Soi Moi Chye.
      Aggregation of α-synuclein (α-Syn) is a defining pathological feature of Parkinson's disease (PD), contributing to progressive neuronal dysfunction and death. Unlike prior reviews focused predominantly on aggregation as an isolated endpoint, this review proposes a neurodevelopmental-neurodegenerative continuum as an interpretive framework, suggesting that α-Syn's physiological roles in synaptic development and circuit maturation may be linked to its later pathological behaviour. Within this context, we discuss recent advances in small-molecule strategies targeting key stages of α-Syn pathology, including synthesis, misfolding, aggregation, post-translational modification, and clearance. These include translation and misfolding inhibitors, aggregation modulators such as minzasolmin (UCB0599), epigallocatechin gallate and anle138b, as well as compounds that enhance α-Syn degradation through autophagy-lysosomal and ubiquitin-proteasome pathways. Additional strategies targeting proteostasis and mitochondrial dysfunction are also considered. Beyond its pathogenic role, α-Syn contributes to synaptic vesicle trafficking, neurotransmitter release, and neuronal maturation, and disruption of these functions may increase vulnerability to later neurodegeneration. In conclusion, small-molecule-based therapies represent a promising multi-targeted strategy for PD; however, key translational challenges and unresolved questions remain, including optimisation of pharmacokinetics, target specificity, and blood-brain barrier (BBB) penetration and validation in clinical settings.
    Keywords:  Alpha-synuclein; Parkinson’s disease; Post-translational modifications; Small molecules
    DOI:  https://doi.org/10.1007/s11011-026-01911-y
  40. Clin Neurol Neurosurg. 2026 Jun 30. pii: S0303-8467(26)00250-7. [Epub ahead of print]270 109558
    Serum miR-423-5p discriminates patients with Parkinson's disease from healthy individuals and is associated with severity and the risk of cognitive dysfunction.
    Pingting Chen, Wei Wang, Hengping Chen, Fang Ye.
       BACKGROUND AND AIMS: Parkinson's disease (PD) is the most prevalent central nervous system (CNS) movement disorder primarily affecting older populations. It lacks reliable diagnostic biomarkers. Emerging evidence suggests a potential association between miR-423-5p dysregulation and PD development.
    METHOD: This single-center study enrolled 83 patients with PD and 56 healthy controls. Serum miR-423-5p levels were quantified via real-time quantitative PCR (qPCR) after fasting blood collection. The significance of serum miR-423-5p in disease diagnosis, severity evaluation, and cognitive dysfunction risk prediction was evaluated by ROC curves, logistic regression analysis, and correlation analyses.
    RESULTS: A significant downregulation of miR-423-5p was observed in patients with PD compared to healthy controls, which effectively discriminated patients with PD (sensitivity of 84.34% and specificity of 76.79%) from healthy individuals. Patients with PD who had cognitive dysfunction showed lower serum miR-423-5p levels. Patients with higher MDS-UPDRS-III, HAMA, HAMD, and SCOPA-AUT scores showed lower miR-423-5p expression. Participants with higher MoCA scores showed higher serum miR-423-5p levels. Both miR-423-5p and the Hoehn-Yahr (HY) stage were identified as risk factors for cognitive dysfunction in patients with PD.
    CONCLUSIONS: Serum miR-423-5p levels showed potential as a clinical biomarker for assisting the early detection and progression monitoring of PD.
    Keywords:  Biomarker; Diagnosis; Expression level; MiR-423–5p; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.clineuro.2026.109558
  41. mSystems. 2026 Jul 22. e0041626
    Integrative multicohort analysis reveals consistent sex differences in gut microbiota of multiple sclerosis patients.
    Irene Soler-Sáez, Cristina Galiana-Roselló, Rubén Grillo-Risco, Gwen Falony, Vanja Tepavčević, Sara Vieira-Silva, Francisco García-García.
      Biological sex is a key determinant in the onset and progression of multiple diseases. In multiple sclerosis (MS), females exhibit higher disease prevalence, earlier onset, and more pronounced inflammatory activity, whereas males tend to experience a more severe neurodegenerative course, characterized by accelerated central nervous system damage and increased brain atrophy. The gut microbiome has emerged as a critical factor in MS, as its composition can either ameliorate or exacerbate disease progression. In this study, we aimed to identify reproducible sex-associated differences in gut microbial composition across independent cohorts of MS patients. Through a systematic search, we identified six independent studies based on 16S rRNA gene sequencing, comprising a total of 337 samples. Despite substantial interstudy variability, sex-associated differences were more pronounced in MS patients than in healthy controls. We identified 11 microbial taxa showing significant sex-associated differences in MS, nine enriched in females, and two in males. Notably, the female-enriched taxa Eggerthella and Eisenbergiella were associated with specific MS subtypes and higher disability. To facilitate the use of our findings by the scientific community, we developed a freely accessible web-based tool that provides full access to our results. Thus, in this work, we identified consistent and reproducible sex differences in the gut microbiota of MS patients, highlighting the importance of incorporating sex as a critical variable in microbiome research, with potential implications for understanding disease heterogeneity in MS.
    IMPORTANCE: Multiple sclerosis (MS) affects females and males differently, but the biological reasons behind these differences are not fully understood. One potential factor is the gut microbiome (i.e., the community of microorganisms living in our intestines), which can influence immune function and disease progression. In this study, we analyzed data from multiple independent cohorts and found consistent differences in gut microbial composition between female and male MS patients. Notably, certain bacteria were more abundant in females and were linked to more severe disease features. We also developed a freely accessible web tool where researchers can explore the complete findings in detail. Our results highlight the importance of considering sex as a key factor in microbiome research and may help guide more personalized approaches to understanding and treating MS.
    Keywords:  Eggerthella; Eisenbergiella; human gut microbiome; interstudy heterogeneity; meta-analysis; multiple sclerosis; sex differences
    DOI:  https://doi.org/10.1128/msystems.00416-26
  42. Mol Neurobiol. 2026 Jul 23. pii: 786. [Epub ahead of print]63(1):
    The New Spine of Access to the Brain's Secrets: Extracellular Vesicles from Cerebrospinal Fluid Liquid Biopsies in CNS Diseases and Blood-Brain Barrier Research.
    Isabeau Vermeulen, Yannick Parmentier, Jill Barber, Arnaud François, Loubna Chadli, Nicolas Provost, Emre M Isin, Kayode Ogungbenro, Aleksandra Galetin, Amin Rostami-Hodjegan, Zubida M Al-Majdoub.
      Liquid biopsy is emerging as a powerful approach for less invasive biomarker discovery, with extracellular vesicles (EVs) in cerebrospinal fluid (CSF) showing promise for the assessment of central nervous system (CNS) disorders without actual tissue biopsy and as a complement to imaging techniques. EVs carry molecular cargo such as proteins, nucleic acids, and lipids that mirror those at the tissue of origin, offering unique opportunities to quantify disease-related changes in biomarkers. Compared with plasma-derived EVs, those from CSF provide more direct insights into the CNS because of direct shedding of brain EVs to CSF and bypass of confounding factors involving entry to systemic circulation. Despite this potential, translation into clinical practice is limited by challenges such as low yields, purity concerns, and lack of standardized isolation protocols. Addressing these difficulties, alongside integrating multiomics approaches, will advance our understanding of EV molecular cargo and their functional roles in CNS diseases. Over time, CSF-derived EVs could become the new driver of precision medicine in neurology, offering biologic insight for both diagnostic and therapeutic applications. This perspective provides a critical evaluation of the current status of EV-based liquid biopsy in CSF and offers recommendations for future research and clinical translation of data from CSF-derived EVs, highlighting their potential to inform physiologically based pharmacokinetic (PBPK) models. This state-of-the-art article evaluates existing evidence and highlights key knowledge gaps.
    Keywords:  Blood–brain barrier; CNS diseases; CSF; Extracellular vesicles; Liquid biopsy
    DOI:  https://doi.org/10.1007/s12035-026-06074-6
  43. ACS Appl Mater Interfaces. 2026 Jul 22.
    Multilevel Assessment of a Carbosilane Dendrimer-siRNA Nanoplatform: Cellular Compatibility, Blood-Brain Barrier Model Integrity, and Murine Model Biodistribution.
    Serafin Zawadzki, Elżbieta Okła, Paula Ortega López, F Javier de la Mata, Maksim Ionov, Madara Kreišmane, Dace Skrastiņa, Juris Jansons, Maria Bryszewska, Katarzyna Miłowska.
      The tight regulation of bidirectional solute flux between the systemic circulation and neural tissue by the blood-brain barrier (BBB) remains a principal obstacle to effective pharmacotherapy of the central nervous system. In this study, we evaluate the biocompatibility and biodistribution of a novel third-generation PEGylated carbosilane dendrimer (G3Si PEG6000) and its siRNA dendriplex with an APOE4-directed siRNA relevant to late-onset Alzheimer's disease using a tiered, upstream strategy that progresses from BBB-relevant monocultures to a capillary-weighted BBB model and in vivo/ex vivo biodistribution in mice, in accordance with current recommendations for nanomaterial testing. In endothelial cells, pericytes, and astrocytes, mitochondrial/redox profiling (MTT, DCF-ROS, and JC-1 ΔΨm) defined tolerated exposure ranges. Complexation with siRNA consistently attenuated apparent cytotoxicity across cell types, yet both free and complexed formulations elicited modest ROS and dose-dependent ΔΨm depolarization, indicating persistent mitochondrial stress. In the BBB model, responses were concentration- and formulation-dependent: 10 µM free dendrimers produced sustained impedance and nuclear confluence loss with sheet-like detachment, whereas the 0.1-2.5 µM free dendrimer and the dendriplex induced transient, recoverable perturbations or increases in impedance and proliferation. In vivo, whole-body IVIS imaging demonstrated prolonged systemic exposure for the dendriplex and an ex vivo kidney-dominant, liver-secondary distribution; no robust dendriplex signal was detected in brain fluorescence by planar NIR-I IVIS under the applied acquisition conditions. Collectively, these data indicate that siRNA complexation broadens the functional window at the BBB model with partially recoverable barrier effects and improved systemic exposure, while not substantially reducing mitochondrial or oxidative stress responses. The results provide a mechanistically informed basis for dose optimization and efficacy testing of this dendrimer-siRNA platform in CNS indications and for advancing this platform in further investigations targeting Alzheimer's disease.
    Keywords:  BBB model; biodistribution; carbosilane dendrimer; nanoparticles; siRNA
    DOI:  https://doi.org/10.1021/acsami.6c06027
  44. Transl Neurodegener. 2026 Jul 23. pii: 33. [Epub ahead of print]15(1):
    Application of the Allen Human Brain Atlas in Alzheimer's disease and Parkinson's disease.
    Yi Xiao, Shichan Wang, Yanbing Hou, Huifang Shang.
      Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common age-related neurodegenerative disorders. Allen Human Brain Atlas (AHBA) provides high-resolution transcriptomic data across 102 brain regions with multi-site sampling from healthy controls, promoting the use of brain-wide transcriptomic data for imaging transcriptomics and cross-modal model construction. Increasingly, researchers are utilizing brain-wide transcriptomic datasets to investigate the transcriptome correlates of the neuroimage phenotypes in AD and PD. Leveraging the AHBA, researchers have analyzed the transcriptomic correlations of regional susceptibility to Aβ deposition, tau deposition, α-synuclein propagation, and disease-related multiple-dominal neuroimage phenotypes. These studies revealed that transcriptomic pathways related to metabolism, immunity, neurotransmission, and synaptic function play critical roles in the neuroimage phenotype of AD and PD. By incorporating transcriptomic data modeling, subsequent analyses further confirmed that transcriptomic differences provide the molecular basis for the varying susceptibility observed across brain regions. The analytical approaches of imaging transcriptomics, multimodal data integration strategies, and model construction methods used in AD and PD provide a novel perspective for exploration and can be extended to other neurodegenerative diseases. Future research is expected to utilize brain-wide transcriptomic data to uncover the gene expression mechanisms driving neurodegenerative disease phenotypes.
    Keywords:  Allen human brain atlas; Alzheimer’s disease; Imaging transcriptomics; Neuroimage; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s40035-026-00566-0
  45. Front Cell Infect Microbiol. 2026 ;16 1867024
    Niacin alleviates cerebral microvascular endothelial cell apoptosis induced by hypervirulent Klebsiella Pneumoniae by reducing the accumulation of reactive oxygen species.
    Yinghai Zhao, Mubin Wang, Xing Che.
       Introduction: Hypervirulent Klebsiella pneumoniae (hvKp) is an important pathogen causing central nervous system infections, including meningitis; however, the mechanisms by which it disrupts the blood-brain barrier remain unclear. Niacin, a vitamin B3 compound related to NAD+ metabolism, has the potential to regulate redox homeostasis. This study aimed to investigate the mechanism of hvKp-induced injury in human cerebral microvascular endothelial cell (HCMEC) and to evaluate the protective effects of niacin.
    Methods: A GFP-labeled hvKp ATCC 43816 strain was used to establish an HCMEC infection model, and an hvKp mouse meningitis model was also constructed. Live-cell imaging was performed to monitor infection dynamics. Flow cytometry was used to assess infection rate, reactive oxygen species (ROS) levels, and Annexin V-FITC/PI-labeled apoptosis, while Western blotting was used to analyze apoptosis-related pathways. The experimental groups included a control group, an hvKp infection group, an hvKp plus niacin treatment group, and a niacin pretreatment group.
    Results: hvKp caused time- and dose-dependent injury to HCMEC, characterized by intracellular proliferation followed by apoptosis induction. Mechanistically, hvKp promoted mitochondrial ROS accumulation and activated the p53-associated mitochondrial apoptotic pathway. Niacin reduced ROS levels, inhibited apoptosis, and alleviated HCMEC injury. In vivo, niacin preserved blood-brain barrier integrity, reduced central nervous system inflammation and hvKp colonization, and improved survival in infected mice.
    Discussion: hvKp damages cerebral microvascular endothelial cells and disrupts the blood-brain barrier through the ROS-p53-mitochondrial apoptosis axis. Niacin exerts protective effects by regulating redox homeostasis, suggesting that it may serve as a host-directed adjunctive therapeutic strategy for hvKp-associated central nervous system infections.
    Keywords:  ROS; apoptosis; hypervirulent Klebsiella pneumoniae; meningitis; niacin
    DOI:  https://doi.org/10.3389/fcimb.2026.1867024
  46. J Neurol Sci. 2026 Jul 15. pii: S0022-510X(26)00380-1. [Epub ahead of print] 126098
    When algorithms speak first: The public health risk of consumer AI in ALS diagnosis.
    Stéphane Mathis, Gwendal Le Masson.
       BACKGROUND: Consumer AI platforms are increasingly used by patients to interpret medical reports, including ENMG results for ALS. While AI shows promise in controlled clinical settings (e.g., stroke imaging, melanoma detection), consumer-facing tools often provide overconfident, context-free diagnostic assertions (e.g., 'definitive evidence of ALS'), leading to premature and potentially harmful life-altering decisions.
    OBJECTIVE: To highlight the clinical, ethical, and regulatory risks of unregulated AI in ALS diagnosis and propose actionable solutions.
    DISCUSSION: We present a case of AI-mediated misdiagnosis, analyze the limitations of consumer-facing AI (lack of clinical context, longitudinal data, and specialist oversight), and discuss the "authority paradox" (patients trusting AI outputs over clinicians' nuanced assessments). We propose a structured 4-step clinical approach for managing AI-mediated self-diagnoses and urge regulators to classify such tools as high-risk under the EU AI Act.
    CONCLUSION: The uncritical adoption of consumer AI in ALS diagnosis represents a public health risk. Clinicians, regulators, and developers must collaborate to ensure AI serves patients safely and ethically.
    Keywords:  Amyotrophic lateral sclerosis; Artificial intelligence; Consumer health informatics; Ethical implications; Misdiagnosis; Regulatory framework
    DOI:  https://doi.org/10.1016/j.jns.2026.126098
  47. ACS Nano. 2026 Jul 21.
    Weaker Hydrophobic Collapse in Peptide Amphiphile Supramolecular Assemblies Enhances Permeation Across a Blood-Brain Barrier Model.
    Zijun Gao, Laura B DeOliveira, Amena Khatun, Ya Li, Zhiwei Li, Dhwanit R Dave, Ruomeng Qiu, Anna Metlushko, Yaseen Ahmed, Liam C Palmer, Samuel I Stupp.
      The blood-brain barrier (BBB) prevents diffusion of most molecules from the vasculature into the brain tissue, and therefore is of great interest for therapeutic delivery into the central nervous system. We investigated the potential of supramolecular assemblies to cross the BBB using peptide amphiphiles (PAs) in which the lipid tail length was varied to modify supramolecular cohesion but maintaining the same tetrapeptide sequence VVEE. Alkyl tails containing 16, 14, or 12 carbon atoms in the PAs studied were found to contain decreasing amounts of β-sheet secondary structure by wide-angle X-ray scattering and Fourier transform infrared spectroscopy. We also found diminishing pKa values as the lipid tails were shortened, and therefore concluded that longer tails resulted in the most cohesive assemblies. Using confocal microscopy and flow cytometry, we demonstrated that PAs with longer tails had significantly higher accumulation in brain endothelial cells, whereas an in vitro BBB transwell assay showed that C12 assemblies were endocytosed but were also able to exocytose most efficiently from confluent layers of the cells. Live cell imaging demonstrated that all assemblies entered lysosomes, but transcytosis occurred to the greatest extent in C12 assemblies and to a lesser degree in the C14 PA. We conclude that strong hydrophobic collapse, combined with high pKa values, creates stable nanostructures that remain sequestered within brain endothelial cells without the possibility of permeation. Our work also indicates that PA supramolecular nanostructures retain the capacity to reassemble after transcytosis, thus offering potential for their development into therapeutic delivery platforms to the brain.
    Keywords:  blood-brain barrier; drug delivery; nanostructures; neural biomaterials; peptide amphiphiles; supramolecular polymers; transwell
    DOI:  https://doi.org/10.1021/acsnano.6c01585
  48. J Parkinsons Dis. 2026 Jul 24. 1877718X261470295
    Greater burden of Alzheimer's Co-pathology in women with Parkinson's disease dementia.
    Nathaniel Dunckley, Erika D Driver-Dunckley, Nan Zhang, Geidy E Serrano, Holly A Shill, Shyamal H Mehta, Christine Belden, Cecilia Tremblay, Alireza Atri, Charles H Adler, Thomas G Beach.
      ObjectiveTo investigate sex differences in Alzheimer's disease (AD) related pathology among autopsy-confirmed Parkinson's disease (PD) cases.BackgroundAD and PD frequently co-occur in older adults, yet the influence of sex on AD pathology in the context of PD remains unexplored.MethodsAll subjects were enrolled in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) and Brain and Body Donation Program (BBDP) and had annual standardized research clinical assessments by neuropsychologists, subspecialty behavioral and movement disorders neurologists, as well as comprehensive neuropathological examinations after death.ResultsAmong 230 autopsy-confirmed PD cases, females exhibited greater amyloid plaque pathology burden than males, regardless of a co-occurring AD diagnosis. Specifically, females with PD had significantly higher mean cortical total plaque scores (mean 6.5/15 vs. 4.9/15, p = 0.045) and greater CERAD neuritic plaque density (mean 1.7/3 vs. 1.3/3, p = 0.035). Females were also more likely to have a higher cortical plaque burden (plaque total ≥ 5: 56.8% vs. 39.7%, p = 0.015). In multivariable logistic regression models, female subjects showed greater than twice the odds of having an amyloid plaque burden ≥5 compared to males (OR = 2.18; 95% CI = 1.17-4.06; p = 0.014), when controlling for ApoE ε4 status, Lewy body density score, and age at death.ConclusionsFemale sex is associated with increased amyloid plaque pathology in PD, independent of ApoE ε4 status. These findings highlight a sex-specific vulnerability to AD pathology in PD patients and support the need for sex-informed approaches to reseach in mixed neurodegenerative disease.
    Keywords:  basal ganglia; biochemistry; cell biology; neurodegeneration; pathophysiology
    DOI:  https://doi.org/10.1177/1877718X261470295
  49. J Parkinsons Dis. 2026 Jul 22. 1877718X261468542
    E326K GBA polymorphism is associated with clinical and pathological features of synucleinopathy in the absence of overt Parkinson's disease or Lewy body dementia.
    Moriah R Arnold, Shawn K Westaway, Randy L Woltjer, Nora E Gray, Joseph F Quinn.
      Heterozygote carriers of Gaucher's disease mutations and other polymorphisms in the glucocerebrosidase (GBA) gene show an increased incidence of Parkinson's disease. We hypothesized that common GBA polymorphisms would be associated with subtle parkinsonian features, mild cognitive impairment, and "silent" Lewy body (LB) pathology in aging individuals without a clinical diagnosis of parkinsonism. The most prevalent GBA variants, T369M and E326K, appear in the general population at rates of approximately 0.6% and 1%, respectively. We evaluated 845 participants from the Oregon Alzheimer's Disease Research Center (OADRC) with SNP data generated by the National Centralized Repository of Alzheimer's Disease (NCRAD). Twenty-one subjects were E326K carriers and eighteen were T369M carriers. Clinical measures and postmortem neuropathology were compared between each SNP group and non-carriers. Although there were no statistically significant clinical differences related to synucleinopathy across groups, neuropathological analyses revealed a significantly higher prevalence of LB pathology in E326K carriers compared to T369M carriers. When stratifying each genetic group by LB status (LB+ or LB-), LB+ E326K carriers demonstrated a significant reduction in Mini-Mental State Examination (MMSE) scores compared with LB- non-carriers and a modest decrease compared with T369M carriers. These preliminary findings from a small, uni-center cohort suggest that the E326K GBA polymorphism may predict LB pathology and subtle cognitive decline in aging individuals who lack overt parkinsonian symptoms. Further validation in a larger cohort is warranted. Identifying at-risk individuals through targeted genetic screening may ultimately support earlier intervention and preventative care strategies.
    Keywords:  GBA polymorphism; Lewy Body Dementia; Parkinson's Disease; aging; alpha-synuclein pathology; cognitive decline
    DOI:  https://doi.org/10.1177/1877718X261468542
  50. Front Aging Neurosci. 2026 ;18 1880374
    JAK/STAT signaling pathway inhibitors in neurodegenerative diseases: current status and future perspectives.
    Hai-Xia Yang, Bo-Wei Su, Ya-Nan Bao, Wen-Hao Wang, Jia-Yi Lao, Hong-Yu Ji, Shuang Han, Xiao-Hui Cui, Hui-Wen Ren, Zhi-Lin Luan.
      Neurodegenerative diseases (NDDs) are a major public health concern characterized by the progressive loss of neurons, ultimately leading to neuronal death and causing a sustained decline in brain function or physical motor abilities. Major examples include Alzheimer's disease (AD) and Parkinson's disease (PD). Currently, NDDs lack effective curative methods, and their pathological process primarily involves misfolded protein aggregation, oxidative stress, and neuroinflammation. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, as a central hub for cytokine signaling, has recently been found to play a key role in neuroinflammation and immune regulation in NDDs. This review systematically elucidates the core mechanisms of the JAK/STAT pathway in NDDs, including the regulation of microglial and astrocytic reactivity, the impact on blood-brain barrier integrity, and involvement in energy metabolism abnormalities. On this basis, we have reviewed and evaluated various therapeutic strategies targeting this pathway, focusing on small-molecule JAK inhibitors such as baricitinib and tofacitinib, and have analyzed their mechanisms of action, preclinical efficacy, and potential side effects. In addition, this article provides a forward-looking perspective on the future research directions of the JAK/STAT pathway from the perspective of anti-neuroinflammation to promote neuroregeneration therapy, aiming to offer theoretical references and new ideas for the clinical translational research of this pathway.
    Keywords:  JAK inhibitors; JAK/STAT signaling pathway; blood–brain barrier; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.3389/fnagi.2026.1880374
  51. Brain Behav Immun Health. 2026 Oct;56 101301
    Associations of viral infections and antiviral vaccinations with anti-NMDAR and other forms of autoimmune encephalitis.
    Sarah Bamberg, Poul M Schulte-Frankenfeld, Jakob Kreye.
       Background: Autoimmune encephalitis (AIE) comprises a diverse group of neurological disorders characterized by autoantibodies targeting specific antigens of the central nervous system (CNS). While the pathophysiological effects of these autoantibodies have been extensively studied, the principles and immunological triggers underlying their generation remain less well understood. Viral infections and antiviral vaccinations have been reported as potential immunological triggers. However, a systematic overview of their specific associations and frequencies across AIE subtypes is lacking.
    Methods: Here, we performed a systematic literature review in PubMed to identify published cases of AIE linked to viral infections or antiviral vaccinations, and to test whether herpes simplex virus (HSV)-associated anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E) represents a disproportionately strong association. We quantified the frequencies of viral infection- or vaccine-related AIE across ten common antibody-defined subtypes, and characterized their epidemiological and clinical features, complemented by data from 23 population-based viral encephalitis cohorts.
    Results: We identified 556 cases, of which 488 were infection-associated and 68 followed vaccination. The most frequent combination was HSV infection in association with NMDAR-E, which outnumbered all other reported virus-AIE associations combined and was almost exclusively attributable to preceding HSV encephalitis (HSE). Other recurrent associations included Japanese encephalitis virus, Epstein-Barr virus (EBV), and SARS-CoV-2 infections, although EBV- and SARS-CoV-2-associated cases were less clearly suggestive of causal post-infectious autoimmunity. Across 23 population-based viral encephalitis cohorts from five continents, HSV was the leading causative pathogen. Despite this high background frequency, HSV was significantly overrepresented among viral CNS infection-associated NMDAR-E cases in our dataset compared with the reference cohorts (P < 0.0001), indicating a disproportionate association. Most reported HSE-associated NMDAR-E cases originated from Europe and occurred in young children (median age 6 years), with a balanced sex distribution and a median interval between infection and NMDAR-E onset of 30 days.
    Conclusion: Collectively, these findings provide the most comprehensive overview of viral infection- and antiviral vaccination-associated AIE to date and support a pathogen-specific link between HSE and secondary NMDAR-E as the most dominant virus-AIE association in the published literature. They underscore the need to elucidate the underlying immunological mechanisms and to develop biomarkers predictive of secondary NMDAR-E.
    Keywords:  Anti-NMDAR encephalitis; Autoantibodies; Herpes simplex virus; Molecular mimicry; Post-infectious autoimmunity; Viral trigger
    DOI:  https://doi.org/10.1016/j.bbih.2026.101301
  52. Saudi Pharm J. 2026 Jul 24. pii: 45. [Epub ahead of print]34(4):
    Phytochemicals with potential NMDAR-inhibitory activities: a review of neuroprotective mechanisms against excitotoxicity.
    Abdulmohsin J Alamoudi.
      The N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors in the central nervous system (CNS) that play a crucial role in synaptic plasticity, learning, and memory. However, NMDAR overstimulation is a critical pathological feature in neurodegenerative diseases, stroke, epilepsy, and traumatic brain injury. This excitotoxic cascade triggers massive intracellular calcium influx, oxidative stress, and mitochondrial dysfunction, ultimately driving neuronal apoptosis. In this regard, phytochemicals have emerged as safe, multitargeting NMDAR inhibitors with significant therapeutic potential. This review synthesizes current experimental evidence regarding the neuroprotective potential of major phytochemical classes, including glycosides (e.g., vitexin, ginsenosides), polyphenols (e.g., quercetin, resveratrol), alkaloids (e.g., cytisine, huperzine A), and terpenoids (e.g., bilobalide, fucoxanthin). The results of these studies demonstrate that these bioactive compounds mitigate excitotoxicity via multiple mechanisms, including direct receptor blockade, inhibiting specific subunits (such as GluN2B), and downregulating NMDAR expression. Furthermore, they restore neuronal homeostasis by modulating downstream signaling pathways; thereby suppressing neuroinflammation and apoptosis. It can be concluded that phytochemicals represent a vital reservoir of modulatory agents that protect against glutamate-induced neurotoxicity. Hence, they offer a compelling framework for future drug discovery in CNS therapeutics.
    Keywords:  Glutamate excitotoxicity; NMDAR; Neurological diseases; Neuroprotective effects; Phytochemicals
    DOI:  https://doi.org/10.1007/s44446-026-00101-2
  53. Curr Neurol Neurosci Rep. 2026 Jul 24. pii: 37. [Epub ahead of print]26(1):
    The Neurology of Menopause.
    Hannah J Roeder, Enrique C Leira.
       PURPOSE OF REVIEW: Menopause is a neuroendocrine process with important implications for neurological health. This review examines the complex, multidirectional relationships between menopause and major central nervous system conditions, including stroke, migraine, epilepsy, multiple sclerosis, Parkinson's disease, and Alzheimer's disease.
    RECENT FINDINGS: Menopause may mark an inflection point for vascular injury, neurodegeneration, and disability accumulation in several neurological conditions. Perimenopausal hormonal fluctuations may exacerbate migraines and seizures in susceptible women. Research increasingly supports the critical window hypothesis for estrogen therapy and highlights the importance of distinguishing reproductive and chronological aging when interpreting neurologic trajectories. Menopause represents an important transition for many conditions. Hormone therapy has heterogenous effects with cognitive benefit in premature ovarian insufficiency, harm related to stroke risk in older women, and greater uncertainty in other conditions. Therefore, individualized risk-benefit assessment is essential. Research gaps remain significant, and menopause should be a priority area for neurologic research.
    Keywords:  Epilepsy; Estrogen; Menopause; Migraines; Multiple Sclerosis; Stroke
    DOI:  https://doi.org/10.1007/s11910-026-01506-1
  54. Adv Mater. 2026 Jul 18. e74148
    Chemically Programmed Prodrug Nanoparticles for Precise Oral Dopamine Delivery to Deep Brain Regions in Parkinson's Disease.
    Cam-Hoa Mac, Yu-Wei Chiang, Hong-Nhung Nguyen, Jui-To Wang, Li-An Chu, Ya-Hui Lin, Van Khanh Nguyen, Sheng-Yao Peng, Shih-Kai Lo, Yen Chang, Mai Thanh Thi Nguyen, Qian Yao Zhang, Yu-Jung Lin, Hsing-Wen Sung.
      Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the inflamed substantia nigra, resulting in striatal dopamine (DA) depletion and severe motor dysfunction. Here, we report a chemically programmed, inflammation-responsive prodrug nanoparticle (NP) system-β-glucans-DA(OAc)2 NPs-that enables precise oral gut-to-brain delivery of DA into deep brain regions. In this design, the acetylated DA prodrug DA(OAc)2 is conjugated to β-glucans via a reactive oxygen species (ROS)-cleavable thioketal linker, thereby preventing DA autooxidation, enhancing stability during transit, and ensuring selective activation at neuroinflammatory sites. Following oral administration in PD mice, the NPs are recognized by Dectin-1, internalized by intestinal macrophages, and trafficked through the lymphatic and systemic circulation to cross the blood-brain barrier, ultimately homing specifically to the inflamed substantia nigra in the deep brain. Within this pathological niche, dual responsiveness to elevated ROS and enzymatic activity triggers controlled prodrug cleavage, sustained DA regeneration, and restoration of striatal DA via the nigrostriatal pathway, ultimately rescuing motor function. This inflammation-guided, modular prodrug platform provides a noninvasive and precise strategy for dopaminergic therapy, underscoring its potential as a transformative approach for PD management.
    Keywords:  Parkinson's disease; dopaminergic therapy; gut‐to‐brain delivery; macrophage‐mediated transport; prodrug nanoparticle
    DOI:  https://doi.org/10.1002/adma.74148
  55. J Intern Med. 2026 Jul 21.
    Targeting progressive multiple sclerosis: Toward mechanism-informed precision medicine.
    Fredrik Piehl, Gonçalo Castelo-Branco, Maja Jagodic, Tomas Olsson.
      Multiple sclerosis has undergone a therapeutic revolution over the past three decades. Randomized clinical trials and real-world data demonstrate that modern disease-modifying therapies substantially reduce relapse rates and acute inflammatory activity detected by magnetic resonance imaging (MRI). However, disability accumulation increasingly occurs independent of relapse activity, highlighting progression biology as the principal unmet need. Converging epidemiological and molecular evidence supports a pivotal role for Epstein-Barr virus (EBV) infection in disease initiation, whereas later stages appear dominated by brain-intrinsic mechanisms, including compartmentalized inflammation, microglial activation, failure of remyelination and accelerated biological ageing. Population-based cohorts demonstrate that early high-efficacy therapy improves long-term outcomes, yet the risk of progression rises markedly after midlife despite effective relapse suppression. Emerging biomarkers, such as serum neurofilament light chain, glial fibrillary acidic protein, paramagnetic rim lesions and advanced quantitative MRI metrics, now enable more granular monitoring of progressive pathology. Integration of imaging, fluid biomarkers, genetics and machine learning offers opportunities for individualized benefit-risk stratification. Brain-penetrant Bruton's tyrosine kinase inhibitors, CD40 ligand-targeting biologics, refined B-cell-depleting strategies and emerging chimeric antigen receptor T-cell therapies represent promising approaches to target different aspects of compartmentalized inflammation and smoldering disease biology. Future management will require mechanism-informed treatment algorithms that align therapeutic choice with dominant disease drivers while incorporating comorbidity management, de-escalation strategies and potential EBV-targeted preventive approaches to optimize outcomes across the entire disease course.
    Keywords:  biomarkers; disease progression; disease‐modifying therapy; lifestyle factors; multiple sclerosis
    DOI:  https://doi.org/10.1111/joim.70125
  56. J Neurol. 2026 Jul 19. pii: 473. [Epub ahead of print]273(8):
    Real-world application of the conventional components of the 2024 McDonald diagnostic criteria for multiple sclerosis in China: a comparative study with the 2017 criteria.
    Meng-Ting Cai, Qi-Lun Lai, Sheng-Yao Su, Yan-Lu Fu, Chun-Hong Shen, Yong-Feng Xu, Yin-Xi Zhang.
       BACKGROUND: The 2024 McDonald criteria for multiple sclerosis (MS) introduced novel biomarkers (central vein sign, paramagnetic rim lesion, kappa free light chain) alongside conventional updates. However, access to these novel markers is regionally limited, making the conventional components the most feasible option in many clinical settings. Yet real-world evidence on their diagnostic performance remains limited, prompting this evaluation in Chinese patients with suspected MS.
    METHODS: We retrospectively enrolled 184 patients aged 12-50 years with a first central nervous system demyelinating event or atypical presentation with MS-suspicious imaging, and lesions in ≥ 2 of 5 anatomical regions. Diagnostic assessments were performed per the 2017 and 2024 criteria.
    RESULTS: The 2024 criteria identified 173 patients (94.0%) versus 166 (90.2%) by the 2017 criteria (p = 0.023), with substantial concordance (κ = 0.739). The 2024 criteria yielded seven additional diagnoses, including two with 4-5 regions without the need for dissemination in time (DIT), three fulfilling dissemination in space (DIS) via the optic nerve as the fifth region, and two atypical presentation cases diagnosed by DIS plus DIT. The 2024 criteria significantly reduced required clinical attacks (p = 0.037). While median diagnostic time did not differ significantly (p = 0.058), five patients achieved markedly earlier diagnosis (median advance 47 months). Subgroup analysis showed a higher diagnostic rate in patients with a single clinical attack (p = 0.041).
    CONCLUSION: Even without novel biomarkers, the conventional components of the 2024 criteria improved sensitivity in high-lesion burden or atypical cases-a conservative estimate supporting real-world clinical use in China.
    Keywords:  China; Clinical practice; Diagnostic criteria; Multiple sclerosis
    DOI:  https://doi.org/10.1007/s00415-026-14004-8
  57. Neurol Sci. 2026 Jul 22. pii: 651. [Epub ahead of print]47(8):
    Differential effects of hormone therapy formulations on Parkinson's disease risk: a systematic review and meta-analysis.
    Victor Fellipe Bispo Macedo, Alana Madeiro de Melo Barboza.
       BACKGROUND: The relationship between menopausal hormone therapy (HT) and Parkinson's disease (PD) risk remains controversial, with inconsistent findings potentially driven by differences in hormonal formulations.
    METHODS: We conducted a systematic review and meta-analysis following PRISMA 2020 guidelines. MEDLINE/PubMed and EMBASE were searched between January 8 and March 14, 2026. Observational studies evaluating the association between menopausal HT and PD risk were included. Effect estimates were pooled using random-effects models. Subgroup analyses were performed according to HT formulation (estrogen-only vs. combined estrogen-progestin therapy). A multilevel meta-analysis was conducted to account for within-study dependence.
    RESULTS: Fourteen studies including 753,749 participants (4,433 PD cases) were analyzed. Overall, HT was not significantly associated with PD risk (RR 1.08; 95% CI 0.94-1.23; I² = 49.4%). In subgroup analyses, combined therapy was associated with an increased PD risk (RR 1.40; 95% CI 1.07-1.82), whereas estrogen-only therapy showed no significant association (RR 1.01; 95% CI 0.81-1.27). Multilevel analysis yielded consistent results (combined: RR 1.33; 95% CI 1.00-1.77; estrogen-only: RR 1.03; 95% CI 0.83-1.27), with no statistically significant interaction between formulations (p = 0.12).
    CONCLUSIONS: Combined menopausal HT was associated with an increased risk of PD, while estrogen-only therapy showed no significant association. Although differences between formulations were not statistically significant, these findings suggest that hormone composition may influence neurological outcomes and warrant further investigation into individualized HT strategies.
    Keywords:  Estrogens; Hormone replacement therapy; Menopause; Parkinson disease; Progestins
    DOI:  https://doi.org/10.1007/s10072-026-09243-6
  58. Neuroimage. 2026 Jul 18. pii: S1053-8119(26)00451-9. [Epub ahead of print]338 122136
    PatientSpace: A multimodal graph-based latent representation framework for modeling neurodegenerative disease heterogeneity.
    Alzheimer’s Disease Neuroimaging Initiative
      Neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD) exhibit substantial biological and clinical heterogeneity, complicating diagnosis, subtype characterization, and prediction of disease progression. We introduce PatientSpace, a multimodal graph-based latent representation framework designed to model neurodegenerative disease heterogeneity using T1-weighted MRI and FDG-PET. PatientSpace is built upon a structured variational autoencoder that integrates multimodal neuroimaging features while organizing patients within a latent space constrained by age, diagnosis, and a consistency regularization term encouraging similarity between neuroimaging phenotypes. This design enables the construction of an interpretable patient graph in which neighborhood relationships reflect biological similarity. Applied to cohorts of cognitively normal individuals, AD, and FTD patients, PatientSpace revealed multiple disease clusters associated with distinct neuroimaging patterns and clinical severity. Diagnostic classification achieved performance comparable to state-of-the-art deep learning models, while graph-based neighborhood inference enabled prediction of structural volumes, metabolic activity, and cognitive severity. Projection of mild cognitive impairment (MCI) subjects from an independent cohort further showed that cluster membership was associated with differential risks of dementia conversion and distinct longitudinal trajectories. Together, these results demonstrate that PatientSpace provides an interpretable framework linking multimodal neuroimaging representations to disease subtypes, patient-level characterization, and progression modeling in neurodegenerative disorders.
    Keywords:  Disease progression; FDG-PET; MRI; Neurodegenerative diseases; Patient stratification; Representation learning
    DOI:  https://doi.org/10.1016/j.neuroimage.2026.122136
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