bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–07–19
78 papers selected by
Luca Bolliger, lxBio
  1. Taking Responsibility.
  2. Focused ultrasound blood brain barrier opening for targeted therapeutics in neurodegenerative diseases.
  3. Proteasome Dysfunction and Aggregation-Prone Proteins in Neurodegenerative Diseases: From Mechanisms to Therapeutic Opportunities.
  4. Vitamin D Signaling in Neurodegenerative Disorders: Mechanisms, Therapeutic Potential, and Clinical Implications.
  5. Therapeutic potential of adipose-derived stem cell transplantation in amyotrophic lateral sclerosis: A combined clinical case and preclinical study.
  6. Development and efficacy of ex vivo expanded autologous regulatory T cells for the treatment of amyotrophic lateral sclerosis.
  7. Nursing a Patient With Amyotrophic Lateral Sclerosis Stage 4B With Epilepsy: A Case Study.
  8. The role of radiologic assessment in evaluating and monitoring respiratory function in amyotrophic lateral sclerosis (ALS) patients: a narrative review.
  9. TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.
  10. Corticospinal Subfiber Neurite Density Index Detects Upper Motor Neuron Degeneration in Prediagnostic Patients With Sporadic Amyotrophic Lateral Sclerosis.
  11. Resveratrol and neuroprotection: modulation of cellular dynamics and signaling networks in neurodegenerative diseases.
  12. An intrathecal therapeutics clinic for administration of tofersen in amyotrophic lateral sclerosis: A Canadian nurse practitioner and neurologist collaborative model.
  13. Exosome Biology at the Interface of Neurodegeneration and Therapeutic Innovation.
  14. Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.
  15. Multi-hit genetic lesions and a stress-imprinted immune transcriptome define the inflammatory pathology in ALS patients.
  16. Oligonucleotide-siRNA conjugate for SOD1 amyotrophic lateral sclerosis: a phase 1 trial.
  17. Plasma exosomal HERV-K transcripts are increased in amyotrophic lateral sclerosis.
  18. Effects of respiratory muscle training on respiratory function in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.
  19. Context of use matters: interpreting extracellular vesicle TDP-43 as a biomarker in ALS.
  20. Cardiac Autonomic Dysfunction and Sudden Cardiac Death in Amyotrophic Lateral Sclerosis: Clinical Implications and Considerations for Care.
  21. Beyond ALS: split-hand syndrome in immune-mediated motor neuropathies.
  22. Precision therapeutics and innovative clinical trial design in neurodegenerative diseases.
  23. FUS-driven zebrafish model of ALS identifies tribenzylamine as a candidate modulator of ALS-associated pathology.
  24. Single-subject auditory ERP-BCI performance enhancement in ALS via an AI coding assistant prompt.
  25. Interventional Procedures for Musculoskeletal Pain in ALS Patients: A Case Series.
  26. Secretory leukocyte protease inhibitor (SLPI) attenuates TLR4/NF-κB-mediated neuroinflammation in amyotrophic lateral sclerosis: a candidate molecule associated with neuro-pathology.
  27. Role of ESCRT pathway and autophagy in neurodegenerative diseases.
  28. Neuromuscular ultrasound as a biomarker in the SOD1 mouse model of amyotrophic lateral sclerosis.
  29. Imaging biomarkers in neurodegenerative diseases: advances and challenges.
  30. Experimental evidence of electroacupuncture in ALS mouse models: a systematic review and meta-analysis.
  31. "Straddling two worlds": complexities of spousal caregiving in amyotrophic lateral sclerosis during younger middle age.
  32. Indole-Derived Compounds as Redox-Modulators: Antioxidant Mechanisms in Neuronal Protection.
  33. Multiplex Panel Detects Glial and Inflammatory Biomarker Signatures in Sporadic and C9orf72-ALS.
  34. Small molecular therapeutic targets for neurodegenerative diseases.
  35. Extracellular vesicles as a liquid biopsy for amyotrophic lateral sclerosis: a systematic review and meta-analysis.
  36. Multimodal biophysical markers of neurodegeneration: Morphology, mechanics, and thermodynamics.
  37. Age-based risk estimates for C9orf72RE-related diseases: Theoretical developments and added value for genetic counseling.
  38. White Matter Functional Dysregulation in Amyotrophic Lateral Sclerosis: Machine Learning-Based Biomarkers and Transcriptomic Signatures.
  39. The Role of Hydrogen Bond Donors and Intramolecular Hydrogen Bonding in Modulating Blood-Brain Barrier Permeability: Implications for CNS Drug Design.
  40. Mechanisms and Therapeutic Targeting of the cGAS-STING Pathway in Central Nervous System Disorders.
  41. Astrocytic lipid dysregulation as an early driver of neurodegeneration.
  42. From unlabeled to labeled: self-supervised deep learning in computational pathology.
  43. Microneedle-mediated drug delivery systems for brain diseases.
  44. Targeting astrocyte-mediated neurotoxicity induced by ALS/FTD-associated RNA binding proteins.
  45. The Immunologic Function of the Choroid Plexus: A Gateway to Immunomodulatory Therapy in Injury Models of the Central Nervous System.
  46. High Levels of Plasma Neurturin Partially Mediate the Protective Effect of Reduced Ruminococcus2 Abundance on Multiple Sclerosis: A Mendelian Randomization Study.
  47. Targeting the APOE4-driven peripheral-central immune axis: A new frontier for Alzheimer's disease therapy.
  48. Hunting for an Antigen: Humoral Immunity in Alzheimer's Disease.
  49. Rethinking blood-brain barrier permeability in Alzheimer's disease: insights from APOE genotype-specific associations.
  50. Gut Microbiota in Neuroinflammation, Neurodegenerative Disorders, and Neuropsychiatric Disorders: A Comprehensive Narrative Review.
  51. Brain-shuttle biologics chart new paths across the blood-brain barrier.
  52. Modeling Neuroimmunological Interactions at the Blood-Brain Barrier Using In Vitro 3D Human Organoids: Inflammation and Ischemia-Reperfusion Injury.
  53. The modulation of the blood-brain barrier by focused ultrasound stimulates oligodendrogenesis.
  54. Decoding the PI3K/Akt/mTOR-JAK/STAT signaling axis in multiple sclerosis: mechanistic crosstalk and therapeutic opportunities.
  55. Rodent models and accompanying in vitro strategies for studying the etiology and therapy of Parkinson's disease.
  56. Investigating the treatment of vascular risk with simvastatin in secondary progressive multiple sclerosis: analysis from the MS-STAT2 randomized controlled trial.
  57. Syntaxin-4 at the Crossroads of Synaptic Plasticity and Neurodegeneration: From Molecular Mechanisms to Biomarker and Therapeutic Potential.
  58. Brain Clearance of Contrast Agent in Intravenous DCE-MRI Is Measurable and Cannot Be Explained by Clearance Across the BBB Alone.
  59. Vascular-Apoptotic Crosstalk in Alzheimer's Disease: The Possible Role of Vascular Senescence in Blood-Brain Barrier Dysfunction.
  60. Breaching the Blood-Brain Barrier: Evolving Strategies for Central Nervous System Disease in Adult Acute Lymphoblastic Leukemia.
  61. Intranasal dopamine: Anatomical pathways, biological mechanisms and neuromodulatory potential.
  62. Relationships Between High Dietary Inflammatory Index Scores and Intestinal and Blood-Brain Barrier Integrity in the Context of Neurodegenerative Diseases.
  63. Integrating Metabolic, Perfusion, and Microstructural Parameters for Quantitative Neuroimaging in Rare Neurodegenerative Diseases: A Hybrid PET/MRI Approach.
  64. Focused ultrasound blood-brain barrier opening reveals a paradoxical remote metabolic response in the primate brain.
  65. Is adenosine signalling entering the precision medicine era? From receptor pharmacology to patient stratification.
  66. Study on retinal pharmacokinetic characteristics and precision drug administration strategy in patients with fundus diseases.
  67. Amyloid-related imaging abnormalities after immunotherapy: How might brain microvascular basement membrane components be involved?
  68. TAAR Immunopharmacology.
  69. FUS-mediated BBB opening reshapes plasma extracellular vesicle size distribution without elevating concentration in glioblastoma patients.
  70. SYNE1-Related motor neuron disease-like phenotype with mild distal contractures and 24-month clinical stability: a case report.
  71. The Role of LRP1 in Glioma Progression and Therapeutic Targeting: A Narrative Review.
  72. Association between selected immune parameters and thalassemia: An analytical study.
  73. Neuron-Targeted Exosomal Delivery of siRNA Against RIPK3 Slows Neurodegenerative Progression in Alzheimer's Disease.
  74. Targeting Sirtuin Signaling in Parkinson's Disease and Neurodegeneration: Molecular Insights and Translational Potential.
  75. Recent Advances in Organofluoroprobes for Brain Imaging: Progress, Challenges, and Future Directions.
  76. Integrative single-cell and spatial transcriptomics combined with machine learning to discover complement-associated biomarkers in temporal lobe epilepsy with hippocampal sclerosis.
  77. Astrocytes in Parkinson's Disease: From Guardians to Accomplices.
  78. Histopathological Evidence of Neurodegenerative Pathology in Epilepsy: A Systematic Review.
  1. J Clin Oncol. 2026 Jul 14. JCO2502100
    Taking Responsibility.
    Katherine Hicks-Courant.
      This essay is about how caring for my complicated father with amyotrophic lateral sclerosis (ALS) unexpectedly shaped how I approached my work as a gynecologic oncologist.
    DOI:  https://doi.org/10.1200/JCO-25-02100
  2. Biol Psychiatry. 2026 Jul 17. pii: S0006-3223(26)01399-5. [Epub ahead of print]
    Focused ultrasound blood brain barrier opening for targeted therapeutics in neurodegenerative diseases.
    Negeen Halabian, Caleb Park, Lauren Omoto, Leonardo Favi Bocca, Gerardo Palacios, Kathleen Wu, Clement Hamani, Jennifer Rabin, Agessandro Abrahao, Benjamin Davidson, Nir Lipsman, Ying Meng.
      Therapeutic focused ultrasound (FUS) leverages the non-invasive ultrasonic waves to modify the biological tissue. When administered alongside intravenous microbubbles, low-intensity FUS enables transient, targeted disruption of the blood-brain barrier (BBB), permitting passage of systemically administered therapeutics into the central nervous system (CNS) with high spatial precision. The ability to selectively modulate BBB permeability at the disease site has the potential to substantially expand the number of therapeutics that can be utilized in treating illnesses afflicting the CNS. Herein, we review the current applications of FUS for treating neurodegenerative disorders and diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). We discuss the research developments to date and future directions.
    DOI:  https://doi.org/10.1016/j.biopsych.2026.07.008
  3. Int J Mol Sci. 2026 Jun 25. pii: 5730. [Epub ahead of print]27(13):
    Proteasome Dysfunction and Aggregation-Prone Proteins in Neurodegenerative Diseases: From Mechanisms to Therapeutic Opportunities.
    Youngwon Kim, Yong-Keun Jung.
      Neurodegenerative diseases are characterized by the accumulation of misfolded and aggregation-prone proteins, reflecting a failure of proteostasis. The ubiquitin-proteasome system (UPS), a major pathway for selective intracellular protein degradation, is essential for maintaining neuronal protein homeostasis. Proteasome dysfunction has been implicated in several major neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), although its extent and mechanisms vary across disease contexts. In this review, we examine current evidence for proteasome dysfunction in neurodegeneration and discuss how disease-associated proteins impair proteasome function through direct inhibition, defective substrate processing, and sequestration into protein aggregates. We also address the contribution of oxidative stress, neuroinflammation, and aging to proteasome dysregulation. Finally, we highlight emerging therapeutic strategies aimed at restoring proteasome function, including pharmacological activation, modulation of proteasome assembly and stability, and targeted protein degradation approaches. Understanding the context-dependent nature of proteasome dysfunction will be important for developing effective proteostasis-based therapies.
    Keywords:  neurodegenerative diseases; proteasome; protein aggregation; proteostasis
    DOI:  https://doi.org/10.3390/ijms27135730
  4. Nutrients. 2026 Jun 25. pii: 2082. [Epub ahead of print]18(13):
    Vitamin D Signaling in Neurodegenerative Disorders: Mechanisms, Therapeutic Potential, and Clinical Implications.
    Naveen Soni, Nabendu Debnath, Ella Rekapally, Ayaan Jabbar, Suresh C Tyagi, Bhawana Bissa, Neetu Tyagi.
      Vitamin D has long been recognized for its role in calcium homeostasis and bone metabolism; however, it is now emerging as an important regulator of central nervous system (CNS) function. Recent evidence suggests that vitamin D signaling contributes to the pathogenesis and progression of several neurodegenerative disorders. Vitamin D exerts neuroprotective effects through multiple mechanisms, including regulation of calcium homeostasis, modulation of immune responses, reduction in oxidative stress, stimulation of neurotrophic factors, and maintenance of blood-brain barrier (BBB) integrity. Vitamin D receptors and metabolizing enzymes are widely distributed across several brain regions, highlighting their direct involvement in neuronal function. This review summarizes the biosynthesis, metabolism, and signaling pathways of vitamin D. It explores its role in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, and traumatic brain injury (TBI). Evidence from experimental and clinical studies indicates that vitamin D deficiency is associated with an increased risk and severity of these conditions, while supplementation may provide therapeutic benefits.
    Keywords:  Alzheimer’s disease; blood–brain barrier; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammation; oxidative stress; vitamin D
    DOI:  https://doi.org/10.3390/nu18132082
  5. Tzu Chi Med J. 2026 Jul-Sep;38(3):38(3): 332-339
    Therapeutic potential of adipose-derived stem cell transplantation in amyotrophic lateral sclerosis: A combined clinical case and preclinical study.
    Hui-I Yang, Kuo-Wei Hsueh, Dah-Ching Ding, Horng-Jyh Harn, Yu-Chen Lin, Chia-Yu Chang, Sheng-Tzung Tsai, Shinn-Zong Lin.
       Objectives: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal neurodegenerative disease with no adequate treatment. Transplantation of adipose-derived stem cells (ADSCs) may be an effective therapeutic strategy for delaying progression or restoring neurological function in ALS.
    Materials and Methods: We evaluated the safety and therapeutic efficacy of intravenous (i.v.) and intracerebral (i.c.) ADSC injection in a late-stage ALS patient and in a SOD1 transgenic (Tg) mouse model. Magnetic resonance imaging (MRI) and computed tomography (CT) were conducted to examine potential cerebral hemorrhage and tumor generation in the treated patient. In addition, maximal inspiratory pressure, maximal expiratory pressure, tidal volume, and respiratory rate were measured as indices of respiratory function.
    Results: ADSC transplantation was safe, with MRI and CT showing no hemorrhage or tumorigenesis up to 12 months. The patient's Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score improved from 7 to 9 at 3 months and remained above baseline for 6 months. Respiratory function was preserved during this period. In SOD1 Tg mice, i.c. and i.v. ADSC infusion significantly prolonged survival (165.0 ± 10.4 and 147.3 ± 4.5 days vs. 129.7 ± 3.9 days) and improved motor scores (P < 0.01).
    Conclusion: This preliminary finding suggests potential therapeutic feasibility, but further studies with larger cohorts are needed to confirm its safety and efficacy.
    Keywords:  Adipose-derived stem cells; Amyotrophic Lateral Sclerosis Functional Rating Scale; Amyotrophic lateral sclerosis; Transgenic mice
    DOI:  https://doi.org/10.4103/tcmj.TCMJ-D-25-00092
  6. Front Immunol. 2026 ;17 1854252
    Development and efficacy of ex vivo expanded autologous regulatory T cells for the treatment of amyotrophic lateral sclerosis.
    Ya You, Huifang Zhu, Qian Zhang, Juntao Wang, Chao Dong, Zheng Yang, Jun Zhang, Yushang Zhang, Maoyan Zhang, Mingqi Lu, Changsheng Du.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited therapeutic options, in which neuroinflammation critically drives disease progression. Regulatory T cells (Tregs) exert potent immunosuppressive and neuroprotective effects, offering great potential for ALS treatment. However, clinical application of Treg therapy is hampered by low peripheral cell abundance and unstable expansion quality. Here, we established and optimized a GMP-grade protocol for sorting and expanding peripheral blood-derived Tregs, and validated cryopreserved apheresis products as feasikble starting materials. Although ALS patient-derived Tregs showed reduced expansion capacity compared with healthy donor counterparts, they maintained comparable purity, stable regulatory phenotypes, and robust immunosuppressive function. Transcriptomic analysis confirmed the lineage fidelity and low pro-inflammatory characteristics of expanded Tregs. Therapeutic efficacy was verified in SOD1G93A ALS and GvHD mouse models with delayed disease progression and relieved inflammation. This study provides standardized GMP manufacturing strategies and solid preclinical evidence to support the ongoing clinical trial (NCT06671236) and facilitate Treg immunotherapy translation for ALS.
    Keywords:  ALS; Treg; autoimmune disease; immunology; neurodegenerative disease
    DOI:  https://doi.org/10.3389/fimmu.2026.1854252
  7. Nurs Crit Care. 2026 Jul;31(4): e70573
    Nursing a Patient With Amyotrophic Lateral Sclerosis Stage 4B With Epilepsy: A Case Study.
    Rong Zhang, Ning Zhang, Bei Li, Qing Liu, Chunna Xu, Bing Li, Jie Zhang.
      Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease characterised by progressive muscle weakness, which can eventually lead to death. So far there is no effective cure for it. This case report discusses the nursing of a patient with stage 4B amyotrophic lateral sclerosis complicated with epilepsy and sudden disturbance of consciousness during his stay in an intensive care unit (ICU). After 34 days of treatment and care, the patient regained consciousness with stable vital signs before being transferred out of the ICU. This report focusses on nursing interventions adopted in terms of respiratory management, nutritional management, psychological care and exercise during both the epileptic seizure and the awake period of the patient in the hope of providing a reference for the nursing of patients with amyotrophic lateral sclerosis with epilepsy in intensive care units.
    Keywords:  amyotrophic lateral sclerosis; case study; critical care; disturbance of consciousness; epilepsy
    DOI:  https://doi.org/10.1111/nicc.70573
  8. J Thorac Dis. 2026 Jun 30. 18(6): 672
    The role of radiologic assessment in evaluating and monitoring respiratory function in amyotrophic lateral sclerosis (ALS) patients: a narrative review.
    Bimaje Akpa.
       Background and Objective: Respiratory failure is the primary cause of mortality in amyotrophic lateral sclerosis (ALS), usually caused by progressive neuromuscular respiratory weakness. Standard pulmonary function tests (PFTs) such as maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and both supine and upright forced vital capacity (FVC) are crucial for objective measurements of diaphragmatic weakness but have limitations, including dependence on the patient's performance and the inability to detect early, subclinical diaphragmatic impairment or be used effectively in patients with bulbar symptoms. Radiological assessments, particularly dynamic imaging, have emerged as potential objective tools for evaluating respiratory function. This review comprehensively summarizes findings on the use of diaphragmatic ultrasound (DUS), dynamic chest magnetic resonance imaging (MRI) and deep learning (DL)-based chest computed tomography (CT) for assessing lung function in ALS patients.
    Methods: Key radiological metrics include diaphragm thickness (DT), thickening fraction during inspiration, real-time diaphragmatic excursion, lung diameter changes and changes in pulmonary length and area. These measures have been compared with conventional PFTs in various studies to validate their use for diagnostic accuracy, particularly in early stages of disease.
    Key Content and Findings: DUS is a non-invasive, widely available tool that strongly correlates with PFT measurements, especially FVC, MIP, and sniff nasal inspiratory pressure (SNIP). Dynamic measures, such as excursion and velocity, appear more sensitive to early dysfunction than thickness alone. Chest dynamic MRI has also shown significant correlations with spirometric parameters. Small cohort studies indicate that dynamic chest MRI is a superior, sensitive tool for detecting early respiratory impairment in asymptomatic patients with normal spirometry.
    Conclusions: Radiological assessments, primarily DUS, DL-based chest CT and dynamic MRI, offer valuable, objective, and non-invasive methods for monitoring respiratory muscle strength in ALS. These techniques serve as complementary tools to traditional PFTs, particularly in selected clinical scenarios such ALS patients with early disease, bulbar involvement and unable to perform PFTs. Further longitudinal research with larger cohorts is needed to standardize protocols and validate their role as early parameters to guide the timely initiation of supportive interventions like non-invasive ventilation (NIV).
    Keywords:  Amyotrophic lateral sclerosis (ALS); neuromuscular respiratory weakness; radiologic assessments
    DOI:  https://doi.org/10.21037/jtd-2026-0763
  9. Cell Commun Signal. 2026 Jul 15.
    TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.
    Haixia Wang, Ruiming Wen, Emily Parker, Luodan Yang.
      Triggering receptor expressed on myeloid cells 2 (TREM2) is a critical myeloid receptor expressed on the surface of central nervous system microglia, capable of integrating signals from lipids, damage-associated molecular patterns, and abnormal protein aggregates to regulate phagocytosis, metabolic adaptation, inflammatory remodeling, and pathology-associated responses. Accumulating evidence indicates that TREM2 is neither uniformly protective nor uniformly pathogenic; rather, its biological effects are highly context-dependent, governed collectively by disease stage, pathological substrates, cellular compartments, and the local microenvironment. By coupling with TYROBP/DAP12 or DAP10, TREM2 actively drives the state remodeling of pathology-associated microglia. It profoundly influences the onset and progression of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), as well as acute central nervous system injuries, including ischemic stroke, spinal cord injury (SCI), and traumatic brain injury (TBI). Concurrently, soluble TREM2 (sTREM2) holds significant potential not only as a biomarker but also as a context-dependent effector molecule actively participating in pathological regulation. This review synthesizes current advancements by focusing on four core themes: the structural and signaling logic of the TREM2 axis; its regulation of disease-associated microglia (DAM) remodeling; the cross-disease significance of sTREM2; and the mechanistic basis for the divergent outcomes observed with TREM2-targeted therapies across different experimental models and disease stages. The objective is to elucidate the context-dependent roles of TREM2 by analyzing consensus mechanisms, sources of discrepancy, and translational implications, thereby providing a theoretical framework and strategic direction for more precise TREM2-targeted interventions.
    Keywords:  Acute nervous system injury; Central nervous system; Microglia; Neurodegenerative diseases; TREM2; sTREM2
    DOI:  https://doi.org/10.1186/s12964-026-03083-9
  10. Eur J Neurol. 2026 Jul;33(7): e70703
    Corticospinal Subfiber Neurite Density Index Detects Upper Motor Neuron Degeneration in Prediagnostic Patients With Sporadic Amyotrophic Lateral Sclerosis.
    Ninglu Gao, Bo Cui, Yan Yun, Wenfei Yu, Xianlei Gao, Xiaohan Sun, Kai Shao, Pengfei Lin, Fuchen Liu, Wei Li, Yuying Zhao, Dexin Yu, Chuanzhu Yan, Shuangwu Liu, Jianwei Lou.
       BACKGROUND: Using multi-shell diffusion MRI, we aimed to identify whether corticospinal tract (CST) subfiber damage can be detected in prediagnostic amyotrophic lateral sclerosis (ALS) patients. We also explored whether the combination of serum neurofilament light chain (NfL) levels and CST subfiber abnormalities may provide better diagnostic performance in differentiating prediagnostic ALS patients from disease controls (DCs) and healthy controls (HCs) than single markers.
    METHODS: In this retrospective study, prediagnostic ALS was used as an operational term for patients who presented at baseline with chronic progressive limb weakness or bulbar symptoms, had no clinically evident typical UMN signs, and were subsequently confirmed to have sporadic ALS according to the Awaji criteria during longitudinal follow-up. Patients whose final diagnosis was not ALS after follow-up were classified as disease controls. Probabilistic tractography was performed on baseline MRI data to assess CST subfiber damage in 47 ALS patients, 20 DCs, and 51 HCs.
    RESULTS: Compared with Controls, ALS patients had significantly lower neurite density index (NDI) values of CST subfibers, particularly those originating from the primary and supplementary motor cortex. The diagnostic performance of the combined model incorporating serum NfL and CST subfiber NDI values in differentiating prediagnostic ALS patients from HCs and DCs was 0.925 and 0.928, respectively, which was better than that of single markers (0.634-0.886 and 0.699-0.856, respectively).
    CONCLUSIONS: Our findings suggest that CST subfibers NDI values are promising neuroimaging markers for detecting in vivo UMN degeneration in prediagnostic ALS. Moreover, combining blood and neuroimaging markers may further improve early diagnostic performance.
    Keywords:  ALS; CST subfiber; NODDI; NfL; early diagnosis
    DOI:  https://doi.org/10.1111/ene.70703
  11. Inflammopharmacology. 2026 Jul 17.
    Resveratrol and neuroprotection: modulation of cellular dynamics and signaling networks in neurodegenerative diseases.
    Md Abul Hassan, Md Al Amin, Sherouk Hussein Sweilam, Mohammad Abohassan, Karthickeyan Krishnan, Jeetendra Kumar Gupta, Patibandla Jahnavi, Rajeshwar Vodeti, R Radha, Prem Shankar Gupta, Konatham Teja Kumar Reddy.
      Progressive loss of neurons, oxidative stress, neuroinflammation, and mitochondrial dysfunction are hallmarks of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Resveratrol, a polyphenolic phytoalexin mainly found in grapes and red wine, is a promising treatment candidate due to its diverse biological effects and neuroprotective properties. This review demonstrates the regulatory effects of resveratrol on cellular signaling pathways linked to NDs and its neuroprotective mechanisms. Resveratrol enhances neuronal survival, boosts mitochondrial biogenesis, and mitigates oxidative stress by affecting key molecular pathways, including SIRT1/AMPK, PI3K/Akt, MAPK, and Nrf2/ARE. The PI3K/Akt and ERK1/2 pathways promote neuronal regeneration by modulating pro-apoptotic and anti-apoptotic factors. Resveratrol inhibits NF-κB, reducing cytokine release and microglial activation, thereby exhibiting anti-inflammatory properties. It improves cognitive function, synaptic plasticity, and neuronal survival. Despite an increasing pharmacological profile, its practical applicability is limited by inadequate bioavailability, rapid metabolism, and restricted brain penetration. This review demonstrates resveratrol's effect on interconnected signaling networks related to neurodegeneration. We critically compare evidence from preclinical and clinical studies, demonstrating both therapeutic potential and translational limitations. Emerging nanotechnology-based delivery strategies are demonstrated to overcome bioavailability and blood-brain barrier penetration challenges. These insights provide a translational perspective for the future development of resveratrol-based interventions in NDs.
    Keywords:  Mitochondrial dysfunction; Neurodegenerative diseases; Neuroprotection; Oxidative stress; Resveratrol; Signaling pathways
    DOI:  https://doi.org/10.1007/s10787-026-02333-z
  12. Can J Neurol Sci. 2026 Jul 13. 1-10
    An intrathecal therapeutics clinic for administration of tofersen in amyotrophic lateral sclerosis: A Canadian nurse practitioner and neurologist collaborative model.
    Gordon Jewett, Ellen Chan, Kris Jagt, Janet Petrillo Ballantyne, Jason Wesolosky, Tefani Perera, Vikram Karnik, Christopher Hahn, Collin Luk, Theo Mobach.
      
    DOI:  https://doi.org/10.1017/cjn.2026.10647
  13. Mol Neurobiol. 2026 Jul 15. pii: 768. [Epub ahead of print]63(1):
    Exosome Biology at the Interface of Neurodegeneration and Therapeutic Innovation.
    Dipan Maity, A Gowtham, Yogesh Mishra, Ravinder K Kaundal.
      Neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are defined by progressive neuronal loss, protein misfolding, and chronic neuroinflammation, yet effective disease-modifying therapies remain absent. Exosomes have emerged as key mediators of central nervous system communication and are increasingly central to the biology of neurodegeneration. These nanoscale vesicles transport proteins, lipids, and nucleic acids across cellular and anatomical barriers, influencing synaptic function, immune signaling, and metabolic homeostasis. Under pathological conditions, exosomes facilitate the spread of misfolded proteins such as amyloid-β, p-tau, α-synuclein, and TDP-43, thereby accelerating network-level degeneration. At the same time, their cargo exhibits disease-specific molecular signatures detectable in peripheral biofluids, supporting their development as minimally invasive biomarkers for early diagnosis and longitudinal monitoring. Advances in exosome engineering further underscore their potential as therapeutic delivery vehicles capable of crossing the blood-brain barrier and targeting pathogenic pathways with RNA-based therapeutics, proteins, or gene-editing systems. Together, these findings position exosomes as pivotal contributors to both the mechanistic progression and translational targeting of neurodegenerative diseases.
    Keywords:  Biomarkers; Exosomes; Neurodegeneration; Neuroinflammation; Protein misfolding; Therapeutic delivery
    DOI:  https://doi.org/10.1007/s12035-026-06052-y
  14. Metabolomics. 2026 Jul 16. pii: 128. [Epub ahead of print]22(4):
    Metabolomic analyses of amyotrophic lateral sclerosis, muscle cramps, and TJ-68 treatment.
    Hiroshi Mitsumoto, Ken Cheung, Takashi Matsumoto, Ian Lanza, Björn Oskarsson, Stephen Johnson, Xuan-Mai T Petterson, Grace E Jang, Howard F Andrews.
       INTRODUCTION: Most patients with amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease, experience painful muscle cramps. Our recent pilot trial of the Japanese Kampo medicine TJ-68 suggested its efficacy in improving muscle cramps in patients with ALS.
    OBJECTIVES: This study analyzed plasma metabolomic changes to identify the underlying mechanisms of muscle cramps in ALS and the effects of TJ-68.
    METHODS: Plasma was obtained from 11 participants with ALS in the repeated crossover trial at five time points (baseline, two placebo phases, and two TJ-68 phases). Metabolites were analyzed using mass spectrometry. Linear mixed-effects models were applied to identify metabolite changes associated with muscle cramps, determine the effects of TJ-68 on metabolites, and predict which participants would respond to TJ-68.
    RESULTS: Higher glutamine/glutamate, arginine, and leucine levels were associated with more severe muscle cramps. TJ-68 treatment increased tryptophan and aconitate levels but reduced serotonin and acetylcarnitine levels. Long-chain acylcarnitine levels were correlated with muscle cramp severity, and their levels tended to decrease with treatment. Uric acid, β-aminoisobutyric acid, α-aminoadipic acid, and acetylcholine emerged as predictors of the efficacy of TJ-68.
    CONCLUSION: This study identified the metabolite profile of muscle cramps in ALS and the changes in metabolite levels after TJ-68 treatment. Several baseline metabolites were associated with the prediction of the response to muscle cramps following TJ-68 treatment. Uric acid might be particularly useful because of its easy measurement in standard assays. Our study affirms the value of metabolomic technology for future pharmacotherapy and studies in ALS.
    Keywords:  ALS; Metabolomics; Muscle cramp scale (MCS); Muscle cramps; N-of-1 trials; TJ-68 (Shakuyakukanzoto)
    DOI:  https://doi.org/10.1007/s11306-026-02499-1
  15. Res Sq. 2026 Jul 10. pii: rs.3.rs-10046801. [Epub ahead of print]
    Multi-hit genetic lesions and a stress-imprinted immune transcriptome define the inflammatory pathology in ALS patients.
    Ao Mei, Dipanarine Jewett, Anahid Jewett, Kawaljit Kaur, Subramaniam Malarkannan.
      Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease whose peripheral immune architecture remains incompletely defined. Here, we integrated whole-genome sequencing and single-cell RNA sequencing to define genomic and immune correlates of ALS. Genome-wide analysis of a monozygotic twin pair discordant for ALS pathology identified shared ALS-associated variants, as well as patient-enriched variants in genes linked to RNA metabolism, neurodegeneration, and immune inflammation, supporting a multilayered genetic architecture. Single-cell profiling of 40,484 peripheral blood mononuclear cells from three ALS patients and two healthy individuals, including 33,667 cells retained after quality control, resolved 13 immune clusters and revealed broad remodeling of the peripheral immune compartment, with relative enrichment of natural killer, mucosal-associated invariant T, and γδ T-cell populations. Across immune subsets, ALS samples exhibited inflammatory and stress-adapted transcriptomic programs, including TNF-α/NF-κB, IFN-γ, hypoxia, and ribosomal stress pathways. These data support a model in which multi-hit genetic susceptibility converges on a stress-induced immune transcriptome, marked uniquely by innate lymphocyte activation in ALS patients.
    DOI:  https://doi.org/10.21203/rs.3.rs-10046801/v1
  16. Nat Med. 2026 Jul;32(7): 2619-2628
    Oligonucleotide-siRNA conjugate for SOD1 amyotrophic lateral sclerosis: a phase 1 trial.
    Weiqi Chen, Lingling Jiang, Chunling Duan, Moorim Kang, Jinyi Ye, Ling Wang, Yuesong Pan, Hui Qu, Xiaoling Liao, Xuejiao Zhou, Yichen Li, Zubao Gan, Junnan Chen, Ian Schacht, Robert F Place, Long-Cheng Li, Yilong Wang.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease partly caused by gain-of-function mutations in superoxide dismutase 1 (SOD1). Here we developed RAG-17, an siRNA-targeting SOD1, using an accessory oligonucleotide conjugate platform for enhanced central nervous system (CNS) delivery. Preclinically, RAG-17 rescued motor neuron degeneration, delayed disease progression, preserved motor function and extended survival in SOD1G93A ALS rodents, even with advanced-stage treatment. In cynomolgus monkeys, intrathecal RAG-17 led to dose-dependent, durable reductions in SOD1 mRNA (CNS) and protein (cerebrospinal fluid (CSF)). In a first-in-human trial in patients with SOD1-ALS (n = 6), participants were assigned to two cohorts-cohort 1 (n = 3) received an initial 60 mg dose (seven doses total) and cohort 2 (n = 3) received an initial 90 mg dose (six doses total). The dose was escalated in 30 mg steps to maintenance doses of 150 mg (n = 5) or 180 mg (n = 1). Thus, the primary safety endpoint was met, showing acceptable safety and tolerability. Treatment-emergent adverse events (TEAEs) occurred in 33% of participants (two of six). All TEAEs were mild to moderate, including muscle tremor (two patients) and elevated alanine aminotransferase (one patient), all of which resolved. No serious adverse events were reported. Furthermore, no other clinically meaningful changes were observed in laboratory parameters, vital signs, the ALS Functional Rating Scale-Revised score, physical or neurological examinations or ECG. The key secondary endpoints showed CSF SOD1 reductions of 69% (cohort 1, day 240) and 56% (cohort 2, day 210), and plasma neurofilament light chain reductions of 62% (cohort 1) and 52% (cohort 2), from baseline; no patient required invasive mechanical ventilation or died by the end of the study. These results demonstrate a favorable safety outcome, supporting the continued clinical evaluation of RAG-17 for SOD1-ALS. ClinicalTrials.gov registration: NCT05903690 .
    DOI:  https://doi.org/10.1038/s41591-026-04491-7
  17. BMC Neurosci. 2026 07 11. pii: 25. [Epub ahead of print]27(1):
    Plasma exosomal HERV-K transcripts are increased in amyotrophic lateral sclerosis.
    Triparna Roy, Misha Ramesh, Nurul Aisha Ahmad Nizam, Steven Tandiono, Khuloud T Al-Jamal, Ammar Al-Chalabi, Alfredo Iacoangeli, Ahmad Al Khleifat.
      Human endogenous retrovirus-K (HERV-K) reactivation is increasingly implicated in amyotrophic lateral sclerosis (ALS), with ongoing clinical trials investigating antiretroviral therapies. However, there is limited understanding of how HERV-K is trafficked in peripheral biofluids, and the role of exosomes, nano-sized extracellular vesicles, in this process remains largely unexplored. Exosomes offer a stable and cell-specific cargo reservoir that may reflect central pathogenic processes and serve as a minimally invasive biomarker source. In this study, we isolated plasma-derived exosomes from ALS patients (n = 21) and healthy controls (n = 16), and quantified exosomal HERV-K gag, env, and pol transcript levels using SYBR Green qPCR with RNase treatment and normalization to both traditional and exosome-enriched reference genes. HERV-K pol expression was significantly elevated in ALS, with fold-changes ranging from 1.59 to 1.85 (P = 0.037-0.051). env and gag also showed increased expression, though with greater variability. Normalization to the exosome-specific gene SOD2 provided the most consistent signal. These findings suggest that exosomal HERV-K transcripts, particularly pol, could serve as accessible biomarkers for patient stratification and treatment monitoring in HERV-K-targeted ALS trials. This work establishes proof-of-concept for using exosomal cargo to track endogenous retroviral activity in neurodegeneration and supports further investigation of liquid biopsy approaches in ALS precision medicine.
    Keywords:  ALS; Biomarkers; Endogenous retrovirus; Exosomes; HERV-K; Motor neuron disease; Nanoparticle tracking analysis; Neurodegeneration
    DOI:  https://doi.org/10.1186/s12868-026-01014-5
  18. J Neurol. 2026 Jul 15. pii: 460. [Epub ahead of print]273(8):
    Effects of respiratory muscle training on respiratory function in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis.
    Yanping Lei, Ju Huang, Min Li, Yan Zhang, Zhi Ye, Xiaoyan He, Zhuojuan Tang, Jun Wei.
       BACKGROUND: Respiratory decline is prognostically important in amyotrophic lateral sclerosis (ALS), but the efficacy of respiratory muscle training (RMT) remains uncertain. We synthesized randomized evidence on respiratory and related outcomes.
    METHODS: We searched databases, specialized registers, and trial registries through June 19, 2025, for randomized RMT trials in ALS. Risk of bias was assessed with the Cochrane tool. Random-effects meta-analyses reported standardized mean differences (SMDs) with 95% confidence intervals (CIs), and certainty was rated with GRADE.
    RESULTS: Six studies were included; five concurrently randomized trials contributed quantitative data, whereas Pinto 2013 was retained for qualitative context. RMT improved maximal expiratory pressure (MEP; SMD 0.387, 95% CI 0.192-0.581; P = 0.008) and showed small favorable effects on maximal inspiratory pressure (MIP; SMD 0.156, 95% CI 0.089-0.224; P = 0.005), sniff nasal inspiratory pressure (SNIP; SMD 0.216, 95% CI 0.039-0.392; P = 0.034), peak expiratory flow (PEF; SMD 0.205, 95% CI 0.088-0.323; P = 0.017), and ALSFRS-R (SMD 0.214, 95% CI 0.039-0.388; P = 0.030). Forced vital capacity showed a borderline favorable trend (SMD 0.129, 95% CI - 0.003 to 0.262; P = 0.053). Low heterogeneity estimates were imprecise because most endpoints included only three to four small studies. Certainty was moderate for MIP, low for MEP, FVC, and PEF, and very low for SNIP and ALSFRS-R. Exploratory analyses identified no reliable effect modifiers.
    CONCLUSIONS: RMT was associated with small, directionally consistent improvements mainly in pressure- and flow-based outcomes, whereas effects on FVC and longer-term clinical outcomes remain uncertain. RMT may be considered an individualized adjunct to ALS respiratory care, not a disease-modifying therapy. Larger, longer, standardized trials with patient-important endpoints are needed.
    Keywords:  Amyotrophic lateral sclerosis; Meta-analysis; Physical therapy; Respiratory muscle training; Systematic review
    DOI:  https://doi.org/10.1007/s00415-026-13982-z
  19. Acta Neuropathol Commun. 2026 Jul 11.
    Context of use matters: interpreting extracellular vesicle TDP-43 as a biomarker in ALS.
    Jenna M Gregory.
      
    Keywords:  Amyotrophic lateral sclerosis; Biomarkers; Clinical trials; Neuron-derived extracellular vesicles; Neuropathology; Pharmacodynamic biomarkers; Surrogate endpoints; TDP-43
    DOI:  https://doi.org/10.1186/s40478-026-02376-x
  20. Cardiol Rev. 2026 Jul 13.
    Cardiac Autonomic Dysfunction and Sudden Cardiac Death in Amyotrophic Lateral Sclerosis: Clinical Implications and Considerations for Care.
    Kelly Fisher, Alexandra Ligay, Michelle Stratford, Rahim Hirani, David T Ober, Ibragim Al-Seykal, William H Frishman, Mill Etienne.
      Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a motor neuron disease that progresses from muscular weakness to respiratory failure and death. Increasing evidence, however, demonstrates clinically meaningful involvement of the autonomic nervous system, particularly in cardiovascular regulation. This narrative review synthesizes current evidence on the mechanisms, clinical implications, and palliative considerations of cardiac autonomic dysfunction in ALS, with particular emphasis on its relationship to sudden cardiac death (SCD). Cardiac autonomic dysfunction is increasingly recognized as a significant contributor to disease burden in ALS, manifesting as abnormalities in heart rate variability, sympathetic overactivity, and corrected QT prolongation. These derangements may contribute to malignant arrhythmias, increasing susceptibility to SCD in combination with respiratory decline. Epidemiologic data suggest that SCD accounts for a meaningful proportion of ALS-related mortality, although it is likely underrecognized due to misclassification and lack of routine cardiac monitoring. Clinical implications include the need for improved risk stratification and earlier detection of autonomic dysfunction using accessible markers, such as electrocardiographic indices, orthostatic vital signs, and ambulatory monitoring. Emerging technologies, including wearable biosensors, may further enhance longitudinal assessment. These considerations also have direct relevance for advanced care planning, as ALS may involve unpredictable and abrupt cardiac death in addition to progressive respiratory decline. Recognizing ALS as a multisystem disorder with significant cardiac involvement supports the integration of structured cardiovascular monitoring into multidisciplinary care models and highlights the need for prospective studies to guide standardized management strategies.
    Keywords:  amyotrophic lateral sclerosis; arrhythmia; autonomic dysfunction; heart rate variability; sudden cardiac death
    DOI:  https://doi.org/10.1097/CRD.0000000000001392
  21. J Neurol. 2026 Jul 17. pii: 471. [Epub ahead of print]273(8):
    Beyond ALS: split-hand syndrome in immune-mediated motor neuropathies.
    Luisa Kreß, Mai Abuzant, Daniel Zeller, Claudia Sommer.
       BACKGROUND AND AIMS: Split-hand syndrome describes selective wasting and weakness of the abductor pollicis brevis (APB) or first dorsal interosseous (FDI) muscles with relative preservation of the abductor digiti minimi (ADM). Beyond clinical definition, two neurophysiological ratios and one index have been proposed to quantify this pattern. It is considered a potential diagnostic criterion for amyotrophic lateral sclerosis (ALS). Its occurrence in immune-mediated neuropathies, as differential diagnoses, remains unclear. We aimed to investigate clinical and electrophysiological manifestations of split-hand syndrome in multifocal motor neuropathy (MMN) and multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) compared to ALS.
    METHODS: We prospectively examined 26 MMN, 16 MADSAM, and 22 ALS patients. All underwent neurological examination and neurophysiological measurements of compound muscle action potentials (CMAP) from the APB, FDI, and ADM bilaterally after median (APB) and ulnar nerve (FDI, ADM) stimulation. Split-hand ratios (APB/ADM; FDI/ADM) and split-hand index (SI) were calculated.
    RESULTS: Clinical split-hand syndrome was present in 16/26 (62%) MMN, 7/16 (44%) MADSAM, and 12/22 (54%) ALS patients. Electrophysiological criteria (abnormal split-hand ratios or SI; ≥ 1 parameter fulfilled) were similarly frequent across groups (MMN 17/26, 65%, MADSAM 11/16, 69%, and ALS 16/22, 73%). CMAP ratios and SI did not differ between groups in the overall analysis and showed no correlation with disease duration or severity. Diagnostic models showed limited discriminatory power (area under the curve ≤ 0.61).
    INTERPRETATION: Split-hand syndrome occurs in MMN, MADSAM, and ALS at comparable frequencies and lacks robust or consistent diagnostic discrimination across disease groups.
    Keywords:  Amyotrophic lateral sclerosis; Multifocal acquired demyelinating sensory and motor neuropathy; Multifocal motor neuropathy; Split-hand syndrome
    DOI:  https://doi.org/10.1007/s00415-026-14006-6
  22. Rev Invest Clin. 2026 Jul 11. pii: S0034-8376(26)00017-3. [Epub ahead of print]78(4): 100050
    Precision therapeutics and innovative clinical trial design in neurodegenerative diseases.
    Ariadna Domínguez-García, Juan Carlos Delgado-Uriarte, Amin Cervantes-Arriaga.
      Neurodegenerative diseases are biologically heterogeneous disorders characterized by progressive neuronal dysfunction, overlapping molecular pathologies, and limited disease-modifying therapies. Advances in biomarker development, molecular staging, and precision medicine are reshaping therapeutic strategies and clinical trial design across Parkinson's disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington's disease, and related disorders. This review summarizes emerging therapeutic approaches, including monoclonal antibodies targeting protein aggregation, immune-modulating and metabolic interventions, antisense oligonucleotides, gene replacement and genome-editing strategies, stem cell-based therapies, and neurosurgical delivery platforms and neuromodulation technologies. It also examines evolving clinical trial methodologies such as biomarker-enriched recruitment, adaptive and delayed-start designs, platform trials, decentralized models, and master protocols. Additional emphasis is placed on diagnostic biomarkers, multimodal artificial-intelligence pipelines, systems-biology perspectives, network-based therapeutic strategies, and the reproducibility and interpretability requirements for computational tools. Despite recent progress, major challenges remain, including biological heterogeneity, limited translatability of preclinical models, delivery barriers, long-term safety concerns, and inequities in access to biomarker-based care and trial participation. Future directions will require combination therapies, integrated biomarker pipelines, preventive strategies, and pragmatic trial systems capable of translating biological advances into durable and equitable clinical benefit.
    Keywords:  Antisense oligonucleotide; CAG repeat; Disease-modifying therapy; Huntingtin; Huntington's disease; Neurofilament light; Somatic instability
    DOI:  https://doi.org/10.1016/j.ric.2026.100050
  23. Biomed Pharmacother. 2026 Jul 17. pii: S0753-3322(26)00797-3. [Epub ahead of print]202 119761
    FUS-driven zebrafish model of ALS identifies tribenzylamine as a candidate modulator of ALS-associated pathology.
    Yongbo Seo, Jeonghyeon Lee, Yunkyoung Lee, Suhyun Kim, Jeong-Soo Lee, Hyunju Ro, Sung-Hee Cho, Jung Sang Park, Myung Ji Kim, Hae-Chul Park.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron loss and declining motor function; however, effective therapies remain limited. To support unbiased therapeutic discovery, we aimed to develop a high-throughput phenotypic screening platform based on a transgenic zebrafish model expressing the human ALS-associated FUS-R521C mutant (mtFUS). This model was generated using a modified QF-based binary expression system and exhibited early-onset pathological features, including elevated oxidative stress, progressive neuronal degeneration, and impaired locomotor activity, thereby recapitulating the key aspects of FUS-associated ALS. Transcriptomic profiling revealed molecular signatures resembling those reported in patient-derived motor neurons, including dysregulated neuroactive ligand-receptor signaling, immune activation, and stress-response pathway alterations. Using this platform, we identified tribenzylamine (TBA) as a candidate compound that improves locomotor performance and significantly reduces reactive oxygen species levels. Integrated transcriptomic and biochemical analyses suggested that TBA induces coordinated molecular changes, including normalization of neuronal activity-related gene expression, modulation of immune and metabolic pathways, and restoration of hormone-related signaling. TBA reversed FUS-induced reductions in key neuronally active sex steroids, including estrogen and progesterone, and increased estrogen-responsive gene expression, suggesting a partial recovery of neuronally active sex steroid homeostasis. These findings support the mtFUS zebrafish model as a useful platform for ALS drug discovery and identify TBA as a candidate modulator of ALS-associated phenotypes, with effects linked to transcriptomic remodeling and neuronally active sex steroid signaling.
    Keywords:  Amyotrophic lateral sclerosis; FUS; High-throughput drug screening; Neuronally active sex steroid; Tribenzylamine; Zebrafish
    DOI:  https://doi.org/10.1016/j.biopha.2026.119761
  24. Front Hum Neurosci. 2026 ;20 1869918
    Single-subject auditory ERP-BCI performance enhancement in ALS via an AI coding assistant prompt.
    Mikito Ogino.
       Introduction: Auditory event-related potential (ERP) brain-computer interfaces (BCIs) offer communication support for individuals with amyotrophic lateral sclerosis (ALS) who eventually progress to completely locked-in states. However, individual-specific BCI pipeline optimization is technically demanding and time-consuming, leaving substantial room for performance improvement in practice. A central challenge is increasing selection speed while maintaining reliable classification accuracy, since slower selections reduce the sense of agency and undermine the motivational and feedback dynamics essential for sustained BCI use.
    Methods: We investigated whether an AI coding assistant could address this challenge for individual patients. A three-class auditory ERP-BCI was optimized for a single ALS patient using Claude Code (Anthropic, Inc.), which iteratively generated and evaluated 23 optimization scripts over approximately 24 hours with minimal human-in-the-loop oversight. The resulting AI-Designed ERP classifier (AIDE) was evaluated on 189 EEG trials spanning 3.5 years using five cross-validation strategies.
    Results: For the baseline models, halving the stimulus repetitions to shorten selection time degraded classification accuracy; AIDE prevented this degradation, achieving 85.03% mean cross-validation accuracy (selection time 17 s; ITR 2.92 bits/min). This doubled the information transfer rate from 1.43 to 2.92 bits/min. Accuracy exceeded 84% across four of five cross-validation strategies. Feature space visualization revealed that the AI autonomously selected and combined EEG features established in prior studies into an effective discriminative architecture, without domain-specific algorithmic guidance from the human researcher. In addition, online test confirmed 66.7% accuracy for AIDE versus 50.0% for the baseline model.
    Discussion: These findings provide proof of concept that single-subject BCI performance can be improved via a single prompt, offering an efficient pathway to individualized optimization in clinical and research settings.
    Keywords:  amyotrophic lateral sclerosis; auditory event-related potential; brain–computer interface; information transfer rate; large language model; linear discriminant analysis; single-subject optimization
    DOI:  https://doi.org/10.3389/fnhum.2026.1869918
  25. Am J Phys Med Rehabil. 2026 Aug 01. 105(8): e117-e120
    Interventional Procedures for Musculoskeletal Pain in ALS Patients: A Case Series.
    Christine Y Gou, Sean E Smith.
      Many patients with amyotrophic lateral sclerosis (ALS) experience musculoskeletal pain, yet data on the safety and efficacy of interventional procedures for pain relief in this population are limited. This study aims to describe the characteristics, outcomes, and procedural considerations of pain interventions performed for musculoskeletal pain in ALS patients. A retrospective chart review was conducted of ALS patients referred for interventional pain management by a neuromuscular physiatrist at a single academic institution's interdisciplinary ALS Center between February 2021 and February 2025. Eleven patients (mean age: 57 y, 64% male) underwent 14 procedures. Shoulder pain was the most common indication (43%), followed by spine (29%) and hip (14%) pain. Procedures mostly consisted of joint and bursal injections peripherally and of epidural injections in the axial spine. Overall, 13 of 14 (93%) procedures provided at least "good" pain relief, and 5 patients elected to repeat their procedures. One patient experienced transient postprocedure hypertension; no major complications occurred. Interventional procedures, particularly corticosteroid injections, appear to be safe and effective for managing focal musculoskeletal pain in patients with ALS. Tailored procedural techniques and multidisciplinary coordination can enhance comfort and optimize outcomes in this complex population.
    Keywords:  Amyotrophic Lateral Sclerosis; Case Report; Interventional Pain Management; Musculoskeletal Pain
    DOI:  https://doi.org/10.1097/PHM.0000000000002964
  26. Mol Med. 2026 Jul 17.
    Secretory leukocyte protease inhibitor (SLPI) attenuates TLR4/NF-κB-mediated neuroinflammation in amyotrophic lateral sclerosis: a candidate molecule associated with neuro-pathology.
    Ming-An Li, Yi-Zhi Song, Ting Li, Jian Wu, Yue Tao, Rui Hu, Chen-Meng Qiao, Chun Cui, Wei-Jiang Zhao, Yan-Qin Shen.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder driven by neuroinflammation involving activated microglia and astrocytes, which accelerates the loss of motor neurons. While Secretory leukocyte protease inhibitor (SLPI) is known for its immunomodulatory properties, its specific role in ALS pathogenesis has not been fully established. This study aimed to characterize the expression patterns and functional significance of SLPI in ALS models.
    METHODS: The study utilized SOD1G93A mice to analyze the spatiotemporal dynamics of SLPI expression in the gastrocnemius muscle, lumbar spinal cord, and serum across different disease stages. In vitro functional assays were conducted using siRNA-mediated knockdown of SLPI in BV2 (microglia), MA (astrocytes), and NSC-34 (motor neurons) cell lines. Additionally, recombinant SLPI protein was applied to LPS-stimulated BV2 cells to investigate its effect on the TLR4/ NF-κB signaling pathway.
    RESULTS: In SOD1G93A mice, SLPI was significantly upregulated in the gastrocnemius muscle from the pre-symptomatic stage (60 days) through the late stage (130 days). In the lumbar spinal cord, SLPI showed a transient initial increase but declined sharply by the end-stage; a similar significant reduction was observed in late-stage serum levels. In vitro, SLPI knockdown exacerbated pro-inflammatory cytokine production in all three cell types and impaired the antioxidant capacity of NSC-34 motor neurons. Mechanistically, recombinant SLPI attenuated inflammation in BV2 cells by modulating the TLR4/NF-κB pathway.
    CONCLUSIONS: The dynamic changes in SLPI levels suggest its potential relevance as a candidate molecule for disease staging. Meanwhile, its protective effects in regulating inflammation suggest that it could be a promising therapeutic candidate for mitigating ALS-associated neuroinflammation.
    Keywords:  ALS; Astrocyte; Microglia; Motor neurons; Neuroinflammation; Oxidative Stress; SLPI; SOD1G93A mice
    DOI:  https://doi.org/10.1186/s10020-026-01572-8
  27. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00052-8. [Epub ahead of print]187 1-16
    Role of ESCRT pathway and autophagy in neurodegenerative diseases.
    Shweta Dongre, Naveen Soni, Bhawana Bissa.
      Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss resulting from impaired proteostasis and vesicular trafficking. Neurons are particularly vulnerable to these processes due to their post-mitotic nature and complex architecture. Autophagy and the endolysosomal system constitute the primary degradative pathways responsible for maintaining neuronal homeostasis. However, increasing evidence indicates that their effective function critically depends on coordination with the endosomal sorting complexes required for transport (ESCRT). Beyond their canonical role in multivesicular body biogenesis and membrane scission, ESCRT components are now recognized as essential regulators of autophagosome closure, amphisome formation, autophagosome-lysosome fusion, and endolysosomal membrane repair. Disruption of this ESCRT-autophagy interface has emerged as a common pathological feature across major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis/frontotemporal dementia. This review synthesizes evidence from genetic, biochemical, and neuropathological studies to highlight shared molecular nodes, such as ESCRT-III components, the VPS4 ATPase, the adaptor protein ALIX, and late endosomal regulators, including Rab7, that couple membrane remodeling to autophagic flux. Failure of these regulatory checkpoints destabilizes endolysosomal integrity, arrests autophagic maturation, and promotes the accumulation of toxic protein species, thereby driving progressive neuronal degeneration. By framing neurodegeneration through the lens of ESCRT-autophagy coupling failure, this review provides a unified mechanistic perspective that links diverse pathogenic proteins to shared cellular vulnerabilities and identifies ESCRT-mediated membrane dynamics as a critical determinant of neuronal survival.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Autophagy; ESCRT; MVB; Neurodegeneration; Parkinson’s disease
    DOI:  https://doi.org/10.1016/bs.irn.2026.05.022
  28. PLoS One. 2026 ;21(7): e0353397
    Neuromuscular ultrasound as a biomarker in the SOD1 mouse model of amyotrophic lateral sclerosis.
    Camilla Wohnrade, Nadine Thau-Habermann, Thomas Gschwendtberger, Julia Rückoldt, Zhong Huang, Stefanie Schreiber, Kirsten Haastert-Talini, Susanne Petri.
      A progression marker that indicates early disease-related changes and treatment responses in the to date incurable neurodegenerative disease amyotrophic lateral sclerosis (ALS) is highly desirable. Translation of therapeutics that have been successful in in vivo models into trials in human patients has proven difficult in recent decades. This failure can be attributed, at least in part, to the lack of specific biomarkers for ALS diagnosis and progression in human ALS patients as well as in in vivo models. Neuromuscular ultrasound is an easily accessible, non-invasive tool to support diagnosis of ALS in humans. Our current study shows for the first time that the disease can be detected in an ALS mouse model with the help of neuromuscular ultrasound. We characterized disease progression regarding changes in the peripheral nerves and muscles of the hind limb in the SOD1G93A mouse model of ALS using different techniques (neuromuscular ultrasound, electroneurography, motor function tests, phenotypic assessments and histology). By neuromuscular ultrasound, we measured the cross-sectional area and diameter of the sciatic nerve and analyzed hind limb muscle texture and thickness. Our results show that motor neuron loss and muscle atrophy - analogous to ALS in humans - can be measured by ultrasound in the SOD1G93A mouse model. Changes in nerve and muscle morphology appear at the same time or even before changes in the established tests (including electroneurographic measurements) performed in vivo in this model. Correlations with histologic features of disease progression make neuromuscular ultrasound a sensitive, non-invasive outcome marker for preclinical studies.
    DOI:  https://doi.org/10.1371/journal.pone.0353397
  29. Front Aging Neurosci. 2026 ;18 1813588
    Imaging biomarkers in neurodegenerative diseases: advances and challenges.
    Shreyasi Majumdar, Puneet K Samaiya, Sahabuddin Ahmed, Santosh Kumar Prajapati.
      Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), represent a major global health burden. Imaging biomarkers have emerged as important tools for improving the diagnosis, monitoring, and biological characterization of neurodegenerative diseases. Structural MRI, diffusion tensor imaging (DTI), functional MRI (fMRI), positron emission tomography (PET), hybrid PET/MRI and molecular imaging have transformed our ability to investigate neurodegeneration in vivo non-invasively. This review highlights updated information on how each imaging modality offers a unique window into different disease pathophysiology including regional atrophy, amyloid-β, tau, dopaminergic terminal degeneration, synaptic density (SV2A), and neuroinflammation. We also focused on the translational and evidence supporting biomarkers, appropriate use criteria for amyloid and tau PET imaging, and standardized quantification methods such as the Centiloid scale. The growing role of multimodal fusion, where imaging is increasingly integrated with scalable fluid biomarkers to enable "blood-first" strategies where high-risk patients are selectively referred to advanced imaging, improving feasibility and equity. Despite tremendous progress, there are still issues with their standardization, sensitivity, specificity, and clinical translation. Moreover, the review emphasizes the frontiers of α-synuclein and glial state-specific PET ligands, advanced diffusion models, and dynamic connectivity analysis to support precision medicine and mechanism-based trial design for NDDs.
    Keywords:  imaging biomarkers; multimodal imaging; neurodegenerative diseases; plasma biomarkers; positron emission tomography (PET); structural MRI
    DOI:  https://doi.org/10.3389/fnagi.2026.1813588
  30. Front Neurol. 2026 ;17 1780176
    Experimental evidence of electroacupuncture in ALS mouse models: a systematic review and meta-analysis.
    Mengwan Hu, Lei You, Xuezhuo Zhang, Zhibo Xuan, Sijia Ma, Xian Wu.
       Objective: This study aimed to systematically evaluate the therapeutic efficacy of electroacupuncture (EA) in amyotrophic lateral sclerosis (ALS) and to elucidate the underlying neurobiological mechanisms by synthesizing preclinical evidence.
    Methods: According to the PICOS principle, relevant studies were searched in the following databases: PubMed, Web of Science, Embase, Cochrane Library, Scopus, and CNKI. Search terms and strategies were determined based on MeSH terms. The methodological quality of the included studies was assessed using the SYRCLE's Risk of Bias tool and the CAMARADES checklist. Meta-analysis was performed using Stata 15.0 and Rstudio software.
    Results: Seventeen studies involving 372 animals were included. The quality scores of the included studies ranged from 5 to 8, with an average score of 7. The meta-analysis of the primary outcome, the rotarod test score, showed a significant improvement in the EA group compared to the control group [SMD = 3.31, 95% CI (2.05, 4.57), Z = 5.151, p < 0.001], indicating that EA can enhance motor function in ALS mice. Regarding secondary outcomes, EA intervention alleviated neuroinflammation, promoted neuronal survival, improved axonal regeneration inhibition, and stabilized RNA metabolism homeostasis. Consequently, it slowed disease progression, improved motor performance, prolonged survival time, and effectively protected motor neurons at the histopathological level (p < 0.05). These findings underscore the potential of EA as a promising multimodal therapeutic strategy for ALS. For the heterogeneity observed in the rotarod test, sensitivity analysis, subgroup analysis, and meta-regression did not identify its source. However, potential publication bias was detected, which might contribute to the heterogeneity. The heterogeneity for other outcome measures might originate from differences in stimulation parameters (e.g., waveform), acupoint selection, or treatment duration.
    Conclusion: This meta-analysis demonstrates that EA confers significant neuroprotective benefits in preclinical ALS models, primarily through multi-target modulation of key pathological processes such as neuroinflammation, aberrant cell death signaling, and RNA metabolism. These preclinical findings underscore the potential of electroacupuncture as a complementary neuroprotective strategy and warrant further investigation in rigorous clinical trials.
    Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251229183.
    Keywords:  amyotrophic lateral sclerosis; animal experiments; electroacupuncture; meta-analysis; motor neuron
    DOI:  https://doi.org/10.3389/fneur.2026.1780176
  31. BMC Palliat Care. 2026 Jul 11.
    "Straddling two worlds": complexities of spousal caregiving in amyotrophic lateral sclerosis during younger middle age.
    Andrea S E Parks, Lesley Gotlib Conn, Agessandro Abrahao, Lorne Zinman, Joanna E M Sale.
       BACKGROUND: Family support is central to amyotrophic lateral sclerosis (ALS) care. Spouses often assume the role of primary caregiver, facing daily challenges as their partner's needs progressively increase. Younger ALS caregivers appear to have distinct experiences and needs, yet age- or life-stage variations and processes of caregiving are seldom considered in studies of ALS family caregiver experience.
    METHODS: We undertook a qualitative study, guided by constructivist grounded theory methodology, to explore the dynamics of family caregiving following an ALS diagnosis in a younger middle-aged family member (≤55 years). Data were coded to identify psychosocial processes, including how family caregivers engage in caregiving.
    RESULTS: In-depth interviews were conducted with ten spousal caregivers between August 2023 and August 2025. Overall, our theoretical understanding of spousal caregiving for younger middle-aged adults with ALS (YMAs) was captured by the core category 'straddling two worlds,' reflecting how caregivers navigated multiple interconnected dichotomies: present and future, familiar and new norms, current and anticipated losses, and the worlds of the living and the dying. To contend with an uncertain future, caregivers anchored themselves in the present as they navigated a shifting sense of normalcy. Middle age expectations and social norms shaped how caregivers engaged in caregiving and experienced losses that were often unending and ambiguous.
    CONCLUSIONS: Caregiving for a spouse with ALS in younger middle age involves temporal, practical, emotional, and existential processes. Caregivers of YMAs may benefit from interventions that help them tolerate uncertainty, stay grounded in the present, maintain normalcy, and grieve losses throughout the caregiving trajectory.
    Keywords:  Amyotrophic lateral sclerosis; Caregiving; Family care; Grounded theory; Loss; Middle age
    DOI:  https://doi.org/10.1186/s12904-026-02230-w
  32. Molecules. 2026 Jul 02. pii: 2323. [Epub ahead of print]31(13):
    Indole-Derived Compounds as Redox-Modulators: Antioxidant Mechanisms in Neuronal Protection.
    Alka Ashok Singh, Ananta Prasad Arukha, Minseok Song.
      Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis, are distinguished by progressive neuronal dysfunction caused primarily by oxidative stress, mitochondrial impairment, neuroinflammation, and redox imbalance. Growing evidence suggests that indole-derived compounds have significant neuroprotective potential due to their antioxidant, anti-inflammatory, and redox-modulating properties. This review summarizes the structural and biological significance of indole scaffolds, focusing on the mechanisms by which natural, endogenous, microbiota-derived, and synthetic indole compounds protect neuronal networks. Indole-3-carbinol, 3,3'-diindolylmethane, indole-3-propionic acid, and melatonin are major indole derivatives that control important neuroprotective pathways like Nrf2/ARE signaling, mitochondrial bioenergetics, neurotrophic factor expression, apoptotic regulation, and suppression of proinflammatory mediators. These compounds also maintain synaptic plasticity, reduce reactive oxygen species production, and improve neuronal survival in neurodegenerative disease models. Additionally, updated information from translational and clinical research indicates that indole-based compounds may have promising therapeutic applications; however, obstacles like low bioavailability, metabolic instability, and blood-brain barrier penetration continue to be major obstacles to clinical application. Development in nanoparticle delivery systems, microbiome-targeted interventions, and rational structural optimization may improve therapeutic efficacy and translational potential. Overall, indole-derived compounds are a versatile class of redox modulators with potential applications in the prevention and treatment of neurodegenerative diseases via integrated antioxidant and neuroprotective mechanisms.
    Keywords:  Nrf2/ARE signaling; indole derivatives; indole-3-carbinol; indole-3-propionic acid; melatonin; neurodegenerative diseases; neuroinflammation; neuroprotection; oxidative stress; redox modulation
    DOI:  https://doi.org/10.3390/molecules31132323
  33. Neurol Neuroimmunol Neuroinflamm. 2026 Sep;13(5): e200618
    Multiplex Panel Detects Glial and Inflammatory Biomarker Signatures in Sporadic and C9orf72-ALS.
    Karthik Baskar, Christina Steffke, Sarah Bernsen, Zeynep Elmas, Jasper Hesebeck-Brinckmann, Joachim Schuster, Thomas Meyer, Patrick Weydt, Jochen Weishaupt, David Brenner, Alberto Catanese.
       BACKGROUND AND OBJECTIVES: CSF proteomics has emerged as a valuable strategy for identifying diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis (ALS). However, the limited availability and volumes of CSF samples restrict the broader clinical application of CSF-based biomarker panels. To address this challenge, we investigated whether the novel nucleic acid-linked immuno-sandwich assay (NULISA) multiplex platform-capable of quantifying multiple neural, glial, and inflammatory markers from minimal biofluid volumes-could validate previously proposed biomarkers and identify additional candidates relevant to ALS.
    METHODS: Using this platform, we measured a targeted panel of 131 biomarkers in cohorts of patients with C9orf72-associated ALS, sporadic ALS (sALS), and matched healthy controls.
    RESULTS: The 6 markers neurofilament heavy chain (NEFH) and neurofilament light chain (NEFL), chitinases-particularly chitotriosidase-1 (CHIT1) and chitinase-3-like protein-1 (CHI3L1), and chemokines CCL2 and CCL3 were significantly elevated in both ALS groups compared with controls. These biomarkers correlated with disease progression and demonstrated strong diagnostic performance when combined into aggregate scores, as reflected by a high area under the receiver operating characteristic curve for ALS. Notably, C9orf72-ALS patients exhibited higher levels of the oxidative stress-related markers PRDX6 and ENO2, compared with sALS patients, suggesting a genotype-specific molecular signature.
    DISCUSSION: Overall, our findings support the use of a multiplexed panel of diverse, inflammatory, glial, and neurodegeneration-associated biomarkers as a complementary diagnostic and prognostic tool alongside established measurements of neurofilaments. This approach may enhance biomarker robustness while minimizing CSF volume requirements, thereby improving clinical feasibility in ALS research and care.
    DOI:  https://doi.org/10.1212/NXI.0000000000200618
  34. Adv Protein Chem Struct Biol. 2026 ;pii: S1876-1623(25)00099-9. [Epub ahead of print]153 135-167
    Small molecular therapeutic targets for neurodegenerative diseases.
    Nagaraj Rangappa, Riddhi Upadhyay, Nathish Lakshman, Sivasamy Ramasamy, Murugan Sevanan, A Justin, Subashchandrabose Chinnathambi.
      Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis disease are characterized by progressive neuronal loss, protein aggregation, and synaptic dysfunction. These diseases share common pathological mechanisms including oxidative stress, mitochondrial impairment, chronic neuroinflammation, protein misfolding, and epigenetic dysregulation. Current therapies offer only symptomatic relief and fail to halt disease progression. Recent advances in transcriptomics and proteomics have enabled the identification of shared molecular pathways and druggable targets across multiple neurodegenerative diseases. The key targets, such as BDNF-TrkB, TREM2, SIRT1, PINK1-Parkin, GSK-3β, NLRP3, and mTOR have shown promise in preclinical models, offering opportunities for broad-spectrum therapeutic development. Importantly, blood-brain barrier disruption and neuroinflammatory crosstalk exacerbate disease pathology and hinder drug delivery. Innovative strategies involving nanocarriers, gene therapy, and epigenetic modulation are emerging to overcome these barriers. This review highlights the convergence of disease mechanisms, discusses common molecular signatures and therapeutic vulnerabilities, and explores novel small molecular interventions targeting shared pathways mainly in AD and PD. A deeper understanding of aging-associated molecular dysfunction is essential to design sustainable, disease-modifying therapeutics with cross-disease relevance.
    Keywords:  Alzheimer’s disease; Blood-brain barrier; Molecular targets; Neurodegeneration; Parkinson’s disease; Protein aggregation
    DOI:  https://doi.org/10.1016/bs.apcsb.2025.10.012
  35. J Transl Med. 2026 Jul 15.
    Extracellular vesicles as a liquid biopsy for amyotrophic lateral sclerosis: a systematic review and meta-analysis.
    Magdalena M Bolsinger, Nandhana Vivek, Javraj Singh, Ashrit Challa, Amanda Zhu, Trent Rothell, Samuel Wang, Timothy Zhang, Shirley Zhu, Nathan Robbins, Leony Fenwick, Grant Ruttenberg, Aleksander Bogoniewski, Hash Brown Taha.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome diagnosed clinically using standardized criteria, with neuropathological confirmation of motor neuron loss and TDP-43 aggregates in postmortem brain tissue. Extracellular vesicles (EVs) have emerged as potential minimally invasive biomarkers for ALS, but studies vary widely in methodology and reproducibility. We conducted a systematic review and meta-analysis to evaluate the diagnostic potential of EV-associated proteins and RNAs in ALS. Following PRISMA guidelines, we searched PubMed and EMBASE from inception to May 21st, 2026. Forty-one studies met inclusion criteria. Where published summary statistics were available, these were used directly; where they were not, data were reconstructed from figures or obtained from authors and re-analyzed to derive standardized effect sizes and exploratory diagnostic accuracy estimates. Random-effects models were used for continuous outcomes, and diagnostic accuracy was assessed using hierarchical summary ROC and bivariate random-effects models. Publication bias was evaluated using Begg, Egger, and funnel plots. EV-associated TDP-43 was the most frequently studied protein. Meta-analysis of five studies showed a moderate but non-significant increase in EVs from ALS vs. controls (SMD = 1.30) with high heterogeneity (I = 97.8%). Sixteen studies assessing EV-RNA biomarkers showed minimal overlap and limited independent replication. Diagnostic accuracy meta-analysis across 11 studies yielded moderate performance (AUC = 0.839). No publication bias was found across both meta-analyses. EV biomarkers for ALS show biological promise but are limited by methodological variability and insufficient replication. This work highlights the need for standardized protocols, transparent data sharing, and independent validation.
    DOI:  https://doi.org/10.1186/s12967-026-08562-8
  36. Curr Opin Struct Biol. 2026 Jul 13. pii: S0959-440X(26)00112-0. [Epub ahead of print]100 103330
    Multimodal biophysical markers of neurodegeneration: Morphology, mechanics, and thermodynamics.
    Tonya Andreeva, Nikolay Tuparev, Stefka G Taneva.
      The identification of novel noninvasive biomarkers remains a major challenge in the diagnosis of neurodegenerative diseases. Significant efforts focus on fluid biomarkers, including proteins, peptides, and miRNAs, detectable in blood plasma and peripheral blood cells. Here, we review recent findings on blood plasma and peripheral blood cells physical parameters in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis emphasizing atomic force microscopy and calorimetry assay. Alterations in morphology, nanostructure, and stiffness of red blood cells and platelets, together with thermodynamic signatures of red blood cells and plasma, provide sensitive indicators of disease-related changes. These integrated biophysical parameters not only distinguish neurodegeneration from healthy states but also enable discrimination among different neurodegenerative disorders, highlighting their potential as minimally invasive diagnostic markers.
    DOI:  https://doi.org/10.1016/j.sbi.2026.103330
  37. PLoS Genet. 2026 Jul;22(7): e1012230
    Age-based risk estimates for C9orf72RE-related diseases: Theoretical developments and added value for genetic counseling.
    Dominique de Vienne, Damien M de Vienne.
      The C9orf72 hexanucleotide repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). In genetic counseling, children of mutation carriers are often told that they have a 50% risk of carrying the mutation, but this figure does not take into account the fact that penetrance is age-related, with a unimodal distribution of disease onset around 58 years of age. Using a Bayesian approach, we developed a theory to calculate the probability of carrying the mutation for asymptomatic relatives (children/siblings and grandchildren/niblings) as well as the probability of developing ALS/FDT within a given time frame, based on their age. Using published data on age-related penetrance, we then calculated these probabilities and developed an online simulator that makes it easy to calculate them on a case-by-case basis. The conditional probabilities obtained can be very different from Mendelian values. For example, a 70-year-old asymptomatic child born to a carrier has approximately a 6% risk of being a carrier, which is far from 50%. For grandchildren, taking into account both their age and that of their parents also leads to figures that are much lower than those obtained if only their age were considered. For consultands, the decision to undergo testing is based in part on risk estimates. In this regard, the refined estimates and simulator we propose may prove to be valuable tools for genetic counseling for families affected by ALS/FTD linked to the C9orf72RE mutation. In addition, the formulas used in this study could also be used to calculate risk estimates for other diseases caused by autosomal dominant mutations with age-dependent penetrance.
    DOI:  https://doi.org/10.1371/journal.pgen.1012230
  38. Curr Neuropharmacol. 2026 Jul 10.
    White Matter Functional Dysregulation in Amyotrophic Lateral Sclerosis: Machine Learning-Based Biomarkers and Transcriptomic Signatures.
    Haifeng Chen, Zhiyuan Yang, Hailan Meng, Zheqi Hu, Zhihong Ke, Qing Ye, Yun Xu, Jiayong Wu, Zhuo Liu.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor system degeneration, yet its white matter (WM) functional pathophysiology remains underexplored.
    METHODS: This study utilized resting-state functional magnetic resonance imaging to decode WM functional abnormalities in 50 ALS patients and 55 healthy controls. Next, machine learning analysis was applied to evaluate the utility of these WM functional patterns in diagnosing ALS and predicting disease progression, and their pathophysiological mechanisms were preliminary explored through neurotransmitter mapping and imaging transcriptomics.
    RESULTS: ALS patients exhibited reduced activity in central WM regions (including bilateral corticospinal tracts), accompanied by elevated activity in anterior and posterior WM territories. The aberrant topological properties and disrupted functional connectivity are predominantly localized within bilateral precentral/postcentral WM networks. A support vector machine model incorporating these features achieved 75.24% classification accuracy and predicted the rate of disease progression (r = 0.56, p = 0.001). The spatial pattern of WM dysfunction in ALS was associated with both the spatial distribution of disease-related neurotransmitters and the expression profiles of specific genes.
    DISCUSSION: Our findings reveal distinct WM functional dysfunction patterns in ALS and their molecular-genetic underpinnings, providing novel insights into the pathophysiological mechanisms of ALS.
    CONCLUSION: ALS involves specific patterns of WM dysfunction, and these WM-centric biomarkers may facilitate the development of therapeutic monitoring frameworks for this devastating disease.
    Keywords:  Amyotrophic lateral sclerosis; imaging transcriptomics; neuro-transmission; resting-state magnetic resonance imaging; white matter functional networks
    DOI:  https://doi.org/10.2174/011570159X465668260629073047
  39. Molecules. 2026 Jul 05. pii: 2366. [Epub ahead of print]31(13):
    The Role of Hydrogen Bond Donors and Intramolecular Hydrogen Bonding in Modulating Blood-Brain Barrier Permeability: Implications for CNS Drug Design.
    Manuel Novás, Nuria Blanco López, Lourdes Santana, Eugenio Uriarte, Maria João Matos.
      The blood-brain barrier (BBB) represents a major challenge in central nervous system (CNS) drug development due to its selective permeability. Multiple molecular properties such as lipophilicity, molecular size, and hydrogen-bonding potential critically influence a compound's ability to cross the BBB. In particular, the presence of hydrogen bond donors (HBDs) and the ability to form intramolecular hydrogen bonds (IMHBs) play a crucial role in modulating brain penetration. This review discusses the mechanistic impact of HBDs and IMHBs on BBB permeability, highlighting key physicochemical parameters and case studies that demonstrate the utility of IMHBs in CNS drug design. Strategies to mask polar functionalities through IMHB formation are emphasized as promising tools to optimize brain delivery without compromising pharmacological activities. The literature reviewed in this work was collected through comprehensive searches of scientific databases, including SciFinder, PubMed, Web of Science, and Scopus, complemented by manual search of reference lists from relevant publications.
    Keywords:  blood–brain barrier; central nervous system; drug design; hydrogen bond donors; intramolecular hydrogen bonding; permeability
    DOI:  https://doi.org/10.3390/molecules31132366
  40. Curr Neuropharmacol. 2026 Jul 10.
    Mechanisms and Therapeutic Targeting of the cGAS-STING Pathway in Central Nervous System Disorders.
    Xiangyu Cai, Yi Bai, Feiyu Ma, Ruicong Xu, YIting Xie, Xiang Cao.
       OBJECTIVE: The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a core DNA-sensing axis in innate immunity and has been increasingly implicated in the pathogenesis of multiple Central Nervous System (CNS) disorders. This review summarizes current knowledge of cGAS-STING signaling in CNS disorders and evaluates its therapeutic potential.
    METHODS: Relevant studies on cGAS-STING signaling in CNS disorders were collected from PubMed and Web of Science, with emphasis on disease mechanisms, neuroinflammatory regulation, and pathway-targeted therapeutic strategies.
    RESULTS: In the CNS, cGAS-STING signaling exhibits marked region-, cell-, and pathology-dependent heterogeneity. Aberrant DNA sensing activates this pathway and amplifies neuroinflammation, cellular stress, and tissue injury in Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), ataxia-telangiectasia (A-T), and ischemic and hemorrhagic stroke. Pharmacological inhibition of cGAS, cyclic GMP-AMP (cGAMP), or STING, together with emerging delivery strategies, has shown promise in preclinical models.
    DISCUSSION: Clinical translation remains limited by incomplete validation of pathway specificity, limited human evidence, restricted brain delivery, and inconsistent efficacy assessment.
    CONCLUSION: The cGAS-STING pathway links aberrant DNA sensing to innate immune activation and CNS pathology. Clarifying its disease-, cell-, and stage-specific roles may support future targeted therapeutic strategies for CNS disorders.
    Keywords:  Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; cGAS-STING pathway; ischemic stroke; targeted therapy
    DOI:  https://doi.org/10.2174/011570159X472988260627201746
  41. Nat Rev Neurol. 2026 Jul 13.
    Astrocytic lipid dysregulation as an early driver of neurodegeneration.
    Woojin Scott Kim, Glenda M Halliday.
      Astrocytes have traditionally been cast as supportive glia, but they are increasingly recognized as metabolic hubs that regulate cholesterol synthesis, fatty acid detoxification, lipid droplet dynamics and redox homeostasis in the CNS. Neurons have a limited intrinsic capacity for lipid storage and detoxification and rely heavily on astrocytes to maintain a safe lipid environment. Emerging evidence indicates that dysregulation of astrocytic lipid homeostasis precedes overt neuronal degeneration in a range of neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia and Huntington disease. Perturbations in astrocytic lipid handling can drive maladaptive reactive states, promote oxidative stress, impair lysosomal and mitochondrial function and disrupt neuron-glia lipid exchange, collectively creating an environment that leads to neurodegeneration. Therefore, lipid dysregulation within astrocytes could trigger or amplify neuronal vulnerability. In this Review, we assess evidence that astrocytic lipid metabolism is not solely protective or pathological but has instructive physiological roles and that astrocytic lipid dysregulation is an early driver of neurodegeneration. We critically evaluate disease-specific evidence, distinguishing correlative observations from causal mechanisms. We propose that targeting of astrocytic lipid homeostasis represents a promising strategy for preventing or minimizing neurodegeneration and opens new avenues for early detection and biomarker development.
    DOI:  https://doi.org/10.1038/s41582-026-01238-3
  42. BioData Min. 2026 Jul 15.
    From unlabeled to labeled: self-supervised deep learning in computational pathology.
    Taymaz Akan, Richa Aishwarya, Md Shenuarin Bhuiyan, Steven A Conrad, John A Vanchiere, Mohammad Alfrad Nobel Bhuiyan.
       PURPOSE: The advancement of decision support systems for pathology and their implementation in clinical practice have been limited by the necessity for extensive, manually annotated datasets. Self-supervised learning (SSL) automates the extraction and interpretation of histopathological features from unannotated images, facilitating efficient model development without dependence on expert labeling. In this study, we introduce the SSL-HistoNet model that learns disease-relevant morphological representations from histopathological images through self-supervised learning.
    MATERIALS AND METHODS: We applied it to WGA-stained skeletal muscle tissues from mouse models of amyotrophic lateral sclerosis (ALS) and Type I diabetes to explore its ability to capture pathological muscle phenotypes in an annotation-free setting. Following pretraining on unlabeled data, the SSL encoder was further integrated with an attention-guided classifier to evaluate its capacity to identify pathological muscle alterations.
    RESULTS: SSL-HistoNet achieved a precision of 0.98, a recall of 0.98, and an AUC of 0.98, demonstrating performance comparable to or outperforming state-of-the-art supervised models. Alongside high discriminative performance, exploratory feature analyses demonstrated consistent class-level changes in morphology-related patterns identified through representation learning.
    CONCLUSION: These findings highlight the capability of SSL-HistoNet as an annotation-free framework for outlining disease-specific tissue structures, reducing manual labeling demands and mitigating inter- and intra-observer variability in histological processes.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Computational pathology; Contrastive learning; Self-supervised learning; Skeletal muscle; WGA staining
    DOI:  https://doi.org/10.1186/s13040-026-00586-6
  43. Nanomedicine. 2026 Jul 17. pii: S1549-9634(26)00097-3. [Epub ahead of print] 102996
    Microneedle-mediated drug delivery systems for brain diseases.
    Jia Li, Yubo Wang, Xin Ma, Xinming Bi, Tianjiao Wu, Ning Zhang, Fashan Wang, Tongfeng Liu, Fang Geng.
      Brain diseases pose a major global health challenge, with the blood-brain barrier (BBB) as the core obstacle for intracranial drug delivery. Microneedles, a minimally invasive technology, can bypass the BBB via intracranial implantation, nose-to-brain, trigeminal nerve, and transdermal systemic routes. This review covers the structural classification, biomaterials, and bypass BBB delivery mechanisms of brain-targeted microneedles. Using glioblastoma, Alzheimer's disease, and Parkinson's disease as models, we overview preclinical microneedle formulations and key signaling pathways, and establish a matching framework linking therapeutic targets, drugs, and microneedle types. We further analyze clinical translation bottlenecks including limited drug loading, unclear long-term biosafety, manufacturing challenges, and regulatory gaps, and propose future directions in technical innovation, standardized evaluation, and regulatory improvement. This work may guide the rational design and clinical translation of microneedle-mediated brain-targeted drug delivery systems.
    Keywords:  Blood–brain barrier; Brain diseases; Drug delivery; Microneedles
    DOI:  https://doi.org/10.1016/j.nano.2026.102996
  44. Cell Commun Signal. 2026 Jul 15.
    Targeting astrocyte-mediated neurotoxicity induced by ALS/FTD-associated RNA binding proteins.
    Myungjin Jo, Seyeon Kim, Junghwa Woo, Jin-Sung Park, Seung Hyun Kim, Minyeop Nahm, Sang Ryong Kim, Shinrye Lee, Hyung-Jun Kim.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders characterized by reactive astrocytes that contribute to neuronal injury through TAR DNA-binding protein 43 (TDP-43)-or fused in sarcoma (FUS)-driven neuroinflammatory signaling. Dehydrocostus lactone (DHE), a blood-brain barrier-permeable sesquiterpene lactone with established anti-inflammatory activity, represents a promising but unexplored therapeutic candidate for ALS/FTD.
    METHODS: The therapeutic effects of DHE were evaluated in primary mouse and human astrocytes expressing ALS/FTD-associated RNA-binding protein pathology, ALS patient-derived fibroblasts, and primary cortical neurons exposed to astrocyte-conditioned medium. Drosophila models expressing mutant FUS or TDP-43 in glial cells were used to assess locomotor performance and survival. Molecular analyses examined nuclear factor kappa B (NF-κB) signaling, nuclear factor erythroid 2-related factor 2 (NRF2)-dependent antioxidant responses, protein aggregation, mitochondrial function, and inflammatory mediator production. Plasma concentrations of inflammatory cytokines and chemokines were measured in patients with sporadic ALS.
    RESULTS: DHE exerted neuroprotective effects through a dual mechanism involving suppression of NF-κB-dependent inflammatory signaling and activation of NRF2-mediated antioxidant pathways in astrocytes exhibiting FUS or TDP-43 proteinopathy. DHE attenuated astrocyte-mediated neurotoxicity and improved neuronal mitochondrial function in conditioned-medium assays. In addition, DHE reduced pathological FUS accumulation in FUS P525L-expressing astrocytes and in stress-challenged patient-derived fibroblasts. In Drosophila models, DHE significantly improved locomotor function and extended survival. Translationally, the chemokines CXCL10, CCL3, and CCL19 were elevated in plasma from patients with ALS, were induced by FUS or TDP-43 pathology in astrocytes, and were suppressed by DHE treatment, supporting the clinical relevance of the inflammatory pathways targeted by DHE.
    CONCLUSION: DHE mitigates astrocyte-driven neurotoxicity associated with ALS/FTD-related RNA-binding protein pathology by suppressing inflammatory signaling and enhancing antioxidant defense mechanisms. The consistent therapeutic effects observed across mouse and human cellular models, patient-derived samples, and in vivo Drosophila models support further investigation of DHE as a potential therapeutic strategy for ALS/FTD and highlight astrocyte-mediated signaling pathways as actionable targets in neurodegenerative disease.
    Keywords:  Amyotrophic lateral sclerosis; Astrocytes; Chemokines; Frontotemporal dementia; Mitochondrial dysfunction; Neuroinflammation; Oxidative stress; RNA-binding proteins
    DOI:  https://doi.org/10.1186/s12964-026-03082-w
  45. Int J Mol Sci. 2026 Jul 07. pii: 6074. [Epub ahead of print]27(13):
    The Immunologic Function of the Choroid Plexus: A Gateway to Immunomodulatory Therapy in Injury Models of the Central Nervous System.
    Roxana Rodriguez-Barrera, Yolanda Cruz-Martínez, Emilio Moreno-González, Elisa Garcia, Guadalupe Gonzalez-Pacheco, Sion Yu Jang, Adan Peña, Antonio Ibarra, Rodolfo David Mayen Quinto, Iván Ignacio Mejía, Exsal Manuel Albores-Méndez, Melchor Castro Marín.
      Over time, our understanding of the central nervous system (CNS) as an immunologically privileged site where immune-cell infiltration takes place has changed; research has transformed the dominant view, showing that the CNS is an immunologically specialized tissue featuring complex interactions between the immune system and CNS processes, where the choroid plexus (CP) has an essential role in regulating neuronal tissue homeostasis and immune-cell trafficking. Although immune-cell entry into the CNS is tightly controlled, small numbers of antigen-experienced lymphocytes can access cerebrospinal fluid (CSF) compartments for immune surveillance under normal conditions. During an injury, such as cerebral ischemia or spinal cord damage, dendritic cell precursors infiltrate the CNS, suggesting their involvement in modulating lymphocyte activity. However, the immunoregulatory function of the CP alone is insufficient to prevent damage. Injury can trigger a cascade of events including activation of microglia toward a pro-inflammatory M1 phenotype, infiltration of peripheral immune cells across the blood-brain barrier (BBB), and uncontrolled neuroinflammation. T cells play a critical role in this process. Th1 cells exacerbate inflammation upon recognizing neural antigens, whereas Th2 cells promote recovery by releasing neurotrophic factors. This highlights the dual role of inflammation in CNS injury and repair.
    Keywords:  choroid plexus; immunological function; immunomodulation; injury model; spinal cord injury; stroke
    DOI:  https://doi.org/10.3390/ijms27136074
  46. Curr Neuropharmacol. 2026 Jul 10.
    High Levels of Plasma Neurturin Partially Mediate the Protective Effect of Reduced Ruminococcus2 Abundance on Multiple Sclerosis: A Mendelian Randomization Study.
    Yalin Liu, Jiaoyan Yang, Jingyang Su, Liying Hao.
       BACKGROUND: Genetic evidence implicates the contribution of the gut-brain axis to neurodegenerative diseases (NDDs). Alterations in gut microbiota and inflammation are key pathophysiological contributors. Elucidating the genetic basis and the role of cytokines can provide insights into mechanisms linking gut microbial composition to neurodegeneration.
    METHODS: Using aggregated statistics from five large-scale Genome-Wide Association Studies (GWAS) on Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple sclerosis, and amyotrophic lateral sclerosis, bidirectional two-sample Mendelian Randomization (MR) was used to examine the associations. A two-step multivariable Mendelian randomization approach incorporates data from 91 cytokines to explore potential mediators.
    RESULTS: The study reveals 18 positive and 17 negative effects between gut microbiota and NDDs, as well as 10 positive and 10 negative effects between cytokines and NDDs. Remarkably, mediation analysis identified a causal pathway, with evidence that plasma neurturin levels partially mediate the association from genus Ruminococcus2 to multiple sclerosis, with a mediation proportion of 19.19% (OR = 1.038, 95% CI = 1.001-1.086, P = 0.044). No pleiotropy or heterogeneity was detected.
    DISCUSSION: These MR findings provide compelling evidence for a genetically anchored gutimmune-brain network in NDDs, with cytokines as intermediates. Bidirectional effects highlight disease-specific microbial signatures and inflammatory contexts. The Ruminococcus2-neurturin pathway in multiple sclerosis may offer mechanistic specificity, aligning with neurotrophic and anti-inflammatory signaling pathways.
    CONCLUSION: This study emphasizes the importance of gut microbiota alterations in NDDs and explores inflammation's partial intermediary role. The findings suggest potential targets for personalized neurodegeneration prevention strategies.
    Keywords:  Neurodegenerative diseases; cytokines; gut microbiota; mediation; mendelian randomization
    DOI:  https://doi.org/10.2174/011570159X468669260626223524
  47. Pharmacol Res. 2026 Jul 11. pii: S1043-6618(26)00254-9. [Epub ahead of print]231 108339
    Targeting the APOE4-driven peripheral-central immune axis: A new frontier for Alzheimer's disease therapy.
    Yunzhi Shang, Zhiyong Zhai, Lin Cong, Xiaoyu Dong.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a growing global health challenge. Despite decades of research dominated by the amyloid cascade hypothesis, single-target therapies aimed at Aβ or tau have largely failed, underscoring the need for a broader framework. Emerging evidence implicates neuroimmune dysfunction as a central driver of AD pathology, with the "peripheral-central immune axis" emerging as a critical node. The APOE4 allele, the strongest genetic risk factor for sporadic AD, plays a pivotal role in both central nervous system (CNS) lipid metabolism and peripheral immune homeostasis. This review synthesizes the association between APOE4 and peripheral immune dysregulation and its impact on neurodegeneration. We discuss APOE expression in CNS and peripheral immune cells, highlighting APOE4-associated alterations in monocyte/macrophage polarization, T cell subsets via IL-7/IL-7R downregulation, and gut microbiota composition. We delineate mechanisms by which APOE4 is associated with blood-brain barrier compromise, may promote conditions for immune cell trafficking, and contributes to neuroinflammation. Integrating preclinical and clinical evidence, we propose an "APOE4-associated peripheral-central immune infiltration cascade" as a unifying framework for understanding systemic AD pathogenesis. Finally, we review emerging therapeutic strategies targeting peripheral immunity and APOE, discussing multi-target approaches guided by APOE genotype and immune biomarkers, shifting from a CNS-centric toward a systemic immunomodulatory paradigm for precision medicine.
    Keywords:  APOE4; Alzheimer's disease; Immunotherapy; Neuroinflammation; Peripheral-central immune axis
    DOI:  https://doi.org/10.1016/j.phrs.2026.108339
  48. Cells. 2026 Jul 07. pii: 1227. [Epub ahead of print]15(13):
    Hunting for an Antigen: Humoral Immunity in Alzheimer's Disease.
    Angel M Delgado, Braxton D Greer, Robert W Maul, Patricia J Gearhart.
      Alzheimer's disease (AD) is the leading cause of dementia, affecting millions of individuals on a global scale. A fatal and incurable neurodegenerative disease, AD is defined by various molecular and cellular abnormalities, such as the formation of intracellular neurofibrillary tangles and extracellular amyloid plaque deposition, leading to increased neuroinflammation, parenchymal tissue breakdown, and cognitive deficiencies. These pathological conditions are associated with the disruption of the blood-brain barrier (BBB), which is the protective network of cells responsible for maintaining homeostasis at the borders of the central nervous system (CNS). The breakdown of the BBB results in a dysregulation of the neuroimmune axis. The induction of inflammatory and autoimmune responses has been a key topic of study in AD, particularly surrounding innate immune cell activation. Recent discoveries focusing on the adaptive immune branch in the diseased CNS show evidence of effector and memory T cell activation and expansion, highlighting the complex relationship of the neuroimmune axis. It is speculated that humoral immunity might play a significant role in pathology through the production of autoantibodies. However, the contribution of B cells and plasma cells is unclear. We aim to review the literature addressing the following questions: are B cells protective or pathogenic in the CNS during AD, and do their antibodies have specific antigenic targets within this niche? The characterization of humoral contributions to immune dysregulation in AD is critical to the development of novel therapeutic strategies to slow or prevent neurodegeneration and cognitive impairment.
    Keywords:  Alzheimer’s disease; B cells; inflammation; neurodegeneration
    DOI:  https://doi.org/10.3390/cells15131227
  49. Neurol Sci. 2026 Jul 14. pii: 627. [Epub ahead of print]47(8):
    Rethinking blood-brain barrier permeability in Alzheimer's disease: insights from APOE genotype-specific associations.
    Qin Wu, Yu Jin.
      
    DOI:  https://doi.org/10.1007/s10072-026-09242-7
  50. CNS Neurol Disord Drug Targets. 2026 Jul 08.
    Gut Microbiota in Neuroinflammation, Neurodegenerative Disorders, and Neuropsychiatric Disorders: A Comprehensive Narrative Review.
    Smita Singh, Sumita Singh, Vishal Khandelwal, Ujjwal Bharti, Pranjal Kumar Singh.
      Neurodegenerative and neuropsychiatric illnesses are characterized by neuroinflammation, which is driven by microglial activation, cytokine production, and breakdown of the blood-brain barrier (BBB). It is currently known that the gut microbiota plays an important role in modulating neuroimmune signaling, which in turn may trigger anxiety-like behaviors and depressive phenotypes through the microbiota-gut-brain axis. This review aims to integrate the most recent mechanistic knowledge on treatment strategies targeting the gut microbiota to modulate neuroinflammation. This review article discusses preclinical and clinical studies that investigated microbial composition, metabolite profiles, and host-microbe interactions involved in neuroinflammatory processes. However, special attention was given to signaling via the vagus nerves and bile acids, as well as to tryptophankynurenine metabolism and short-chain fatty acids (SCFAs). To examine the potential connection between the two, researchers used animal models such as germ-free animals and antibiotic-injected mice for fecal microbiota transplantation (FMT). This article defines dysbiosis as amplifying neuroinflammatory responses by altering microglial phenotypes, disrupting the blood-brain barrier, and triggering the production of pro-inflammatory cytokines. In contrast, microbiome diversity rehabilitation through the use of probiotics, prebiotics, synbiotics, and dietary modifications reduces neuroinflammatory markers and enhances cognitive and behavioral status. Clinical trials have shown considerable promise in diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), autism spectrum disorder (ASD), and depression. However, variability in treatment protocols, treatment resistance, and host-specific factors continue to pose significant challenges. This narrative review integrates mechanistic insights into microglial activation, cytokine signaling, blood-brain barrier regulation, vagal pathways, tryptophan metabolism, and short-chain fatty acids with emerging clinical evidence and therapeutic strategies, including probiotics, prebiotics, dietary modulation, and personalized microbiome-based interventions. Despite promising therapeutic potential, microbiome engineering faces important challenges, including safety concerns, lack of standardized intervention protocols, and substantial inter-individual variability in host-microbiome responses, which currently limit clinical translation. This review focuses on both neurodegenerative and neuropsychiatric disorders, examining shared neuroinflammatory mechanisms mediated by the gut-brain axis and evaluating microbiotatargeted therapeutic strategies across these disease categories. The review discusses both preventive strategies, including dietary modulation, prebiotics, and lifestyle-based microbiome interventions, as well as therapeutic approaches such as microbiota-targeted treatments aimed at mitigating neuroinflammation and disease progression.
    Keywords:  Gut microbiota; gut-brain axis; microbiome; neurodegenerative disorders; neuroinflammation; neuropsychiatric disorders.
    DOI:  https://doi.org/10.2174/0118715273455874260702045636
  51. Nat Rev Drug Discov. 2026 Jul 16.
    Brain-shuttle biologics chart new paths across the blood-brain barrier.
    Elie Dolgin.
      
    DOI:  https://doi.org/10.1038/d41573-026-00121-6
  52. Cells. 2026 Jun 27. pii: 1173. [Epub ahead of print]15(13):
    Modeling Neuroimmunological Interactions at the Blood-Brain Barrier Using In Vitro 3D Human Organoids: Inflammation and Ischemia-Reperfusion Injury.
    Aya A Eltaibany, Kathleen McGovern, Goodwell Nzou, Daniel Porada, Michael C Seeds, Anthony Atala.
      Numerous central nervous system pathological conditions involve blood-brain barrier (BBB) disruption and the egress of immune cells in the brain. Controlling immune cell transmigration into the brain represents a potential therapeutic target. This study describes the application of a 3D human BBB spheroidal model that consists of six major brain cell types to test the transmigration of immune cells under normal and pathological conditions of inflammation and ischemia-reperfusion injury (IRI). The cell types in the BBB organoid include brain microvascular endothelial cells (HBMVECs) and pericytes at the spheroids' surface, surrounding a core of astrocytes, microglia, oligodendrocytes, and neural progenitor cells. The model recapitulates the interaction of CD4+ T-cells and immunomodulators with HBMVECs at the BBB including changes in cell adhesion molecules expressed on their surface. This study demonstrated that the human 3D BBB model recapitulates many features of the barrier under normal and pathological conditions of inflammation and hypoxia-reperfusion injury. Proinflammatory cytokines and hypoxia disrupt the barrier and increase its permeability, decreasing the expression of tight junctions. Proinflammatory cytokines and reperfusion increase the expression of cell adhesion molecules and increase immune cell transmigration. Immune cell transmigration could be reduced with anti-cell adhesion molecule antibodies, further validating the model for studying neuroimmune interactions and for conducting high-throughput screening of therapeutic targets that modulate immune cell transmigration into the brain.
    Keywords:  blood–brain barrier; cell adhesion molecules; immune cells; inflammation; ischemia–reperfusion; neuroimmune
    DOI:  https://doi.org/10.3390/cells15131173
  53. Acta Neuropathol Commun. 2026 Jul 11.
    The modulation of the blood-brain barrier by focused ultrasound stimulates oligodendrogenesis.
    Kate Noseworthy, Joseph Silburt, Alessia Apa, Luis Fernando Rubio-Atonal, Sheng-Kai Wu, Carol Schuurmans, Kullervo Hynynen, Isabelle Aubert.
      Focused ultrasound (FUS) combined with intravenous microbubbles (MB) enables precise and reversible modulation of the blood-brain barrier (BBB) to enhance the delivery of therapeutics from the blood to targeted brain areas. Beyond this application, we discovered over a decade ago that FUS-BBB modulation, without the addition of exogenous therapeutics, activates endogenous regenerative events, "most notably" hippocampal neurogenesis. Here, we investigate the effects of FUS on oligodendrogenesis, a key process for myelination and white matter integrity. In adult mice, we targeted FUS-BBB modulation unilaterally to the hippocampus. The proliferation of oligodendrocyte precursor cells (OPCs) was quantified at 1, 4, 7, and 10 days post-treatment and myelinating oligodendrocytes were assessed at 30 days. At 1 and 4 days post-sonication, the proliferation of hippocampal OPCs increased by 6.8-fold and 2.3-fold, respectively; this resulted in a 5.3-fold increase in myelinating oligodendrocytes one month later. Next, we tested the robustness of FUS-induced oligodendrogenesis using an independent experimental design and targeting the striatum in a separate cohort of mice. The proliferation of striatal OPCs increased by 3.9-fold at 7 days post-FUS. This led to a 5.2-fold increase in oligodendrogenesis 30 days post-treatment, as observed in the hippocampus. Finally, we found that treatments at the same FUS parameters but without MB and without altering the BBB, did not lead to the proliferation of OPCs or oligodendrogenesis. Therefore, with these FUS parameters, MB-induced BBB modulation emerged as a key factor that promoted oligodendrogenesis. Given the long-validated application of FUS-BBB modulation for drug delivery, the additional stimulation of oligodendrogenesis broadens the therapeutic potential of this modality for white matter repair.
    Keywords:  Blood–brain barrier; Focused ultrasound; Oligodendrocyte progenitor cells; Oligodendrocytes; Oligodendrogenesis
    DOI:  https://doi.org/10.1186/s40478-026-02364-1
  54. Immunol Res. 2026 Jul 17. pii: 72. [Epub ahead of print]74(1):
    Decoding the PI3K/Akt/mTOR-JAK/STAT signaling axis in multiple sclerosis: mechanistic crosstalk and therapeutic opportunities.
    Chandrayee Banerjee, Rohit Kumar Singh, Divya Choudhary, Md Nasiruddin Khan, Pankaj Kumar Maurya, Zuber Khan, Sidharth Mehan, Rajaram Samant, Manoj Tongra.
      Multiple Sclerosis (MS) is a chronic immune-mediated neurodegenerative disorder characterized by demyelination, axonal injury, and progressive neurological dysfunction. Emerging evidence identifies the phosphoinositide-3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways as interconnected regulators of neuroinflammation and immune dysregulation in MS. This review critically examines the mechanistic crosstalk between these signaling networks and their contribution to disease progression. Dysregulated PI3K/Akt/mTOR signaling influences T-cell activation, immunometabolic reprogramming, autophagy, and oligodendrocyte survival, whereas aberrant activation of the JAK2/STAT3 axis promotes Th17-cell differentiation, cytokine amplification, and sustained inflammatory responses within the central nervous system. Importantly, convergence between Th17/STAT3 signaling and PI3K/Akt-mediated metabolic pathways establishes a regulatory network that enhances microglial activation, blood-brain barrier disruption, and neuronal injury. The review further highlights the context-dependent role of mTOR signaling, which may simultaneously support remyelination and oligodendrocyte maturation while contributing to neurodegeneration when excessively activated. In addition to immune-cell-mediated mechanisms, emerging evidence demonstrates critical contributions of neuronal, glial, endothelial, and oligodendrocyte precursor cell signaling to MS pathology. Preclinical and clinical findings indicate that pharmacological modulation of these pathways can attenuate inflammatory responses and improve neuroprotection; however, therapeutic translation remains challenging because of their dual physiological and pathological functions. Collectively, this review provides an integrated perspective on PI3K/Akt/mTOR-JAK/STAT signaling interactions and highlights cell-specific molecular targets that may facilitate the development of more precise therapeutic strategies for MS.
    Keywords:  Immune dysregulation; JAK/STAT signaling pathway; Multiple sclerosis; Neuroinflammation; PI3K/Akt/mTOR signaling pathway; Therapeutic targets
    DOI:  https://doi.org/10.1007/s12026-026-09808-9
  55. J Parkinsons Dis. 2026 Jul 14. 1877718X261463389
    Rodent models and accompanying in vitro strategies for studying the etiology and therapy of Parkinson's disease.
    Kristina Lau, Tiago F Outeiro, Franziska Richter.
      The lack of disease-modifying therapies for Parkinson's disease (PD) places a severe burden on patients, their caregivers and aging societies. While the incomplete knowledge of underlying causes and pathophysiology remains a major bottleneck towards the development of rational therapies, there have been important advances in our understanding of neurodegenerative processes. Here, animal models have contributed substantially by allowing researchers to decipher PD-relevant pathology and the development of corresponding behavioral signs, which enabled development and refinement of treatment options. Without animal models, hypotheses of mechanisms underlying the development of motor symptoms after dopamine depletion, dyskinesia as side effects, the impact of diverse environmental neurotoxins, or the formation of alpha-synuclein pathology and spreading could not have been conclusively tested. Likewise, novel technologies are enabling the use of patient derived tissues for generating in vitro models that further enhance our understanding of mechanisms and of the effects of specific genetic modifications and their role in neurodegeneration. However, animal models are, as of yet, still required to model a fully functional central nervous system connected to the immune system and peripheral organs, which are impacted by the diversity of PD pathology and symptoms. Here, we provide an overview of key contributions of animal models, their ongoing role in PD research, and how this research can be enhanced by the concomitant use of advanced in vitro systems.
    Keywords:  Parkinson's disease; animal models; in vitro; neurodegeneration; organoids
    DOI:  https://doi.org/10.1177/1877718X261463389
  56. Brain Commun. 2026 ;8(4): fcag240
    Investigating the treatment of vascular risk with simvastatin in secondary progressive multiple sclerosis: analysis from the MS-STAT2 randomized controlled trial.
    the MS-STAT2 investigators
      Vascular comorbidity is associated with more severe disability in multiple sclerosis. However, it is unknown whether treating vascular risk will lead to a disease modifying effect. Given the established role of simvastatin as a modifier of vascular risk, we aimed to investigate whether randomization to simvastatin could mitigate the relationships between serum cholesterol profiles and disease worsening, compared with placebo, in the MS-STAT2 trial. MS-STAT2 (NCT03387670) recruited 964 patients with secondary progressive multiple sclerosis, who were randomized to simvastatin (80 mg) or placebo for 3 years. 246 participants additionally underwent yearly magnetic resonance imaging (MRI). Vascular risks were systematically assessed at trial baseline. In this exploratory analysis, the relationships between cholesterol ratio (total cholesterol/high-density lipoprotein) and longitudinal clinical and MRI outcomes were assessed, comparing simvastatin to placebo groups. At baseline, median (IQR) age was 55 (50-60) years and median cholesterol ratio 3.4 (2.8 to 4.3). 73% were female, and 72% required a walking aid. Higher cholesterol ratio was associated with more severe baseline disability. No longitudinal relationships were observed between cholesterol ratio and clinical or brain atrophy outcomes. However, for each unit increase in cholesterol ratio, T2 lesion volume increased by +2.47% (95% CI: +0.03 to +4.97) from baseline in the placebo group. This relationship was significantly reduced in those randomized to simvastatin (-3.10% [-0.06 to -6.06]). Randomization to simvastatin appeared to mitigate the relationship between higher cholesterol ratios and longitudinal increases in T2 lesion volume in patients with secondary progressive multiple sclerosis. Further multi-modal interventional studies targeting vascular risk in patients with multiple sclerosis are warranted.
    Keywords:  cholesterol; multiple sclerosis; secondary progressive multiple sclerosis; statins; vascular risk
    DOI:  https://doi.org/10.1093/braincomms/fcag240
  57. CNS Neurol Disord Drug Targets. 2026 Jul 08.
    Syntaxin-4 at the Crossroads of Synaptic Plasticity and Neurodegeneration: From Molecular Mechanisms to Biomarker and Therapeutic Potential.
    Yue Li, YunSong Wei, JingBo Zhao, PuSheng Quan, Cheng Wang, Mingfang Jiang.
      Syntaxin-4 (Stx4), a member of the Qa-SNARE protein family, is a pivotal regulator of membrane trafficking. Stx4 is predominantly localized at the postsynaptic membrane of neurons and in glial cells, where it is essential for synaptic plasticity and the maintenance of neuronal homeostasis. Stx4 facilitates the activity-dependent exocytosis of glutamatergic receptors, thereby governing the balance between Long-Term Potentiation (LTP) and Long-Term Depression (LTD). Emerging evidence suggests that dysregulation of Stx4 is intricately linked to the pathogenesis of neurodegenerative diseases. In Alzheimer's disease, Stx4 is involved in synaptic dysfunction and cognitive impairment through its interactions with amyloid-β (Aβ) and tau pathologies, affecting receptor recruitment at dendritic spines. In Parkinson's Disease (PD), Stx4 contributes to α-synuclein proteostasis, dopaminergic signaling, neuroinflammation, and the maintenance of blood-brain barrier integrity. While its presence in cerebrospinal fluid highlights its potential as a candidate biomarker for these diseases, further validation is required to establish clinical utility. This review summarizes current mechanistic insights into Stx4's multifaceted roles in the neurodegenerative disorders and explores the therapeutic prospects of targeting Stx4-mediated pathways due to its translational potential.
    Keywords:  Syntaxin-4; biomarker; molecular mechanisms; neurodegeneration; synaptic plasticity; therapeutic potential
    DOI:  https://doi.org/10.2174/0118715273465885260623094946
  58. Magn Reson Med. 2026 Jul 18.
    Brain Clearance of Contrast Agent in Intravenous DCE-MRI Is Measurable and Cannot Be Explained by Clearance Across the BBB Alone.
    Martin Kozár, Ioana-Emilia Mosneag, Sarah Al-Bachari, Igor Chernyavsky, Geoff J M Parker, Hervé Boutin, Laura M Parkes, Ingo Schiessl, Ben R Dickie.
       PURPOSE: To determine the feasibility of measuring brain clearance of gadolinium contrast agent using standard intravenous DCE-MRI acquisitions and evaluate the contribution of blood-brain barrier (BBB) and non-BBB clearance routes.
    METHODS: Uptake and extended Tofts models were fit to DCE-MRI data from people with Parkinson's disease, post-stroke and controls. Models were compared using the Akaike information criterion. Key parameters (Ktrans, vp, ve, and k) were extracted from gray and white matter ROIs. In mice, two-photon microscopy of intravenously injected Sulforhodamine 101 was used to confirm small tracer clearance kinetics without the confounds of partial volume effects or water exchange.
    RESULTS: The extended Tofts model provided a superior fit compared to all uptake-only models. Extended Tofts estimates of the extravascular extracellular volume fraction ve were underestimated by a factor of 10-20 compared to known literature values (1.5% vs. 20%-30%). We hypothesized this bias may be due to an additional competing non-BBB clearance mechanism not accounted for by the extended Tofts model. In both MRI and two-photon data, we found that ve estimates trended toward literature values as BBB permeability (and thus BBB clearance) increased, supporting our hypothesis.
    CONCLUSION: Modeling clearance of extravasated contrast agent from the brain improves fit quality compared to models that neglect clearance. Estimates of interstitial volume fraction were underestimated at low Ktrans but tended toward literature values as BBB permeability (and clearance) increased. This study indicates that estimating brain clearance of contrast agent using DCE-MRI is feasible, and that estimates reflect a combination of BBB and non-BBB clearance pathways.
    DOI:  https://doi.org/10.1002/mrm.70514
  59. Eur J Neurol. 2026 Jul;33(7): e70679
    Vascular-Apoptotic Crosstalk in Alzheimer's Disease: The Possible Role of Vascular Senescence in Blood-Brain Barrier Dysfunction.
    Carlangelo Carrese, Chiara Giuseppina Bonomi, Francesca Bernocchi, Martina Gaia Di Donna, Martina Poli, Guido Greco, Nicola Biagio Mercuri, Alessandro Martorana, Caterina Motta.
       BACKGROUND: Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD), influenced by amyloid pathology, astrocyte activation, and vasoactive mediators such as endothelin-1 (ET-1). ET-1 has been implicated in apoptosis and vascular senescence through induction of p53, a pro-apoptotic factor, whereas BCL-X exerts antiapoptotic effects. We investigated the interplay between ET-1, p53, and BCL-X in AD and their contribution to BBB permeability.
    METHODS: We studied 101 individuals (70 AD, 31 controls) who underwent cerebrospinal fluid (CSF) analysis for Aβ42, p-tau, ET-1, p53, BCL-X, and the CSF/serum albumin quotient (QAlb), an index of BBB permeability. Correlations between biomarkers were explored, followed by multiple regression and mediation analysis to assess whether p53 mediated the ET-1-BBB relationship.
    RESULTS: No absolute differences in ET-1, p53, or BCL-X were found between AD and controls. However, in AD, ET-1 correlated positively with p53 and negatively with BCL-X, whereas no such associations were seen in controls. None of these biomarkers related to the p-tau/Aβ42 ratio. Regression analysis identified both ET-1 and p53 as independent predictors of BBB permeability. Mediation analysis further revealed that ET-1 influenced BBB permeability both directly and indirectly through p53.
    CONCLUSION: Our findings suggest that AD is characterized less by absolute biomarker changes and more by altered interrelationships linking ET-1, apoptosis, and BBB integrity. ET-1 may promote BBB dysfunction partly via p53, which is consistent with the mechanisms of vascular senescence. These results highlight apoptosis-vascular interactions as potential drivers of BBB impairment in AD.
    Keywords:  Alzheimers disease; apoptosis; blood–brain barrier; endothelin‐1; senescence
    DOI:  https://doi.org/10.1111/ene.70679
  60. Curr Hematol Malig Rep. 2026 Jul 13. pii: 14. [Epub ahead of print]21(1):
    Breaching the Blood-Brain Barrier: Evolving Strategies for Central Nervous System Disease in Adult Acute Lymphoblastic Leukemia.
    Liesl S Eibschutz, Samuel Crow, Caroline Tatum, Daniel Reed, Michael Keng.
       PURPOSE OF REVIEW: Central nervous system (CNS) involvement in adult acute lymphoblastic leukemia (ALL) remains a critical determinant of treatment failure and long-term survival. This review provides a comprehensive, evidence-based framework for the diagnosis, risk stratification, prophylaxis, and treatment of CNS disease in adult ALL, with emphasis on the evolving challenges introduced by immunotherapy-based and chemotherapy-sparing regimens and presents our institutional approach to CNS-directed therapy.
    RECENT FINDINGS: Modern CNS prophylaxis combining intrathecal chemotherapy with CNS-penetrating systemic agents has dramatically reduced CNS relapse rates, yet diagnostic and therapeutic limitations persist. The increasing use of immunotherapies, such as blinatumomab and inotuzumab ozogamicin, has improved systemic disease control, while CNS relapse is increasingly recognized in this context, particularly among heavily pretreated patients. This pattern likely reflects multiple factors, including limited CNS penetration, improved disease control that unmasks previously subclinical CNS involvement, and the high-risk biology of relapsed/refractory disease. In contrast, CD19-directed CAR T-cell therapies have demonstrated meaningful activity in CNS disease, while investigational strategies targeting leukemic trafficking pathways and IL-15 signaling offer additional preclinical promise. As adult ALL treatment has shifted toward chemotherapy-sparing regimens, new concerns have emerged regarding disease control within the CNS compartment. Durable remission will require integration of rigorous intrathecal prophylaxis, risk-adapted systemic therapy, and novel agents capable of penetrating the CNS microenvironment into every treatment algorithm.
    Keywords:  Acute lymphoblastic leukemia; Blinatumomab; CAR T-cell therapy; CNS prophylaxis; Central nervous system; Inotuzumab ozogamicin; Intrathecal chemotherapy
    DOI:  https://doi.org/10.1007/s11899-026-00782-5
  61. Neurosci Biobehav Rev. 2026 Jul 11. pii: S0149-7634(26)00323-4. [Epub ahead of print]189 106866
    Intranasal dopamine: Anatomical pathways, biological mechanisms and neuromodulatory potential.
    Owen Y Chao, Susanne Nikolaus, Claudia Mattern, Lih-Chu Chiou, Joseph P Huston.
      Dopamine (DA) regulates motor control, motivation, learning and memory, cognition, and social behavior, and its dysregulation underlies a wide range of neurological and psychiatric disorders. In Parkinson's disease (PD), degeneration of dopaminergic neurons in the substantia nigra depletes striatal DA, making dopaminergic restoration a central therapeutic target. Because DA does not cross the blood-brain barrier (BBB), treatment relies on its precursor L-DOPA. Intranasal (IN) administration offers a non-invasive alternative: it enables rapid absorption, avoids hepatic first-pass metabolism, and provides partial brain access via nose-to-brain pathways, positioning IN-DA as a potential tool to directly influence central dopaminergic function. This review integrates current knowledge on IN-DA. We first examine nasal anatomy, the biological and physicochemical variables governing IN delivery, and the mechanisms of nose-to-brain transport, followed by a focused synthesis of IN-DA findings. Preclinical evidence shows that IN-DA and IN-L-DOPA increase extracellular DA levels and turnover in the striatum, with IN-DA appearing to enhance dopaminergic tone through presynaptic uptake and storage. Behaviorally, IN-DA produces state-dependent improvements across cognitive, emotional, and social domains, particularly in neuropsychiatric rodent models. Although nanoparticle-based DA formulations are being developed primarily to improve delivery efficiency for PD therapy, emerging evidence suggests that IN-DA may serve more broadly as a neuromodulatory approach for disorders involving catecholamine dysregulation.
    Keywords:  ADHD; Autism; Cognitive function; Nanoparticles; Schizophrenia
    DOI:  https://doi.org/10.1016/j.neubiorev.2026.106866
  62. Nutrients. 2026 Jun 28. pii: 2106. [Epub ahead of print]18(13):
    Relationships Between High Dietary Inflammatory Index Scores and Intestinal and Blood-Brain Barrier Integrity in the Context of Neurodegenerative Diseases.
    Dariusz Szukiewicz, Juliana Almeida-de-Souza, Małgorzata Gryka-Marton, Mateusz Wątroba, Anna D Grabowska.
      The impact of diet on human health is constantly being researched. Nutrition is one of the most powerful tools for influencing gene expression, and dietary habits can promote the expression of genetic predisposition to obesity, diabetes, cardiovascular disease, cancer, and neurodegenerative diseases (NDs). The dietary inflammatory index (DII) is a numerical score that assesses the pro-or anti-inflammatory potential of a given diet. According to high DII scores, a Western diet or a standard American diet (SAD) has proinflammatory properties. By disrupting the gut microbiome, SAD creates an unfavorable environment in the intestine that is associated with a low-grade systemic inflammatory response and oxidative changes that may promote the development of NDs. An increased intestinal permeability and loss of blood-brain barrier (BBB) integrity play key roles in the pathomechanisms of diet-dependent NDs, leading to proinflammatory signaling via the gut-brain axis. The aim of this narrative review is to present in detail the current state of knowledge on the function of the gut-brain axis depending on the pro-/anti-inflammatory potential of the diet, measured by the DII, in the context of the contributions of intestinal and BBB permeability disorders to the development of NDs.
    Keywords:  biomarkers of inflammation; blood–brain barrier integrity; chronic low-grade inflammation; dietary inflammatory index; inflammatory markers; intestinal barrier integrity; neurodegenerative diseases; resoleomic disorders
    DOI:  https://doi.org/10.3390/nu18132106
  63. Diagnostics (Basel). 2026 Jul 05. pii: 2104. [Epub ahead of print]16(13):
    Integrating Metabolic, Perfusion, and Microstructural Parameters for Quantitative Neuroimaging in Rare Neurodegenerative Diseases: A Hybrid PET/MRI Approach.
    Joachim Strobel, Hans-Peter Müller, Laura Michelberger, Anastasia Nosanova, Wolfgang Thaiss, Karl Georg Haeusler, Jochen H Weishaupt, Kornelia Kreiser, Ambros J Beer, Meinrad Beer, Jan Kassubek, Nico Sollmann.
      Background/Objectives: The use of quantitative neuroimaging to establish objective biomarkers in neurodegenerative diseases (NDD) has attracted increasing interest over the last decade. Advanced magnetic resonance imaging (MRI) such as arterial spin labeling (ASL) and diffusion tensor imaging (DTI), as well as [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET), could provide clinically meaningful biomarkers and may support differential diagnosis. The aim of this investigator-initiated, single-center, retrospective comparative study was to implement a framework for multimodal neuroimaging to evaluate cases with rare NDD, using a methodological approach that integrates metabolic, perfusion, and microstructural parameters from simultaneous FDG-PET/MRI, and to investigate its potential to facilitate diagnosis. Methods: Three patients with pathological motor signs (1f/2m; 63, 73, and 52 years) and 19 control subjects with subjective cognitive deficits (SCDs) underwent combined FDG-PET/MRI with pseudo-continuous ASL and DTI. Standardized uptake values (SUVs), relative cerebral blood flow (rCBF), and fractional anisotropy (FA) were calculated to identify pattern alterations in individual patients based on parameterization mapping. The final diagnosis was corticobasal degeneration (CBD, n = 1) or primary lateral sclerosis (PLS, n = 2). Results: At the individual patient level, disease-specific changes in defined brain regions could be demonstrated and quantified compared to control subjects. All three patients showed significantly decreased FA, primarily along parts of the course of the corticospinal tract (CST). In the patient with CBD, asymmetric SUVR and rCBF decreases were observed, mostly overlapping with motor regions. In the two patients with PLS, SUVR revealed mostly unspecific findings (hypothetically due to a slow progression rate or due to potentially early disease stages), while ASL indicated decreased rCBF primarily overlapping within the motor cortex. Changes at the gray matter level were primarily located adjacent to changes in white matter, as indicated by the multimodal analysis approach using simultaneously acquired FDG-PET/MRI data. Conclusions: According to this proof-of-concept study, multimodal neuroimaging by the combination of quantitative MRI and FDG-PET has the potential to guide differential diagnosis in rare NDDs, especially if clinical diagnosis is not straightforward to achieve. Since particularly early diagnosis remains essential for patient counseling, effective treatment, and clinical management, the present framework appears helpful to be developed further until it aligns and integrates with clinical routine.
    Keywords:  arterial spin labeling; corticobasal degeneration; diffusion tensor imaging; magnetic resonance imaging; positron emission tomography; primary lateral sclerosis
    DOI:  https://doi.org/10.3390/diagnostics16132104
  64. Sci Adv. 2026 Jul 17. 12(29): eaed4944
    Focused ultrasound blood-brain barrier opening reveals a paradoxical remote metabolic response in the primate brain.
    Soroosh Sanatkhani, Dong Liu, Fabian Munoz, Jack Grinband, Elisa E Konofagou, Vincent P Ferrera.
      Low-intensity focused ultrasound (LIFU) is a promising technique for opening the blood-brain barrier (BBB) for drug delivery, but its physiological consequences in remote brain regions remain a major blind spot for clinical safety and efficacy. To address this gap, we performed the quantitative mapping of brain metabolism following a focal LIFU-induced BBB opening in a nonhuman primate model, using quantitative BOLD MRI to measure the oxygen extraction fraction (OEF). We report a paradoxical response: While the targeted striatum showed no significant metabolic changes, we observed a profound and spatially specific increase in OEF in the homologous contralateral striatum, an effect predominantly driven by the putamen. These findings demonstrate that focal BBB opening is not merely a localized vascular event but a potent neuromodulatory intervention that induces metabolic stress in distant, untreated brain regions, a discovery with critical implications for the safe and effective clinical translation of all focal brain therapies.
    DOI:  https://doi.org/10.1126/sciadv.aed4944
  65. Purinergic Signal. 2026 Jul 17. pii: 63. [Epub ahead of print]22(4):
    Is adenosine signalling entering the precision medicine era? From receptor pharmacology to patient stratification.
    Luca Antonioli, György Haskó.
      Over the past three decades, adenosine signalling has emerged as a fundamental regulatory system controlling immune responses, tissue homeostasis, metabolism, and repair processes. The identification of four adenosine receptor subtypes and the development of selective agonists and antagonists generated substantial enthusiasm for therapeutic targeting across a broad spectrum of inflammatory, autoimmune, metabolic, and neoplastic diseases. However, despite compelling preclinical evidence, the clinical translation of adenosine-based therapies has often yielded inconsistent or disappointing results. Increasing evidence suggests that these limitations may not primarily reflect inadequate pharmacological tools, but rather an incomplete understanding of the remarkable spatial, temporal, and cellular heterogeneity of adenosine signalling in human disease. Advances in immunology, systems biology, single-cell technologies, spatial transcriptomics, metabolomics, and artificial intelligence are revealing highly diverse purinergic landscapes across tissues and patient populations. These findings challenge the traditional "one receptor-one disease" paradigm and support a transition toward precision medicine approaches capable of identifying disease-specific and patient-specific purinergic signatures. In this commentary, we discuss how the field is moving beyond classical receptor pharmacology toward biomarker-driven patient stratification. We propose that the next generation of purinergic therapeutics will depend not only on improved drugs but also on the ability to define when, where, and in whom adenosine signalling should be manipulated. Such a shift may ultimately represent the long-awaited bridge between decades of successful experimental research and meaningful clinical implementation.
    Keywords:  Adenosine; Adenosine receptors; Biomarkers; Personalized therapy; Precision medicine; Purinergic signalling
    DOI:  https://doi.org/10.1007/s11302-026-10175-1
  66. Pak J Pharm Sci. 2026 Sep;39(9): 2825-2836
    Study on retinal pharmacokinetic characteristics and precision drug administration strategy in patients with fundus diseases.
    Liang Fu, Lei Huang, Ruxue Guo, Li Wu, Xiang Zeng, Zhihe Fu.
       BACKGROUND: Fundus diseases are major causes of irreversible visual impairment. Retinal pharmacokinetic behavior may differ between diabetic retinopathy (DR) and age-related macular degeneration (AMD), but disease-specific dosing principles remain insufficiently defined.
    OBJECTIVES: Disease-stratified retinal pharmacokinetic characteristics were evaluated, and a precision drug administration strategy for patients with fundus diseases was developed.
    METHODS: Blood-retinal barrier (BRB) cell models, retinal organoids, retinal pigment epithelium (RPE) models, optical coherence tomography (OCT), serum biomarkers and clinical records were integrated. A retrospective, controlled clinical analysis was performed in patients with DR or AMD, in accordance with ethics approval No. 20240923.
    RESULTS: DR was characterized by greater barrier permeability and transporter-related retention, whereas AMD was characterized by lipid-associated RPE dysfunction and restricted trans-retinal penetration. The DR model predicted retinal peak concentration with R2 = 0.89, and the AMD model predicted drug half-life with 86% accuracy. Precision administration was associated with reduced injection frequency in DR and AMD and improved anatomical and visual outcomes.
    CONCLUSION: Disease-specific retinal pharmacokinetic differences support individualized dosing strategies for fundus diseases. The proposed platform provides a practical framework for precision anti-VEGF therapy and targeted retinal drug delivery.
    Keywords:   Blood-retinal barrier ; Fundus diseases ; Nano-drug delivery system ; Precision drug administration ; Retinal pharmacokinetics
    DOI:  https://doi.org/10.36721/PJPS.2026.39.9.263.1
  67. J Alzheimers Dis. 2026 Jul 11. 13872877261467705
    Amyloid-related imaging abnormalities after immunotherapy: How might brain microvascular basement membrane components be involved?
    Harry V Vinters, Shino Magaki.
      Basement membrane components are integral to the physiologic function of cerebral microvessels. Immunotherapy (including by the use of lecanemab) in Alzheimer's disease patients may result in vascular complications identified by neuroimaging (ARIA-E and ARIA-H). This pilot study (on a relatively small number of human brain specimens) suggests one mechanism might be through the effects of lecanemab on a collagen component of said microvessel walls. It utilizes microvessels isolated from human brains (of Alzheimer's disease patients) and maintained in a viable state, to examine this mechanism using novel biochemical and molecular approaches. These yield preliminary evidence of how lecanemab may influence a specific component of the cerebral microvasculature and suggest other studies that may be used to address this important question.
    Keywords:  Alzheimer's disease; neurodegeneration; neurodegenerative diseases; neuropathology
    DOI:  https://doi.org/10.1177/13872877261467705
  68. Handb Exp Pharmacol. 2026 Jul 17.
    TAAR Immunopharmacology.
    Anna Magnesa, Andrea Pacini, Grazia Rutigliano.
      Trace amine-associated receptors (TAARs) were originally identified as G protein-coupled receptors involved in monoaminergic signaling within the central nervous system. However, accumulating evidence indicates that TAARs, particularly TAAR1 and TAAR2, are also expressed in the immune system, including circulating leukocytes, lymphocytes, macrophages, and microglia. This chapter reviews current evidence regarding TAAR expression, functional pharmacology, and potential translational relevance within the immune system.Expression studies support a predominant TAAR1/TAAR2 pattern across both innate and adaptive immune-cell populations. Functional studies indicate that TAAR signaling can modulate inflammatory responses through chemotaxis, cytokine production, and immunoglobulin secretion. However, these effects are highly context-dependent, preventing a simple classification of TAAR signaling as either pro-inflammatory or anti-inflammatory.The chapter also discusses the emerging role of TAAR signaling in the pathophysiology of diseases, including inflammatory bowel disease, methamphetamine-associated immune dysfunction during HIV infection, multiple sclerosis, Parkinson's disease, fibromyalgia, and hematological malignancies.Despite growing interest in TAAR immunopharmacology, the current evidence remains largely preclinical and methodologically heterogeneous. Major limitations include incomplete protein-level validation, reliance on immortalized cell lines or mixed-cell populations, species-specific pharmacology of available ligands, and limited understanding of physiological trace amine signaling under basal conditions. Further integrative studies will be required to clarify TAAR pathophysiological significance and determine whether TAAR-targeted strategies may have translational relevance in immune-mediated disorders.
    Keywords:  Cytokine signaling; Gut microbiome; Gut-brain axis; Immune system; Leukocytes; Microglia; Neuroimmunology; Neuroinflammation; TAAR1; Trace amine-associated receptors; Trace amines
    DOI:  https://doi.org/10.1007/164_2026_819
  69. Neuro Oncol. 2026 Jul 14. pii: noag155. [Epub ahead of print]
    FUS-mediated BBB opening reshapes plasma extracellular vesicle size distribution without elevating concentration in glioblastoma patients.
    Massimiliano Del Bene, Daniela Osti, Marta Bonada, Riccardo Pascuzzo, Annica Piccardi, Giovanni Carone, Lisa Meanti, Mario Stanziano, Valentina Caldiera, Carla Carozzi, Antonio Silvani, Elisa Francesca Maria Ciceri, Marina Grisoli, Giuliana Pelicci, Francesco DiMeco.
       BACKGROUND: Focused ultrasound-mediated blood-brain barrier opening (BBBO) is hypothesized to enhance liquid biopsy by facilitating the release of tumor material into the circulation. This study aimed to evaluate the impact of MR-guided FUS-BBBO on plasma extracellular vesicle (EV) concentrations and size distributions, alongside cell-free DNA (cfDNA) profiles, to determine the clinical efficacy of this approach in glioblastoma (GB) patients.
    METHODS: We performed 14 MR-guided focused ultrasound (FUS)-BBBO procedures in patients with GB with blood sampling 1 h before and 1 h after sonication. Plasma EVs were isolated by size-exclusion chromatography and quantified by tunable resistive pulse sensing technology. Cell-free DNA (cfDNA) concentration and fragment profiles were assessed using fluorometric and electrophoretic methods.
    RESULTS: EV concentration showed no consistent change after FUS-BBBO, with marked inter-patient and inter-procedure heterogeneity. In contrast, EV size displayed a reproducible diameter reduction of ∼8-10 nm, driven predominantly by contraction of the upper tail of the size distribution, indicating selective modulation of larger vesicle subpopulations. cfDNA concentrations and fragmentation showed a heterogeneous pattern, with occasional patient-specific increases. Exploratory analyses revealed no significant associations between biomarker changes and procedural parameters except for treated volume.
    CONCLUSIONS: Our findings challenge the assumption that clinical BBBO uniformly increases biomarker abundance. The consistent shift toward smaller EVs suggests a selective modulation rather than an increased release. While BBBO may enhance the detectability of analytes that poorly cross the BBB, this may not apply to EVs, which are able to traverse the BBB under physiological conditions, further supporting their value as liquid-biopsy substrates in neuro-oncology. Future studies integrating clinical data with mechanistic models are necessary to refine FUS-enhanced diagnostic strategies.
    Keywords:  Blood-Brain Barrier Opening; Extracellular vesicles; Focused ultrasound; Glioblastoma; Liquid biopsy
    DOI:  https://doi.org/10.1093/neuonc/noag155
  70. BMC Neurol. 2026 Jul 17.
    SYNE1-Related motor neuron disease-like phenotype with mild distal contractures and 24-month clinical stability: a case report.
    Zehra Özbilici, Elif Simin Issı.
       BACKGROUND: SYNE1 encodes nesprin-1, a nuclear envelope protein involved in cytoskeletal linkage, nuclear positioning, and neuromuscular integrity. Biallelic SYNE1 variants cause a broad spectrum ranging from cerebellar ataxia to arthrogryposis multiplex congenita and motor neuron disease-like phenotypes. Distinguishing these entities can be difficult when subtle distal contractures coexist with neurogenic electrophysiological findings.
    CASE PRESENTATION: A 22-year-old woman born to consanguineous parents presented with bilateral intrinsic hand muscle wasting, impaired fine motor performance, and mild gait difficulty. Examination showed distal hand atrophy, mild weakness of the abductor pollicis brevis and first dorsal interosseous muscles, brisk deep tendon reflexes, preserved sensation, and mild distal finger contractures. Sensory nerve conduction studies were normal. Motor studies showed reduced compound muscle action potential amplitude in the right abductor pollicis brevis and borderline-low amplitude on the left. Needle electromyography showed widespread chronic neurogenic motor unit changes affecting the upper and lower extremities, with active denervation most evident in the bilateral abductor pollicis brevis muscles. Genioglossus examination was normal. SMN1 deletion testing and selected familial amyotrophic lateral sclerosis gene testing were negative. Whole exome sequencing identified a homozygous truncating SYNE1 variant, NM_182961.4:c.21009G > A; p.(Trp7003Ter). Segregation analysis confirmed heterozygous carrier status in both parents and two unaffected siblings. At 24-month follow-up, weakness, atrophy, contractures, reflex pattern, and functional status remained clinically stable, without bulbar, cerebellar, sensory, or clinically evident respiratory involvement.
    CONCLUSIONS: This case supports classification as a SYNE1-related motor neuron disease-like phenotype with mild distal contractures rather than an isolated arthrogryposis multiplex congenita type 3 (AMC3) phenotype. The case also supports including SYNE1 in genetic testing panels for young patients with unexplained motor neuron disease-like presentations, particularly when consanguinity, normal sensory conduction, and subtle distal contractures coexist.
    Keywords:   SYNE1 ; AMC3; Arthrogryposis multiplex congenita; Case report; Distal contractures; Juvenile amyotrophic lateral sclerosis; Motor neuron disease; Nesprin-1; Whole exome sequencing
    DOI:  https://doi.org/10.1186/s12883-026-05142-7
  71. Cells. 2026 Jun 26. pii: 1163. [Epub ahead of print]15(13):
    The Role of LRP1 in Glioma Progression and Therapeutic Targeting: A Narrative Review.
    Muhanad Alhujaily.
      Gliomas are the most frequently encountered tumors in the central nervous system, with limited therapeutic effectiveness owing to their highly invasive nature, intratumoral heterogeneity, and presence of the blood-brain barrier (BBB). Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) is a large, multifunctional transmembrane endocytic receptor that regulates lipid metabolism, cell signaling, and endocytosis in various body tissues, including the brain. LRP1 mediates tumor cell proliferation, invasion, and angiogenesis in gliomas through various cellular signaling mechanisms, including the SP1/PI3K/AKT pathway and MAPK/ERK. The occurrence of LRP1 in the BBB and the recent identification of its increased expression in gliomas have suggested it as a promising therapeutic target for receptor-mediated nanoparticle delivery and treatment of gliomas. LRP1-mediated transcytosis is now being used to enhance the BBB penetration of chemotherapy drugs and radiosensitizers in gliomas, which has resulted in increased overall survival of patients secondary to increased antitumor effectiveness of therapies. Despite the effective preclinical role of LRP1-targeted therapy in glioma models, clinical translation is challenging due to significant heterogeneity in the expression patterns of LRP1 across various subtypes of gliomas, which may affect the clinical responsiveness of drug therapy. Furthermore, concerns related to the pharmacokinetics of therapy and receptor saturation kinetics have rendered its clinical applicability challenging.
    Keywords:  LDL; blood–brain barrier; glioma; lipoproteins; prognosis; transcytosis
    DOI:  https://doi.org/10.3390/cells15131163
  72. Egypt J Immunol. 2026 Jul;33(3): 27-35
    Association between selected immune parameters and thalassemia: An analytical study.
    Hanan F Salman, Thefaf A Ahmed, Sura K Mahmood, Rana T Mohsen, Ali Mahdi.
      Existing genetic blood disorders are referred to as hereditary anemia. Such disease is especially high in the Mediterranean area. In Iraq, the prevalence of carriers was estimated between 4.5% -5% of the general population. The disease can be clinically presented by mild anemia up to severe manifestations that need transfusion and its complications can usually affect many different organ systems. During the past few years, focus was diverted to the cytokines and electrolyte status as potential disease severity markers. ELISA was used to identify serum cytokines. The analysis of serum sodium, chloride and potassium was performed using the colorimetric technique. The study included two categories, 50 patients (37.96 years) and 40 controls (40.475 years). The results revealed that thalassemia patients possessed significantly higher serum levels of all studied immunological markers (IL-40, TNF-α, and MCP-1) when compared to the control group (p<0.05). Serum sodium, potassium and chloride levels were also significantly different between the two groups, but serum potassium was not so significant (p<0.05). While there were no significant connections between IL-40 and MCP-1 or IL-40 and TNF-α, there was a significant positive association between MCP-1 and TNF-α. However, there was no significant link between potassium and chloride or between sodium and potassium. The Pearson's correlation analysis also showed a substantial positive association between levels of sodium and chloride. In conclusion, this study showed that thalassemia patients exhibit elevated levels of key immune parameters (IL-40, TNF-α, MCP-1) alongside significant changes in certain electrolyte concentrations, particularly sodium and chloride.
    DOI:  https://doi.org/10.55133/eji.330304
  73. Adv Sci (Weinh). 2026 Jul 11. e76558
    Neuron-Targeted Exosomal Delivery of siRNA Against RIPK3 Slows Neurodegenerative Progression in Alzheimer's Disease.
    Chi Zhang, Jiaqi Zhang, Yuzhi Wang, Yaodong Wang, Peng Lin, Yanling Wang, Zixuan Tang, Jintai Yu, Qin Zhou, Feiyun Cui.
      A major challenge in RNA therapeutics for central nervous system disorders is the lack of delivery systems capable of crossing the blood-brain barrier (BBB) while achieving cell-type-specific targeting. Herein, we develop an engineered exosomal siRNA delivery platform for systemic, neuron-targeted RNA transport to the brain. The platform leverages exosomes derived from an immortalized mouse hippocampal neuronal cell line as a biomimetic and functionally privileged material source, enhancing neuronal uptake and intracellular delivery efficiency. Through surface functionalization with a rabies virus glycoprotein-derived peptide, the system enables receptor-mediated BBB transcytosis and programmable siRNA loading. In human cortical organoids, the platform achieves efficient cytosolic delivery and robust gene silencing in neurons, demonstrating high delivery precision and bioavailability. As a proof of concept, targeting receptor-interacting protein kinase 3 (RIPK3) modulates necroptosis, a key pathway in inflammatory neurodegeneration. In transgenic mouse models, systemic administration suppresses RIPK3/MLKL signaling, reduces neuronal loss, and alleviates neuroinflammation and tau-associated pathology. Transcriptomic analyses further indicate stabilization of neuronal homeostasis across vulnerable brain regions. Collectively, the study establishes a modular and programmable exosomal RNA delivery platform and highlights age-defined, cell-derived biomaterials as a generalizable strategy for overcoming delivery barriers in neurological diseases.
    Keywords:  RNA interference; blood–brain barrier (BBB); drug delivery; necroptosis; neuroprotection; synaptic plasticity
    DOI:  https://doi.org/10.1002/advs.76558
  74. Mol Neurobiol. 2026 Jul 17. pii: 775. [Epub ahead of print]63(1):
    Targeting Sirtuin Signaling in Parkinson's Disease and Neurodegeneration: Molecular Insights and Translational Potential.
    Shobha Kumari, Hemraj Singh, Shravani Vaidya, Rajeev Taliyan.
      Neurodegenerative diseases are characterized by progressive neuronal loss driven by protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Among these, Parkinson's disease (PD) is a prevalent disorder marked by degeneration of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein aggregates. Emerging evidence indicates that mitochondrial dysfunction and metabolic dysregulation are central contributors to PD pathogenesis. Sirtuins (SIRT1-SIRT7), a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, have emerged as key regulators of neuronal survival and metabolic homeostasis. Mechanistically, SIRT1 regulates α-synuclein aggregation, autophagy, and neuroinflammatory signaling, while SIRT3 preserves mitochondrial integrity and reduces oxidative stress. In contrast, SIRT2 has been implicated in microtubule destabilization and neurotoxicity, and its inhibition has demonstrated neuroprotective effects in experimental models. This review provides a comprehensive, up-to-date synthesis of the molecular mechanisms underlying sirtuin-mediated neuroprotection in PD and related neurodegenerative disorders. We further discuss the translational potential of targeting sirtuin pathways, including pharmacological modulators and NAD+-boosting strategies, while addressing current limitations and future directions for clinical translation.
    Keywords:  Epigenetic regulation; Mitochondrial dysfunction; NAD+ metabolism; Neurodegeneration; Neuroinflammation; Parkinson’s disease; Sirtuins
    DOI:  https://doi.org/10.1007/s12035-026-06062-w
  75. ACS Pharmacol Transl Sci. 2026 Jul 10. 9(7): 1652-1703
    Recent Advances in Organofluoroprobes for Brain Imaging: Progress, Challenges, and Future Directions.
    Vaishnavi Anil, Daisy R Sherin.
      The precise and early diagnosis of neurodegenerative diseases remains a major challenge because of their highly complex and multifactorial pathophysiology. However, in recent years, the potential of organofluoroprobesorganic molecules designed to function as fluorescent probes in bioimaginghas become increasingly prominent. These probes enable visualization of essential biomarkers, including amyloid-beta (Aβ), tau, reactive oxygen and nitrogen species (ROS/RNS), neurotransmitters, and abnormal metal ions, facilitating early detection and monitoring of diseases such as Alzheimer's and Parkinson's. This review focuses on small-molecule organofluoroprobes, which consist of curcumin-, boron-dipyrromethane (BODIPY)-, cyanine-, coumarin-, benzothiazole-, thiophene-, naphthalene-, oxazine-, and organometallic-based systems. We also address biomarker-activated probes, nanoengineered aggregation-induced emission (AIE) luminogens, and photoacoustic probes that provide greater tissue penetration and multimodal imaging. Nevertheless, these imaging probes still have shortcomings, including poor specificity, limited penetration through the blood-brain barrier (BBB), and inefficient near-infrared II (NIR-II) emission. Notably, the design and optimization of fluoroprobes are being revolutionized by the integration of artificial intelligence (AI) and computational methods, such as deep learning, generative models, and virtual screening. These approaches provide new avenues for predictive modeling of physicochemical properties, target affinity and in vivo performance, thereby significantly reducing the time and cost of development. The review concludes by discussing current challenges and future perspectives, including the convergence of AI-assisted molecular design and synthetic chemistry in bioimaging, ultimately leading to the clinical translation of next-generation brain imaging probes.
    Keywords:  artificial intelligence-assisted probe design; blood−brain barrier; brain imaging; donor−acceptor system; near-infrared fluorescence; organofluoroprobes
    DOI:  https://doi.org/10.1021/acsptsci.6c00096
  76. Funct Integr Genomics. 2026 Jul 16. pii: 191. [Epub ahead of print]26(1):
    Integrative single-cell and spatial transcriptomics combined with machine learning to discover complement-associated biomarkers in temporal lobe epilepsy with hippocampal sclerosis.
    Zesheng Li, Jianwei Shi, Yanfeng Yang, Penghu Wei, Yongzhi Shan, Guoguang Zhao.
      Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) poses significant challenges in therapeutic management. While studies have demonstrated seizure-induced alterations in peripheral immune molecules, the complement system, a central component of immune function, remains insufficiently characterized at single-cell resolution and spatial distribution in TLE-HS. This study aimed to comprehensively investigate the spatiotemporal dynamics of complement system components and their clinical implications in patients with TLE-HS. We first identified patterns of complement activity changes in epilepsy using bulk RNA sequencing. Then, we employed a TLE-HS mouse model for single-cell RNA sequencing and S1000 high-resolution spatial transcriptomics. We performed integrative bioinformatic analyses on single-cell data to quantify complement-system activity and define microglial heterogeneity, leading to the identification of complement-associated microglial subpopulations. Spatial transcriptomic data then validated the anatomical localization of these identified subpopulations. Finally, we developed and evaluated two machine-learning models based on complement-related gene signatures. Complement activity was elevated in epilepsy. The levels were higher in hippocampal sclerosis (HS) tissue than in normal hippocampus. They were also increased in mesial temporal lobe epilepsy with hippocampal sclerosis compared with mesial temporal lobe epilepsy without hippocampal sclerosis, and in patients with high seizure frequency (HSF) compared with those with low seizure frequency (LSF). Complement-related signatures were further associated with antiseizure medication response. Candidate biomarkers including IRF2, GNB2, EHD1, CTSB, and CFH were identified using statistical modeling and machine learning. Among multiple classifiers, the support vector machine model showed the best predictive performance, and SHAP analyses indicated distinct contribution directions for these candidate genes. In the kainic acid (KA) mouse model, single-cell analyses showed that complement activity was upregulated across cell types in HS. Microglia exhibited the highest complement activity. Re-clustering and trajectory inference defined HS-associated microglial subpopulations that were enriched in terminal differentiation states. hdWGCNA together with differential expression highlighted Ctsb, C1qa, and Fcer1g as core complement-linked genes. Using Ctsb-defined microglial states, eight diagnostic biomarkers were selected, and a multi-layer perceptron model achieved superior classification accuracy in epilepsy diagnosis. Finally, cell-cell communication and spatial transcriptomics consistently implicated an Spp1-related signaling axis associated with Ctsbhigh microglia in hippocampal sclerosis regions. The resulting diagnostic and response-prediction models were deployed as exploratory web-based research tools pending independent validation. Our study systematically characterized the complement system in TLE-HS by integrating multi-level omics data, including bulk RNA sequencing, single-cell sequencing, and spatial transcriptomics. We revealed the potential value of complement system gene signatures in clinical diagnosis and personalized treatment of epilepsy.
    Keywords:  Complement; Hippocampal sclerosis; Machine learning; Single-cell transcriptomics; Spatial omics; Temporal lobe epilepsy
    DOI:  https://doi.org/10.1007/s10142-026-01975-0
  77. Clin Interv Aging. 2026 ;21 606639
    Astrocytes in Parkinson's Disease: From Guardians to Accomplices.
    Dan Gu, Yu Lei, Jiayi Lu, Wenmin Yi, Qinbin Zhang, Chuanling Wang, Zhiyou Cai.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of nigral dopaminergic neurons and misfolded α‑synuclein (α‑Syn) aggregation. However, increasing evidence indicates that astrocytes occupy a central position in the multifactorial pathogenesis of PD. As the most abundant glial cells in the Central Nervous System (CNS), astrocytes maintain neural homeostasis via neurotransmitter clearance, ion balance, metabolic support, synaptic regulation, and blood-brain barrier (BBB) integrity. In early PD, astrocytes exert neuroprotective effects; with disease progression, persistent pathological stimuli-including aggregated α-Syn, chronic neuroinflammation, mitochondrial dysfunction, oxidative stress, and iron dyshomeostasis-drive astrocytes into a reactive, neurotoxic state. This review systematically summarizes how astrocytes regulate α-Syn handling, mitochondrial function, neuroinflammation, and oxidative stress in PD, explaining how these pathways reshape astrocyte states across disease stages, and highlights stage-dependent dual roles of astrocytes as guardians and accomplices, with implications for astrocyte-targeted therapies.
    Keywords:  Parkinson’s disease; astrocyte; mitochondrial dysfunction; neuroinflammation; α-synuclein
    DOI:  https://doi.org/10.2147/CIA.S606639
  78. Ann Clin Transl Neurol. 2026 Jul 15.
    Histopathological Evidence of Neurodegenerative Pathology in Epilepsy: A Systematic Review.
    Syeda Amrah Hashmi, Aleksander Luniewski, Vanessa Smith, Matthew McCord, Jaideep Kapur, Mark Quigg, Catherine Joshua, Ifrah Zawar.
      Epilepsy affects > 50 million people worldwide and is associated with a disproportionate burden of cognitive impairment. Emerging evidence suggests that neurodegenerative proteinopathies, particularly hyperphosphorylated tau (p-tau) and amyloid-β (Aβ), may contribute to cognitive dysfunction in people with epilepsy (PWE), even in the absence of dementia. However, the prevalence, distribution, and clinical significance of these proteins in epilepsy remain unclear. We conducted a systematic review of neuropathological studies examining neurodegenerative pathology in PWE without primary neurodegenerative disease. The review followed PRISMA guidelines and was registered with PROSPERO (CRD42024612990). A search of PubMed/MEDLINE, Ovid MEDLINE, Ovid Embase, and the Cochrane was performed from database inception to 7/8/2024. Eligible studies included human observational studies, case series, and post-mortem or surgical pathology assessing p-tau, amyloid, TDP-43, or related proteinopathies in PWE. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Forty-two studies met the inclusion criteria. Most studies involved drug-resistant temporal lobe epilepsy (TLE) with hippocampal sclerosis. P-Tau was the most consistently reported finding, identified across multiple epilepsy types with a prevalence ranging from 3%-95%. Amyloid was detected less consistently but occurred in both temporal and extratemporal epilepsies. Several studies reported associations between p-tau burden and seizure frequency, epilepsy duration, and cognitive impairment, particularly in mesial TLE, although findings were heterogeneous. Neurodegenerative pathology, especially p-tau, is frequently observed in epilepsy and may represent a biological link between seizures, hyperexcitability, and cognition. These findings suggest that epilepsy may intersect with neurodegenerative mechanisms and underscore the need for studies integrating neuropathology, biomarkers, and cognitive outcomes.
    Keywords:  cognitive impairment; epilepsy; histopathology; neurodegeneration
    DOI:  https://doi.org/10.1002/acn3.70486
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