bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–06–28
77 papers selected by
Luca Bolliger, lxBio
  1. Amyotrophic Lateral Sclerosis.
  2. Mutant SOD1 expressed by oligodendrocytes aggregates in myelinic nanochannels and accelerates disease progression in familial ALS mice.
  3. Amyotrophic lateral sclerosis: A rare but aggressive adult-onset disease.
  4. Extracellular Pgk1 or Its Derived Short Peptide Interacted with Membrane-Associated Enolase 2 Receptor: A Potential Therapy for ALS Motor Neuron Degeneration.
  5. Neuropathological and Molecular Features Associated With a Heterozygous DNAJC7 Mutation in Amyotrophic Lateral Sclerosis.
  6. Therapeutic frontiers in ALS: iPSC-based drug discovery, cell therapy, and gene therapy-Advances through 2026.
  7. The connection between unproven stem cell-based interventions and complementary and alternative medicine in crowdfunding for Amyotrophic Lateral Sclerosis.
  8. Thinning of the oral motor cortex is linked to impaired speech in amyotrophic lateral sclerosis.
  9. Immune checkpoint LAG-3 governs stage-dependent and disease-associated microglial modules in ALS model mice.
  10. Nonlinear combinatorial analysis of blood transcriptomes identifies PRKAR1A as a regulator of TDP-43 pathophysiology in amyotrophic lateral sclerosis.
  11. The Dual Role of Glial Extracellular Vesicles in Neurodegeneration: Insights from iPSC-Based Models.
  12. The Impact of Sponsored Genetic Testing in 170 Consecutive Consenting Patients With Amyotrophic Lateral Sclerosis: A Single-Site Retrospective Review.
  13. Advancing MSC-EV Therapies: Harnessing Preconditioning and Mito-EVs to Tackle Neuroinflammation and Neurodegeneration.
  14. Noninvasive assessment of cardiovascular autonomic reflexes in amyotrophic lateral sclerosis: a systematic review.
  15. Comparison of Proteomic Analysis of Cerebrospinal Fluid From Neurological Patients With and Without Amyotrophic Lateral Sclerosis.
  16. IRE1 regulates the proteostasis of TDP-43/TARDBP in ALS/FTD through ribosome-associated quality control.
  17. Learning a distance for the clustering of patients with amyotrophic lateral sclerosis.
  18. [Effect of electroacupuncture at "Zusanli" (ST36) on TREM2-mediated microglial activation in amyotrophic lateral sclerosis mice].
  19. Compartmentalized biomarker correlations in HIV: plasma-CSF relationships vary by blood-brain/blood-CSF barrier permeability and viral suppression.
  20. Are patient-derived models of amyotrophic lateral sclerosis a game changer for novel drug discovery?
  21. Interplay between B vitamins, fiber, and Bacteroides abundance: a predictive model for anxiety and depression in amyotrophic lateral sclerosis.
  22. Association Between Clinical Dysphagia Assessment Tools and Videofluoroscopic Findings in Amyotrophic Lateral Sclerosis: A Retrospective Study.
  23. Applications of electromyography in Amyotrophic Lateral Sclerosis: A systematic review.
  24. FMRP-Mediated Proteasome Regulation: A Novel Mechanism in ALS Pathology.
  25. Targeting mitochondrial dysfunction and neuroprotection in neurodegenerative disorders: emerging therapeutic potential of berberine and polymeric nanoparticle-based delivery systems.
  26. Behavioral variant frontotemporal dementia associated with a NEK1 missense variant: exploring a possible phenotypic association.
  27. IMMUND: A Diagnostic and Therapeutic Pipeline to Uncover the Convergence in Functional Perturbation at Early Stages of Neurodegenerative Diseases and Multiple Sclerosis Based on Protein Markers.
  28. Intravenous administration of an engineered AAV9-gene-silencing vector suppresses human SOD1 and extends survival in an ALS mouse model.
  29. Tolerability, Safety and Effectiveness of Sigh Introduction During Non-Invasive Mechanical Ventilation Cycles in Patients With Amyotrophic Lateral Sclerosis.
  30. Characterization of sensory nerve conduction abnormalities at the time of ALS diagnosis.
  31. A rare missense variant impacting NEK1 kinase function is associated with ALS.
  32. Isoform-specific steric zippers drive aberrant assembly and mislocalization of shortened TDP-43.
  33. Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.
  34. Trace Elements Dyshomeostasis and Toxic Metals Neurotoxicity in Neurodegenerative Diseases.
  35. Muscle Ultrasound Is a Sensitive Outcome Measure in ALS.
  36. Toll-Like Receptor-Mediated Neuroinflammation and Its Role in Neurocognitive Functions.
  37. STMN2 protein depletion via translation deficits and stress granules in amyotrophic lateral sclerosis.
  38. Rewiring ALS by modulating the autophagy receptor SQSTM1.
  39. Transcriptomic and pathological analysis of the hnRNP network reveals glial involvement in frontotemporal lobar degeneration pathological subtypes.
  40. ECAS-Based Neuropsychological Phenotyping in Amyotrophic Lateral Sclerosis: A Retrospective Study Comparing Different Algorithms.
  41. A multi-centre prospective evaluation of post-gastrostomy outcomes in patients with amyotrophic lateral sclerosis.
  42. Validation of the German version of the Dimensional Apathy Scale (G-DAS): Application in amyotrophic lateral sclerosis.
  43. An emergent disease-associated motor neuron state precedes cell death in ALS.
  44. Innate immune crosstalk in ALS/FTD pathogenesis.
  45. The Immune-Chemokine Axis in Alzheimer's Disease: Roles of Adaptive Immune System in Neuroinflammation and Disease Progression.
  46. Direct evidence of upper motor neuron excitability changes in a patient with ALS.
  47. The ALS- and FTD-associated proteins annexin A11 and CHMP2B act sequentially in plasma membrane repair.
  48. Associations influencing quality of life in caregivers of patients with amyotrophic lateral sclerosis: a stress-process model approach.
  49. The complement system in Alzheimer's disease: evaluating biomarker potential in a complex neuroimmune context.
  50. Programmed axon degeneration gene variants in human disease.
  51. Nanotheranostics for Alzheimer's Disease: The Rising Promise of Fluorescent Carbon Dots.
  52. Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.
  53. Blood-brain barrier dysfunction in surgery and anesthesia: a potential mechanistic contributor to postoperative cognitive dysfunction.
  54. Formaldehyde neurotoxicity: Effects on the mammalian brain, cognitive function, and neurodegenerative risk. A scoping review.
  55. Predicting Blood-Brain Barrier Permeability from Experimental Data: An Interpretable and Externally Validated Machine Learning Framework.
  56. Exploring Olfactory Bulb Volume and Its Shrinkage in Aging and Neurodegeneration: A Systematic Review and Meta-Analysis of Observational Studies.
  57. Global research trends and hotspots of exosome-mediated drug delivery across the blood-brain barrier: a bibliometric study from 2015 to 2025.
  58. LPS-Induced Neuroinflammation in Neurodegenerative Diseases: A Double-Edged Sword?
  59. Apolipoprotein E Mimetics in Targeted Drug Delivery: Advances and Therapeutic Potential for Neurodegenerative and Cardiovascular Diseases.
  60. Exosomes: A new frontier in the treatment of neurological diseases.
  61. Brain-on-a-Chip and Blood-Brain Barrier-on-a-Chip Modeling for Neurodegenerative Disorders: Recent Progress.
  62. Quantitative determination of longitudinal CNS cholesterol loss during myelin damage and repair.
  63. Conjugates of desferrioxamine with 5-aminolevulinic or γ-aminobutyric acid: synthesis, theoretical studies, iron-chelating ability, and penetration in human Caco-2 cells.
  64. Chronic Diazepam Reveals Excessive Homeostatic Gain in SOD1G93A Mouse Spinal Motoneurons.
  65. Longitudinal Biomarker Trajectories for EVD-Associated Infection Prediction: A Trajectory-Based Machine Learning Framework with Biological Onset Characterization.
  66. Research Progress on Novel Lead Compounds for Central Nervous System Diseases.
  67. Dual-target inhibitors based on BuChE: A review from medicinal chemistry perspective.
  68. Novel approach for direct drug delivery to the central nervous system via intratympanic administration.
  69. Spiritual Care Needs and Challenges Among Caregivers and Families of People with Neurodegenerative Diseases in Palliative and End-of-Life Care: A Scoping Review.
  70. Infectious Agents in Multiple Sclerosis: Viral Triggers, Antibody-Mediated Autoimmunity, and Parasitic Immunomodulation.
  71. Immune cell-specific genetic architecture of Alzheimer's disease revealed by multi-omics analysis for therapeutic target discovery and prioritization.
  72. Advances in tailored intraparenchymal delivery of regenerative medicine for spinal cord injury: a review of preclinical studies and clinical trials.
  73. The Gut-Brain-Immune Axis: Multi-Omics Insights into Neurodegenerative and Metabolic Diseases.
  74. Human BBB-brain organoid on a millifluidic plate for modeling brain parenchymal pathology-induced barrier dysfunction.
  75. Metaheuristic-driven machine learning study for early detection and classification of Parkinson's disease using feature prioritization with pelican optimization algorithm.
  76. Role of Microbial Toxins in Neurodegenerative Diseases: Insights and Future Perspectives.
  77. Deciphering the Neuroautophagic Interactome: Molecular Circuits Linking Selective Autophagy to Neuropathological Cascades in Neurological Disorders.
  1. JAMA. 2026 Jun 25.
    Amyotrophic Lateral Sclerosis.
    Kristin L Walter.
      
    DOI:  https://doi.org/10.1001/jama.2026.9755
  2. bioRxiv. 2026 Jun 11. pii: 2026.06.09.731100. [Epub ahead of print]
    Mutant SOD1 expressed by oligodendrocytes aggregates in myelinic nanochannels and accelerates disease progression in familial ALS mice.
    Alexandra I Mot, Ying Li, Payam Dibaj, Iva D Tzvetanova, Ulrike C Gerwig, Tizibt A Bogale, Sandra Goebbels, Wiebke Möbius, Dwight E Bergles, Brett M Morrison, Jeffrey D Rothstein, Don W Cleveland, Julia M Edgar, Klaus-Armin Nave.
      Amyotrophic lateral sclerosis (ALS) is a highly debilitating and fatal disease characterized by the progressive loss of motor neurons. Reduced oligodendroglial support has been implicated in ALS progression but remains mechanistically unexplained. Here, using a mutant superoxide dismutase 1 (SOD1-G37R) mouse model of familial ALS, Cre-mediated excision of the mutant SOD1 gene within the oligodendrocyte lineage prior to myelin compaction is shown to slow disease onset, improve motor performance, and prolong survival. In contrast, silencing mutant SOD1 expression within oligodendrocytes after myelin compaction failed to ameliorate disease phenotype. Electron microscopy is used to identify aggregation of mutant SOD1 within paranodal loops and the inner periaxonal tongue of 'myelinic nanochannels', narrow cytosolic compartments for the diffusion of metabolites and motor-driven transport processes. In a second mouse model (SOD1-G93A) of familial, SOD1 mutant-mediated ALS, we show that induction of excessive myelin compaction and myelinic channel collapse (by depletion of CNP from myelin) accelerates disease and diminishes survival. Our data support loss of myelinic channel integrity as a contributor to familial ALS disease initiation and progression, findings likely relevant to neurodegenerative disease involving other aggregation prone proteins that are expressed in myelinating oligodendrocytes.
    Significance Statement: Oligodendrocytes have been implicated in the progression of amyotrophic lateral sclerosis (ALS) but the underlying mechanisms have remained obscure. Here we show in genetic mouse models that the familial ALS causing isoform of a ubiquitously expressed mutant enzyme (SOD1) aggregates in cytosolic channels within myelin that are responsible for delivery of transporters and nutrients necessary to support the axonal compartment. ALS disease progression was accelerated in mice when myelinic channels were collapsed by deleting CNP, a structural protein necessary for myelinic channel maintenance. Disruption of transport through myelinic channels by aggregation of mutant SOD1 may perturb oligodendrocyte support of motor axons and contribute to disease in this form of ALS.
    DOI:  https://doi.org/10.64898/2026.06.09.731100
  3. Trends Mol Med. 2026 Jun 24. pii: S1471-4914(26)00134-6. [Epub ahead of print]
    Amyotrophic lateral sclerosis: A rare but aggressive adult-onset disease.
    Luca Brodribb, Phil Camden, Thanuja Dharmadasa, Catherine Blizzard.
      
    Keywords:  ALS; motor system; neurodegeneration; paralysis
    DOI:  https://doi.org/10.1016/j.molmed.2026.06.001
  4. Biomolecules. 2026 Jun 17. pii: 893. [Epub ahead of print]16(6):
    Extracellular Pgk1 or Its Derived Short Peptide Interacted with Membrane-Associated Enolase 2 Receptor: A Potential Therapy for ALS Motor Neuron Degeneration.
    Bing-Chang Lee, Juey-Jen Hwang, Huai-Jen Tsai.
      Amyotrophic lateral sclerosis (ALS) remains an intractable motor neuron (MN) disease with a growing patient population and few effective treatments. Here, we review how extracellular phosphoglycerate kinase 1 (ePgk1) improves neurite outgrowth of MNs (NOMN) and axonal growth, both in vitro and in vivo. Our group first elucidated a novel non-canonical function of ePgk1 as a cross-tissue mediator between nerve and muscle tissues. We then discovered that neural membranous Enolase 2 (Eno2) serves as a receptor of ligand ePgk1 and that ePgk1-Eno2 interaction suppresses the Rac1-GTP/p-Pak1-T423/p-P38-T180/pMK2-T334/p-Limk1-S323 axis, reducing p-Cofilin and promoting NOMN and axonal growth, finally suggesting that the 419th aspartic acid residue of Eno2 mediates this interaction. In a crucial preclinical step, we truncated two short 16-amino-acid derivatives from Pgk1, FD-1/-2, each mediating neuroprotection comparable to that of full-length 417-amino-acid Pgk1 in ALS animal models, in terms of improvements of innervated neuromuscular junction, MN cell bodies, motor performance, and endpoint prolongation. In this context, we also discuss the opposite function driven by Eno1-plasminogen interaction and by Eno2-ePgk1 interaction; the latter results in unfavorable for tumorigenesis. Unlike intracellular Pgk1 roles, ePgk1 is an extracellular factor with anti-angiogenic properties, further positioning ePgk1 and its FD-1/-2 as promising protein/peptide drugs for ALS treatment.
    Keywords:  amyotrophic lateral sclerosis; enolase; motor neuron; neurodegeneration; phosphoglycerate kinase; therapeutic peptide
    DOI:  https://doi.org/10.3390/biom16060893
  5. Neuropathol Appl Neurobiol. 2026 Aug;52(4): e70086
    Neuropathological and Molecular Features Associated With a Heterozygous DNAJC7 Mutation in Amyotrophic Lateral Sclerosis.
    Yoshiaki Nakayama, Kodai Kume, Takashi Baba, Takashi Ayaki, Keisuke Hanada, Katsuichi Miyamoto, Norimitsu Inoue, Hideshi Kawakami, Hidefumi Ito.
       AIMS: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with unclear molecular mechanisms. Heterozygous protein-truncating variants of DNAJC7, which encode a cochaperone involved in Hsp70/90-mediated protein quality control, are potential risk factors for ALS. However, the neuropathological consequences of heterozygous DNAJC7 mutations are unclear. We aimed to clarify the molecular and neuropathological features associated with a heterozygous DNAJC7 mutation in ALS.
    METHODS: We genetically screened 39 Japanese patients with ALS and identified a novel heterozygous frameshift mutation in DNAJC7 (c.157_163del, p.Lys53Ter) in one patient that was neuropathologically diagnosed with Kii ALS. We performed biochemical and neuropathological analyses using postmortem tissues from this patient, from cases of ALS without the mutation and from control cases.
    RESULTS: In the cases of ALS without DNAJC7 mutation, there was elevation of both DNAJC7 mRNA and protein levels compared with controls. The patient with DNAJC7 mutation showed relatively lower DNAJC7 mRNA and protein levels compared with the nonmutated cases of ALS, although mRNA expression remained relatively higher. DNAJC7 may be upregulated as a protective response against ALS pathogenesis, whereas a heterozygous mutation may attenuate this response. Immunohistochemistry and double immunofluorescence demonstrated partial colocalization of DNAJC7 with phospho-TDP-43-positive neuronal cytoplasmic inclusions, which supports a direct role for DNAJC7 in modulating pathological TDP-43 aggregation.
    CONCLUSIONS: These findings provide neuropathological evidence linking heterozygous DNAJC7 mutation to ALS, demonstrating impaired protein expression and suggesting a loss-of-function mechanism that compromises protective responses to TDP-43 pathology. DNAJC7 may represent a key modulator of ALS pathogenesis and potential therapeutic target.
    Keywords:  ALS; ALS/PDC; DNAJC7; Kii ALS; Parkinsonism‐dementia complex; amyotrophic lateral sclerosis
    DOI:  https://doi.org/10.1111/nan.70086
  6. Regen Ther. 2026 Dec;33 101150
    Therapeutic frontiers in ALS: iPSC-based drug discovery, cell therapy, and gene therapy-Advances through 2026.
    Satoru Morimoto, Chris Kato, Shinichi Takahashi, Hideyuki Okano.
      Three converging therapeutic paradigms-iPSC-based drug discovery, cell transplantation, and gene therapy-have substantially expanded the therapeutic pipeline for amyotrophic lateral sclerosis (ALS) between 2020 and 2026. The FDA's accelerated approval of tofersen (Qalsody) in April 2023 marked the first treatment targeting a genetic cause of ALS. iPSC-derived drug candidates, including ropinirole and bosutinib, have completed early-phase clinical trials led by Japanese institutions. Cell therapies targeting neuroinflammation through regulatory T cells are being actively explored as immunomodulatory strategies, although efficacy remains to be established in adequately powered trials. Next-generation gene-silencing approaches-including RNA interference (RNAi) therapeutics and AAV-delivered microRNA-entered first-in-human trials in 2024-2025. The identification of STMN2 as a downstream target of TDP-43 dysfunction has opened a potential TDP-43-downstream nucleic acid therapeutic avenue for sporadic ALS, which constitutes approximately 90% of all cases, with company-reported interim data suggesting target engagement in the ongoing Phase 1/2 ANQUR trial (QRL-201). This review synthesizes the latest evidence across all three therapeutic domains, with attention to the hierarchy of evidence, regulatory milestones, and the pioneering contributions of Japanese research groups.
    Keywords:  Amyotrophic lateral sclerosis; Cell therapy; Gene therapy; Induced pluripotent stem cells; Regulatory T cell; Ropinirole
    DOI:  https://doi.org/10.1016/j.reth.2026.101150
  7. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jun 24. 1-10
    The connection between unproven stem cell-based interventions and complementary and alternative medicine in crowdfunding for Amyotrophic Lateral Sclerosis.
    Michael Jewer, Jeremy Snyder, Timothy Caulfield, Marco Zenone.
      Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disease associated with substantial medical and non‑medical costs. In the absence of effective treatments, patients and families may turn to crowdfunding to finance care, including unproven stem cell‑based interventions (SCBIs) that are frequently marketed directly to consumers.
    OBJECTIVE: conduct content analysis of English‑language GoFundMe campaigns seeking funds for SCBIs for ALS to better understand the market for unproven direct‑to‑consumer SCBIs.
    METHODS: 247 campaigns were identified, and their data were collected and analyzed to determine the characteristics of the campaigns, campaigners, and their desired treatments.
    RESULTS: ALS crowdfunding campaigns that collectively requested over $16 million USD. In addition to SCBIs, campaigns frequently requested funding for international travel to access these treatments. Campaigners express relatively high confidence that stem cell treatments would slow disease progression, improve symptoms, or, in some cases, cure or reverse ALS; conclusions that exceed the scientific evidence. Confidence in SCBIs is linked to requests for other alternative therapies and unsupported causes of ALS, supporting an emerging link between proponents of alternative medicines and unproven stem cell therapies.
    CONCLUSION: Crowdfunding for unproven stem cell interventions exposes ALS patients and donors to financial risk, misinformation, and medical exploitation. The frequent linkage between SCBIs, CAM, and exaggerated claims highlights gaps in regulation, patient protection, and access to credible treatment options. These findings underscore the need for stronger oversight of direct‑to‑consumer stem cell markets and greater support for patients facing catastrophic illness.
    Keywords:  Stem cell therapies; amyotrophic lateral sclerosis; complementary and alternative medicine; crowdfunding
    DOI:  https://doi.org/10.1080/21678421.2026.2685157
  8. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jun 23. 1-12
    Thinning of the oral motor cortex is linked to impaired speech in amyotrophic lateral sclerosis.
    CANADIAN ALS NEUROIMAGING CONSORTIUM (CALSNIC)
      Most individuals with amyotrophic lateral sclerosis (ALS) develop bulbar impairment as their disease progresses. The ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subscore and neurological examination of upper (UMN) and lower motor neurons (LMN) are routinely used to assess this dysfunction but have inherent limitations. Speech‑derived measures have shown promise for capturing bulbar decline with greater sensitivity, but their neurobiological correlates remain unclear. This study examined the associations between quantitative speech measures and cortical thinning in ALS. Data from the Canadian ALS Neuroimaging Consortium were analyzed. Speech measures were extracted from audio recordings of the standardized "Bamboo Passage". Cortical thickness was calculated from T1‑weighted MRI scans. General linear models first compared cortical thickness between patients with ALS and healthy controls. Associations between the speech measures and cortical thickness were then assessed within the ALS group. Patients with ALS showed cortical thinning across bilateral frontotemporal regions, with the largest clusters in the bilateral motor cortices. Reduced speaking and articulation rates were associated with thinning in both oral motor cortices. In contrast, the ALSFRS-R bulbar subscore and UMN and LMN bulbar burden showed no significant associations. Measures of pausing behavior were negatively associated with frontal cortical regions. Thinning of the oral motor cortex in ALS was linked to reduced oral motor function, supporting speaking and articulation rate as sensitive markers of bulbar motor neuron degeneration. These measures demonstrated neuroanatomical associations that the ALSFRS-R bulbar subscore and neurological examination findings did not, highlighting their potential value for monitoring bulbar dysfunction in ALS.
    Keywords:  Bulbar impairment; amyotrophic lateral sclerosis; biomarker; neuroimaging; speech production
    DOI:  https://doi.org/10.1080/21678421.2026.2688247
  9. J Neuroinflammation. 2026 Jun 25.
    Immune checkpoint LAG-3 governs stage-dependent and disease-associated microglial modules in ALS model mice.
    Yuta Morisaki, Nanaka Nomura, Motoki Ohshima, Miruto Matsuda, Okiru Komine, Takashi Okuda, Koji Yamanaka, Hidemi Misawa.
      Immune checkpoint molecules, inhibitory receptors originally characterized in T cell biology, have recently emerged as regulators of microglial function in neurodegeneration, yet their roles in amyotrophic lateral sclerosis (ALS) remain unexplored. Here, we investigated LAG-3, an inhibitory immune checkpoint receptor, in microglial regulation during ALS pathogenesis using SOD1G93A mice. LAG-3 expression was progressively upregulated in spinal cord microglia during disease progression, and LAG-3-high microglia exhibited a disease-associated microglia (DAM) transcriptional signature. Genetic deletion of LAG-3 produced a biphasic phenotype, with accelerated disease onset but significantly prolonged disease duration. LAG-3 deficiency enhanced inflammatory microglial responses at the early disease stage, whereas at the late stage it suppressed inflammatory signaling while selectively preserving phagocytic effector gene expression, demonstrating that LAG-3 dissociates the inflammatory and phagocytic modules within the DAM program in a stage-dependent manner. These transcriptional changes translated into enhanced phagocytic capacity in primary microglia and amelioration of the spinal cord environment through suppression of inflammatory pathways and restoration of oxidative phosphorylation. Our findings identify LAG-3 as a stage-dependent regulator of microglial functional states in ALS and support the concept that immune checkpoint molecules constitute a class of module-level regulators of microglial function in neurodegeneration.
    Keywords:  Amyotrophic lateral sclerosis; Disease-associated microglia; Immune checkpoint; LAG-3; Microglia; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12974-026-03919-8
  10. Biol Methods Protoc. 2026 ;11(1): bpag023
    Nonlinear combinatorial analysis of blood transcriptomes identifies PRKAR1A as a regulator of TDP-43 pathophysiology in amyotrophic lateral sclerosis.
    Keiko Imamura, Ayako Nagahashi, Aya Okusa, Takuya Yamamoto, Yuishin Izumi, Naonori Ueda, Yoshinobu Kawahara, Haruhisa Inoue.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Accurate and accessible blood-based diagnostics for neurodegenerative diseases, including ALS, are being progressively required. Although blood cell gene expression profiles have potential clinical utility for distinguishing ALS, robust transcriptomic biomarkers for supportive diagnosis have not yet been established. Here, we analyzed publicly available peripheral blood mononuclear cell (PBMC) transcriptomic data from ALS patients using Maximum Mean Discrepancy, a kernel-based method that captures nonlinear distributional differences in a reproducing kernel Hilbert space and enables the extraction of informative gene combinations while minimizing multicollinearity, a common issue in multiple regression models. Using this approach, we identified a nonlinear three-gene combination-PRKAR1A, QPCT, and TMEM71-that distinguished ALS from healthy controls with an area under the curve (AUC) of 0.83 in a public PBMC dataset. This achievement was confirmed in laboratory PBMC samples with an AUC of 0.85, supporting the robustness of the identified gene signature in independent samples. Furthermore, these genes also enabled ALS classification in induced pluripotent stem cell-derived motor neurons with an AUC of 0.79. Knockdown of PRKAR1A, QPCT, or TMEM71 in motor neurons increased the TDP-43 expression levels, and PRKAR1A knockdown induced the mislocalization of TDP-43, accompanied by phosphorylation, suggesting a potential link to ALS-related pathophysiology. These findings suggest that nonlinear gene combinations may provide a useful strategy for identifying blood-based biomarkers and offer insights into ALS pathogenesis. This nonlinear, data-driven analytical framework enabled the transition from unbiased gene discovery to the identification of pathophysiology-associated molecules by in vitro functional validation.
    Keywords:  amyotrophic lateral sclerosis; biomarker; blood-based diagnosis; maximum mean discrepancy; nonlinear
    DOI:  https://doi.org/10.1093/biomethods/bpag023
  11. Int J Mol Sci. 2026 Jun 08. pii: 5182. [Epub ahead of print]27(12):
    The Dual Role of Glial Extracellular Vesicles in Neurodegeneration: Insights from iPSC-Based Models.
    Aurora Scrivo, Liliana Bernardino, Antonella Consiglio.
      Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication in the brain, with glial cell-derived EVs increasingly recognized for their roles in maintaining brain homeostasis and contributing to the progression of neurodegenerative diseases. By transferring a diverse cargo of bioactive molecules, including proteins, RNAs, and organelles, EVs influence recipient cell behavior and overall brain function. In neurodegenerative conditions, glial EVs can either propagate pathogenic signals or deliver neuroprotective and regenerative cues, depending on their cellular origin and molecular composition. This context-dependent heterogeneity highlights the need for physiologically relevant human models to investigate EVs biology. Human induced pluripotent stem cell (iPSC)-derived glial models provide a disease-relevant platform, as they recapitulate key pathological features of Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). When further integrated with brain organoid platforms, these iPSC-based systems enable the generation of three-dimensional environments that closely resemble in vivo EVs dynamics. Importantly, glial EVs can modulate cellular pathways involved in neuronal survival and function. Indeed, their potential to interact with and, under specific experimental conditions, traverse the blood-brain barrier (BBB) has contributed to growing interest in their application for biomarker discovery and therapeutic development. Engineered and patient-specific EVs derived from iPSCs are emerging as promising tools for targeted, cell type-specific, therapeutic approaches, although their clinical applicability still requires further validation. This review discusses the emerging evidence supporting the dual role of iPSC-derived glial EVs in health and disease, underscores the translational potential of iPSC-based platforms for mechanistic studies, and outlines their promise as precision medicine tools for diagnostics and therapy.
    Keywords:  extracellular vesicles; glial cells; iPSC; neurodegenerative disease
    DOI:  https://doi.org/10.3390/ijms27125182
  12. Muscle Nerve. 2026 Jun 21.
    The Impact of Sponsored Genetic Testing in 170 Consecutive Consenting Patients With Amyotrophic Lateral Sclerosis: A Single-Site Retrospective Review.
    Kevin J Felice, Dottie B Leighton, Annie S Daniel, Natalie I Cartwright, Lucas Meira Benchaya.
       INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) is often categorized as sporadic (sALS) or familial (fALS) based on the family history. Several recent genetic studies have found disease-causing variants in 50%-85% of patients with fALS and 10%-15% of those with sALS. The aim of our study is to review our clinical experience with sponsored genetic testing (i.e., pharmaceutical company-sponsored and cost-free to patient) since its inception.
    METHODS: We reviewed the medical records on all ALS patients seen at our Center who consented to sponsored genetic testing from August 2021 through October 2025.
    RESULTS: Of the 170 medical records reviewed, 22 patients (12.9%) tested positive for a disease-causing variant in a known autosomal dominant disorder. Thirteen of 35 patients with fALS (37.1%) were found to have a disease-causing variant, in contrast to 9 of 135 patients (6.7%) with sALS. Of the 22 disease-causing variants found, the following genes were involved in decreasing frequency: C9orf72 11 (50%), SOD1 6 (27.3%), FUS 2 (9.1%), and one each (4.5%) of SQSTM1, TARDBP, and TBK1. Twenty-eight patients (16.5%) harbored 29 variants of uncertain significance (VUS).
    DISCUSSION: Results of testing led to medically actionable activities including genetic counseling for patients and at-risk family members with positive results, and treatment (i.e., intrathecal tofersen) for the two patients harboring pathogenic SOD1 variants. The lower diagnostic yields than previously published for fALS and sALS patients likely are related to lower numbers of genes tested in the sponsored genetic panels, and these are expected to improve as more genes are added.
    Keywords:  amyotrophic lateral sclerosis; familial ALS; genetic testing; motor neuron disease; sponsored testing
    DOI:  https://doi.org/10.1002/mus.70313
  13. Pharmaceutics. 2026 Jun 12. pii: 730. [Epub ahead of print]18(6):
    Advancing MSC-EV Therapies: Harnessing Preconditioning and Mito-EVs to Tackle Neuroinflammation and Neurodegeneration.
    Eva Costanzi, Luca Fontana, Francesca Giroldo, Silvia Coco.
      Neuroinflammation plays a central role in the onset and progression of neurodegenerative disorders. Several disease-modifying therapies have been developed to target neuroinflammatory pathways in specific disorders. However, their ability to stop disease progression or restore neuronal and mitochondrial homeostasis remains limited. This is still a major unmet clinical need. In this context, mesenchymal stromal cell (MSC)-derived Extracellular Vesicles (EVs) have emerged as a promising cell-free therapeutic strategy due to their ability to modulate immune responses and promote neuroprotection through the delivery of bioactive cargo. Recent evidence has identified a distinct subset of EVs, known as mitochondrial EVs (mito-EVs), which carry mitochondrial DNA, proteins, and functional components. These vesicles may uniquely influence cellular bioenergetics, redox balance, and neuroinflammatory signaling, offering additional therapeutic potential compared to conventional MSC-EVs. This review summarizes the role of MSC-derived EVs in neuroinflammatory disorders, with a particular focus on mito-EVs. It also discusses preconditioning strategies to enhance EV efficacy, including hypoxic, inflammatory, pharmacological priming and genetic engineering approaches. Finally, we critically evaluate current preclinical evidence regarding the treatment of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis, as well as Traumatic Injury, highlighting the key challenges for clinical translation.
    Keywords:  extracellular vesicles; immunomodulation; mesenchymal stromal/stem cells; mitochondrial EVs; neurodegeneration; neuroinflammation; preconditioning
    DOI:  https://doi.org/10.3390/pharmaceutics18060730
  14. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jun 26. 1-19
    Noninvasive assessment of cardiovascular autonomic reflexes in amyotrophic lateral sclerosis: a systematic review.
    Sorfina Ilham Rozman, Nur Azah Hamzaid, Einly Lim, Norhamizan Hamzah.
      Dysautonomia is gradually recognized in amyotrophic lateral sclerosis (ALS), raising concerns of secondary complications from heightened autonomic burden. Autonomic disturbances, particularly cardiac dysautonomia, significantly impact patient outcomes, contributing to increased cardiovascular risks and mortality rate. While the ALS Functional Rating Score-Revised (ALSFRS-R) measures functional decline as disease progress, it overlooks autonomic criteria - a critical factor in ALS progression. This review aims to analyze noninvasive applications of cardiovascular signal variability for continuous real-time monitoring of autonomic dysfunction in ALS, while addressing gaps in current clinical assessments. A total of 584 literatures were gathered from four databases (WoS, PubMed, Science Direct and MEDLINE EBSCOhost) - published from inception till December 2023. 21 peer-reviewed studies were included in this review after screening and meeting the inclusion criteria. Various cardiovascular signal variability metrics and autonomic protocols were discussed. Key findings highlight cardiac autonomic dysfunction in ALS is marked by reduced heart rate variability, absent blood pressure regulation upon orthostatic stress and circadian changes, prolonged QTc interval and low baroreflex sensitivity. Moreover, increased autonomic burden is associated with a shift from sympathetic to parasympathetic dysregulation as the disease progresses. Evidence highlights the need to integrate noninvasive autonomic biomarkers into digital ALS monitoring frameworks, enabling earlier detection of autonomic involvement and more precise longitudinal monitoring beyond motor decline.
    Keywords:  Motor neuron disease; amyotrophic lateral sclerosis; cardiac autonomic dysfunction; cardiovascular signal variability; digital monitoring
    DOI:  https://doi.org/10.1080/21678421.2026.2692135
  15. J Neurochem. 2026 Jun;170(6): e70508
    Comparison of Proteomic Analysis of Cerebrospinal Fluid From Neurological Patients With and Without Amyotrophic Lateral Sclerosis.
    Eleonora Sabetta, Karin Rallmann, Pille Taba, Abigail L Pfaff, Bal Hari Poudel, Davide Ferrari, Massimo Locatelli, Sulev Kõks, Jonas Bergquist.
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness in both bulbar and extremity muscles, leading to a diverse clinical phenotype with motor and non-motor symptoms. Approximately 85% of ALS cases are sporadic (sALS), while the remaining 10%-15% are familial (fALS). Biological biomarkers of sporadic ALS remain poorly understood, hindering precise patient screening, delaying diagnosis and negatively affecting prognosis. This study aims to identify potential proteomic biomarkers by comparing the cerebrospinal fluid (CSF) of sALS patients with that of patients suffering from other neurological diseases. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for proteomic profiling of CSF samples from 24 sALS patients and 26 patients with other neurological diseases. The complete protein expression profiles were compared using a two-tailed Student's t-test, with a p < 0.05 considered statistically significant with additional FDR correction at the 0.1 level. Proteomic analysis of CSF samples identified significant quantitative changes in 96 proteins with threshold p < 0.05 and 74 proteins with FDR < 0.1 between sALS and non-ALS patients, including alterations in proteins associated with neurodegenerative processes, such as amyloid precursor proteins and inflammatory markers. CSF proteomic analysis reveals altered inflammatory and neurodegenerative metabolic pathways, providing valuable insights into the proteomic landscape of sALS. Several dysregulated proteins were consistent with the disease mechanisms highlighted in previous studies. These findings represent a step forward in developing personalised approaches for diagnosing and managing the disease.
    Keywords:  genetic architecture; neurodegenerative disorders; protein profiling; proteomic biomarkers; sporadic amyotrophic lateral sclerosis (sALS)
    DOI:  https://doi.org/10.1111/jnc.70508
  16. Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2610001123
    IRE1 regulates the proteostasis of TDP-43/TARDBP in ALS/FTD through ribosome-associated quality control.
    Dongyue Liu, Yu Li, Shuai Huang, Yufang Xu, Lei Sun, Wen Li, Cahir J O'Kane, David C Rubinsztein, Bingwei Lu, Shuangxi Li.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders characterized by motor neuron degeneration, leading to muscle weakness, atrophy, and cognitive impairments. A defining pathological hallmark of ALS/FTD is the cytosolic mislocalization and accumulation of TAR DNA-binding protein 43 (TDP-43), highlighting its critical role in ALS pathogenesis. However, the molecular mechanisms underlying TDP-43 proteostasis remain poorly understood. Through a genetic screening approach, we identify inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum-resident transmembrane protein, as a potent suppressor of TDP-43 protein levels. Furthermore, we show that ribosome-associated quality control (RQC) factors play a crucial role in regulating TDP-43 proteostasis and cellular toxicity. Activation of the RQC pathway prevents excessive accumulation of TDP-43 and associated toxicity. Mechanistically, our findings suggest that IRE1 regulates TDP-43 protein level by promoting the degradation of aberrant TDP-43 translation product through the RQC pathway. IRE1 acts canonically to enhance the transcription of the RQC core component Clbn/NEMF and noncanonically to physically interact with Clbn/NEMF, thereby ameliorating TDP-43-induced proteotoxicity. Moreover, ectopic expression or pharmacological activation of IRE1 alleviates TDP-43 pathology and restores cognitive function in the TDP-43 A315T ALS mouse models. Collectively, our study identifies a role for IRE1 in the translational quality control of TDP-43 and establishes its potential as a therapeutic target for ALS/FTD.
    Keywords:  IRE1; TDP-43/TARDBP; ribosome-associated quality control (RQC)
    DOI:  https://doi.org/10.1073/pnas.2610001123
  17. BioData Min. 2026 Jun 25.
    Learning a distance for the clustering of patients with amyotrophic lateral sclerosis.
    Guillaume Tejedor Y Dominguez, Hugo Alarcan, Veronika Peralta, Nicolas Labroche, Philippe Corcia, Patrick Marcel, Hélène Blasco.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with median survival of 3-5 years. Patient responses to treatments vary widely, highlighting the need for personalized care. Clustering patients based on disease progression could improve prognosis, guide clinical decision-making, and optimize clinical trial design. This study aimed to identify robust ALS patient clusters using ALS Functional Rating Scale-Revised (ALSFRS-R) scores and to determine diagnostic parameters predictive of cluster membership, enabling earlier stratification and targeted management.
    METHODS: Data from the Tours ALS center registry (April 1997-October 2023) were analyzed; after preprocessing, 353 patients monitored every three months between January 2004 and July 2023 with ALSFRS-R, clinical, biological, and demographic data were retained. After preprocessing to handle missing or aberrant data, a weakly supervised approach labeled patient pairs based on their ALSFRS-R sequences. These labels were used to train a classifier to learn a distance for off-the-shelf clustering algorithms. Multiple configurations were tested, varying clustering algorithms, dimensionality reduction method, and number of clusters. Random Forest (RF) model predicted cluster membership from diagnostic parameters. Optimal clustering was selected using silhouette score, validated with Kaplan-Meier survival analysis. Stability and robustness were assessed with the Adjusted Rand Index (ARI) and silhouette score respectively. Predictive performance was evaluated using specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV). Diagnostic parameters associated with clusters were identified using Kruskal-Wallis and chi-squared tests for continuous and categorical variables.
    RESULTS: Three clusters (n = 139, 121, 93) were identified, demonstrating strong separation (silhouette ≈ 0.6) and high stability of results (ARI ≈ 0.7). Survival differed significantly among clusters: over 50% of patients in the third cluster survived beyond 50 months, compared to less than 25% in the other clusters. Thirteen diagnostic parameters-including ALSFRS-R subscores, IgG levels, albumin quotient, and time to diagnosis-were key predictors of cluster membership. Cluster prediction achieved specificity and NPV ≈ 0.75, with close sensitivity and PPV compared to state-of-the-art methods.
    CONCLUSION: This framework successfully stratifies ALS patients into clinically meaningful clusters, revealing underlying disease heterogeneity and providing strong prognostic insight. Such classification can facilitate personalized care, guide therapeutic decisions, and inform the design of targeted interventions to improve outcomes.
    CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Amyotrophic lateral sclerosis; Clustering; Generative model; Prediction; Survival; Weak-supervision
    DOI:  https://doi.org/10.1186/s13040-026-00579-5
  18. Zhongguo Zhen Jiu. 2026 Jun 12. 46(6): 948-955
    [Effect of electroacupuncture at "Zusanli" (ST36) on TREM2-mediated microglial activation in amyotrophic lateral sclerosis mice].
    Lei Sun, Jun Chen, Yunru Wu, Shuai Bian, Qiang Wang, Lue Ha.
       Objective: To observe the effect of electroacupuncture (EA) at "Zusanli" (ST36) on amyotrophic lateral sclerosis (ALS) in mouse models based on myeloid cell trigger receptor 2 (TREM2)-mediated microglial activation.
    Methods: Thirty-six SPF-grade male human mutant superoxide dismutase 1 (SOD1-G93A) transgenic mice were divided into a model group, an EA group, and a drug group, 12 mice in each group. Besides, 12 wide-type littermates were collected as a control group. In the EA group, EA was performed at the "Zusanli" (ST36), with an intermittent wave, at the frequency of 15 Hz, and for 10 min each intervention; once every other day, 3 interventions a week and for 4 continuous weeks. In the drug group, the intragastric administration of riluzole solution was given at 8 mg/kg, once daily, for 4 continuous weeks. After intervention completion, behavioral assessment of mice was conducted using rotarod test and wire hang test. With HE and Nissl staining adopted, morphology of motor neurons in the anterior horn of the spinal cord was observed. Immunofluorescence was used to detect the fluorescence intensity of TREM2 in the anterior horn of spinal cord. Western blot analysis was performed to measure the protein expression of interleukin (IL)-1β, γ interferon (IFN-γ), IL-4 and IL-10 in spinal cord tissue. Flow cytometry was used to analyze the proportion of CD86+ and CD206+ in spinal cord monocyte suspension.
    Results: Compared with the control group, in the model group, motor neurons in the anterior horn of the spinal cord exhibited disordered arrangement; accompanied by nuclear pyknosis and cytoplasmic shrinkage; the latency to fall in the rotarod test and the cut-off time in the wire hang test were shortened, fluorescence intensity of TREM2 in the spinal anterior horn, the protein expression of IL-1β, IFN-γ, IL-4, and IL-10, and the proportion of CD86+ and CD206+ in spinal cord tissue increased(P<0.01). When compared with the model group, in the EA and drug groups, motor neurons in the anterior horn of the spinal cord were arranged regularly; nuclear pyknosis and chromatolysis were attenuated, and the structural integrity of neurons was improved; the latency to fall and the the cut-off time were prolonged, fluorescence intensity of TREM2 in the spinal anterior horn was reduced, the protein expression of IL-1β and IFN-γ decreased, and that of IL-4, and IL-10 increased in the spinal cord tissue; the proportion of CD86+ in spinal cord tissue was reduced and that of CD206+ elevated(P<0.01, P<0.05). Compared with the drug group, the EA group showed the increase of protein expression of IL-1β,and the decrease of IL-4, IL-10 in the spinal cord tissue and the proportion of CD206+ (P<0.05).
    Conclusion: Electroacupuncture at "Zusanli" (ST36) exhibits a certain improvements in motor function of SOD1-G93A transgenic mice. The underlying mechanism may be related to attenuating neuroinflammation via the modulation of microglial activation mediated by TREM2.
    Keywords:  Point ST36 (Zusanli); amyotrophic lateral sclerosis; electroacupuncture; microglial activation; neuroinflammation
    DOI:  https://doi.org/10.13703/j.0255-2930.20250113-k0001
  19. Sci Rep. 2026 Jun 24.
    Compartmentalized biomarker correlations in HIV: plasma-CSF relationships vary by blood-brain/blood-CSF barrier permeability and viral suppression.
    Ronald J Ellis, Bin Tang, Patricia K Riggs, Jennifer E Ludicello, Maria Cecilia G Marcondes, Violaine Delorme-Walker, Robert K Heaton, Scott L Letendre.
      Neuroinflammation is common in people with HIV (PWH) and may be reflected also in plasma biomarkers; the latter are sometimes used as surrogates for CSF. However, use of plasma biomarkers in this way risks obscuring compartment-specific processes since distribution across the blood-brain barrier (BBB) varies between proteins with some reaching the CNS more readily than others. We tested the hypothesis that BBB and viral suppression status shape cross-compartment biomarker coupling, clarifying when plasma proteins do or do not represent neuroinflammation. Paired CSF and plasma samples from 567 PWH in the CHARTER cohort were analyzed with the Olink Target-96 Inflammation Panel. Using regression, canonical correlation, and machine learning, we evaluated viral suppression and BBB permeability (indexed by CSF total protein levels, which are more readily available clinically and highly correlated with the CSF to serum albumin ratio) as effect modifiers of CSF-plasma biomarker correlations. Intra-CSF and intra-plasma correlations were consistently strong, but cross-compartment correlations were weak and inconsistent. Some proteins had strong correlations when CSF total protein was high, including CD8A, IL-12B, TNFRSF9, and TNFB. Unsuppressed viremia amplified broader cross-compartment signaling (e.g., IL-12B, CXCL9, CXCL10). BBB permeability and viral suppression moderate biomarker compartmentalization in PWH. These findings support a hypothesis-driven framework in which biomarkers can be classified as CNS-restricted, peripherally driven, or BBB-dependent. This mechanistic structure informs biomarker selection for clinical trials and provides testable models of neuroinflammation in PWH.
    Keywords:  blood-CSF barrier; compartmentalization; proteomics
    DOI:  https://doi.org/10.1038/s41598-026-59301-4
  20. Expert Opin Drug Discov. 2026 Jun 23. 1-8
    Are patient-derived models of amyotrophic lateral sclerosis a game changer for novel drug discovery?
    Satoru Morimoto, Hideyuki Okano.
       INTRODUCTION: ALS drug discovery has long depended on model systems that incompletely capture human disease heterogeneity, aging, and TDP-43 proteinopathy. Patient-derived platforms have therefore emerged as increasingly important human-relevant complements to animal and molecular models.
    AREAS COVERED: This Critical Perspective examines when patient-derived ALS models genuinely change therapeutic decision-making rather than merely add mechanistic insight. The authors then propose a heuristic framework based on disease-relevant phenotype recapitulation, capture of patient-to-patient heterogeneity, and generation of findings that influence therapeutic prioritization or clinical translation. Furthermore, the authors evaluate iPSC-derived motor neurons, directly reprogrammed neurons, glial co-cultures, organoids, neural networks, and organ-chip systems against these conditions, while also addressing aging fidelity, reproducibility, upper motor neuron modeling, and regulatory implementation.
    EXPERT OPINION: Patient-derived models are not yet standalone decision-grade tools for ALS drug development. Their present value lies in functioning as a human-biology filter for target discovery, reverse translation, biomarker development, and patient stratification when used within rigorous, standardized, and clinically linked workflows. The strongest current evidence supports proof-of-principle rather than generalized predictive validity.
    Keywords:  Amyotrophic lateral sclerosis; assembloid; drug discovery; induced pluripotent stem cells; organ-on-chip; precision medicine; reverse translation
    DOI:  https://doi.org/10.1080/17460441.2026.2689746
  21. Front Microbiol. 2026 ;17 1815390
    Interplay between B vitamins, fiber, and Bacteroides abundance: a predictive model for anxiety and depression in amyotrophic lateral sclerosis.
    Claudia Emmanuela Sanchis-Sanchis, David Sancho-Cantus, Elena Sanchis-Sanchis, Jesús Privado, Francisco J Roig, María Cuerda-Ballester, Guillermo Bargues-Navarro, Laura Cubero-Plazas, Palmira Martínez Bolós, Ruth Gabriela Cárdenas Salazar, José Enrique de la Rubia Ortí.
       Background: Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease that not only affects motor function but is also associated with gastrointestinal and emotional disturbances. Recent research highlights the potential role of gut microbiota and diet in modulating these symptoms, suggesting a complex interaction between nutrition, intestinal health, and presence of anxiety and depression in ALS patients. This study aims to investigate the relationship between dietary intake, gut microbiota composition, and presence of anxiety and depression in patients with amyotrophic lateral sclerosis (ALS).
    Methodology: A cross-sectional study conducted with a sample of 48 patients with bulbar-onset or spinal-onset ALS from different regions of Spain. Dietary intake was assessed through 24-h records and food frequency questionnaires, while anxiety and depression were evaluated using validated scales that formed a latent factor called emotional distress. Stool consistency was assessed following the Bristol Stool Scale and the abundance of bacterial microbiota was quantified.
    Results: Confirmatory factor analysis identified a nutritional factor composed of vitamins B1, B2, B9, C, and fiber, revealing a significant inverse association with anxiety and depression levels. The predictive model revealed both direct and indirect effects of this factor on presence of anxiety and depression, mediated by Bacteroides abundance and stool consistency.
    Conclusion: This model explained 19% of the variance in psychological distress. Our findings suggest that a diet rich in B vitamins, C vitamin and fiber may help improve emotional well-being in patients with ALS, highlighting the importance of nutritional strategies, as well as the role of Bacteroides related to stool consistency in patients with ALS.
    Keywords:  amyotrophic lateral sclerosis; anxiety; depression; gut microbiota; vitamin B complex
    DOI:  https://doi.org/10.3389/fmicb.2026.1815390
  22. Medicina (Kaunas). 2026 May 27. pii: 1039. [Epub ahead of print]62(6):
    Association Between Clinical Dysphagia Assessment Tools and Videofluoroscopic Findings in Amyotrophic Lateral Sclerosis: A Retrospective Study.
    Burak Manay, Demet Aygün, Alperen Şentürk, Mustafa İbas, Ramazan Güven, Şeyda Belli.
      Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease frequently associated with dysphagia and aspiration risk. This study aimed to investigate the relationship between clinical dysphagia assessment tools (EAT-10, GUSS, RSST, and sialorrhea severity) and videofluoroscopic swallowing study (VFSS) findings in patients with ALS. Materials and Methods: This retrospective observational study included 60 patients with ALS classified as spinal-onset (n = 38) or bulbar-onset (n = 22). Relationships between clinical assessments and VFSS findings were analysed using Spearman correlation analysis. Exploratory multivariable regression and receiver operating characteristic (ROC) analyses were performed to evaluate associations and aspiration risk discrimination. Results: Strong negative correlations were observed between PAS-Liquid and RSST and GUSS scores, whereas EAT-10 showed a strong positive correlation (all p < 0.001). ROC analyses demonstrated good discriminative ability for aspiration risk for GUSS (AUC = 0.89), RSST (AUC = 0.88), and EAT-10 (AUC = 0.82). Patients with bulbar-onset ALS demonstrated higher penetration-aspiration severity and lower functional oral intake. Conclusions: Clinical dysphagia assessment tools showed significant associations with instrumental swallowing findings in ALS. GUSS and RSST demonstrated good discriminative ability for aspiration risk and may be clinically useful bedside screening tools. However, instrumental swallowing assessment remains essential whenever feasible.
    Keywords:  Penetration–Aspiration Scale; amyotrophic lateral sclerosis; clinical swallowing assessment; dysphagia; videofluoroscopic swallowing study
    DOI:  https://doi.org/10.3390/medicina62061039
  23. PLoS One. 2026 ;21(6): e0350029
    Applications of electromyography in Amyotrophic Lateral Sclerosis: A systematic review.
    Ana Paula Mendonça Fernandes, Luiz Henrique Bertucci Borges, Ledycnarf Januário de Holanda, Bruno Henrique E Silva Bezerra, Anna Clara Sales Miranda Lopes, Maria Clara Fernandes da Silva, Ricardo A de M Valentim, Laurent Bougrain, Gabriel Alves Mendes Vasiljevic, Ana Raquel Rodrigues Lindquist.
      This systematic review examined the use of surface electromyography (sEMG) for the neuromuscular assessment of individuals with Amyotrophic Lateral Sclerosis (ALS), focusing on clinical parameters, the muscle groups evaluated, acquisition protocols, technical properties of the recording systems, integration with other technologies, and signal processing strategies. We included observational studies that applied sEMG to individuals diagnosed with ALS, with or without comparison to healthy controls, and without restrictions on publication year. The analyses included signals recorded at rest and during voluntary contractions, with or without the use of biofeedback. Most studies employed conventional or high-density surface electrodes, with sampling frequencies ranging from 500 Hz to 3000 Hz. The results showed that the primary parameters assessed were muscle fatigue, fasciculation patterns, the number of motor units (MUNE/MUNIX), motor unit firing rates, and signal complexity. These parameters demonstrated sensitivity to disease progression and may contribute to early diagnosis, phenotypic stratification, and functional monitoring of ALS. Additionally, the studies highlighted the increasing use of advanced computational approaches, such as machine learning, for feature extraction and automated classification. In conclusion, sEMG is a promising tool for functional assessment in ALS, with the potential to improve diagnostic accuracy and support new therapeutic strategies based on electrophysiological biomarkers. However, despite technological advances, the included studies displayed substantial methodological heterogeneity and limited protocol standardization. Integration with other neurophysiological modalities also remains underexplored, despite its significant clinical potential.
    DOI:  https://doi.org/10.1371/journal.pone.0350029
  24. FASEB J. 2026 Jul 15. 40(13): e72063
    FMRP-Mediated Proteasome Regulation: A Novel Mechanism in ALS Pathology.
    Pritha Majumder, Asmar Ahsan, Pitchapa Bubphachat, Khadiza Akter, Jeffrey K Huang, Chi-Chen Sarah Huang.
      Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disease characterized by the hallmark cytoplasmic accumulation and aggregation of TAR DNA binding protein 43 (TDP-43), which impairs proteasome activity through its interaction with Tankyrase (TNKS). Using molecular and imaging techniques, we have identified a novel role for the Fragile X Mental Retardation Protein (FMRP) in regulating the TNKS/PI31-mediated proteasome activation mechanism in co-operation with TDP-43. Our results demonstrate that depletion of FMRP causes nuclear translocation of TDP-43, reducing cytoplasmic TNKS/TDP-43 co-localization, thereby releasing TNKS in the cytoplasm. Free TNKS gets associated with proteasome inhibitor of 31 kDa (PI31), reversing PI31-mediated inhibition of proteasome assembly, trafficking, and activity. Thus, FMRP regulates proteasome activity by modulating the subcellular distribution of TDP-43. Interestingly, FMRP expression is elevated in specific brain regions and spinal cords of TDP-43A315T transgenic ALS mice that helps more TDP-43 to stay in cytoplasm to sequester more TNKS with it, resulting in proteasome dysfunction in ALS disease system. We have demonstrated for the first time that FMRP can act as a disease modifier for ALS. ALS patients with high FMRP expression in the brain and spinal cord may exhibit more severe protein aggregation due to proteasome dysfunction.
    Keywords:  ALS; FMRP; PI31; TDP‐43; TNKS; nuclear/cytoplasmic localization; ubiquitin proteasome system
    DOI:  https://doi.org/10.1096/fj.202600563R
  25. Inflammopharmacology. 2026 Jun 22.
    Targeting mitochondrial dysfunction and neuroprotection in neurodegenerative disorders: emerging therapeutic potential of berberine and polymeric nanoparticle-based delivery systems.
    Basith Rehman Sathick Batcha, Deevan Paul Amarnath, Devasena Srinivasan, Prakash Ramakrishnan.
      Major neurodegenerative disorders, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are pathologically driven by mitochondrial failure and persistent neuroinflammation. Defects in oxidative phosphorylation, excess Reactive Oxygen Species (ROS), and impaired mitophagy cause an imbalance in neuronal energy and promote the release of mitochondrial Damage-Associated Molecular Patterns (DAMPs) that activate microglial inflammasomes and enhance inflammatory signalling. Current therapeutic strategies have largely targeted individual pathways and have been unable to effectively modulate this interrelated mitochondrial immune axis or achieve efficient delivery to the Central Nervous System (CNS). This review addresses the dual promise of berberine therapy, a biologically active plant alkaloid that enhances mitochondrial production via AMPK/PGC-1α and SIRT1, restores membrane potential, promotes mitophagy, and inhibits NF-κB and NLRP3-mediated inflammation. Nevertheless, this compound's weak solubility, limited bioavailability, and extremely poor Blood-Brain Barrier (BBB) penetration limit its therapeutic application. Encapsulation of berberine in polymeric nanoparticles, including Polyethylene glycol (PEG)-based polymeric nanoparticle systems, offers improved stability, bioavailability, and targeted mitochondrial delivery. An effective method for reducing neuroinflammation and mitochondrial dysfunction is this comprehensive phytochemical nanotechnology technique.
    Keywords:  Berberine; Mitochondrial dysfunction; Neurodegeneration; Neuroinflammation; Phytochemicals; Polymeric nanoparticles
    DOI:  https://doi.org/10.1007/s10787-026-02276-5
  26. Neurogenetics. 2026 Jun 23. pii: 45. [Epub ahead of print]27(1):
    Behavioral variant frontotemporal dementia associated with a NEK1 missense variant: exploring a possible phenotypic association.
    Ozlem Totuk, Sevki Sahin.
      NEK1 variants are recognized genetic contributors to amyotrophic lateral sclerosis (ALS) and have occasionally been reported within the ALS-frontotemporal dementia (FTD) spectrum. However, their association with isolated behavioral variant frontotemporal dementia (bvFTD) remains unclear. Here, we describe a 69-year-old man who developed progressive behavioral symptoms beginning in his early 60s. Cognitive evaluation demonstrated reduced verbal fluency with relative preservation of memory functions. Structural and functional neuroimaging demonstrated right-predominant frontotemporal atrophy and hypometabolism. Genetic testing for common FTD-associated genes (MAPT, GRN, and C9orf72) was negative. Whole-exome sequencing identified a heterozygous NEK1 c.899T > C (p.Ile300Thr) missense variant, currently classified as a variant of uncertain significance. This observation raises the possibility that NEK1-associated disease may extend beyond ALS or ALS-FTD phenotypes and may include isolated bvFTD presentations. However, further genetic and functional studies are required to clarify the clinical significance of this variant.
    Keywords:   NEK1 ; Amyotrophic lateral sclerosis; Behavioral variant frontotemporal dementia; Frontotemporal dementia; Whole-exome sequencing
    DOI:  https://doi.org/10.1007/s10048-026-00916-0
  27. Int J Mol Sci. 2026 Jun 22. pii: 5627. [Epub ahead of print]27(12):
    IMMUND: A Diagnostic and Therapeutic Pipeline to Uncover the Convergence in Functional Perturbation at Early Stages of Neurodegenerative Diseases and Multiple Sclerosis Based on Protein Markers.
    Ashmita Dey, Dwipanjan Sanyal, Krishnananda Chattopadhyay, Ujjwal Maulik, Vladimir N Uversky, Sagnik Sen.
      Neuroinflammation is a key hallmark of both neurodegenerative and neurospecific autoimmune diseases, including multiple sclerosis (MS), where immune dysregulation contributes to cellular stress, autophagy, and disease progression in Alzheimer's disease (AD), Parkinson's disease (PD), and MS. Emerging evidence suggests a shared mechanism behind MS, AD, and PD, driven by chronic interaction between the peripheral immune system and the central nervous system (CNS). While MS was traditionally viewed as a primary autoimmune condition, recent research indicated that all three disorders involve a breakdown of the blood-brain barrier (BBB). This structural failure enables peripheral immune cells and cytokines to enter the brain, causing sustained neuroinflammation and accelerating disease progression. Here, we propose an end-to-end framework for identification of the diagnostic and therapeutic cell-specific protein markers commonly regulated in mild-moderate AD (MMAD), early-stage PD (ESPD), and MS within peripheral blood mononuclear cells (PBMCs). PBMC markers were first identified based on shared differential protein expression, followed by filtering for BBB permeability. Subsequently, sorted cell markers were mapped to disease-specific neural cell types. Our analysis suggests that PBMC-derived cells, including astrocyte- and monocyte-like populations, share overlapping transcriptional signatures and functional similarity with macrophages and neuroglial cells, indicating potential transcriptional similarity or functional convergence. Furthermore, intra- and inter-cellular pathway analysis suggested both shared and disease-specific signaling mechanisms, with kinase-integrin interactions emerging as key regulatory factors. Selected potential seed markers, primarily kinases and immunoglobulins, were further analyzed through evolutionary sequence-structure space to identify druggable structural features. Next, protein moonlighting possibilities were tested to enhance the temporal functional trajectory of the markers for precise therapeutic impact. Hence, the framework provides a robust strategy to identify immune-based disease-specificcandidate diagnostic andpotential therapeutic targets.
    Keywords:  blood–brain barrier dysfunction; cell-specific protein markers; druggable targets; immune–CNS crosstalk; neuroinflammation; transcriptomics
    DOI:  https://doi.org/10.3390/ijms27125627
  28. Nat Commun. 2026 Jun 25. pii: 5566. [Epub ahead of print]17(1):
    Intravenous administration of an engineered AAV9-gene-silencing vector suppresses human SOD1 and extends survival in an ALS mouse model.
    Fang Wan, Jinchen He, Hong Ma, Debora PiresFerreira, Veena Kumanan, Ji Sun Lee, Xiupeng Chen, Ran He, Qin Su, Thomas L Gallagher, Sha Zhu, Gabriela Toro Cabrera, Lingzhi Zhao, Joan Shen, Alisha Gruntman, Robert H Brown, Zuoshang Xu, Guangping Gao, Jun Xie.
      Adeno-associated virus (AAV)-mediated gene silencing offers a promising strategy for achieving durable therapeutic effects with a single administration. Mutations in the human superoxide dismutase 1 (hSOD1) gene, inherited in an autosomal dominant manner, lead to motor neuron degeneration in amyotrophic lateral sclerosis (ALS)-a fatal neurodegenerative disease with no effective treatment. In this study, we employed AAV9 to deliver to the SOD1G93A ALS mouse model artificial microRNAs targeting SOD1, embedded in dual miR-33 scaffolds driven by the promoter of the human survival motor neuron 1 (hSMN1) gene. A single intravenous injection achieved widespread and sustained suppression of SOD1, preserved α-motor neurons, maintained neuromuscular junctions (NMJs), and improved muscle function. These benefits are translated into significantly improved respiratory function, motor performance, and survival. Therapeutic efficacy was observed both when the treatment was administered pre-symptomatically and during symptomatic stages. Compared with previous AAV-based interventions, the survival benefit achieved in this IV delivery approach is unprecedented, supporting its potential for clinical translation in SOD1-linked ALS and other central nervous system (CNS) diseases caused by gain-of-toxicity gene mutations.
    DOI:  https://doi.org/10.1038/s41467-026-74169-8
  29. Eur J Neurol. 2026 Jun;33(6): e70660
    Tolerability, Safety and Effectiveness of Sigh Introduction During Non-Invasive Mechanical Ventilation Cycles in Patients With Amyotrophic Lateral Sclerosis.
    Nilo Riva, Paride Schito, Tommaso Russo, Ottavia Eleonora Ferraro, Gianluca Durante, Andrea Tettamanti, Elisa Riboldi, Teuta Domi, Laura Pozzi, Angelo Quattrini, Mauro Comola, Federica Agosta, George Cremona, Massimo Filippi.
       BACKGROUND: Respiratory failure is the main cause of death in Amyotrophic lateral sclerosis (ALS), in which the physiological sigh reflex is impaired due to inspiratory muscle weakness. Aim of this study is to assess the tolerability, safety, and effectiveness of adding a sigh cycle to non-invasive mechanical ventilation (NIMV) settings in ALS patients.
    METHODS: In this randomized, blind-controlled proof-of concept study, 44 consecutive ALS patients with indication for NIMV were randomized to: Group I: NIMV with Sigh cycles; Group II: NIMV without Sigh. The primary outcome was the reduction in the Oxygen Desaturation Index (ODI); secondary outcomes included: Overnight Oximetry (OvOx), Arterial blood gas (ABG), and Visual Analog Scale (VAS; 0-10) scores to assess sleep quality, symptom intensity, mask interface, and NIMV tolerance. Assessments were conducted at baseline, after NIMV adaptation (T1) and at 1-month follow-up (T2).
    RESULTS: The Sigh cycle was safe and well tolerated. No significant group differences were observed at T1 or T2 in the primary outcome ODI (median ΔODI: Group A:-4.2; Group B:-4.6: p = 0.54), as well as in the OvOx parameters and pO2 and pCO2 ABG values. At T2, secondary analysis showed a significant difference in HCO₃- in favor of the Sigh arm (ΔHCO3 -: -1.60 vs. 1.35 mmol/L, p = 0.042). Exploratory Cox-regression models suggested a potential independent effect of SIGH on survival.
    CONCLUSIONS: Sigh is safe, well tolerated in ALS patients. Although this study did not reach the primary outcome, we also cannot rule out that sigh doesn't benefit the patient.
    Keywords:  NIV; motor neuron disease; rehabilitation; respiratory failure; survival
    DOI:  https://doi.org/10.1111/ene.70660
  30. Neurol Sci. 2026 Jun 26. pii: 591. [Epub ahead of print]47(7):
    Characterization of sensory nerve conduction abnormalities at the time of ALS diagnosis.
    Arsh Ketabforoush, W David Arnold, Armin Ariaei, Faezeh Faghihi, Fereshteh Azedi, Maryam Khalili, Fereshteh Gholami, Mohammad Taghi Joghataei, Bahram Haghi Ashtiani.
       OBJECTIVES: Although sensory nerve abnormalities have been reported in amyotrophic lateral sclerosis (ALS), their distribution at diagnosis, relative to motor involvement and clinical onset phenotype remains incompletely characterized. We aimed to systematically compare sensory and motor nerve conduction abnormalities at ALS diagnosis and determine whether sensory involvement follows an onset-dependent pattern similar to motor dysfunction.
    METHODS: In this prospective cross-sectional study, 40 newly diagnosed ALS patients enrolled in the Iran University ALS Registry (March 2022-March 2023) underwent standardized motor and sensory nerve conduction studies (NCS). For between-group comparisons, a matched ALS subgroup was compared with matched healthy controls, while the expanded ALS cohort was used for subgroup and correlation analyses.
    RESULTS: SNAP amplitudes of the median, ulnar, and sural nerves were reduced by 45%, 34%, and 43%, respectively, compared with healthy controls, with similar reductions observed across upper- and lower-limb onset phenotypes and no significant onset-dependent differences. In contrast CMAP amplitudes were markedly reduced in ALS patients, most prominently in the peroneal (79%), median (47%), tibial (42%), and ulnar (37%) nerves. Motor abnormalities were most severe in the clinically affected limb but were also detectable in asymptomatic extremities, consistent with early subclinical spread.
    CONCLUSION: At ALS diagnosis, sensory and motor nerve conduction abnormalities exhibited divergent spatial patterns, with asymmetric, onset-related motor involvement and relatively uniform sensory axonal dysfunction. These findings support the presence of measurable sensory nerve conduction abnormalities in a subset of ALS patients, while highlighting the need for cautious interpretation of sensory NCS changes in ALS.
    Keywords:  Amyotrophic lateral sclerosis; Compound muscle action potentials; Nerve conduction study; Peripheral nerve involvement; Sensory nerve action potentials
    DOI:  https://doi.org/10.1007/s10072-026-09203-0
  31. Acta Neuropathol Commun. 2026 Jun 25. pii: 135. [Epub ahead of print]14(1):
    A rare missense variant impacting NEK1 kinase function is associated with ALS.
    David Brenner, Anna Ponomarenko, Iris Petrut, Sofia Beyrle, Matilde Contardo, Isabel Loss, Constantin Radke, Jonas Frank, Eleni Zimmer, Matthias Schlesner, Pascal Achenbach, Wendy Scheveneels, Amr Aly, Hülya Nazlican, Jasper Hesebeck-Brinkmann, Patrick Oeckl, Kathrin Müller, Reiner Siebert, Tobias Böckers, Kristel van Eijk, Jan Veldink, Alexander Kleger, Medhanie Mulaw, Peter M Andersen, Karin Forsberg, Jochen H Weishaupt, Seyed Babak Loghmani, Thorsten Grehl, Philip van Damme, Joachim Weis, Alberto Catanese.
      Heterozygous truncating loss-of-function (LoF) variants in NEK1 are a known cause of amyotrophic lateral sclerosis (ALS). NEK1 encodes the pleiotropic serine/threonine kinase NIMA-related kinase 1, and prior in vitro studies have implicated kinase dysfunction as the principal pathogenic mechanism underlying NEK1-associated ALS. However, bona fide pathogenic missense variants causally linked to ALS have not previously been reported, leaving this hypothesis unconfirmed. Here, we identify a rare NEK1 missense variant, p.N598S, that co-segregates with disease in a familial ALS pedigree and is enriched in European ALS cohorts. This variant exhibits normal protein expression levels, indicating a functional rather than quantitative defect. Using isogenic human motor neurons, we directly compared the effects of p.N598S with those of the ALS-associated truncating variant p.R812* to delineate disease mechanisms. The p.N598S variant induced pathological phenotypes consistent with NEK1 haploinsufficiency, including increased susceptibility to DNA damage, increased apoptosis, ciliary dysmorphia, and nucleocytoplasmic translocation of TDP-43. Importantly, p.N598S impaired NEK1 kinase activity, and pharmacological inhibition of NEK1 recapitulated the cellular phenotypes observed in both p.N598S- and p.R812*-mutant motor neurons. Collectively, these findings provide strong genetic and functional evidence for a disease-causing role of NEK1 kinase disruption in NEK1-ALS. Our findings provide immediate diagnostic and therapeutic implications, particularly for the functional interpretation of missense variants of uncertain significance and the development of targeted treatment strategies.
    Keywords:  ALS; Autophagy; Genetics; Kinase; Missense variant; NEK1; TDP-43 pathology
    DOI:  https://doi.org/10.1186/s40478-026-02351-6
  32. Sci Adv. 2026 Jun 26. 12(26): eady0256
    Isoform-specific steric zippers drive aberrant assembly and mislocalization of shortened TDP-43.
    Katie E Copley, Megan M Dykstra, Morgan R Miller, Miriam Linsenmeier, Longsheng Lai, Yuanhang Wang, Yi-Wei Chang, Sami J Barmada, James Shorter.
      Prion-like domain (PrLD)-mediated aggregation and concomitant dysfunction of the essential RNA-binding protein transactive response (TAR) DNA-binding protein of 43 kilodaltons (TDP-43) is a common feature of multiple debilitating neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). However, shortened TDP-43 (sTDP-43) splice isoforms where the PrLD is largely replaced by an 18-residue carboxyl-terminal tail also contribute to ALS pathophysiology and are enriched in motor neurons. Curiously, despite lacking most of the PrLD, sTDP-43 exhibits pronounced insolubility in cells and tissue of patients with ALS. Here, we establish that the short, isoform-specific carboxyl-terminal tail of sTDP-43 confers high aggregation propensity, which is encoded by two clusters of steric zippers, and can be mitigated by short RNA chaperones. Disrupting these zippers enhances sTDP-43 solubility at the pure protein level and in neurons. Notably, these steric zippers, rather than a predicted nuclear export signal in the carboxyl-terminal tail, drive cytoplasmic mislocalization and aggregation of sTDP-43 in neurons. Thus, we define the sequence-encoded determinants of aberrant sTDP-43 assembly and provide mechanistic insights into sTDP-43 disease pathology.
    DOI:  https://doi.org/10.1126/sciadv.ady0256
  33. Mol Neurobiol. 2026 Jun 26. pii: 728. [Epub ahead of print]63(1):
    Targeting mtDNA to Modulate Mitochondrial Dysfunction in Neurodegenerative Diseases.
    Sanket Pramanik, Biplab Debnath, Aganta Chakraborty, Anas Islam, Shrabasti Mullick, Priya Chaudhary, Rajarshi Nath, Dinesh Kumar Chellappan, Mohini Mondal, Sumel Ashique.
      Mitochondrial dysfunction is a common pathological feature of neurodegenerative diseases namely Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Although these disorders are primarily driven by disease-specific genetic and proteopathic mechanisms, increasing evidence suggests that secondary mitochondrial DNA (mtDNA) damage and heteroplasmy shifts may exacerbate bioenergetic failure and neuronal vulnerability. Distinguishing primary disease mechanisms from downstream mtDNA alterations is critical to accurately evaluate emerging therapeutic strategies. Recent advances in mtDNA-targeted genome editing have enabled the direct manipulation of mitochondrial genomes. Mitochondrially targeted zinc finger nucleases and TALENs can selectively alter mutant mtDNA to induce heteroplasmy shifts, whereas DddA-derived cytosine base editors allow precise base editing without double-strand breaks. However, each platform has distinct limitations related to the target scope, off-target risk, design complexity, and delivery efficiency. The application of CRISPR/Cas-based systems to mammalian mtDNA remains constrained by the unresolved challenges in guiding RNA import. This review critically examines mitochondrial dysfunction and mutant mtDNA accumulation in neurodegenerative diseases. It also evaluates current and emerging mtDNA-editing techniques, and highlights key translational barriers. We highlighted that mtDNA-targeted interventions can be a promising approach for disease-modifying or adjunctive strategies, rather than curative approaches.
    Keywords:  DdCBE (DddA-derived Cytosine Base Editors); Heteroplasmy Correction; MitoTALENs; Mitochondria-Targeted CRISPR/Cas Systems; Mitochondrial Genome Editing; Neurodegenerative Disorders; Oxidative Stress & Mitochondrial Dysfunction; Precision Medicine
    DOI:  https://doi.org/10.1007/s12035-026-06008-2
  34. Biol Trace Elem Res. 2026 Jun 22.
    Trace Elements Dyshomeostasis and Toxic Metals Neurotoxicity in Neurodegenerative Diseases.
    Min Tang, Emmanuel Fleming, Jie Gu, Haifeng Shi, Yuzhen Xu, Xun Gong.
      Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, are defined by the progressive loss of neurons through interconnected pathological mechanisms, including oxidative stress, mitochondrial dysfunction, protein aggregation, and neuroinflammation. Accumulating evidence implicates metal dyshomeostasis as a central and multifaceted contributor to these mechanisms, with roles ranging from a primary pathogenic driver in AD and PD, to a secondary amplifier of genetic pathology in HD and ALS, and as a contextual risk modifier in the presence of toxic metals. Essential trace metals such as iron, zinc, copper, manganese, selenium, iodine, and molybdenum are vital for neurotransmission, antioxidant defense, and cellular metabolism. Dysregulation of these metals disrupts redox balance, impairs proteostasis, and activates regulated cell death pathways, including ferroptosis and cuproptosis. Toxic metals, such as lead, cadmium, and mercury, exacerbate neurodegeneration by displacing essential metals, inducing oxidative injury, and promoting protein misfolding and neuroinflammation. This narrative review synthesizes mechanistic, experimental, genetic epidemiological, and clinical evidence to critically evaluate the contributions of both essential and toxic metals to neurodegeneration in AD, PD, HD, and ALS. We examine the genetic, environmental, and physiological determinants of metal homeostasis; the analytical techniques for quantifying metals in clinical samples; and clinical trial data on metal-targeted therapeutic strategies. Notably, iron chelation with deferiprone consistently reduces brain iron on neuroimaging but worsens clinical outcomes in both PD and AD, presenting a translational paradox that requires mechanistic re-evaluation. We also provide methodological recommendations for interpreting Mendelian randomization studies of metal exposures and propose translational priorities to advance metal-targeted diagnostics and therapeutics for neurodegenerative diseases.
    Keywords:  Inflammation; Neurodegeneration; Neuroprotection; Oxidative stress; Toxic metals; Trace elements
    DOI:  https://doi.org/10.1007/s12011-026-05187-2
  35. Muscle Nerve. 2026 Jun 21.
    Muscle Ultrasound Is a Sensitive Outcome Measure in ALS.
    Andrew M Hannaford, Isabella E Supnet, Nathan Pavey, Parvathi Menon, Mehdi A J van den Bos, Matthew C Kiernan, Nens van Alfen, Neil G Simon, Steve Vucic.
       INTRODUCTION/AIMS: Muscle ultrasound is a potential outcome measure in amyotrophic lateral sclerosis (ALS), although prospective, multicenter longitudinal studies are lacking. This study aimed to evaluate muscle ultrasound as an outcome in ALS and compare its sensitivity with clinical and neurophysiological metrics.
    METHODS: In this prospective two-center cohort study, adults with ALS underwent baseline and follow-up assessments at least 3 months apart. Clinical measures included the ALS Functional Rating Scale-Revised (ALSFRS-R) and Medical Research Council sum scores. Median nerve abductor pollicis brevis and ulnar nerve first dorsal interosseous compound motor action potential (CMAP) amplitudes were recorded. Muscle ultrasound of 11 bulbar and limb muscles was performed using harmonized protocols, with offline analysis of muscle thickness and echogenicity. Longitudinal change and effect sizes were calculated.
    RESULTS: Twenty-two patients were included (median age 59.3 years, follow-up 9.6 months, disease duration 23.1 months). ALSFRS-R declined by -3.0 points (-0.7% per month; effect size 0.84). Median nerve CMAP amplitude decreased by -1.6 mV (-1.2% per month; effect size 0.77). Muscle echogenicity increased by 0.8 units (+6.0% per month), yielding the largest effect size (1.09), with increases across multiple muscles. Responsiveness improved with onset-specific muscle selection, with biceps brachii (effect size 1.12) and gastrocnemius (1.18) showing the strongest changes. Muscle thickness and fasciculation frequency did not change.
    DISCUSSION: Muscle ultrasound echogenicity is a sensitive structural biomarker of ALS progression, demonstrating greater responsiveness than ALSFRS-R and CMAP over 3-12 months. Its accessibility and sensitivity support its utility as an outcome measure in clinical trials.
    Keywords:  amyotrophic lateral sclerosis; disease progression; echogenicity; muscle ultrasound; outcome measures
    DOI:  https://doi.org/10.1002/mus.70317
  36. Curr Rev Clin Exp Pharmacol. 2026 Jun 19.
    Toll-Like Receptor-Mediated Neuroinflammation and Its Role in Neurocognitive Functions.
    Vivek Srivastava, Suman Chakraborty, Richa Srivastava.
      Toll-like receptors (TLRs) are a family of pattern recognition receptors that recognise both pathogen-associated and damage-associated molecular patterns. While their expression was initially believed to be restricted to immune cells, accumulating evidence now demonstrates their presence across multiple neural cell types. Due to their significant involvement in neuroinflammatory and neurodegenerative processes, TLRs have garnered growing attention for their potential contributions to neurocognitive disorders, including Alzheimer's disease, Parkinson's disease, stroke, amyotrophic lateral sclerosis, and other forms of dementia. Potential treatment targets for lowering neuroinflammation and slowing the evolution of neurocognitive diseases include TLR signalling pathways, namely the MYD88-dependent and TRIF-dependent cascades. To initiate signalling, Toll-like receptors (TLRs) recruit specific adaptor molecules that activate the transcription factors NF-κB and IRFs, which regulate the induction of innate immune responses. Over the past decade, a combination of genetic, biochemical, structural, cellular, and bioinformatics approaches has been utilised to elucidate the detailed molecular mechanisms underlying TLR signalling. These studies have clarified how TLRs interact with cytosolic innate immune sensors to orchestrate effective immunological reactions. The function of different TLRs expressed in various brain immune cells and their contribution to the pathophysiology of neuroinflammation are described. This paper discusses the involvement of TLRs in autoimmune and neuroinflammatory circumstances like multiple sclerosis (MS), bacterial meningitis, viral encephalitis, stroke, Alzheimer's disease, and Parkinson's disease. It is intended for TLR biologists and immunologists studying neuroinflammation, as well as neuroscientists delving into central nervous system processes mediated by TLRs.
    Keywords:  MYD88-dependent; Neurocognition; TRIF-dependent; astrocyte TLRs.; cytokine activation
    DOI:  https://doi.org/10.2174/0127724328415188260605204430
  37. Brain. 2026 Jun 25. pii: awag222. [Epub ahead of print]
    STMN2 protein depletion via translation deficits and stress granules in amyotrophic lateral sclerosis.
    Brittany C S Ellis, Anna Sanchez Avila, Wan-Ping Huang, Sabin J John, Sam Bonsall, Rachel E Hodgson, Vedanth Kumar, Matthew Nolan, Ryan J H West, Susan G Campbell, Kurt J De Vos, Clotilde Lagier-Tourenne, J Robin Highley, Johnathan Cooper-Knock, Tatyana A Shelkovnikova.
      STMN2 is an abundant neurospecific protein dysregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously reported that cellular stress can lead to STMN2 loss due to TDP-43 nuclear condensation. Here, using human and murine neuronal cell models, multiple pharmacological tools, in situ single-molecule analysis of translation and RNA localisation, and longitudinal analysis of neuronal fitness/survival, we establish TDP-43-independent mechanisms of STMN2 depletion under stress. We find that human STMN2 protein level is extremely labile under acute high-magnitude stress. Early in stress, STMN2 is suppressed via activated proteasomal degradation, phosphorylation and translation repression by stress granules, independently of TDP-43 loss of function in splicing. We further show that STMN2 protein level is highly sensitive to chronic translation deficits, such as those elicited by prolonged low-grade stress. We find that low pre-stress STMN2 sensitises neuronal cells to stress-induced apoptosis, whereas moderately increased STMN2 is protective under stress. Finally, we demonstrate that STMN2 mRNA is upregulated in non-TDP ALS (ALS-FUS) models, which may compensate for translation/stress granule defects in this disease subtype. Consistent with the compensation hypothesis, STMN2 mRNA is also upregulated in the relatively spared (cortex), but not severely affected (spinal cord), CNS regions in ALS-TDP. In conclusion, our study implicates two common denominators in neurodegeneration - dysregulation of translation and stress granules - in STMN2 depletion, independent of TDP-43 loss of function. It also describes an RNA-based compensatory mechanism in ALS underling the unique vulnerability of neurons with developing TDP-43 pathology.
    Keywords:  ALS; FUS; STMN2; TDP-43; protein translation; stress granule
    DOI:  https://doi.org/10.1093/brain/awag222
  38. Stem Cell Reports. 2026 Jun 25. pii: S2213-6711(26)00187-6. [Epub ahead of print] 102976
    Rewiring ALS by modulating the autophagy receptor SQSTM1.
    Laetitia Aubry, Viktor I Korolchuk, Sovan Sarkar.
      Drug screening for genetic disorders is limited by difficulty identifying disease-relevant phenotypes. In this issue, Roussange et al., show that reverse phenotypic mapping could uncover therapeutic gene expression signatures. Using this approach, they identified prazosin, which increases SQSTM1 expression and rescues disease phenotypes in iPSC-derived motor neurons and zebrafish model of amyotrophic lateral sclerosis with SQSTM1 haploinsufficiency.
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102976
  39. Brain Commun. 2026 ;8(3): fcag197
    Transcriptomic and pathological analysis of the hnRNP network reveals glial involvement in frontotemporal lobar degeneration pathological subtypes.
    Ariana Gatt, Yazead Buhidma, Katherine Fodder, Jack Humphrey, Sandrine C Foti, Barbara Frias, Bridget C Benson, Priya Gami-Patel, Lauren M Gittings, Christina E Toomey, Tammaryn Lashley.
      Frontotemporal dementia is a neurodegenerative disorder with a strong heritable component. Frontotemporal lobar degeneration refers to the pathological changes seen in frontotemporal dementia, characterized by atrophy of the frontal and temporal lobes and the presence of abnormal protein inclusions. In the case of frontotemporal lobar degeneration with hyperphosphorylated TDP-43 positive inclusions (FTLD-TDP), five pathological subtypes (A, B, C, D and E) are observed based on the types and distribution of inclusions found in the brain. In all subtypes, there tends to be a large variability in the number of pathological inclusions observed between cases, with limited correlation to clinical manifestations. TDP-43 is an RNA-binding protein belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family, which along with other hnRNPs, modulates multiple aspects of RNA processing. HnRNPs other than TDP-43 have been implicated in several neurological diseases, including Amyotrophic Lateral Sclerosis, FTLD-TDP, frontotemporal lobar degeneration with fused in sarcoma (FTLD-FUS) and Alzheimer's disease. Multiple hnRNPs have been found in pathological inclusions in specific subtypes of FTLD-TDP, suggesting potential roles in the disease process. The role of the hnRNP network in frontotemporal lobar degeneration disease pathogenesis, however, has not yet been investigated. This study aimed to comprehensively evaluate the presence and expression of hnRNP proteins in two pathological subtypes of sporadic FTLD-TDP (A and C) as well as the genetic form FTLD-TDP A C9orf72 using immunohistochemistry and gene expression analysis by single-nuclei RNA-sequencing. We found that there was great variability in the frequency of TDP-43 pathology across and within FTLD-TDP pathological subtypes. Our findings suggest that distinct global transcriptomic profiles may underlie the different pathological subtypes of FTLD-TDP. The most prominent transcriptomic changes were observed in oligodendrocytes and astrocytes, involving multiple hnRNPs across frontotemporal lobar degeneration subtypes compared to controls. Transcriptomic co-expression analysis further revealed that glial clusters were more strongly associated with RNA-processing dysfunction and contributed to disease classification. Together, these findings highlight the involvement of the hnRNP network and glial-specific RNA-processing alterations in FTLD-TDP pathophysiology, offering new insight into the molecular distinctions between pathological subtypes and potential targets for future investigation.
    Keywords:  RNA-binding proteins; astrocytes; dementia; frontotemporal lobar degeneration; oligodendrocytes
    DOI:  https://doi.org/10.1093/braincomms/fcag197
  40. Neurol Ther. 2026 Jun 20.
    ECAS-Based Neuropsychological Phenotyping in Amyotrophic Lateral Sclerosis: A Retrospective Study Comparing Different Algorithms.
    Barbara Poletti, Edoardo N Aiello, Monica Consonni, Barbara Iazzolino, Silvia Torre, Veronica Faltracco, Alessandra Telesca, Francesca Palumbo, Beatrice Curti, Giulia De Luca, Arianna Moreschi, Francesca Frisco, Eleonora Dalla Bella, Enrica Bersano, Nilo Riva, Federico Verde, Stefano Messina, Alberto Doretti, Alessio Maranzano, Claudia Morelli, Stefano F Cappa, Andrea Calvo, Michael J Strong, Vincenzo Silani, Giuseppe Lauria, Adriano Chiò, Nicola Ticozzi.
       INTRODUCTION: This study aimed to compare different algorithms based on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) to classify patients with amyotrophic lateral sclerosis (ALS) according to their neuropsychological phenotype to identify possible discrepancies among these systems.
    METHODS: ECAS-Cognitive and -Carer Interview (ECAS-C/-CI) scores of N = 901 patients with ALS without a formal diagnosis of dementia were retrospectively retrieved. Patients were classified, pursuant to Strong et al.'s criteria, as cognitively and behaviourally normal (ALScbn), cognitively and/or behaviourally impaired (ALSci/bi/cbi), or Possible ALS-FTD, according the following ECAS-based algorithms: (1) Abrahams', solely addressing ECAS-C total and ALS-Specific subtotals; (2) Poletti et al.'s, addressing single task-level ECAS-C scores; (3) "Subscale", addressing ECAS-C subscales (i.e., Language, Executive, Fluency, Memory and Visuospatial). All algorithms relied on single-item-level ECAS-CI scores for behavioural classifications.
    RESULTS: Whilst agreement rates among these classifications were moderate to high (84-86%; Cohen's k = 0.78-0.81), and some discrepancies emerged: (1) "ALScbn-to-ALSci" and "ALSci-to-ALScbn" re-classifications occurred across the three comparisons, ranging from ~ 11% to ~ 24%; (2) the most classificatory disagreements (~ 43%) occurred for the ALScbi category when comparing single task-level (Poletti) to total-level (Abrahams) algorithms, with patients being re-classified as either ALSbi or Possible ALS-FTD; (3) ~ 24% of Abraham's Possible ALS-FTD cases were re-classified as either ALScbi or ALSbi by the Subscale approach.
    CONCLUSIONS: Different ECAS-based algorithms for deriving Strong's phenotypes might yield slight discrepancies that could under- or overestimate a given classification.
    Keywords:  Amyotrophic lateral sclerosis; Diagnostic criteria; Edinburgh Cognitive and Behavioural ALS Screen; Frontotemporal degeneration; Neuropsychology
    DOI:  https://doi.org/10.1007/s40120-026-00955-7
  41. Clin Nutr ESPEN. 2026 Jun 23. pii: S2405-4577(26)00456-0. [Epub ahead of print] 103360
    A multi-centre prospective evaluation of post-gastrostomy outcomes in patients with amyotrophic lateral sclerosis.
    PostGas study group
       INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) often causes significant nutritional decline and weight loss, which negatively impacting prognosis. Gastrostomy is a standard intervention to provide long-term nutritional support, yet its efficacy in stabilising nutritional status and preventing post-procedure weight loss is uncertain. This study explored factors influencing weight change post-gastrostomy.
    METHODS: This multicentre, prospective observational cohort study was conducted across 17 UK sites and involved longitudinal assessments at placement (M0) and at three (M3), six (M6), and nine (M9) months. Data collection included nutritional, clinical and functional parameters. The primary outcome was the percentage weight change between M0 and M3. Secondary outcomes included nutritional intake, functional decline, and survival. Statistical analysis employed hierarchical logistic regression to identify independent predictors of weight change post-gastrostomy.
    RESULTS: Successful gastrostomy was performed in 155 included participants, of which 64 had complete M0 and M3 weight data. Mean percentage weight change from M0 to M3 was -3.3% (SD 7.4%), with 51.6% losing >1 kg in the first three months (p<0.01). Amongst those with available dietary data weight loss (n=21/43) was associated with lower mean daily energy (1620 kcal vs 2022 kcal, p=0.017) and protein intake (64g vs 77g, p=0.048) compared to those who maintained stable or gained weight (n=22/43). At M3, 50% (n=29/58) used a combination of oral and gastrostomy intake, 27.6% (n=16/58) used gastrostomy only, and 22.4% (13/58) were not using the gastrostomy. Based on available data for total daily expenditure energy expenditure (TDEE) calculation (n=39), 61.5% did not meet predicted total daily energy expenditure. Participants who lost weight (>1kg) post-gastrostomy had shorter median survival (270 days) compared to the weight stable/gain group (p=0.018). Hierarchical logistic regression suggested that mean daily water intake may potentially be an independent predictor of weight maintenance or gain, though this finding should be considered exploratory due to the limitations of our study (OR=1.003, p=0.040).
    DISCUSSION: Despite gastrostomy placement, over half of participants in our final analytical cohort continued to lose weight. For a smaller subset of participants, for whom nutritional intake were available, this was potentially due to insufficient energy, macronutrient, and fluid intake, alongside disease-specific catabolism. As post-gastrostomy weight loss negatively impacts survival, these findings highlight a need for proactive, tailored, and ongoing nutritional support and monitoring, to optimise post-gastrostomy outcomes and survival in ALS.
    Keywords:  gastrostomy; home enteral nutrition (HEN); nutritional status; survival; weight loss; xAmyotrophic lateral sclerosis (ALS)
    DOI:  https://doi.org/10.1016/j.clnesp.2026.103360
  42. J Neuropsychol. 2026 Jun 25.
    Validation of the German version of the Dimensional Apathy Scale (G-DAS): Application in amyotrophic lateral sclerosis.
    Judith Wesenberg, Paula Matthies, Kati Schwiecker, Verena Bittner, Samra Hamzic, Stefan Vielhaber, Ratko Radakovic.
      Apathy is a common behavioural impairment in neurodegenerative conditions and is conceptualized within the Dimensional Apathy Framework as comprising Executive, Emotional and Initiation subtypes. The Dimensional Apathy Scale (DAS) is widely used to assess these domains, yet no validated German version has been available. This study aimed to translate and validate the German DAS (G-DAS) in control participants (HC) and to characterize apathy profiles in German-speaking people with amyotrophic lateral sclerosis (pwALS). Seventy-seven HC and 32 pwALS completed self-rated and caregiver-rated measures of apathy, depression, disinhibition and executive dysfunction. The G-DAS was translated using a multi-round back-translation procedure. Psychometric validation was undertaken in the HC cohort. A subsample of HC matched to pwALS on age and sex was used for between-group comparisons and for deriving exploratory reference thresholds. The G-DAS demonstrated good to high internal consistency across subscales (α = .76-.85) and total scores (self-rated: α = .88; caregiver-rated: α = .86). Convergent validity was supported by significant correlations with the Apathy Evaluation Scale and Frontal Systems Behavior subscales, particularly for the Initiation and Executive subscales. Divergent validity was evidenced by the absence of associations with anxiety and depression. PwALS showed significantly higher Executive and Initiation apathy compared with matched HC, whereas Emotional apathy did not differ. Exploratory threshold scores derived from matched HC indicated that up to 47% of pwALS exhibited clinically elevated Initiation apathy. The G-DAS is a reliable and valid German-language measure of multidimensional apathy. It effectively captures the characteristic Executive and Initiation apathy profile in ALS, supporting its clinical and research utility.
    Keywords:  ALS; Dimensional Apathy Scale; apathy; validation
    DOI:  https://doi.org/10.1111/jnp.70061
  43. Cell. 2026 Jun 23. pii: S0092-8674(26)00647-1. [Epub ahead of print]
    An emergent disease-associated motor neuron state precedes cell death in ALS.
    Olivia Gautier, Jacob A Blum, Thao P Nguyen, Shaolong Cao, Sandy Klemm, Mai Yamakawa, Dann Huh, Jessica A Hurt, Nasa Sinnott-Armstrong, Yi Zeng, Chung-Ha O Davis, Juliane Bombosch, Chang Liu, Lisa N Encarnacion, Kevin A Guttenplan, Derek Chen, Arwa Kathiria, Luke Zhao, Stephen Moore, Alex Meng, Kailee Ong, Don W Cleveland, John Ravits, Jessica E Rexach, William J Greenleaf, Aaron D Gitler.
      To define molecular determinants of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons together with spatial transcriptomics from the SOD1-G93A mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a distinct cell state we named "disease-associated motor neurons" (DMs). We identified transcription factor networks that govern how healthy cells transition into DMs and those associated with motor neuron subtype-selective vulnerability. Upregulation of DM-associated transcription factors in human motor neurons induced key features of DMs, demonstrating an active regulatory component. Human ALS spinal cord single-nucleus RNA sequencing data demonstrated conservation of the DM signature in alpha motor neurons, and human orthologs of regions differentially accessible in SOD1-G93A mouse motor neurons were enriched for ALS genetic risk variants. Together, these findings establish a conserved, genetically linked motor neuron signature in ALS.
    Keywords:  ALS; cell states; microglial activation; motor neuron; neurodegeneration; selective vulnerability; snATAC-seq; snRNA-seq; spatial transcriptomics; spinal cord
    DOI:  https://doi.org/10.1016/j.cell.2026.05.047
  44. Cell Insight. 2026 Aug;5(4): 100340
    Innate immune crosstalk in ALS/FTD pathogenesis.
    Xiaoqiu Shu, Xinyuan Yu, Pinglong Xu, Ailian Wang.
      Marked by protein aggregation, impaired proteostasis, organelle stress, and chronic neuroinflammation, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) form a clinically, genetically, and pathologically overlapping disease spectrum. Increasing evidence indicates that innate immune activation is not merely a secondary response to neuronal injury, but an active driver of disease progression. In this review, we elaborate on how ALS/FTD-associated genetic lesions and pathogenic protein aggregates, including TDP-43, SOD1, FUS, and C9orf72-derived dipeptide repeat proteins, engage three interconnected innate immune pathways: cGAS-STING, NLRP3 inflammasomes, and TREM2-DAP12 signaling. We further highlight emerging crosstalk among these pathways, in which cGAS-STING and NLRP3 reinforce inflammatory signaling, while NLRP3-driven TREM2 shedding may impair microglial clearance and perpetuate proteostatic failure. Understanding this immune network may help define disease subtypes, identify biomarkers, and guide combinatorial therapeutic strategies that suppress harmful inflammation while preserving protective microglial functions.
    Keywords:  Amyotrophic lateral sclerosis; Frontotemporal dementia; Microglia; NLRP3 inflammasome; Neuroinflammation; TREM2; cGAS-STING
    DOI:  https://doi.org/10.1016/j.cellin.2026.100340
  45. Biomolecules. 2026 Jun 11. pii: 855. [Epub ahead of print]16(6):
    The Immune-Chemokine Axis in Alzheimer's Disease: Roles of Adaptive Immune System in Neuroinflammation and Disease Progression.
    José Joaquín Merino, José Julio Rodríguez-Arellano, Xavier Busquets, Isabel Álvarez-Vicente, María Eugenia Cabaña-Muñoz, Ana Isabel Flores, Adolfo Toledano Gasca.
      Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) and the accumulation of tau in the brain, which triggers robust innate immune responses. Growing evidence indicates that neuroinflammation contributes to AD progression by overactivating microglia through the release of cytokines and chemokines. In general, chemokines can disrupt neuronal communication and promote blood-brain barrier permeability. Peripheral immune cells are mobilized into the brain by a gradient of chemokines. These processes link peripheral immune responses with substantial T-cell infiltration into the CNS parenchyma, leptomeninges and cerebrospinal fluid of both AD mice and AD patients. This finding underscores the relevance of the adaptive immune system, particularly T and B cells, in AD neuropathology. T-cell infiltration into the brain can influence amyloid clearance through chemokine signalling. However, chemokines play a critical role in AD by either promoting or suppressing disease progression. The infiltration of peripheral T and B cells into the brain parenchyma can exacerbate neuronal loss, yet it may also exert neuroprotective effects. Despite the presence of CD4+ and CD8+ T cells in postmortem brains of AD patients, debate continues about their role in AD brains, in terms of whether they are protective or detrimental. Understanding the complex role of chemokines in controlling innate and adaptive immune responses by modulating neuron-glia interactions (involving astrocytes and microglia) may provide novel therapeutic approaches for AD. Targeting chemokine signalling or treating with drugs that can prevent the recruitment of immune cells may be promising strategies for treating AD neuropathology. Therapies that prevent the overactivation of T cells in the brain could lead to protective strategies against AD. In fact, regulatory T cells (Tregs) could delay the onset of cognitive symptoms, because they suppress inflammation and slow the accumulation of Aβ plaques and p-Tau in the brain. Complementary strategies, such as photobiomodulation, nanoparticle, and T-cell-based approaches, could mitigate AD progression in patients.
    Keywords:  Alzheimer’s disease and neurodegenerative diseases; CX3CR1/fractalkine; CXCL0; CXCR6; T cells; Treg; adaptive immune system; amyloid-β; chemokines; glial activation; immunobiology; immunology; inflammation; innate immune system; monocytes; neuroimmunology; neuroinflammation; neurology; neuromodulation; photobiomodulation; regulation of microglia activation
    DOI:  https://doi.org/10.3390/biom16060855
  46. J Neurophysiol. 2026 Jun 21.
    Direct evidence of upper motor neuron excitability changes in a patient with ALS.
    Vincenzo Di Lazzaro, Giovanni Pellegrino, Daniel T Corp, Gabriella Musumeci, Fioravante Capone, Fabio Pilato, Paolo Mazzone, Angelo Insola, Federico Ranieri.
      A key feature of amyotrophic lateral sclerosis (ALS) pathophysiology is motor neuron hyperexcitability. However, the mechanisms of hyperexcitability are not well understood. Prior studies have used transcranial magnetic stimulation (TMS) to demonstrate increased motor cortex excitability and reduced intracortical inhibition in human ALS. Yet interpretation of these findings is limited because measurement of muscles responses cannot disentangle specific contribution of upper and lower motor neurons and of cortical interneurons to excitability changes. We had the rare opportunity to record directly the corticospinal output evoked by TMS upstream of the spinal circuitry in an ALS patient who had undergone epidural electrode implantation for intractable pain. Single pulse stimulation was performed both with a coil orientation inducing a current that activates corticospinal neurons directly, and with a coil orientation inducing a current that activates corticospinal neurons trans-synaptically. Short interval intracortical inhibition (SICI) was also studied using paired pulse stimulation. Data obtained in the patient were compared with those recorded in 10 conscious control subjects. Compared to control subjects, patient showed a reduced amplitude in response to direct corticospinal neuron activation, yet an enhanced amplitude of corticospinal output after trans-synaptic corticospinal neuron activation together with a SICI reduction. Present findings provide direct evidence of hyperexcitability of monosynaptic glutamatergic inputs to corticospinal neurons that, in association with reduced intracortical inhibition, can trigger neurodegeneration. Taken together with the extensive body of evidence generated by non-invasive TMS studies, the findings from this single-case study may provide valuable insights into the pathophysiological mechanisms of the disease.
    Keywords:  amyotrophic lateral sclerosis; epidural recording; excitoxicity; motor neuron hyperexcitability
    DOI:  https://doi.org/10.1152/jn.00208.2026
  47. Dev Cell. 2026 Jun 25. pii: S1534-5807(26)00198-X. [Epub ahead of print]
    The ALS- and FTD-associated proteins annexin A11 and CHMP2B act sequentially in plasma membrane repair.
    Catherine M Heffner, Georgina P Starling, Lorian C Straker, Philippa C Hawes, Adrian M Isaacs, Jeremy G Carlton.
      Maintenance of plasma membrane integrity is essential for compartmentalization of the cytosol and for cellular viability. Upon membrane damage, several factors including endosomal sorting complex required for transport-III (ESCRT-III) proteins, annexins, stress granules, lipids, and membrane fusion proteins are mobilized to orchestrate membrane repair. However, whether these factors operate independently or act together is unclear. Here, using human cell lines, we expose temporal differences and interdependencies in the recruitment of ESCRT-III and annexin proteins to sites of plasma membrane damage. We show that annexin proteins are recruited immediately and form a plug at the damage site, restricting membrane permeability. We find that ESCRT-III assembles later and acts to release plug-containing damaged membranes from the cell. Further, frontotemporal dementia (FTD)- and amyotrophic lateral sclerosis (ALS)-associated mutations in the ESCRT-III protein, CHMP2B, and the annexin protein, ANXA11, compromise plasma membrane repair, suggesting that defects in this process may contribute to these pathologies. These data present an integrated "sealing and healing" model of membrane repair.
    Keywords:  ALS; ANXA11; CHMP2B; ESCRT-III; FTD; annexin; membrane repair; pore-forming toxin
    DOI:  https://doi.org/10.1016/j.devcel.2026.05.014
  48. Qual Life Res. 2026 Jun 23. pii: 216. [Epub ahead of print]35(8):
    Associations influencing quality of life in caregivers of patients with amyotrophic lateral sclerosis: a stress-process model approach.
    Nafiye Turkmenel, Ersin Uskun.
       BACKGROUND: Caring for patients with amyotrophic lateral sclerosis (ALS) involves demands that reduce caregivers' quality of life. Although caregiver burden and perceived social support was conceptualized as an independent correlate of quality of life rather than a factor operating primarily through caregiver burden. This study examined these associations within a stress-process framework in which perceived social support was conceptualized as an independent correlate rather than a buffering factor.
    METHODS: This cross-sectional analytical study included 118 informal caregivers of patients with ALS. Primary stressors were defined as patient functional status (ALSFRS-R), caregiving duration, and communication difficulty. Caregiver burden (Zarit Burden Interview) was considered a secondary stressor. Physical and mental quality of life were assessed using the SF-12, and perceived social support was measured with the Multidimensional Scale of Perceived Social Support. Hierarchical regression analyses were performed to examine associations specified in the conceptual model while controlling for caregiver sociodemographic and socioeconomic variables. Additional mediation analyses were conducted to examine whether caregiver burden mediated the relationship between perceived social support and quality of life.
    RESULTS: Poorer patient functional status was significantly associated with higher caregiver burden, whereas communication difficulty showed a positive but non-significant association after adjustment for caregiver characteristics. Caregiver burden showed negative associations with both physical and mental quality of life. Perceived social support remained positively associated with quality of life after adjustment for caregiver burden and contributed additional explained variance in the models. Mediation analyses showed no evidence that caregiver burden mediated the association between perceived social support and either physical or mental quality of life.
    CONCLUSIONS: The findings are consistent with a stress-process framework in ALS caregiving, in which caregiver burden represents a central factor statistically associated with both caregiving stressors and quality of life, while perceived social support shows an independent association with quality of life. These findings suggest that both caregiver burden and perceived psychosocial resources may be relevant to caregiver well-being, although causal and intervention-related implications require further investigation.
    Keywords:  ALSFRS-R; Amyotrophic lateral sclerosis; Caregiver burden; Informal caregivers; Perceived social support; Quality of life; SF-12; Stress-process model
    DOI:  https://doi.org/10.1007/s11136-026-04318-5
  49. J Neuroinflammation. 2026 Jun 23.
    The complement system in Alzheimer's disease: evaluating biomarker potential in a complex neuroimmune context.
    Heli Soni, Greg T Sutherland, Markus J Hofer.
      Neuroinflammatory processes are increasingly recognised as important modulators of Alzheimer's disease (AD) progression, driving interest in immune-related biomarkers beyond classical pathological measures. Among these, the complement system has attracted attention because of its interactions with amyloid-β (Aβ) and tau pathology, genetic associations with AD risk, and evidence of activation within affected brain regions. However, these biological observations do not directly translate into straightforward biomarker signals. Complement activity is highly dynamic, spans multiple activation and regulatory states, and may reflect both central and peripheral immune processes. This complexity limits interpretation when complement markers are assessed in isolation, as age, systemic inflammation, vascular comorbidity, and blood-brain barrier integrity can influence measured levels. Current evidence does not support complement-derived biomarkers as stand-alone diagnostic classifiers comparable to established amyloid, tau, and neurodegeneration (AT(N)) measures. Their independent or additive value within multimodal biomarker frameworks remains unclear, partly because of cohort heterogeneity, incomplete assay harmonisation, uncertain tissue-source attribution, and limited longitudinal validation. This review critically evaluates complement-derived measures as biologically informative markers of neuroimmune activity in AD, distinguishing biological plausibility from analytical and clinical utility. We argue that their most defensible current role is within multimodal biomarker frameworks, where they may provide context-specific information on inflammatory state rather than function as independent diagnostic, staging, or treatment-monitoring tools. Progress toward clinical application will require rigorous standardisation, mechanistic clarification, and validation across large, longitudinal, and diverse cohorts.
    Keywords:  Alzheimer’s disease; Blood-Brain barrier; Blood-based biomarkers; Cerebrospinal fluid biomarkers; Complement biomarkers; Complement system; Innate immunity; Longitudinal validation; Multimodal biomarkers; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12974-026-03927-8
  50. Exp Neurol. 2026 Jun 24. pii: S0014-4886(26)00256-6. [Epub ahead of print] 115891
    Programmed axon degeneration gene variants in human disease.
    Eleanor L Hopkins, Pete A Williams.
       BACKGROUND: Programmed axon degeneration (PAD; also known as Wallerian degeneration) is a conserved pathway controlling axon breakdown following injury or metabolic stress. PAD is driven by the depletion of nicotinamide adenine dinucleotide (NAD) through loss of the pro-survival enzyme NMNAT2 and activation of the pro-degenerative NADase SARM1. Recent genetic studies have identified pathogenic variants in PAD pathway enzymes associated with severe neurodegenerative phenotypes.
    MAIN BODY: Pathogenic variants in NAMPT, NMNAT1, NMNAT2, and SARM1 have been identified and will be discussed in this review. NAMPT variants cause sensory and motor neuropathy with neurodevelopmental symptoms. NMNAT1 variants are well-characterized causes of Leber Congenital Amaurosis type 9, while NMNAT2 variants result in peripheral neuropathies with childhood onset. SARM1 gain-of-function variants with constitutively active NADase activity are enriched in amyotrophic lateral sclerosis patients.
    CONCLUSION: These findings demonstrate that maintaining proper NAD homeostasis is crucial for axon survival, and disruption through genetic variants leads to distinct neurodegenerative outcomes. Understanding these rare variants provides insight into PAD mechanisms and supports development of broad-spectrum neuroprotective therapies targeting this pathway. Current therapeutic approaches include SARM1 inhibitors in clinical trials, gene therapy, and NAD precursor supplementation, offering hope for treating multiple neurodegenerative diseases.
    Keywords:  Axon pathology; NAD metabolism; NAMPT; NMNAT; Neurodegeneration; Peripheral neuropathy; Programmed axon degeneration; SARM1; Wallerian degeneration
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115891
  51. ACS Biomater Sci Eng. 2026 Jun 26.
    Nanotheranostics for Alzheimer's Disease: The Rising Promise of Fluorescent Carbon Dots.
    Gayatri Prasad, Mansi Srivastava, Vikram Singh.
      Alzheimer's disease is a commonly observed neurodegenerative disease among older adults worldwide nowadays. It is characterized by a gradual decline in neuronal structural features and function in the brain owing to the aggregation and deposition of prion protein (amyloid beta), hyperphosphorylation of tau proteins, the production of excessive reactive oxygen species, and elevated levels of metal ions. However, various traditional drugs have been developed and used, but some of them have mild or severe side effects, and a few of them are incapable of crossing the complex blood-brain barrier. Due to this reason, these traditional drugs had only modest success in clinical studies. Early diagnosis is also one of the most concerning prospects for Alzheimer's disease treatment. As a result, preparation of such materials capable of crossing the blood-brain barrier and detecting early-stage changes that lead to symptoms in Alzheimer's disease is in demand in the biomedical field. Carbon dots have recently grabbed the attention for the remediation of Alzheimer's and other neurodegenerative diseases, due to their ability to cross the blood-brain barrier because of their zero-dimensional structure, apart from possessing various fascinating properties like, biocompatibility, low cytotoxicity, non-invasiveness, water dispersibility, tunable emission, surface functionalization and, enhanced physicochemical characteristics foster targeted drug delivery, early diagnosis, and higher therapeutic efficacy. In this review, we outline the latest developments in the use of carbon dots for both imaging and therapeutic strategies in Alzheimer's disease, and conclude with a thorough evaluation of their future applications in the management of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; amyloid beta; blood-brain barrier; fluorescent carbon dots; nanotheranostics; reactive oxygen species; tau protein
    DOI:  https://doi.org/10.1021/acsbiomaterials.6c00290
  52. Biomolecules. 2026 Jun 09. pii: 842. [Epub ahead of print]16(6):
    Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.
    Giampaolo Morciano, Ruggiero Gorgoglione, Vito Porcelli, Amer Ahmed, Pasquale Scarcia, Angelo Vozza, Francesco Massimo Lasorsa, Giuseppe Fiermonte, Luigi Palmieri.
      Neurodegenerative diseases are increasingly recognized as disorders of due to disrupted cellular homeostasis, with mitochondrial dysfunction playing a central and early role in disease progression. This review explores the intricate relationship between mitochondrial function and neuronal health, emphasizing the pivotal role of the solute carrier family 25 (SLC25) transporters in maintaining mitochondrial homeostasis. We provide a comprehensive overview of mitochondrial biology in the central nervous system, including energy metabolism, calcium signaling, redox regulation, organelle interactions and mitochondrial dynamics. We delve into the SLC25 transporter family, highlighting their transport mechanisms, substrates and roles in brain metabolism and neuroprotection. SLC25 on one hand and proteins involved in the regulation of mitochondrial morphology and calcium signaling on the other hand are two sides of the same coin influencing each other. A critical analysis follows, examining how mitochondrial dysfunction contributes to mitochondrial abnormalities in a spectrum of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, ALS and rare mitochondrial encephalopathies. Finally, we assess emerging therapeutic strategies targeting mitochondrial pathways and SLC25 function, including metabolic modulation, gene therapies, antioxidants and pharmacological agents. This review underscores mitochondria and the SLC25 transporters as promising targets for disease-modifying interventions in neurodegeneration and raises key questions about the causality between mitochondrial failure and neuronal death.
    Keywords:  SLC25 carriers; metabolism; mitochondrial dynamics; neurodegeneration
    DOI:  https://doi.org/10.3390/biom16060842
  53. Neuroscience. 2026 Jun 25. pii: S0306-4522(26)00419-7. [Epub ahead of print]
    Blood-brain barrier dysfunction in surgery and anesthesia: a potential mechanistic contributor to postoperative cognitive dysfunction.
    Abdulrahman Khaled Alwesabi, Boxiong Gao, Jinxiang Xie, Bokang Yang, Jiayi Xie, Yuhu Ma, Yatao Liu.
      The blood-brain barrier (BBB) is essential for maintaining central nervous system homeostasis by regulating selective permeability and protecting neural tissue. Surgical interventions and anesthesia can compromise BBB integrity, particularly in elderly patients, contributing to postoperative cognitive dysfunction (POCD). This narrative review provides a BBB-centered perspective on postoperative cognitive dysfunction by critically evaluating blood-brain barrier dysfunction as a potential unifying mechanistic pathway linking surgical stress, systemic inflammation, anesthetic exposure, neuroinflammation, and cognitive decline. While previous reviews have examined these perioperative factors individually, this review integrates current experimental and clinical evidence to highlight BBB disruption as a central contributor to postoperative neurocognitive impairment and discusses its translational implications for perioperative neuroprotection. Surgical trauma triggers an acute inflammatory response with elevated cytokines, increasing BBB permeability and facilitating the entry of neurotoxic substances into the brain, thereby promoting neuroinflammation. Anesthetic agents may further exacerbate these effects. Emerging evidence suggests that BBB dysfunction may represent an important mechanistic contributor linking perioperative stress, neuroinflammation, and cognitive impairment; however, direct evidence establishing causality in humans remains limited. Interventions targeting BBB stabilization and perioperative neuroprotection may represent promising strategies to reduce the risk of POCD. A better understanding of these mechanisms is crucial for developing strategies to preserve cognitive function and improve postoperative outcomes. However, much of the current evidence is derived from preclinical studies, and direct causal relationships in humans remain limited. Future research should clarify neuroinflammatory pathways and identify effective protective therapies.
    Keywords:  Anesthesia; Blood–brain barrier; Neuroinflammation; Postoperative cognitive dysfunction; Surgery
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.06.030
  54. Adv Clin Exp Med. 2026 Jun 25.
    Formaldehyde neurotoxicity: Effects on the mammalian brain, cognitive function, and neurodegenerative risk. A scoping review.
    Mateusz Drążyk, Zuzanna Pyc, Szymon J Pietrzyk, Antonina Gajda-Janiak, Filip Godziszewski, Oliwier Pioterek, Michał Tulski, Mateusz Mazurek, Zygmunt A Domagała.
      Aqueous formaldehyde (FA) solution, known as formalin, is currently the primary agent used for preserving tissue samples and anatomical specimens. Formaldehyde is widely used in laboratories and the chemical industry; it also occurs as an air pollutant and endogenous cellular metabolite. The potential carcinogenic effects of formalin on the respiratory tract are well documented. A less recognized consequence of occupational exposure to FA is its detrimental effect on the central nervous system (CNS) and brain function. A literature review was conducted to investigate the effects of FA on the brain. Five databases were searched: PubMed, Web of Science (WoS), Embase, ScienceDirect, and Google Scholar. To describe the effects of FA exposure and endogenous FA generation, 35 relevant publications were collected and analyzed. The literature review demonstrated that inhalation is the most common route of FA exposure. Several studies have shown that FA may cause hippocampal damage, disrupt melatonin secretion, and induce a wide range of cognitive disorders with varying characteristics and severity. These disorders include memory impairment, disturbances in balance and spatial orientation, learning difficulties, sleep disturbances, impaired judgment, and prolonged reaction times to stimuli. Increased endogenous FA concentration has also been associated with a higher risk of neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis. The literature analysis demonstrated the high neurotoxicity of FA, which may lead to numerous neuropsychiatric disorders. We aim to draw attention to the risks associated with the routine use of formalin, particularly among anatomists and pathologists, and to encourage consideration of less harmful alternative preservation agents.
    Keywords:  cognitive impairment; formaldehyde; neurodegenerative diseases; neurotoxicity; occupational exposure
    DOI:  https://doi.org/10.17219/acem/209617
  55. Pharmaceutics. 2026 May 28. pii: 670. [Epub ahead of print]18(6):
    Predicting Blood-Brain Barrier Permeability from Experimental Data: An Interpretable and Externally Validated Machine Learning Framework.
    Saurabh Tiwari, Katarzyna Mądra-Gackowska, Marcin Gackowski, Nokeun Park, Łukasz Szeleszczuk.
      Background: The blood-brain barrier (BBB), which restricts the brain penetration of most small molecules and almost all biologics, continues to be a significant hurdle in the development of drugs for the central nervous system (CNS). During early-stage screening, a reliable computational prediction of BBB permeability, typically expressed as log BB, can help reduce the experimental load. Methods: We provide a well-validated machine learning system created solely using the B3DB experimental database, which includes 7807 chemicals with BBB+/BBB- annotations and 1058 compounds with in vivo log BB values. Using the Mordred library, a carefully selected set of 40 two-dimensional chemical descriptors was calculated from SMILES notation without the use of artificial data augmentation. Stratified five-fold cross-validation was used to comprehensively benchmark the nine methods used in this study. Results: On a held-out test set (n = 212), gradient boosting produced the greatest regression performance, with R2 = 0.6043, RMSE = 0.4740 log units, and MAE = 0.3326, which is in line with the upper range recorded for experimental BBB datasets. On an internal test set (n = 1562), the corresponding classifier obtained an AUC-ROC of 0.9476 and a balanced accuracy of 0.8568; on an independent external validation set (n = 175), it achieved an AUC-ROC of 0.9137. Topological polar surface area was found by SHAP analysis to be the primary factor influencing BBB permeability, with lipophilicity and ionization-related characteristics being the second and third most important factors, respectively. Nonlinear relationships in accordance with accepted pharmacokinetic principles were validated using partial dependence analysis. Conclusion: This study provides a reliable technique for predicting BBB permeability in CNS drug discovery.
    Keywords:  B3DB; CNS drug design; SHAP interpretability; blood–brain barrier; gradient boosting; machine learning; mordred descriptors
    DOI:  https://doi.org/10.3390/pharmaceutics18060670
  56. Indian J Radiol Imaging. 2026 Jul;36(3): 374-393
    Exploring Olfactory Bulb Volume and Its Shrinkage in Aging and Neurodegeneration: A Systematic Review and Meta-Analysis of Observational Studies.
    Adil Asghar, Ravi Kant Narayan, Rajesh Kumar, Pradosh Kumar Sarangi, Apurba Patra, Ashutosh Kumar, Md Zabihullah.
       Background: The olfactory bulb (OB) plays a crucial role in processing smells and has significant neuroplasticity throughout life. Age-related changes in OB volume (OBV) are associated with declining olfactory function, potentially impacting quality of life and serving as an early marker of neurodegenerative diseases. This study conducted a meta-analysis to assess OBV changes across diverse age groups in healthy individuals, explored its association with olfactory function, and further examined OB atrophy in Parkinson's disease (PD) and Alzheimer's disease (AD).
    Materials and Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines. Studies evaluating OBV through MRI in healthy individuals and patients with PD or AD were included. Data were extracted on age, sex, olfactory function, and OBV. Meta-regression was performed to assess the correlation between OBV and age, while subgroup analyses examined the effects of sex and laterality.
    Results: Twenty-nine studies were analyzed, including 12 on healthy individuals, 7 on AD, and 11 on PD. The pooled mean OBV was 54.5 mm 3 (95% CI, 42.03-66.98) for the right OB and 55.56 mm 3 (95% CI, 42.96-68.15) for the left OB, with no significant sex or laterality differences. OBV showed a moderate negative correlation with age ( r  = -0.53 to -0.59, p  < 0.05), suggesting progressive atrophy with aging. Olfactory function, assessed through the Threshold, Differentiation, and Identification (TDI) and the University of Pennsylvania Smell Identification Test (UPSIT) scores, was also moderately correlated with OBV ( r  = 0.48, p  < 0.01). In neurodegenerative diseases, OBV reduction was greater, with shrinkage of 0.9 to 0.93 SD in PD and 1 to 1.05 SD in AD, primarily attributed to pathological degeneration.
    Conclusion: Age-related OBV reduction is a normal physiological process with a moderate impact on olfactory function. While neurodegenerative diseases exacerbate OB atrophy, at least 40% of OB shrinkage observed in PD appears to be age-related. OBV could serve as a potential biomarker for aging and early neurodegeneration.
    Keywords:  Alzheimer's disease; Parkinson's disease; aging; magnetic resonance imaging; neurodegenerative diseases; olfactory bulb; olfactory dysfunction
    DOI:  https://doi.org/10.1055/s-0045-1811932
  57. Front Pharmacol. 2026 ;17 1835883
    Global research trends and hotspots of exosome-mediated drug delivery across the blood-brain barrier: a bibliometric study from 2015 to 2025.
    Zhipeng Chen, Yang Jiang, Xingxiao Yin, Yanqi Li, Hezhi Sai, Yanping Song, Zhen Shen, Qigang Chen.
       Background: The blood-brain barrier (BBB) is a major obstacle to targeted drug delivery for central nervous system (CNS) diseases. Although liposomes and polymeric nanoparticles have improved brain drug delivery, limitations remain in BBB targeting, long-term biocompatibility, and in vivo clearance. Exosomes are endogenous nanoscale extracellular vesicles with favourable biocompatibility, low immunogenicity, and BBB-crossing potential. Therefore, this bibliometric study summarises the current research status, future research trends, and challenges in the more specific field of exosome-mediated BBB drug delivery.
    Methods: A comprehensive search was conducted across the Web of Science Core Collection (WoSCC), PubMed, and Embase databases for relevant English-language literature on exosome-mediated drug delivery across the blood-brain barrier from 2015 to 2025. WoSCC served as the primary source for bibliometric analysis. PubMed and Embase databases were used for supplementary validation. Software such as VOSviewer, CiteSpace, and R-bibliometrix was employed for literature visualisation analysis.
    Results: This study included 1,365 relevant articles from the WoSCC database, and the annual publication volume showed a steady upward trend. China and the United States significantly lead in both the number of publications and the number of core contributing institutions in this field. Co-occurrence analysis of keywords showed that research hotspots are mainly focused on exosomes, the blood-brain barrier, drug delivery, and Alzheimer's disease. PubMed and Embase were used as supplementary validation databases, including 1,089 and 1,517 records, respectively. Their annual publication trends, major countries/regions, core journals, and keywords/themes were generally consistent with WoSCC, supporting the macro-level stability of the bibliometric findings.
    Conclusion: Unlike previous bibliometric analyses that mainly focused on overall trends in CNS exosome research, this study focuses specifically on the direction of exosome-mediated drug delivery across the BBB. The findings show a shift from basic vesicle characterisation toward engineered delivery systems, CNS disease applications, and translational evaluation. Mammalian-derived exosomes remain dominant, while plant-derived vesicles, AI-assisted design, biomimetic hybrid nanovesicles, and gut-brain axis strategies are emerging areas of focus. Future research should prioritise systematic platform comparisons, standardised evaluation, quality control, scalable production, long-term safety, and regulatory pathways.
    Keywords:  bibliometrics; blood-brain barrier; central nervous system diseases; drug delivery systems; exosomes; extracellular vesicles
    DOI:  https://doi.org/10.3389/fphar.2026.1835883
  58. Mol Neurobiol. 2026 Jun 20. pii: 711. [Epub ahead of print]63(1):
    LPS-Induced Neuroinflammation in Neurodegenerative Diseases: A Double-Edged Sword?
    Alaleh Mohammadi, Ali Aghajan, Morteza Alipour, Avin Ghorbani, Samim Momennejad Limoodehi, Mojtaba Hedayati Ch.
      Lipopolysaccharide (LPS), a glycolipid endotoxin derived from Gram-negative bacteria, activates Toll-like receptor 4 (TLR4) signaling in microglia and astrocytes, initiating neuroimmune cascades characterized by pro-inflammatory cytokine release, oxidative stress, and glial reactivity. Chronic or high-dose LPS exposure promotes sustained neuroinflammation, blood-brain barrier disruption, impaired amyloid-β (Aβ) clearance in Alzheimer's disease (AD), and exacerbated α-synuclein pathology in Parkinson's disease (PD). In contrast, low-dose or intermittent exposure may promote adaptive neuroimmune responses characterized by regulated glial signaling and enhanced neuronal resilience. Emerging evidence suggests that these divergent outcomes are shaped by the biological context of LPS exposure, including dose, duration, route of administration, and host inflammatory status. The gut-brain axis further modulates these effects by linking peripheral inflammatory signals and microbial metabolites to central nervous system responses. Despite growing mechanistic insight, important knowledge gaps remain, particularly regarding the translational relevance of region-specific glial responses in humans. Improved understanding of context-dependent LPS signaling may help explain inconsistencies across experimental studies, refine neuroinflammation models, and support the development of therapeutic strategies targeting TLR4 signaling, autophagy, and gut-brain interactions. Collectively, current evidence suggests that LPS-induced neuroinflammation exists along a dynamic continuum, with transient immune activation potentially supporting adaptive neuroimmune responses, whereas chronic or dysregulated exposure promotes sustained neuroinflammation and progressive neurodegenerative changes.
    Keywords:  Alzheimer's disease; Gut-brain axis; LPS; Neuroimmune adaptation; Neuroinflammation; Parkinson's disease; TLR4
    DOI:  https://doi.org/10.1007/s12035-026-06004-6
  59. Curr Alzheimer Res. 2026 Jun 19.
    Apolipoprotein E Mimetics in Targeted Drug Delivery: Advances and Therapeutic Potential for Neurodegenerative and Cardiovascular Diseases.
    Chauhan Rishika.
      The need to improve the delivery of therapeutic compounds that require effective intracranial delivery across the Blood-Brain Barrier (BBB) has generated significant interest in apolipoprotein E (ApoE) mimetic peptides. These synthetic equivalents of the lipid-binding receptorsinteracting domains of natural ApoE are frequently reproducible when incorporated into nanocarriers or nano platforms, including reconstituted low-high density lipoproteins, polymeric nanoparticles, and liposomal systems. The progress in formulation science has led to the development of ApoE- functionalized nanoparticles and multifunctional liposomes with improved BBB translocation, cellular internalization, and Amyloid-beta (Aβ) affinity compared to conventional delivery vehicles. This review provides a comprehensive discussion of the process by which ApoE mimetics can be used to deliver therapeutic drugs and evaluates the different nanocarrier designs adapted to deliver drugs into the nervous system. Emphasis is also placed on new multifunctional systems in which ApoE mimetics are conjugated to therapeutic or diagnostic molecules, enabling imaging of the targeted area, delivery to the disease site, and disease-specific activity. Although the right direction has been taken, several issues still need to be addressed before ApoE-based strategies can be implemented in clinical practice. The problems that continue to limit larger use include formulation stability, unintended off-target interactions, pharmacokinetics, and scalability of complex nanocarrier systems. This review identifies key concerns needed to move ApoE-mimetic technologies toward effective, clinically viable therapies for central nervous system diseases, identifies the issues that inhibit progress, and analyzes possible methods for their management.
    Keywords:  Alzheimer's; ApoE; amyloidbeta; blood-brain barrier; clinical translation; liposomes.; nanocarriers; neurodegenerative diseases
    DOI:  https://doi.org/10.2174/0115672050464479260610102042
  60. iScience. 2026 Jul 17. 29(7): 116331
    Exosomes: A new frontier in the treatment of neurological diseases.
    Xin Li, Hong Chen, Peixin Xu, Xin Guo, Jing Gao, Dongmei Yao, Yurong Wang, Tong Wang, Bingchun Liu, Jianlong Yuan.
      Exosomes (Exos) are an essential class of extracellular vesicles enriched with a wide range of biologically active molecules, which gives them a unique advantage in participating in intercellular signaling and communication and serving as carriers for drug delivery. Exo-based diagnostic and therapeutic strategies are currently hot topics in disease research. Owing to their naturally low immunogenicity, good biocompatibility, ability to penetrate the blood‒brain barrier (BBB), and engineered modifications, exos have significant advantages and possible applications in the treatment of nervous system diseases. Due to the serious harm of neurological diseases to human health, they have been widely studied by researchers. Exos can be administered in a variety of ways, including intranasal administration, intracranial administration, local stereotactic injection, and encapsulation in biomaterials, each of which has its own advantages and disadvantages. However, several requirements need to be met before exo-based therapies can be implemented, such as the standardization of isolation and purification techniques, an in-depth understanding of the mechanism of action, and safety assessments and regulation for clinical translation. The aim of this review is to provide a comprehensive overview of the biogenesis, molecular composition, function, and delivery modes of exos and their therapeutic roles and mechanisms in neurological diseases (e.g., multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and stroke) and to discuss the current challenges and future perspectives to support ongoing research and clinical applications.
    Keywords:  Biological sciences; Drug delivery system; Health sciences; Internal medicine; Medical manufactured object; Medical specialty; Medicine; Natural sciences; Neurology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2026.116331
  61. Neuroscientist. 2026 Jun 23. 10738584261453915
    Brain-on-a-Chip and Blood-Brain Barrier-on-a-Chip Modeling for Neurodegenerative Disorders: Recent Progress.
    Duraisamy Kempuraj, Huachen Shi, Travis D Truong, Daniel Kong, Arjun Sharma, Prathiv Raj Ramesh Babu, Mohit G Belur, Sai Puneeth Kothuru, Baskaran Chinnappan, Claudia Pena, Prarthana Patel, Avi Shah, Divya Komandooru, Daniel Seth Valladares, Thomas Freeman, Theoharis C Theoharides.
      Brain-on-a-chip is a microphysiologic platform that comprises cultured brain cells to understand brain disease pathogenesis and treatment. The blood-brain barrier (BBB) of the neurovascular unit serves as a highly selective molecular transport interface for brain homeostasis. BBB dysfunction promotes neuroinflammation, exacerbates disease progression, and contributes to neurodegenerative diseases. However, the mechanisms of BBB disruption underlying brain disorders remain poorly understood; thus, developing neurotherapeutics that can effectively cross the BBB remains a major challenge. Recent advances in microfluidic brain-on-a-chip platforms now enable the creation of BBB-on-a-chip systems that replicate key structural and functional aspects of the human BBB under dynamic flow conditions. Integration of microelectrode arrays into these microfluidic systems enhances their utility by enabling high-throughput drug screening and targeted delivery, allowing real-time monitoring of neuronal activity and network behavior. Although current brain organoid, brain-on-a-chip, and BBB-on-a-chip platforms remain in developmental stages, significant progress has been made using induced pluripotent stem cell-derived neurons, astrocytes, endothelial cells, pericytes, and microglia from healthy individuals and patients with neurodegenerative diseases. This review highlights recent advances in brain- and BBB-on-a-chip technologies and their potential applications in studying disease pathogenesis and preclinical drug screening for neurodegenerative disorders.
    Keywords:  brain-on-a-chip; induced pluripotent stem cells; microelectrode arrays; neurodegenerative diseases; neurovascular unit
    DOI:  https://doi.org/10.1177/10738584261453915
  62. bioRxiv. 2026 Jun 09. pii: 2026.06.04.729895. [Epub ahead of print]
    Quantitative determination of longitudinal CNS cholesterol loss during myelin damage and repair.
    Disni Dedunupitiya, Eden P Go, Travis Witte, Ashlynn Elliott, Nishama De Silva Mohotti, Jenna M Williams, Hiroko Kobayashi, Rashmi Binjawadagi, Heather Desaire, Meredith D Hartley.
      1. Cholesterol in the central nervous system (CNS) is largely unesterified (>99%) and is predominantly present in the myelin sheath (∼70% of total CNS cholesterol). Damage to the myelin sheath can result in the conversion of cholesterol to cholesterol esters, which occurs in many neurological diseases, including multiple sclerosis. In this study, we measured longitudinal CNS free cholesterol and cholesterol ester levels in a genetic mouse model during postnatal myelination, demyelination, and remyelination using gas chromatography-mass spectrometry with single ion monitoring technique (GC-MS-SIM) and liquid chromatography mass spectrometry (LC-MS). Cholesterol levels in healthy mouse brains increased up to 38 weeks. In contrast, cholesterol in the healthy spinal cord increased during postnatal timepoints, but then remained steady out to 38 weeks. Interestingly, cholesterol esters in the spinal cord were highest at P1 and drastically reduced by P42, while the brain had similar levels during all postnatal time points. During demyelination, both brain and spinal cord cholesterol levels were significantly reduced as compared to healthy mice and failed to return to normal cholesterol levels even during remyelination. Absolute quantification of cholesterol esters during peak demyelination revealed that cholesterol esters comprise 19% of the total cholesterol pool in the brain and 65% in the spinal cord. The lack of recovery in CNS cholesterol levels after demyelination suggests that healthy de novo cholesterol synthesis pathways are disrupted in this model. Absolute quantification of CNS cholesterol is critical for revealing mechanisms of cholesterol regulation during disease and identifying targets for restoring cholesterol to promote myelin repair.
    DOI:  https://doi.org/10.64898/2026.06.04.729895
  63. Biometals. 2026 Jun 24.
    Conjugates of desferrioxamine with 5-aminolevulinic or γ-aminobutyric acid: synthesis, theoretical studies, iron-chelating ability, and penetration in human Caco-2 cells.
    Ernani Lacerda, Vasilii D Khripun, M Teresa Machini, Breno Pannia Espósito.
      Iron overload (IO) is a harmful condition in humans that promotes oxidative damage to DNA and lipids. As IO has been associated with the onset of neurodegenerative diseases (NDs), chelation therapy has been extensively used for treating IO and considered potentially suitable for NDs treatment. Desferrioxamine (DFO) presents high affinity and selectivity for iron(III), however, its clinical use as chelator is limited due to its low cell permeability. To circumvent this limitation, synthetic routes and conditions were selected for conjugating DFO to 5-aminolevulinic acid (5-ALA) or γ-aminobutyric acid (GABA), non-proteinogenic amino acids previously reported as permeable to the blood-brain barrier (BBB). Once obtained and purified, the conjugates 5-ALA-DFO and GABA-DFO were characterized by LC/ESI-MS and 1H and 13C NMR. Both exhibited iron binding abilities comparable to that of DFO, displayed identical antioxidant activity, weak interactions with human serum albumin, and were unable to remove iron from transferrin (Tf). Based on DFT calculations, a theoretical model was developed that allows to predict the efficiency of iron chelation with DFO and its conjugates, in good agreement with experimental results. In assays with human colorectal adenocarcinoma (Caco-2) cells, a model for the blood-brain barrier (BBB), both chelators were non-toxic, and unlike DFO or 5-ALA-DFO, GABA-DFO was able to bind intracellular iron. Altogether, these results demonstrate that the chemical conjugation proposed here was highly effective and that GABA-DFO is a promising intracellular iron chelator.
    Keywords:  Aminoacyl-desferrioxamine; Cell permeability; DFT calculations; Iron overload; Iron-chelating conjugates
    DOI:  https://doi.org/10.1007/s10534-026-00841-7
  64. Int J Mol Sci. 2026 Jun 13. pii: 5342. [Epub ahead of print]27(12):
    Chronic Diazepam Reveals Excessive Homeostatic Gain in SOD1G93A Mouse Spinal Motoneurons.
    Emily J Reedich, Yi-Tzai Chen, Rebecca Imhoff-Manuel, Deyu Li, Marin Manuel.
      Motoneurons are under strong pressure to maintain stable motor output throughout an individual life, through homeostatic regulation of their electrical properties. Dysregulated spinal motoneuron excitability has long been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Recent work in SOD1G93A mice suggests that the homeostatic response of motoneurons becomes dysregulated as cellular processes are disrupted by the disease, causing fluctuations in motoneuron electrical properties. Yet, few studies directly test whether ALS motoneurons respond differently than wild-type motoneurons to a common chronic perturbation. Here, we used in vivo electrophysiology to test whether motoneurons from pre-symptomatic SOD1G93A mice modulate excitability differently than wild-type motoneurons in response to the same homeostatic perturbation: chronic inhibition exerted by the benzodiazepine diazepam. Using linear mixed-effects statistical models, we assessed whether diazepam treatment differentially modulated passive properties, firing behavior, spike properties, and/or synaptic inputs in SOD1G93A versus wild-type motoneurons. We identified a significant genotype × treatment interaction effect selectively for properties related to passive membrane integration and spike initiation, including membrane time constant, peak input resistance, and recruitment current. In contrast, firing gain, spike waveform characteristics, and synaptic inputs were largely unaffected. These findings indicate that sustained inhibitory perturbation selectively triggered overactive intrinsic compensatory mechanisms in SOD1G93A motoneurons rather than inducing widespread changes in firing or synaptic transmission. Together, our results provide direct evidence for over-active homeostatic control of motoneuron excitability and support a view of motoneuron dysfunction in ALS as a problem of altered feedback regulation rather than simply hyper- or hypo-excitability.
    Keywords:  diazepam; homeostasis; in vivo electrophysiology; inhibition; plasticity; spinal cord; synaptic scaling
    DOI:  https://doi.org/10.3390/ijms27125342
  65. World Neurosurg. 2026 Jun 24. pii: S1878-8750(26)00368-2. [Epub ahead of print] 125152
    Longitudinal Biomarker Trajectories for EVD-Associated Infection Prediction: A Trajectory-Based Machine Learning Framework with Biological Onset Characterization.
    Hraq Sarkis, Abed Alrazzak Kerhani, Inka K Berglar, Chiara Negwer, Arthur Wagner, Bernhard Meyer.
       BACKGROUND: EVD-associated infection occurs in 1-40% of patients with indwelling external ventricular drains. Assessing cerebrospinal fluid (CSF) parameters remains challenging, especially in hemorrhagic neurological disease. This study developed and validated a machine learning framework for real-time prediction of EVD-associated infection.
    METHODS: A retrospective cohort of 367 neurocritical patients with EVDs across 8,419 EVD patient-days (2020-2025) was analyzed. Seven serially monitored biomarkers - white blood cell count (WBC); C-reactive protein; procalcitonin; and CSF cell count, lactate, glucose, and protein - were used to derive temporal features. A biological onset sub-study applied a composite scoring algorithm to 52 infected patients to identify the earliest day of coordinated multi-marker biomarker deterioration preceding clinical diagnosis.
    RESULTS: Among 367 patients, 88 (24%) developed infection at a median of 9 days after drain insertion, with a median EVD duration of 17 days (IQR 12-24) for the full cohort. The ensemble achieved AUC-ROC of 0.833 at 24 hours and 0.822 at 48 hours, with area under the precision-recall curve of 0.469 and 0.478 respectively. Sensitivity was 69%, specificity 92%, and negative predictive value 100% at 24 hours. The most influential predictors included dynamic changes in WBC and CSF lactate dynamics. In the biological onset sub-analysis, coordinated biomarker deterioration preceded clinical diagnosis by a median of 2 days (IQR 1-4).
    CONCLUSIONS: Longitudinal biomarker trajectory monitoring, combined with machine learning, enables timely prediction of EVD-associated infection. Biomarker changes precede clinical recognition by a median of two days, supporting prospective evaluation of daily risk monitoring in neurocritical care.
    Keywords:  SHAP; biomarker trajectory; external ventricular drain; gradient boosting; machine learning; ventriculitis
    DOI:  https://doi.org/10.1016/j.wneu.2026.125152
  66. Pharmaceuticals (Basel). 2026 Jun 11. pii: 922. [Epub ahead of print]19(6):
    Research Progress on Novel Lead Compounds for Central Nervous System Diseases.
    Yuhan Qiao, Junwei Chen, You Zhou, Wenchao Shi.
      Central nervous system (CNS) diseases, including ischemic stroke, Alzheimer's disease, and Parkinson's disease, impose a heavy socioeconomic burden worldwide. Current therapeutic strategies for CNS diseases primarily include modulating ion channels, inhibiting excitotoxicity, and applying anti-inflammatory, antioxidant, and anti-apoptotic approaches. However, existing drugs have not yet met the growing clinical demands. This paper summarizes novel lead compounds recently reported for CNS diseases and discusses the current challenges and emerging strategies in CNS drug development, aiming to provide a reference and scientific basis for future drug discovery and research.
    Keywords:  central nervous system diseases; challenges and emerging strategies; novel lead compounds; therapeutic strategies
    DOI:  https://doi.org/10.3390/ph19060922
  67. Eur J Med Chem. 2026 Jun 23. pii: S0223-5234(26)00526-X. [Epub ahead of print]317 119081
    Dual-target inhibitors based on BuChE: A review from medicinal chemistry perspective.
    Changyu Ren, Xuning Wang, Yang Yao, Shaojie Liang, Wen Liao, Zuoyi Yao.
      Butyrylcholinesterase (BuChE) plays a crucial role in maintaining neurotransmission homeostasis as a key complementary hydrolase to acetylcholinesterase (AChE), making it an essential target for addressing neurodegenerative diseases, neuroinflammation, and chemical toxin metabolism. A variety of selective BuChE inhibitors have been developed; however, their clinical translation remains constrained by insufficient efficacy, off-target effects, and poor blood-brain barrier (BBB) permeability. Recently, dual-target inhibitors have emerged as a promising strategy to circumvent these limitations. By integrating BuChE inhibition with complementary targets, researchers have designed multifunctional ligands through rational structural fusion and hybridization strategies and combinatorial library screening. These inhibitors exhibit enhanced neuroprotective efficacy, improved selectivity, and reduced side effects. This review highlights recent advances in the rational design, structure-activity relationship (SAR), and preclinical efficacy of novel BuChE dual-target inhibitors, focusing on their therapeutic potential for Alzheimer's disease (AD).
    Keywords:  BuChE dual-target inhibitors; Butyrylcholinesterase; Neurodegenerative diseases; Structure-activity relationship
    DOI:  https://doi.org/10.1016/j.ejmech.2026.119081
  68. Eur J Pharm Biopharm. 2026 Jun 24. pii: S0939-6411(26)00180-3. [Epub ahead of print] 115159
    Novel approach for direct drug delivery to the central nervous system via intratympanic administration.
    Masayoshi Saito, Noriyasu Sano, Shinji Nakayama, Yuichi Yokoyama, Naomi Takeba, Nao Torimoto.
      Therapeutic drugs for central nervous system (CNS) diseases need to reach CNS tissues. However, the blood-brain barrier often limits their therapeutic effects. To address this issue, highly invasive drug administration routes, such as intracerebroventricular or intrathecal administration, can be used. In addition, intranasal (i.n.) administration is increasingly being recognized as a non-invasive route, although its application in humans is limited. Hence, we explored intratympanic (i.t.) administration as a novel, minimally invasive route for direct drug delivery to the CNS. The aim of this study was to develop a new administration route that enables efficient and comprehensive evaluation of CNS drug transport by employing cassette dosing. Using this approach, we assessed multiple low- and high-permeability drugs concurrently in rodents and non-human primates. Pharmacokinetics were evaluated in cerebrospinal fluid (CSF) and brain tissues to investigate the potential for enhanced CNS penetration. Furthermore, the effects of cetirizine, a second-generation histamine receptor antagonist, on spontaneous locomotor activity were examined following i.t. and intravenous (i.v.) administration. I.t. of low-permeable drugs such as cetirizine markedly increased their penetration into CSF and brain in both rats and monkeys. Pharmacologically, i.t. of cetirizine significantly decreased spontaneous locomotor activity in rats, whereas such effects were not observed following i.v.. This study demonstrates that i.t. may serve as a promising route (Ear-to-Brain) for treating neurodegenerative diseases that currently lack effective treatment options.
    Keywords:  Central nervous system; Cerebrospinal fluid; Direct drug delivery; Intratympanic administration
    DOI:  https://doi.org/10.1016/j.ejpb.2026.115159
  69. Brain Sci. 2026 Jun 04. pii: 611. [Epub ahead of print]16(6):
    Spiritual Care Needs and Challenges Among Caregivers and Families of People with Neurodegenerative Diseases in Palliative and End-of-Life Care: A Scoping Review.
    Enrico De Luca, Andreina Saba, Laura Bertarini, Antonio Brusini, Giovanna Artioli, Federica Dellafiore.
      Background/Objectives: Spirituality is increasingly recognised as a core dimension of holistic and palliative care. Neurodegenerative diseases such as dementia, amyotrophic lateral sclerosis and Parkinson's disease involve prolonged trajectories of loss, uncertainty and relational change, which may heighten spiritual and existential needs for patients, particularly among those involved in caregiving, such as family caregivers and, to a lesser extent, healthcare professionals. However, evidence on how spirituality is understood, experienced and addressed within neurodegenerative palliative care remains fragmented and conceptually heterogeneous. This scoping review aimed to map the literature on caregivers' spiritual needs and challenges. Methods: A scoping review was conducted in accordance with the Joanna Briggs Institute (JBI) methodology for scoping reviews and the Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for Scoping Reviews (PRISMA ScR). Searches were conducted across PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), APA PsycINFO, and Scopus, with no date or geographical restrictions. Grey literature was searched through Google Scholar and relevant organisational and policy sources in the field of palliative care and spirituality. Reference list screening of included studies and relevant reviews was also conducted. Quantitative, qualitative, and mixed methods studies published in English or Italian were included. Results: Twenty-four studies published between 2007 and 2025 were included. Findings were organised into three interconnected domains: spiritual needs, spiritual processes and spiritual care. Spirituality emerged as a dynamic, relational and context-dependent dimension of caregiving, encompassing meaning, identity, connection and coping with vulnerability and loss. Spiritual needs and processes were widely described, while spiritual care was inconsistently recognised within healthcare systems. Conceptual ambiguity, under-representation of end-of-life dementia and cultural imbalances were evident. The evidence predominantly focused on family caregivers, with limited representation of healthcare professionals. Conclusions: This scoping review highlights a persistent gap between caregivers' lived spiritual experiences and system-level responses in neurodegenerative palliative care in caregiving contexts globally. The findings support integrated, caregiver-inclusive and culturally responsive approaches to spiritual care.
    Keywords:  caregivers; neurodegenerative disease; palliative care; scoping review; spiritual care
    DOI:  https://doi.org/10.3390/brainsci16060611
  70. Biomolecules. 2026 Jun 18. pii: 899. [Epub ahead of print]16(6):
    Infectious Agents in Multiple Sclerosis: Viral Triggers, Antibody-Mediated Autoimmunity, and Parasitic Immunomodulation.
    Dafni F T Frohman, Stella E Tsirka.
      Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by demyelination, neuroinflammation, and progressive neurodegeneration. While there is a small component of genetic susceptibility to MS risk, environmental factors, including infectious exposures, are gaining increased recognition as playing a critical role in MS initiation and progression. Viral infections, especially by Epstein-Barr virus (EBV), have emerged as strong candidates and triggers of MS symptoms, through antibody-mediated molecular mimicry and B-cell dysregulation. In contrast, parasitic infections, including helminths and select protozoa, appear to exert neuroprotective effects by skewing immune responses toward regulation and tolerance. In this review, we examine antibody-driven mechanisms by which viral pathogens promote autoimmunity in MS and contrast these with parasite-induced immunoregulatory pathways that suppress pathogenic inflammation. We further discuss diagnostic and therapeutic implications, highlighting how insights from infectious immunology may inform novel strategies for MS treatment.
    Keywords:  Epstein–Barr virus; antibodies; helminths; hygiene hypothesis; immune regulation; molecular mimicry; multiple sclerosis; neuroinflammation
    DOI:  https://doi.org/10.3390/biom16060899
  71. Transl Psychiatry. 2026 Jun 23.
    Immune cell-specific genetic architecture of Alzheimer's disease revealed by multi-omics analysis for therapeutic target discovery and prioritization.
    Tian-Long Gao, Shan Geng, Jia Chen, Liu Yang, Yun-Juan Nie, Haitao Yu, Gao-Shang Chai.
      Alzheimer's disease (AD) is a multifactorial neurodegenerative condition in which accumulating genetic and molecular evidence implicates dysregulation of peripheral immune processes in disease pathogenesis. Nevertheless, the contribution of distinct peripheral immune cell subsets and associated gene regulatory landscapes to AD risk remains incompletely defined. To address this gap, we integrated single-cell expression quantitative trait loci (sc‑eQTL) data from the OneK1K cohort with AD GWAS summary statistics. We systematically interrogated immune cell-specific genes for their contributions to AD risk by integrating genetic causal inference with Bayesian colocalization analyses, and identified 24 eGenes that passed both the MR significance threshold (P < 0.05) and the criterion for strong shared genetic signals (PP.H4 > 0.8). Notable candidates included GATS, HLA-DOB, HLA-DQA1, PM20D1, and others, with each gene demonstrating a cell-type-specific association restricted to its corresponding immune cell type, such as monocytes, CD8 + T cells, or B cells. Independent peripheral blood single-cell transcriptomic data further supported disease-associated shifts in cell-type-specific expression patterns in AD. Phenome-wide association studies (PheWAS) indicated limited associations with off-target traits, indicating a favorable safety profile for therapeutic intervention, with the exceptions of B4GALNT3, PM20D1, and CNN2. Integration of immune gene targets with pharmacological databases yielded three candidate compound, including NSC321521 (targeting HLA-DQA1), phenoxybenzamine (targeting GSTP1), and rimexolone (targeting BIN1). Among these compounds, Predicted blood-brain barrier permeability was observed only for phenoxybenzamine and rimexolone, with docking studies indicating stable interactions, such as those between NSC321521 and HLA-DQA1, phenoxybenzamine and GSTP1, and rimexolone and BIN1. This integrative approach highlights key immune‑cell‑specific genes involved in AD and proposes repurposable drugs with central nervous system potential, paving the way for more targeted immunomodulatory strategies in AD.
    DOI:  https://doi.org/10.1038/s41398-026-04199-9
  72. Neurochirurgie. 2026 Jun 26. pii: S0028-3770(26)00080-9. [Epub ahead of print] 101846
    Advances in tailored intraparenchymal delivery of regenerative medicine for spinal cord injury: a review of preclinical studies and clinical trials.
    Nicolas Serratrice.
      Intramedullary (intraparenchymal) injection has emerged as a promising and highly targeted approach for the treatment of spinal cord injury (SCI), enabling direct delivery of therapeutic agents into the spinal cord parenchyma. This technique bypasses systemic barriers-such as the blood-spinal cord barrier-and allows high local concentrations of therapeutic agents to be delivered precisely at or around the lesion site. In preclinical SCI models, including rodents, rabbits, pigs, and non-human primates, various agents-such as mesenchymal stem cells, gene therapy vectors, neurotrophic factors, and biomaterial-based hydrogels-have been delivered intraparenchymally to promote neuroprotection, modulate immune responses, and support axonal regeneration. The timing of injection is critical and is often aligned with the acute (≤48 hours), subacute (7-14 days), or early chronic phases after injury, depending on therapeutic objectives. Imaging and histological analyses, including high-resolution 7-T MRI, have demonstrated the accuracy and spatial precision of this approach in large-animal SCI models. Early-phase clinical trials have shown that intraparenchymal injections-particularly of stem cells or viral vectors-can be performed safely and are technically feasible when conducted using stereotactic or microsurgical guidance. Although functional outcomes remain variable, the ability to safely target the spinal cord parenchyma highlights the potential of this strategy as a component of future combinatorial regenerative therapies for SCI.
    Keywords:  Spinal cord injury; animal models; clinical trials; intraparenchymal (intramedullary) delivery; precision medicine; preclinical studies; review
    DOI:  https://doi.org/10.1016/j.neuchi.2026.101846
  73. Cells. 2026 Jun 16. pii: 1089. [Epub ahead of print]15(12):
    The Gut-Brain-Immune Axis: Multi-Omics Insights into Neurodegenerative and Metabolic Diseases.
    Salah-Ud-Din Khan, Varun Chauhan, Anis Ahmad Chaudhary, Mohsin Khan.
      The axis linking the gut to the brain to the immune system connects all tissues involved-bacteria, immune cells, metabolism and the CNS-through a multidirectional communication network. Several studies have confirmed that when this axis is disrupted, it can be responsible for Alzheimer's disease, Parkinson's disease, obesity, type 2 diabetes, and NAFLD, and the main consequences come from increased systemic inflammation, altered regulation of immune cells, the production of microbial metabolites that alter signals to the immune cells and nervous system, increase in oxidative stress, breakdown of the gut barrier, and more. In recent years, advanced multi-omics technologies, such as metagenomics, transcriptomics, metabolomics, proteomics, and single-cell sequencing, have provided significant advancement in our understanding of all of the interacting nodes involved in the gut-brain-immune axis. These advanced sequencing technologies can characterize the microbial communities, host immune cells, metabolic profiles, and the degree of cell heterogeneity during a specific disease. Combining multi-omics information can reveal a few shared pathways between neurodegenerative and metabolic disorders, such as NF-κB, NLRP3 inflammasome activation, mitochondrial dysfunction, changes in SCFA metabolism, and the alteration of microbial populations in Alzheimer's and Parkinson's disease; metabolic dysbiosis and increased risk for Parkinson's disease; or changes in gut-to-brain-to-immune signaling contributing to diabetes complications and NAFLD. Artificial intelligence (AI) and machine learning are becoming promising tools for detecting biomarkers from these datasets, extracting knowledge, interpreting systems biology, and helping with developing precision medicine. In this review, we summarize current evidence that supports the role of the gut-brain-immune axis in neurodegenerative and metabolic diseases, highlighting results gained with the utilization of multi-omics approaches. We will describe the key microbial, immune, and metabolic pathways involved in pathogenesis and therapeutic approaches including psychobiotics, tailored nutrition, modulation of the microbiome, and metabolite interventions, discussing future perspectives of the translation of the gut-brain-immune axis knowledge into clinical practice.
    Keywords:  dysbiosis; gut–brain–immune axis; metabolic diseases; metabolomics; multi-omics; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/cells15121089
  74. J Adv Res. 2026 Jun 21. pii: S2090-1232(26)00506-0. [Epub ahead of print]
    Human BBB-brain organoid on a millifluidic plate for modeling brain parenchymal pathology-induced barrier dysfunction.
    Lili Zhu, Wen Zhao, Min Shen, Yuwen Wang, Jibo Wang, Yunnan Liu, Tao Chen, Xuemei Huan, Bo Tang, Jian Shen, Linlin Bi, Dong Wang, Zhentao Zhang, Andreas Dietzel, Pu Chen, Longqiu Yang.
       INTRODUCTION: The blood-brain barrier (BBB) maintains brain homeostasis, and its dysfunction is a critical pathological mechanism for many neurological disorders. However, current BBB models lack functional brain parenchyma, hindering mechanistic studies of BBB-parenchyma interactions and limiting drug evaluation for barrier penetration and neural targeting.
    OBJECTIVES: To develop an integrated human blood-brain barrier-brain organoid-on-a-chip (BBOC) model that replicates physiological interaction and pathological disruption between the BBB and brain parenchyma.
    METHODS: A bioengineered BBB model was constructed on a millifluidic plate using human brain microvascular endothelial cells and pericytes under dynamic flow. Human pluripotent stem cell-derived brain organoids (hBOs) were co-cultured to form the BBOC system. Parenchymal pathology was induced by Aβ42 oligomers (Aβ42O) to examine their effects on BBB function and integrity.
    RESULTS: Conditioned medium and dynamic flow improved endothelial cell viability. Co-culture with hBOs significantly enhanced the engineered BBB function, increasing TEER values and reducing molecular permeability. Aβ42O-treated hBOs exhibit the pathological phenotypes of brain parenchyma, including notable neurite loss, impaired stem cell proliferation, increased cell apoptosis, and transcriptional upregulation of cytokine genes. The pathological hBOs disrupted the BBB, including decreased tight junction protein expression, increased barrier permeability, and impaired barrier integrity.
    CONCLUSION: The BBOC model reproduced physiological and pathological interactions between parenchyma and the BBB, collectively confirming that brain parenchymal activity directly regulates BBB integrity. Functionally, hBOs strengthened endothelial barrier integrity, indicating that parenchymal-derived signals actively promote the BBB maturation and stability. In contrast, pathological hBOs induced pericyte degeneration and tight junction disruption of BBB, demonstrating that pathological brain environments can directly impair BBB function. By bridging neurobiology and bioengineering, the BBOC model will facilitate investigations into neurological mechanisms and drug discovery for barrier penetration and neural targeting.
    Keywords:  BBB dysfunction; Brain organoid on a chip; Brain parenchymal pathology; Millifluidic plate; Neurodegenerative disease
    DOI:  https://doi.org/10.1016/j.jare.2026.06.024
  75. Medicine (Baltimore). 2026 Jun 26. 105(26): e48699
    Metaheuristic-driven machine learning study for early detection and classification of Parkinson's disease using feature prioritization with pelican optimization algorithm.
    Proloy Kumar Mondal, Haewon Byeon.
      Parkinson disease (PD) is a degenerative disorder of the brain and afflicts approximately 6 in 10 people aged 50 years or older. PD patients have motor and speech problems, so regular visits to and monitoring of the patients are hard. It is necessary to detect the presence of PD promptly and accurately, since early treatment will contribute greatly to enhancing patients' lives. As the number of aging people increases, there is a great demand for noninvasive, reliable, and remote diagnosis. In the current work, we studied 31 patients with PD and healthy subjects, their voice recordings, to create an automatic classification system. A Light Gradient Boosting Machine (LightGBM) classifier was adapted and boosted using metaheuristic-based feature selection (FS), namely the Pelican Optimization Algorithm (PAO). Hyperparameter optimization was made to optimize predictive performance. The models have been assessed on typical classification measures, i.e., accuracy, sensitivity, specificity, precision, and AUC. We classified using the baseline LightGBM classifier, with an accuracy of 95%. The resulting model had a better prediction accuracy of 97% after using PAO-based FS and hyperparameter optimization. More than that, the model was also sensitive, specific, precise, and had a high area under the curve, which validates its effectiveness at classifying PD. The paper shows that FS and hyperparameter tuning are effective approaches when applied to voice data and combined with LightGBM to detect PD as early as possible. The results point to the promise of noninvasive diagnostic systems based on the use of telemedicine to allow early intervention and enhance the lives of people with PD.
    Keywords:  LightGBM; Metaheuristic optimization; Pelican optimization algorithm; explainable AI; feature selection; machine learning
    DOI:  https://doi.org/10.1097/MD.0000000000048699
  76. Biomolecules. 2026 May 27. pii: 790. [Epub ahead of print]16(6):
    Role of Microbial Toxins in Neurodegenerative Diseases: Insights and Future Perspectives.
    Alka Ashok Singh, Fazlurrahman Khan, Minseok Song.
      Neurodegenerative disorders, including Parkinson's, Alzheimer's, and multiple sclerosis, are significant global health issues characterized by escalating neuronal dysfunction and cognitive decline. Studies suggest that microbial toxins originating from fungi and bacteria may contribute to neurodegenerative processes by altering neuronal homeostasis in several ways. Toxins formerly associated with infectious diseases have now been associated with neuroinflammation, oxidative stress, and protein misfolding, all of which are common in neurodegenerative diseases. According to recent studies, microbial toxins generated by the gut microbiota may cross the blood-brain barrier and possibly contribute to neuroinflammatory cascades linked to the development of neurodegenerative diseases. The complex interplay of microbial metabolites, microbial responses, and mitochondrial dysfunction demonstrates the diverse character of neurodegenerative processes. This review delves into the current understanding of microbial toxins, which are produced by diverse bacteria and can have a direct or indirect impact on neuronal health via multiple signaling pathways. Understanding the signaling mechanisms of microbial and toxin-mediated neurodegenerative diseases could result in the development of effective alternative therapeutics for neurological disorders.
    Keywords:  bacterial toxins; fungal toxins; microbial toxins; mycotoxins; neurodegenerative diseases; neurological disorders; neurotoxicity; oxidative stress; therapeutic strategies
    DOI:  https://doi.org/10.3390/biom16060790
  77. Int J Biol Sci. 2026 ;22(11): 6132-6148
    Deciphering the Neuroautophagic Interactome: Molecular Circuits Linking Selective Autophagy to Neuropathological Cascades in Neurological Disorders.
    Pengfei Luo, Zachary D Travis, Cameron Lenahan, Haijian Wu, Jianmin Zhang, Jun Yu, Weilin Xu.
      Selective autophagy, a lysosome-dependent degradation pathway targeting specific substrates (e.g., mitochondria, protein aggregates), plays a pivotal role in maintaining neuronal homeostasis. Its dysregulation is intricately linked to neurodegenerative diseases, acute brain injuries, and neuroinflammatory disorders. This review elucidates the crosstalk between selective autophagy and key neuropathophysiological processes, including apoptosis, neuroinflammation, oxidative stress, and blood-brain barrier disruption. We delineate the dual roles of selective autophagy through the framework of the neuroautophagic interactome-a network in which kinases (ULK1, TBK1) and effectors (PINK1/Parkin, SQSTM1/p62) collaboratively interpret ubiquitin codes. This integrated signaling nexus functions as a decisive hub that bidirectionally modulates disease progression. Furthermore, we evaluate emerging therapeutic strategies targeting selective autophagy to mitigate neuronal damage, emphasizing its dual role as both a protector and a contributor to disease progression.
    Keywords:  neuroautophagic interactome; neurological disorders; selective autophagy; therapeutic targets
    DOI:  https://doi.org/10.7150/ijbs.127431
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒28 at 7:39.