bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–06–14
fifty-four papers selected by
Luca Bolliger, lxBio
  1. PAD2 knockout reduces myelin protein aggregates, modulates neuroinflammation and protects motor neurons, axons and neuromuscular junction in a SOD1-ALS mouse model.
  2. Human iPSC-derived motor neurons as a platform for elucidating TDP-43-related amyotrophic lateral sclerosis pathogenesis: a mini review.
  3. Naringenin as a Multi-Target Neuroprotective Agent in Neurodegenerative Diseases.
  4. 18F FDG-PET correlates of motor neuron disease motor variants.
  5. Association of anti-glycolipid IgG with respiratory function decline in amyotrophic lateral sclerosis.
  6. Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis.
  7. Glutamate and glutamine metabolism in neurodegenerative diseases.
  8. Advancing amyotrophic lateral sclerosis research in Egypt.
  9. Intrathecal Administration of Riluzole in Amyotrophic Lateral Sclerosis.
  10. [Re-evaluating ALS Medical Care in Japan: An International Comparison of Japan, Europe, the United States, and Canada-Insights from Mechanical Ventilation, Support for Social Participation, End-of-Life Care Options, Approved Drugs, and Precision Medicine].
  11. Sensory abnormalities and entrapment neuropathies identified by nerve conduction studies in patients with amyotrophic lateral sclerosis.
  12. Two Patients With Juvenile-Onset, Rapidly Progressive Amyotrophic Lateral Sclerosis Associated With an SOD1 Variant (p.Asp125Gly) With Incomplete Penetrance.
  13. Early respiratory decline around diagnosis and short-term post-landmark outcomes in amyotrophic lateral sclerosis: a 6-month landmark cohort study.
  14. Clinical evaluation of communication brain computer interfaces in amyotrophic lateral sclerosis: a landscape analysis.
  15. PBMC DEG/miRNA biomarkers of TDP-43 pathology in ALS.
  16. Histological and Tissue-Level Outcomes of Stem Cell Therapies in Neurodegenerative Disorders: A Systematic Review.
  17. FUS-associated ALS in Taiwan: genetic spectrum, clinical features, and a founder haplotype of p.H517D.
  18. Brain delivery of proteins with shuttle peptides.
  19. Developmental circuit instability in amyotrophic lateral sclerosis: from hyperexcitability to network collapse.
  20. Impact of treatment burden on medication adherence and quality of life in amyotrophic lateral sclerosis: a prospective multicentre study.
  21. The Pivotal Role of HDAC6 in Amyotrophic Lateral Sclerosis: Neuroprotective Protagonist or Degenerative Adversary?
  22. Progressive choroid plexus enlargement across disease stages in patients with sporadic amyotrophic lateral sclerosis.
  23. Data-driven subtyping and staging of ALS: A multicenter, longitudinal, deformation-based morphometry study.
  24. ALS-associated protein TDP-43 disturbs axonal projections in the somatosensory cortex.
  25. NEK1 variants and reduced protein levels in Chinese ALS patients: a descriptive study.
  26. Functional Motor Change Across Time and Phenotypes in Patients With Amyotrophic Lateral Sclerosis: A Descriptive Study.
  27. The Role of Iron in Neuronal Homeostasis: A Double-Edged Sword.
  28. Polypharmacology of Pathway Crosstalk in Neurodegenerative Diseases: Chemical Modulation of Interconnected Signaling Networks.
  29. Toward non-invasive CNS delivery: The emergence of brain shuttle peptides.
  30. Optimizing Research Operations and Resource Utilization in ALS Care: Insights From the Tofersen Antisense Oligonucleotide Expanded Access Protocol.
  31. Inhibitory effect of silymarin on amyloid formation in ALS-associated hSOD1 P66R mutant.
  32. The tango of immune and neural cells: orchestrating neuroinflammation mediated brain disorders.
  33. Battle of the wall for aromatic "orifice-opening" agents: defending and breaching the blood-brain barrier.
  34. Phosphodiesterase 8 (PDE8), a novel target for neurodegenerative diseases.
  35. A mechanistic framework linking the oral microbiome to Alzheimer's disease through neuroinflammation.
  36. The Use of Statins in Parkinson's and Alzheimer's Disease: A 2021-2025 State-of-the-Art Review of Clinical and Preclinical Evidence.
  37. Brain shuttle peptides: From permeability assay toolbox to data-driven discovery.
  38. Clinical Research for the Use of 7 T Magnetic Resonance Imaging for Spinal Pathologies: a Scoping Review.
  39. Circadian gatekeepers of the gut-brain-immune axis: implications for neuroinflammation and neurodegeneration.
  40. Safety evaluation of Tofersen in amyotrophic lateral sclerosis based on the FAERS database.
  41. Luteolin and neuroinflammation: a multi-target therapeutic strategy for central nervous system disorders.
  42. Physiological strategies for brain delivery.
  43. Treg-microglia crosstalk in Alzheimer's disease: stage-dependent dynamics, molecular mechanisms, and translational challenge.
  44. Brain shuttle peptides derived from natural proteins.
  45. Complement System-Mediated Immunomodulation in Epilepsy: From Pathogenesis to Therapeutic Opportunities.
  46. CRISPR-Based Gene Therapy for Brain Disease.
  47. Association between influenza infection and subsequent Parkinson's disease diagnosis: a systematic review and meta-analysis.
  48. The triple-hit hypothesis of Alzheimer's disease: blood-brain barrier breakdown, infection, and neuroimmune activation as a unified etiological framework.
  49. Blood-brain barrier integrity and brain entropy in reversible cerebral vasoconstriction syndrome.
  50. Neurofilament light chain reflects motor impairment in myotonic dystrophy type 1.
  51. Adaptive immune signals shape neural circuit development through CNS Border-Glia pathways.
  52. Chemically enhanced brain shuttle peptides.
  53. Preclinical in vitro evaluation of a new nasal formulation combining xylometazoline and hyaluronic acid: Permeability and penetration analysis using an advanced characterized human nasal model.
  54. Natural monomer compounds in neurodegenerative diseases: Targeting ferroptosis and neuroinflammation.
  1. bioRxiv. 2026 Jun 03. pii: 2026.05.30.729013. [Epub ahead of print]
    PAD2 knockout reduces myelin protein aggregates, modulates neuroinflammation and protects motor neurons, axons and neuromuscular junction in a SOD1-ALS mouse model.
    Issa O Yusuf, Rogerio L A Silva, George G Amoako, Paul R Thompson, Zuoshang Xu.
       Background: Dysregulated peptidyl deiminase 2 (PAD2) and aberrant protein citrullination (PC), a posttranslational modification (PTM), are involved in various inflammatory and neurodegenerative diseases. We previously showed in transgenic mice and postmortem human tissues that PC and PAD2 are altered in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neurons loss, paralysis, and death. Herein, we investigated the role of PAD2 in ALS by PAD2 knockout in a SOD1-ALS mouse model.
    Methods: To investigate the role of PAD2-induced citrullination in ALS pathogenesis, we generated PAD2 knockout (PAD2KO) in SOD1 G93A ALS mouse model and investigated the consequent modulation on the neuropathology and clinical symptoms, using molecular biology techniques such as qPCR, Western blotting, confocal microscopy, and electron microscopy. Additionally, we identified C3 as being citrullinated in human ALS using ionFinder.
    Results: Our results show that PAD2KO blocked the increased PC and reduced myelin basic protein (MBP) aggregates in the ALS model. PAD2KO also improved motor neuron survival and the integrity of myelin, axons, and neuromuscular junctions, and reduced microgliosis in the white matter and C3 protein levels in astrocytes. Clinically, data from monitoring the body weight changes suggests that PAD2KO modulates the course of the disease in the ALS mouse model, accelerating the onset while slowing the progression after the onset, and modestly extending the survival of male mice.
    Conclusion: These results show that PAD2 is responsible for the increased PC in ALS and PC contributes to neuroinflammation and degeneration of motor neurons and myelinated axons. The modest modulation of the disease phenotype suggests that the role of PC in ALS is complex, involving altered PC in numerous proteins and in multiple cell types. Future studies are needed to investigate how PC modulates individual protein functions in various cell types to understand the contribution of PC to ALS pathogenesis.
    DOI:  https://doi.org/10.64898/2026.05.30.729013
  2. Front Mol Neurosci. 2026 ;19 1864964
    Human iPSC-derived motor neurons as a platform for elucidating TDP-43-related amyotrophic lateral sclerosis pathogenesis: a mini review.
    Satoshi Yokoi, Yohei Iguchi, Masahisa Katsuno.
      TAR DNA-binding protein 43 (TDP-43) is a major pathogenic RNA-binding protein associated with amyotrophic lateral sclerosis (ALS). Heterozygous mutations in TDP-43 cause familial ALS, known as ALS10. TDP-43 is predominantly localized in the nucleus under physiological conditions. Not only ALS patients with TARDBP mutations but also the majority of sporadic ALS patients exhibit TDP-43 pathology, which is defined by nuclear clearance and cytoplasmic aggregation. The inclusion of cryptic exons in genes such as STMN2 and UNC13A has emerged as a hallmark of TDP-43 loss of function, as demonstrated in TDP-43 knockdown models and postmortem analyses. However, it is not yet clear how TDP-43 levels and location change from healthy to pathological conditions in ALS. Motor neurons derived from induced pluripotent stem cells (iPSCs) have been widely used in ALS research and provide a promising platform to investigate early-stage disease mechanisms. However, challenges remain in generating models that faithfully recapitulate ALS pathogenesis. In this review, we summarize recent advances in TDP-43-related iPSC-derived motor neuron models and discuss future perspectives for elucidating ALS pathogenesis. We propose that longitudinal analyses of TDP-43 dynamics and co-culture systems will be essential to better model early ALS pathogenesis.
    Keywords:  RNA-binding protein; TDP-43; amyotrophic lateral sclerosis; co-culture; iPSC-derived motor neuron
    DOI:  https://doi.org/10.3389/fnmol.2026.1864964
  3. Neurochem Int. 2026 Jun 11. pii: S0197-0186(26)00094-X. [Epub ahead of print] 106203
    Naringenin as a Multi-Target Neuroprotective Agent in Neurodegenerative Diseases.
    Nista Gurung, Dong-Young Choi, Pil-Hoon Park.
      Neurodegenerative diseases (ND) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) are characterized by progressive neuronal loss driven by complex and multifactorial pathogenic mechanisms. Naringenin (NAR), a citrus-derived flavanone, has attracted considerable interest as a neuroprotective molecule due to its pleiotropic pharmacological activities such as antioxidant, anti-inflammatory and ability to modulate multiple cellular targets. This review provides a comprehensive overview of NAR pharmacokinetic profile, mechanistic actions, and therapeutic potential across major ND. We highlight how NAR's multi-target effects-including redox homeostasis maintenance, suppression of neuroinflammation, protein aggregation inhibition, and modulation of signaling pathways-contribute to neuroprotection in various experimental models of AD, PD, HD, ALS, and MS. Preclinical studies demonstrate that NAR can ameliorate cognitive and motor deficits in toxin and transgenic models of neurodegeneration, attenuate pathological hallmarks such as amyloid-beta toxicity, dopaminergic neuronal loss, and neuroinflammation, and induce cytoprotective pathways including Nrf2-mediated antioxidant response and autophagy. However, NAR's clinical translation is challenged by poor bioavailability; thus, novel delivery systems are being explored to enhance brain uptake. NAR emerges as a promising multi-functional neuroprotective agent that can simultaneously target diverse pathogenic processes in ND. Further research including advanced formulation development and well-designed clinical trials is warranted to fully establish NAR's therapeutic efficacy and safety in humans.
    Keywords:  Alzheimer’s disease; Multiple sclerosis; Naringenin; Neuroprotection; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.neuint.2026.106203
  4. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jun 09. 1-5
    18F FDG-PET correlates of motor neuron disease motor variants.
    Boris Deleu, Patrick Dupont, Kato Bracaval, Fouke Ombelet, Frederik Hobin, Nikita Lamaire, Koen Van Laere, Philip Van Damme, Joke De Vocht.
      While 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is an established biomarker in amyotrophic lateral sclerosis (ALS), the metabolic correlates of motor neuron disease (MND) motor variants remain poorly defined. This is why we investigated patterns of cerebral glucose metabolism across the spectrum of MNDs, including progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), and ALS. We retrospectively included 18 PMA, 25 PLS, and 43 matched non-hereditary ALS patients according to most recent diagnostic criteria. FDG-PET imaging revealed similar widespread hypometabolism in PMA, as in ALS, whereas PLS showed a more focal motor cortical pattern of hypometabolism. Despite clinical differences between MND subtypes, PMA and ALS showed similar FDG-PET metabolic patterns, whereas PLS exhibited a more restricted cortical signature in this retrospective study.
    Keywords:  18F FDG PET; Nuclear imaging; amyotrophic lateral sclerosis; motor neuron disease; primary lateral sclerosis; progressive muscular atrophy
    DOI:  https://doi.org/10.1080/21678421.2026.2682820
  5. J Neurol Sci. 2026 Jun 03. pii: S0022-510X(26)00321-7. [Epub ahead of print]488 126039
    Association of anti-glycolipid IgG with respiratory function decline in amyotrophic lateral sclerosis.
    Junji Nakasako, Rena Yaguchi, Atsushi Terayama, Motoi Kuwahara, Yoshinori Nishimoto.
       OBJECTIVE: Effective treatments for amyotrophic lateral sclerosis (ALS) remain limited, underscoring the need to identify robust biomarkers associated with disease severity and prognosis. This study investigated whether immunoglobulin G (IgG) and immunoglobulin M (IgM) anti-glycolipid antibodies are associated with clinical manifestations of ALS, particularly decline in respiratory function.
    METHODS: This was a retrospective observational cohort study of the patients with ALS. Among patients with definite or probable limb-onset ALS, 11 patients in the glycolipid IgG-positive group were compared with 15 patients in the IgG-negative group, and 5 patients in the glycolipid IgM-positive group were compared with 9 patients in the IgM-negative group, with adjustment for age. Associations between anti-glycolipid antibody status and respiratory function were assessed using Kaplan-Meier survival analysis and Cox proportional hazards models.
    RESULTS: The time to decline of percent forced vital capacity (%FVC) below 80% and 60% was significantly shorter in the IgG-positive group than in the IgG-negative group (p = 0.002 and p = 0.025, respectively). Cox proportional hazards analysis demonstrated that IgG antibody positivity was an independent risk factor for earlier decline in %FVC to 80%.
    INTERPRETATION: These findings suggest that anti-glycolipid IgG antibodies may be associated with respiratory function decline in ALS. Larger comprehensive studies will be required to validate these results and to elucidate the underlying pathophysiological mechanisms.
    Keywords:  Amyotrophic lateral sclerosis; Anti-glycolipid antibody; Respiratory function
    DOI:  https://doi.org/10.1016/j.jns.2026.126039
  6. JCI Insight. 2026 Jun 11. pii: e198842. [Epub ahead of print]
    Fatty acid amide hydrolase inhibition for treatment of amyotrophic lateral sclerosis.
    Daisuke Ito, Madoka Iida, Yohei Iguchi, Atsushi Hashizume, Shinichiro Yamada, Yoshiyuki Kishimoto, Shota Komori, Kazuki Obara, Shuto Nishisaki, Satoshi Yokoi, Teppei Shimamura, Yuto Takemoto, Masahiro Nakatochi, Tomohiro Akashi, Kunihiko Hinohara, Hyeon-Cheol Lee-Okada, Yohei Okada, Junichi Niwa, Gen Sobue, Shinji Tanaka, Ken Takashina, Takehiko Yokomizo, Masahisa Katsuno.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the selective loss of upper and lower motor neurons. There is a considerable variability in the disease progression of sporadic ALS, but the molecular basis for phenotypic heterogeneity remains largely unknown. ALS patients often manifest systemic metabolic abnormalities such as glucose intolerance and hypermetabolic state. We conducted reverse translational research to explore therapeutic targets in ALS based on the systemic metabolic alterations in patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of N-acyl taurines (NATs) were correlated with the longitudinal change in the revised ALS functional rating scale and survival. Experiments with ALS cellular models, iPS cells derived from ALS patients and SOD1G93A transgenic mice revealed that PF-04457845, a fatty acid amide hydrolase inhibitor, upregulated the expanded ECS, particularly the levels of NATs and ameliorated motor neuron degeneration through the regulation of microglial environment, synapse plasticity, and neuronal development. These results collectively indicate that dysregulation of NATs is associated with ALS progression and PF-04457845 may represent a potential disease-modifying therapy for ALS.
    Keywords:  ALS; Biomarkers; Drug therapy; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.198842
  7. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00008-5. [Epub ahead of print]186 1-24
    Glutamate and glutamine metabolism in neurodegenerative diseases.
    Kesharthini Karthikeyan, Gowshika Velmurugan, Riddhi Upadhyay, Murugan Sevanan, Subashchandrabose Chinnathambi.
      Glutamate is known as the most important excitatory neurotransmitter in brain. Glutamate and glutamine recycling is very essential to maintain the nitrogen metabolism. Despite of its major functions, its dysregulation is a basic pathology which is common to neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic lateral sclerosis (ALS). Amyloid-β and Tau in AD disrupt glutamate uptake and the glutamate-glutamine cycle, accelerating synaptic failure, whereas loss of astrocytic EAAT2 in ALS generates unrelenting excitotoxicity and motor neuron demise. Toxic α-synuclein aggregation in PD exacerbates dopamine-glutamate imbalance through destabilizing corticostriatal transmission. This review explores on the key mechanisms by which glutamate impairment leads to the pathogenies of neurogenerative disorders and also about current medications like amantadine, memantine, and riluzole which are glutamate antagonists, are shown to partially alleviative but cannot halt the advancement of the disease. One of the potential targets for disease-modifying treatments could be the receptor modulation, astrocytic function, and elimination of excess glutamate.
    Keywords:  EAAT2 dysfunction; Excitotoxicity; Glutamate dysregulation; Glutamine; VGLUT
    DOI:  https://doi.org/10.1016/bs.irn.2026.01.008
  8. Nat Rev Neurol. 2026 Jun 10.
    Advancing amyotrophic lateral sclerosis research in Egypt.
    Heather Wood, Nabila Hamdi.
      
    DOI:  https://doi.org/10.1038/s41582-026-01230-x
  9. Neurosurgery. 2025 Nov 24.
    Intrathecal Administration of Riluzole in Amyotrophic Lateral Sclerosis.
    Alexandre Bétourné, Pavlos Texakalidis, Roy Raheb Khelo, Melissa Campbell, Saud A Sadiq, Nicholas M Boulis.
       BACKGROUND AND OBJECTIVES: Riluzole is the only treatment known to improve survival in amyotrophic lateral sclerosis (ALS) patients. However, its efficacy and dosing are limited by hepatic toxicity and interindividual pharmacokinetic variability. Recent experimental studies in hounds have shown that continuous intrathecal (IT) administration of riluzole is well tolerated and achieves significantly higher spinal cord tissue levels. We report the first 2 human ALS cases treated with IT riluzole.
    METHODS: A catheter was inserted into the lumbar cistern and advanced to the midcervical region under fluoroscopic guidance and connected to a subcutaneous pump. Therapy was initiated at 0.1 mg/h of riluzole. The infusion rate was gradually increased until it reached a maximum of 4.8 mg/d.
    RESULTS: The 2 patients tolerated dose escalation and treatment for over 2 years without apparent motor or sensory complications. Patients reported no asthenia, a central side effect often reported as a reason to abandon oral therapy.
    CONCLUSION: This is the first report of chronic IT riluzole infusion in humans at a dose found to be safe in canines. A phase 1 study is planned to establish the maximum tolerated human dose, followed by a randomized placebo-controlled trial to determine the safety and tolerability of IT riluzole in patients with ALS.
    Keywords:  Amyotrophic lateral sclerosis; Intrathecal; Riluzole
    DOI:  https://doi.org/10.1227/neu.0000000000003859
  10. Brain Nerve. 2026 Jun;78(6): 654-657
    [Re-evaluating ALS Medical Care in Japan: An International Comparison of Japan, Europe, the United States, and Canada-Insights from Mechanical Ventilation, Support for Social Participation, End-of-Life Care Options, Approved Drugs, and Precision Medicine].
    Michiya Ito.
      Amyotrophic lateral sclerosis (ALS) care in Japan should be re-evaluated not simply as a matter of clinical choice but as a function of the public support system structure. In Japan, care is distinguished by a publicly funded model that supports home-based living and social participation following tracheostomy invasive ventilation. In contrast, Europe reflects a model centered on non-invasive ventilation and palliative care, and the United States reflects a system in which precision therapies are approved earlier but access remains highly unequal. Further, Canada reflects a model integrating multidisciplinary ALS clinics with Medical Assistance in Dying within a shared policy framework. These differences extend beyond treatment preferences and instead reflect broader social, institutional, and ethical configurations that shape the future of individuals with ALS. As access to emerging disease-modifying therapies increasingly depends on genetic testing, the central challenge in ALS care is shifting from end-of-life decision-making to the equitable distribution of precision medicine. Comparative reappraisal of national care models is therefore critical for understanding ALS not only as a neurological disease but also as a condition shaped by welfare systems, care infrastructure, and policy design.
    DOI:  https://doi.org/10.11477/mf.188160960780060654
  11. Neuromuscul Disord. 2026 May 22. pii: S0960-8966(26)00131-8. [Epub ahead of print]64 106463
    Sensory abnormalities and entrapment neuropathies identified by nerve conduction studies in patients with amyotrophic lateral sclerosis.
    Şule Deveci, Zeliha Matur, Safiye Serra Erzurumluoğlu.
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily affecting motor neurons; however, non-motor symptoms, including sensory and autonomic disturbances, are increasingly recognized. This retrospective cross-sectional study evaluated the frequency of sensory and entrapment neuropathies in 114 patients with ALS using electrodiagnostic (EDX) studies. Demographic characteristics, comorbidities, and sensory and autonomic symptoms were documented. Electrophysiological evidence of sensory neuropathy was identified in 20 patients overall (20/114, 17.5%), including 10 patients without diabetes mellitus (DM), whereas entrapment neuropathy was detected in 28 patients overall (28/114, 24.6%), including 16 of those without DM or hypothyroidism. Sensory neuropathy was significantly associated with both DM and a history of chronic disease. In contrast, these comorbid conditions were not significantly associated with entrapment neuropathy. Furthermore, patient-reported symptoms showed no correlation with electrophysiological evidence of sensory involvement on EDX. Sensory neuropathy was more frequent in patients with spinal-onset than bulbar-onset disease, although the difference was not statistically significant. This study confirms that sensory involvement is not uncommon in ALS. Although clinical symptoms are poor predictors, electrophysiological abnormalities consistent with sensory and entrapment neuropathies are common. A significant proportion of these abnormalities are idiopathic and may directly reflect the disease process itself, particularly in spinal-onset cases.
    Keywords:  Amyotrophic lateral sclerosis; Autonomic involvement; Electrophysiology; Pain; Sensory involvement
    DOI:  https://doi.org/10.1016/j.nmd.2026.106463
  12. Muscle Nerve. 2026 Jun 09.
    Two Patients With Juvenile-Onset, Rapidly Progressive Amyotrophic Lateral Sclerosis Associated With an SOD1 Variant (p.Asp125Gly) With Incomplete Penetrance.
    Can Ozlu, Abigail Schwaede, Bridget McGowan, Li Zhang, Martha Finch, Lisa F Wolfe, Senda Ajroud-Driss, Colin Franz, Nancy Kuntz.
       INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) patients are rarely encountered before age 25 years, often associated with genetic variants. SOD1 gene variants are well-known to account for a subset of adult-onset ALS but have only been described in a handful of early onset patients. Variants affecting residue 125 in SOD1 have been described in adult-onset ALS patients with a rapid progression. Here we report two such patients.
    METHODS: The clinical, genetic, and electrodiagnostic findings of two unrelated adolescents with juvenile onset rapidly progressive SOD1-ALS are described.
    RESULTS: Patient 1 presented at 16 and patient 2 at 15 years-of-age with lower limb onset of weakness, lower motor neuron examination findings, and rapid progression over months to involve all body regions. Both patients underwent extensive laboratory, electrophysiologic, and radiologic testing ruling out any alternate etiologies. For both patients, whole-exome sequencing revealed the pathogenic variant p.Asp125Gly in the SOD1 gene inherited from asymptomatic fathers.
    DISCUSSION: These two patients expand the phenotypic spectrum of SOD1-ALS, demonstrating a rapidly progressive juvenile lower limb onset phenotype associated with the p.Asp125Gly variant inherited with incomplete penetrance. Recognition and further characterization of juvenile SOD1-ALS are important in light of the advances in targeted therapies.
    Keywords:  SOD1; familial ALS; juvenile ALS
    DOI:  https://doi.org/10.1002/mus.70314
  13. Neurol Sci. 2026 Jun 08. pii: 550. [Epub ahead of print]47(7):
    Early respiratory decline around diagnosis and short-term post-landmark outcomes in amyotrophic lateral sclerosis: a 6-month landmark cohort study.
    Kazuhiro Horiuchi, Shuntaro Nakamura, Kaede Ishikawa, Sumire Nunomura, Kazuki Yamada, Takashi Inoue, Kei Oiwa, Shintaro Fujii, Yuki Oshima, Akihiko Kudo, Ichiro Yabe.
       BACKGROUND: In amyotrophic lateral sclerosis (ALS), respiratory decisions rely on serial trends rather than a single value. We evaluated whether early respiratory decline around diagnosis provides prognostic information in a real-world landmark framework.
    METHODS: This single-center retrospective cohort screened 94 consecutive patients diagnosed between April 2019 and December 2025. A 6-month landmark was used. Early decline was estimated from %FVC values between - 30 and + 180 days around diagnosis. The primary model included age and early %FVC decline; robustness analyses included time-varying Cox, piecewise Cox, RMST, included-vs-excluded comparison, death-only analysis, and slope-quality filtering.
    RESULTS: Of 94 screened patients, 62 met baseline eligibility, 56 had calculable early slope, and 45 entered the landmark cohort; 28 post-landmark composite events occurred. In the Cox model, faster early %FVC decline was associated with higher hazard of death or invasive mechanical ventilation via tracheostomy (HR 1.33 per 1%/month faster decline, 95% CI 1.14-1.55, p < 0.001). PH diagnostics suggested non-proportionality (%FVC p = 0.031; NIV p = 0.034 in the expanded model), so this HR was interpreted as an average follow-up association and complemented by PH-robust analyses. The signal was stronger early than late, remained consistent in a death-only analysis, and favored the slower-decline group by RMST at 24 and 36 months.
    CONCLUSIONS: In this selected measurement-capable landmark cohort, early respiratory decline provided a clinically meaningful short-to-medium term prognostic signal for post-landmark adverse outcomes. External validation is required before broader generalization beyond measurement-capable landmark populations.
    Keywords:  Amyotrophic lateral sclerosis; Forced vital capacity; Landmark analysis; Proportional hazards; Restricted mean survival time
    DOI:  https://doi.org/10.1007/s10072-026-09166-2
  14. Front Hum Neurosci. 2026 ;20 1771146
    Clinical evaluation of communication brain computer interfaces in amyotrophic lateral sclerosis: a landscape analysis.
    Shana R Melby, Jaganth Nivas Asok Kumar, Erin R Bigus, Spencer Kellis.
       Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that leads to severe motor impairment, including loss of communication ability, and ultimately death. Communication brain computer interfaces (cBCIs) have the potential to restore communication without reliance on motor function, thereby improving quality of life, independence, and palliative care. However, standardized methods to evaluate cBCI efficacy necessary for clinical implementation are not yet established.
    Methods: We conducted a systematic literature review, semi structured interviews with key opinion leaders (KOLs), and a clinical assessment review panel to (1) identify clinical outcome assessments (COAs) relevant to cBCIs in ALS, (2) obtain expert feedback, and (3) synthesize the current clinical and scientific landscape.
    Results: A total of 21 COAs were identified as potentially relevant and may serve as a foundation for cBCI specific measures. However, no existing COA was found to comprehensively capture the clinical benefit or functional impact of cBCIs in ALS.
    Discussion: Current COAs are insufficient to evaluate cBCIs in ALS, highlighting a critical gap. Development of cBCI specific outcome measures is needed to support clinical validation, regulatory evaluation, and adoption.
    Keywords:  ALS; BCI; COA; amyotrophic lateral sclerosis; brain computer Interface; cBCI; clinical outcome assessment; communication BCI
    DOI:  https://doi.org/10.3389/fnhum.2026.1771146
  15. Neurobiol Dis. 2026 Jun 06. pii: S0969-9961(26)00218-4. [Epub ahead of print]226 107473
    PBMC DEG/miRNA biomarkers of TDP-43 pathology in ALS.
    Maria Francesca Manchinu, Michela Congiu, Matteo Massidda, Giuseppe Borghero, Jacopo Marongiu, Isabella Marzi, Andrea Maschio, Vincenzo Rallo, Marcello Serra, Clara Porcedda, Michela Etzi, Maria Francesca Palmas, Andrea Angius, Valeria Sogos, Maria Ida Pateri, Maristella Steri, Valentina Coroneo, Alfonso De Simone, Giovanni Cossu, Fabrizio Chiti, Anna Rosa Carta.
      Amyotrophic lateral sclerosis (ALS) lacks reliable, disease-specific, and minimally invasive biomarkers, representing a major barrier to early diagnosis and patient stratification. The primary aim of this translational pilot study was to identify a disease-specific, TDP-43-related, gene-microRNA (miRNA) signature in peripheral blood mononuclear cells (PBMCs) of ALS patients with potential diagnostic value. To this end, we first identified differentially expressed disease-specific genes (dsDEGs) using a TDP-43-based rat model of ALS, generated by stereotaxic infusion of full-length (FL) TAR DNA-binding protein 43 (TDP-43) into the motor cortex. Transcriptomic profiling of the motor cortex revealed candidate dsDEGs, which were subsequently validated by RT-qPCR in motor cortex, spinal cord, and PBMCs from the same animals. To assess translational relevance, expression levels of these dsDEGs were analyzed in PBMCs from early- to mid-stage ALS patients and matched healthy controls, while disease specificity was evaluated using Parkinson's disease (PD) samples. In parallel, conserved miRNAs predicted to target the identified dsDEGs were examined in both rat and human PBMCs. Five dsDEGs, Mctp1, Penk, Mt2A, Drd1, and Rasgrp2, were consistently dysregulated across central and peripheral tissues in the TDP-43 rat model. RT-qPCR analysis of human PBMCs confirmed significant and selective dysregulation of these genes in ALS, but not in PD, supporting disease specificity. Moreover, exposure of human neuroblastoma cells and healthy PBMCs to TDP-43 recapitulated the ALS-like expression changes. Computational and experimental analyses identified seven conserved miRNAs targeting these dsDEGs, of which four were significantly downregulated in ALS PBMCs, supporting a coordinated regulatory network. Receiver operating characteristic (ROC) analyses demonstrated strong discriminative performance for both the gene signature (AUC 0.87-1.00) and the associated miRNAs (AUC 0.95-1.00). Together, these findings define a novel PBMC-based gene-miRNA signature that mirrors central ALS pathology and shows high diagnostic accuracy and disease specificity, highlighting its potential as a minimally invasive biomarker for ALS.
    Keywords:  Amyotrophic lateral sclerosis; Diagnostic biomarker; PBMC; TDP-43; Transcriptomic; miRNA
    DOI:  https://doi.org/10.1016/j.nbd.2026.107473
  16. Clin Anat. 2026 Jun 12.
    Histological and Tissue-Level Outcomes of Stem Cell Therapies in Neurodegenerative Disorders: A Systematic Review.
    Heba Fikry, Lobna A Saleh, Doaa Ramadan Sadek.
      Neurodegenerative diseases, which afflict millions worldwide and threaten public health, have no cure. Neurodegenerative diseases lack effective therapies, burdening society and the economy. Over the past 20 years, regenerative cell therapy (stem cell therapy) has advanced, opening novel neurodegenerative disease treatments. Thus, the current review aimed to systematically highlight experimental and clinical studies of potentially effective therapeutic strategies for stem cells and report histological, cellular, or ultrastructural outcomes following stem cell interventions in neurodegenerative diseases. PRISMA-compliant computerized literature searches of PubMed, Scopus, and Web of Science identified studies on embryonic, induced pluripotent, mesenchymal, or neural stem cells (NSCs) in neurodegenerative disease models and histological and tissue-level outcomes. Search terms included nervous system diseases, histology, neuron regeneration, stem cells, stem cell treatment, and transplantation. Peer-reviewed articles published between 2000 and 2025 were selected. Experimental animal and clinical studies that reported histological or tissue-level results after stem cell treatments were included. Eighty-six studies met the eligibility criteria, covering models of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. Across these studies, stem cell therapies were linked to improved neuron survival, better synaptic structure, diminished gliosis, and some restoration of tissue structure. These effects depended on the type of stem cell used, the disease model, and how the treatment was given. Overall, the evidence suggests that stem cell therapies can lead to significant histological and tissue-level improvements in neurodegenerative diseases, supporting their potential for regeneration. Further standardized and translational studies are needed to clarify the underlying mechanisms and improve treatment strategies.
    Keywords:  cellular outcomes; histological; mesenchymal stem cells; neural stem cells; neurodegeneration; neurodegenerative diseases; stem cell therapy; stem cell transplantation; stem cells; tissue outcomes
    DOI:  https://doi.org/10.1002/ca.70147
  17. J Neurol. 2026 Jun 10. pii: 387. [Epub ahead of print]273(7):
    FUS-associated ALS in Taiwan: genetic spectrum, clinical features, and a founder haplotype of p.H517D.
    Hou-Ping Sytwu, Kang-Yang Jih, Yu-Sheun Tsai, Shih-Yu Fang, Yi-Chu Liao, Yi-Chung Lee.
       OBJECTIVE: To characterize the genetic spectrum and clinical features of FUS-associated amyotrophic lateral sclerosis (ALS) in a Taiwanese cohort and to investigate whether the recurrent p.H517D variant represents a founder mutation.
    METHODS: All coding exons and flanking intronic regions of FUS were analyzed by Sanger sequencing in 650 unrelated Taiwanese patients with ALS. Clinical characteristics of patients carrying FUS variants were evaluated. Haplotype analysis using polymorphic microsatellite markers flanking FUS was performed to assess a potential founder effect of the p.H517D variant.
    RESULTS: Eight distinct heterozygous pathogenic FUS variants were identified in 11 probands and five affected relatives, including six missense and two frameshift variants. The most frequent variant was p.H517D, detected in four probands. A novel frameshift variant, p.G499Vfs*30, was identified as a de novo mutation in a juvenile-onset ALS patient. Compared with the non FUS-associated ALS cohort, patients with FUS-associated ALS had a significantly younger mean age at onset (40.1 vs 56.6 years) and more frequent bulbar onset (50% vs 19%). Haplotype analysis suggested a common founder for the p.H517D variant.
    CONCLUSIONS: FUS mutations accounted for 1.7% of ALS cases in this Taiwanese cohort. The recurrent p.H517D variant appears to represent a population-specific founder mutation. Patients with FUS variants presented with earlier disease onset and heterogeneous clinical phenotypes, and de novo variants contributed to juvenile-onset disease.
    Keywords:   FUS ; ALS; Amyotrophic lateral sclerosis; Founder effect
    DOI:  https://doi.org/10.1007/s00415-026-13929-4
  18. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00023-2. [Epub ahead of print]105 171-211
    Brain delivery of proteins with shuttle peptides.
    Alejandro Benítez-Troncoso, Macarena Sánchez-Navarro, Marina Plaza-Garrido.
      Therapeutic proteins have emerged as potential candidates for the management of neurodegenerative disorders affecting the central nervous system (CNS). However, their effective delivery to the CNS remains a major challenge, primarily due to the presence of the blood-brain barrier (BBB). To overcome this challenge, several brain-targeted delivery strategies based on peptides have been developed. These peptides harness endogenous BBB transport pathways to enhance the delivery of therapeutic proteins to the CNS. In order to develop new potential protein-based therapeutic candidates, considerable efforts have focused on engineering fusion proteins that combine therapeutic efficacy with enhanced BBB permeability.
    Keywords:  Blood-brain barrier; Brain delivery; Cell-penetrating peptides; Shuttle-peptides; Therapeutic proteins
    DOI:  https://doi.org/10.1016/bs.apha.2026.02.006
  19. Brain. 2026 Jun 10. pii: awag185. [Epub ahead of print]
    Developmental circuit instability in amyotrophic lateral sclerosis: from hyperexcitability to network collapse.
    Ilaria Donati Della Lunga, Letizia Cerutti, Valerio Barabino, Gioele G Figus, Francesca Callegari, Luca Oneto, Mariateresa Tedesco, Francesca Bacchetti, Marco Milanese, Paolo Massobrio, Martina Brofiga.
      Amyotrophic lateral sclerosis (ALS) is traditionally viewed as a late-onset motor neuron disease, yet how cortical dysfunction originates and contributes to pathogenesis remains unresolved. In this study, we reconstruct the developmental trajectory of cultured cortical networks derived from SOD1G93A mouse embryos using a multimodal approach, by combining morphometric, electrophysiological, pharmacological, molecular, computational, and machine-learning techniques. We prove that ALS neurons fail to acquire mature polarization and connectivity, displaying a transient phase of hyperexcitability that precedes a progressive collapse of network organization. Astrocytic dysfunction emerges early and impairs synchronization, establishing a causal link between glial dysfunction and neuronal instability. The analysis of synaptic transmission reveals an excitatory bias followed by maladaptive inhibitory recruitment and GABA/glutamate co-release, causing fragmented and inefficient network topologies. Finally, in silico modelling identified deficient intrinsic adaptation as a key driver of hyperexcitability. Together, our findings position ALS as a developmentally rooted disorder of cultured cortical network homeostasis, driven by glial, synaptic, and intrinsic adaptation failures. By demonstrating that cortical dysfunction is embedded before degeneration, this work provides a unifying framework connecting early network instability to disease progression and establishes electrophysiological network signatures, detected by machine learning classifiers, as candidate biomarkers for early diagnosis and therapeutic screening.
    Keywords:  ALS; astrocyte dysfunction; electrophysiology; excitatory/inhibitory imbalance; in silico modeling; machine learning
    DOI:  https://doi.org/10.1093/brain/awag185
  20. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jun 11. 1-9
    Impact of treatment burden on medication adherence and quality of life in amyotrophic lateral sclerosis: a prospective multicentre study.
    Andrea Lizio, Matteo Farè, Francesca Gerardi, Marianna Collesi, Valeria Ada Sansone, Christian Lunetta, Luca Diamanti, Federica Cerri.
       BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) face substantial barriers to medication adherence as disease progression necessitates complex drug formulation adjustments, such as crushing tablets, mixing with liquids, or delivering via feeding tubes. These modifications may not only increase the time and effort required but could also impact drug efficacy and safety.
    OBJECTIVE: To evaluate the prevalence and the impact of treatment burden on medication adherence and patient-reported quality of life (QoL) in ALS.
    METHODS: This prospective multicenter study enrolled ALS patients across three Italian reference centers, with assessments at baseline, 6, and 12 months. Key measures included the Multimorbidity Treatment Burden Questionnaire (MTBQ), ALSFRS-R, DYALS (dysphagia), Morisky Medication Adherence Scale, SSS-8 (somatic symptoms), INQoL (QoL), SWAMECO (swallowing/medication difficulties), alongside comorbidities and current therapies. Associations between treatment burden, QoL, and adherence were analyzed using multivariable models.
    RESULTS: A total of 114 consecutive ALS patients were enrolled. Clinically significant treatment burden was observed in 69.3% of patients, with over half reporting moderate-to-high levels according to the MTBQ classification. Elevated burden was independently related to greater somatic symptom severity and formulation modification needs. Moreover, higher burden associated with poorer QoL and diminished adherence after confounder adjustment. Longitudinally, patients experiencing worsening burden over 1 year showed accelerated QoL decline compared to those remaining stable, though adherence trajectories were unaffected.
    CONCLUSION: Treatment burden, particularly driven by drug formulation complexities and somatic symptoms, emerges as a pivotal, modifiable determinant of adherence and QoL in ALS. Targeted interventions to alleviate modifiable burden components hold promise for optimizing clinical outcomes and enhancing patient-centred care.
    Keywords:  Treatment burden; adherence to treatment; amyotrophic lateral sclerosis; drug formulation; quality of life
    DOI:  https://doi.org/10.1080/21678421.2026.2683691
  21. Curr Neuropharmacol. 2026 Jun 08.
    The Pivotal Role of HDAC6 in Amyotrophic Lateral Sclerosis: Neuroprotective Protagonist or Degenerative Adversary?
    Ekta Shirbhate, Vaibhav Singh, Om Kumar Mishra, Biplob Koch, Amit K Tiwari, Haya Khader Ahmad Yasin, Harish Rajak.
      The review specifically examines the pivotal role of HDAC6 in the pathophysiological pathway of Amyotrophic Lateral Sclerosis (ALS), an escalating neurodegenerative ailment marked by the discerning damage to motor neurons. Several lines of evidence implicate inadequate proteostasis in significantly influencing neuronal degeneration. The accumulation of misfolded proteins and proteotoxicity are highlighted as significant factors in ALS pathophysiology. Key pathological hallmarks include ubiquitin-positive inclusions, disrupted RNA metabolism, cytoskeletal perturbations, and compromised axonal transport systems. HDAC6 dysregulation disrupts axonal transport, impairing mitochondrial function and increasing oxidative stress, leading to rapid motor neuron damage and cell death. The enzyme's aberrant deacetylation of α-tubulin destabilizes microtubules and impairs intracellular trafficking. Despite HDAC6's participation in these unfavorable processes, it also exerts neuroprotective properties. It deacetylates tubulin, promoting efficient axonal transport and autophagic clearance. HDAC6 helps form aggresomes and stress granules, which are essential for cellular defence against proteotoxic stress. Through its zinc finger ubiquitin-binding domain, HDAC6 interacts with polyubiquitinated proteins, facilitating their autophagic degradation. HDAC6 inhibition can boost autophagic flux and reduce protein aggregation, while its activation may amplify the protective effects. This dichotomous behaviour of HDAC6 may pose an obstacle to the design of targeted therapy. Illuminating the complex mechanisms through which HDAC6 influences neurodegeneration and neuroprotection is important before constructing effective treatments for ALS. The review provides a clear understanding of the complex role of HDAC6 in ALS pathogenesis and highlights potential strategies to improve the prognosis of people affected by this neurological illness.
    Keywords:  ALS; FUS; HDAC6; HDAC6 inhibitors; de-acetylation; neurodegenerative diseases.
    DOI:  https://doi.org/10.2174/011570159X462214260429080002
  22. Neurobiol Dis. 2026 Jun 10. pii: S0969-9961(26)00226-3. [Epub ahead of print] 107481
    Progressive choroid plexus enlargement across disease stages in patients with sporadic amyotrophic lateral sclerosis.
    Mingjie Ma, Bo Cui, Xiaohan Sun, Shuangwu Liu, Kai Shao, Fuchen Liu, Pengfei Lin, Wei Li, Yuying Zhao, Dexin Yu, Jianwei Lou, Yan Yun.
       BACKGROUND: The choroid plexus (CP), a key structure involved in cerebrospinal fluid homeostasis and glymphatic function, is increasingly recognized as an interface for neuroimmune communication. Recent studies have identified CP abnormalities as potential neuroimaging markers in several neurodegenerative disorders, including sporadic amyotrophic lateral sclerosis (sALS). However, whether CP enlargement occurs early and progresses across clinical stages or over time in patients with sALS remains unclear. Given the role of the CP in peripheral-central nervous system immune crosstalk, the association between neuroinflammation and CP abnormalities in sALS also requires clarification. In this prospective study, we used structural MRI to examine cross-sectional and longitudinal CP volume changes in patients with sALS and to evaluate their associations with CSF inflammatory markers.
    METHODS: This prospective study included 161 newly diagnosed patients with sALS who underwent genetic testing and structural MRI, and 64 healthy controls (HCs) who underwent structural MRI. Disease stage in patients with sALS was assessed using the King's staging system. Longitudinal MRI was performed in a subset of 42 patients, of whom 38 also underwent baseline CSF inflammatory protein assessment.
    RESULTS: Compared with HCs, patients with sALS at all King's stages showed significantly larger CP volumes after Bonferroni correction (all p < 0.05). CP volumes were significantly greater in patients at King's stage 3 than in those at King's stage 1 or stage 2 after Bonferroni correction (all p < 0.05). In the longitudinal subgroup, CP volume increased significantly from baseline to follow-up. Multivariable analysis showed that higher CSF CHIT1 and IL-6 levels were independently associated with larger CP volume in patients with sALS (β = 0.348-0.456; p < 0.01).
    CONCLUSIONS: Our findings provide evidence that CP enlargement occurs early and progresses across disease stages and over time in patients with sALS. Higher CSF CHIT1 and IL-6 levels were associated with larger CP volume, supporting a potential link between neuroinflammation and CP abnormalities in sALS. These findings support CP enlargement as a promising neuroimaging marker for monitoring disease progression and neuroinflammatory processes in patients with sALS.
    Keywords:  Amyotrophic lateral sclerosis; Choroid plexus; MRI; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.nbd.2026.107481
  23. Imaging Neurosci (Camb). 2026 ;pii: IMAG.a.1264. [Epub ahead of print]4
    Data-driven subtyping and staging of ALS: A multicenter, longitudinal, deformation-based morphometry study.
    Isabelle Lajoie, Sanjay Kalra, Mahsa Dadar.
      Amyotrophic lateral sclerosis (ALS) is clinically and biologically heterogeneous, yet data-driven imaging subtyping approaches have rarely been validated longitudinally or linked to clinical and survival outcomes. We aimed to identify and validate distinct ALS subtypes and disease stages using deformation-based morphometry (DBM) and the Subtype and Stage Inference (SuStaIn) model, and to characterize their cross-sectional and longitudinal imaging, clinical, cognitive, and survival profiles. Data from 198 ALS patients and 144 healthy controls in the Canadian ALS Neuroimaging Consortium (CALSNIC) multicenter cohort were analyzed. Baseline regional DBM w-scores from 14 ALS-relevant regions served as input to SuStaIn to infer subtypes and stages. Longitudinal consistency of subtype and stage assignments (e.g. adherence to the expected disease evolution) was assessed using follow-up visits. Imaging and clinical trajectories were compared across subtypes using linear mixed-effects models incorporating stage and elapsed time. Associations between longitudinal variables and SuStaIn stage were estimated using mixed models, while baseline clinical and cognitive differences were assessed with ordinary least squares regression. Survival differences were evaluated using Kaplan-Meier curves and log-rank tests. SuStaIn identified one normal-appearing group (S0) and three ALS atrophy subtypes. S0 showed no baseline atrophy but exhibited longitudinal motor decline and the most favorable survival (log-rank p < 0.05 to p < 0.01). S1 exhibited classical motor/corticospinal tract-dominant degeneration, greater lower motor neuron burden, and intermediate survival. S2 showed limbic-onset atrophy progressing toward motor pathways, with preserved cognition and a milder course. S3 demonstrated extensive fronto-parietal and striatal atrophy, longitudinal motor-thalamic degeneration, and the shortest survival. Subtype and stage assignments demonstrated high longitudinal consistency (>90%). SuStaIn stage was strongly associated with widespread brain atrophy (and ventricular expansion), with the strongest effects in limbic-subcortical regions. Stage also correlated with ALS Functional Rating Scale-Revised (ALSFRS-R) decline and forced vital capacity (FVC) reduction, indicating that stage reflects disease-linked progression. This study establishes a robust, longitudinally validated model of ALS heterogeneity, showing that SuStaIn-derived subtypes define distinct disease trajectories, whereas the normal-appearing group reflects an early, structurally preserved state with a more favorable survival profile. By integrating probabilistic staging with longitudinal modeling, these findings clarify dynamic subtype-specific progression patterns and support the use of SuStaIn for biologically informed patient stratification, prognostication, and clinical trial enrichment in ALS.
    Keywords:  longitudinal; machine learning; progression modeling; subtype and stage inference
    DOI:  https://doi.org/10.1162/IMAG.a.1264
  24. Neurosci Res. 2026 Jun 11. pii: S0168-0102(26)00066-0. [Epub ahead of print] 105079
    ALS-associated protein TDP-43 disturbs axonal projections in the somatosensory cortex.
    Elvira Abzhanova, Yuzuki Kawae, Hiromi Mizuno, Terumasa Umemoto, Halilibrahim Ciftci, Masafumi Tsuboi, Yusuke Hirabayashi, Hidenobu Mizuno.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons that gradually causes muscle weakness and paralysis, eventually resulting in death. While ALS was once believed to specifically target motor neurons, recent clinical studies have revealed sensory involvement. The pathological hallmark of ALS is TAR DNA-binding protein 43 (TDP-43) aggregation in cytoplasm, with increasing evidence of its presence in both motor　and sensory neurons. However, sensory abnormalities remain poorly characterized. To address this research gap, we analyzed the effects of TDP-43 expression on layer 2/3 (L2/3) pyramidal neurons of the primary somatosensory cortex in mice projecting through corpus callosum. In utero electroporation (IUE) was performed to express GFP alone (control) or in combination with TDP-43. Compared with the control, mice co-expressing GFP and TDP-43 showed disturbed callosal axonal projections of L2/3 neurons. Mutant TDP-43 variants displayed a more pronounced phenotype, indicating pathogenic role during fetal cortical development. To distinguish developmental from maintenance effects, tamoxifen-inducible TDP-43 expression was used to initiate postnatal TDP-43 expression. Postnatal induction resulted in shorter axonal length and reduced branching rather than gross projections disturbance. Taken together, these results demonstrate that TDP-43 expression can disturb the integrity of axonal projections, such as callosal projections of L2/3 neurons in the somatosensory cortex.
    Keywords:  ALS; TDP-43; axonal projections; corpus callosum; layer 2/3 cortical neurons; neuronal aggregates
    DOI:  https://doi.org/10.1016/j.neures.2026.105079
  25. Front Aging Neurosci. 2026 ;18 1831861
    NEK1 variants and reduced protein levels in Chinese ALS patients: a descriptive study.
    Xiaodan Chen, Yan Mo, Haishan Jiang.
       Objective: NIMA-related kinase 1 (NEK1) have been implicated in amyotrophic lateral sclerosis (ALS). But genetic spectrum and clinical presentation have not been systematically defined.
    Methods: We screened 378 ALS patients and identified NEK1 variant carriers. Clinical records were reviewed retrospectively to characterise phenotypes. Leukocytes were isolated after routine testing and NEK1 protein abundance was quantified by western blot to assess the relationship between NEK1 protein levels and the rate of clinical progression. In parallel, we conducted a structured narrative review of published NEK1-ALS cases based on a systematic search of PubMed, Embase, and Web of Science. We extracted genetic and clinical information to summarise the variant spectrum, co-mutation profiles, and phenotype differences across populations.
    Results: NEK1 variants were identified in 8 of 378 patients (2.12%). Protein analysis showed lower peripheral NEK1 levels among carriers than among controls in this small exploratory sample. An exploratory analysis further suggested that lower systemic NEK1 protein levels may be associated with faster disease progression; however, because these measurements were obtained from peripheral leukocytes at highly heterogeneous sampling times and without adjustment for major clinical confounders, they should be interpreted strictly as descriptive observations and do not support biomarker claims. While phenotypic heterogeneity and population-specific variant distributions were observed, these findings remain descriptive due to the small sample size.
    Conclusion: This regional case series provides a descriptive overview of NEK1 variants in a Chinese ALS cohort and offers preliminary exploratory evidence consistent with reduced peripheral NEK1 protein levels in variant carriers. The observed inverse relationship between lower measured protein levels and faster clinical decline should be regarded as hypothesis-generating only. Given the small sample size, highly heterogeneous sampling times, use of peripheral leukocytes, and lack of adjustment for major clinical confounders, these protein data do not support biomarker claims at this stage. Validation in larger, prospective multi-center cohorts with standardized longitudinal sampling is required.
    Keywords:  NEK1 variants; amyotrophic lateral sclerosis; clinical progression; genetic spectrum; population differences; protein levels
    DOI:  https://doi.org/10.3389/fnagi.2026.1831861
  26. Neurorehabil Neural Repair. 2026 Jun 10. 15459683261445435
    Functional Motor Change Across Time and Phenotypes in Patients With Amyotrophic Lateral Sclerosis: A Descriptive Study.
    Elissa C Held-Bradford, Elisabeth DeMarco, Samantha Zocher, Kate Weaver, Kathryn Forsman, Ghazala Hayat, Divya S Subramaniam, Meghan Doherty.
       PURPOSE: Progressive disability occurs in persons with amyotrophic lateral sclerosis (pALS), but change over time across phenotypes remains understudied, limiting clinical decision-making. This descriptive study describes functional motor change with detailed measures across ALS phenotypes to enhance clinical decision making.
    MATERIALS AND METHODS: Electronic health record data from an interdisciplinary ALS clinic (n = 109 pALS, 2018-2022) including demographics, disability (ALS Functional Rating Scale-[ALSFRS-R]), and functional motor scores (10 m Walk, Handheld dynamometry [grip and ankle]) was utilized. Phenotype groups were defined by site of onset (bulbar, limb onset; upper limb or lower limb). Analysis was conducted using R and included changes scores and measures of central tendency in 3-month intervals.
    RESULTS: PALS included n = 43 bulbar, n = 32 upper limb, n = 34 lower limb onset, age 65, 60 to 71 (median, interquartile range). ALFSRS-R decline was greatest in bulbar, and similar in upper and lower limb. Patterns of change within motor scores suggest greatest loss of grip strength in bulbar and upper limb, ankle strength in upper limb, walking speed in lower limb, and preservation of community ambulation in upper limb.
    CONCLUSION: While ALSFRS-R scores were similar in upper and lower limb, detailed functional motor measures indicated differences in groups. These patterns provide insight to guide clinical decision making and future research to enhance care in pALS.
    Keywords:  amyotrophic lateral sclerosis; function; health outcomes; phenotypes
    DOI:  https://doi.org/10.1177/15459683261445435
  27. Cells. 2026 May 29. pii: 999. [Epub ahead of print]15(11):
    The Role of Iron in Neuronal Homeostasis: A Double-Edged Sword.
    Bibiana Sgalletta, Francesco Agostini, Marco Bisaglia.
      Iron is an essential micronutrient that plays a central role in numerous biological processes. Despite its relatively low abundance in the human body, iron is particularly critical for brain function. Systemic and cerebral iron homeostasis is tightly regulated through coordinated mechanisms involving absorption, transport, storage, and recycling. Within the brain, iron metabolism is further controlled by the blood-brain barrier and specialized neural cell populations, including neurons, astrocytes, oligodendrocytes, and microglia. Iron is indispensable for neurodevelopment, supporting neurogenesis, myelination, and neurotransmitter synthesis. However, both iron deficiency and iron overload have detrimental consequences. Early-life iron deficiency disrupts neural development and leads to long-lasting cognitive, motor, and behavioral impairments, whereas excessive iron accumulation promotes oxidative stress, ferroptosis, and neuroinflammation. These mechanisms have been described to contribute to the pathogenesis of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, neurodegeneration with brain iron accumulation, and amyotrophic lateral sclerosis. This review first outlines systemic and brain iron metabolism, highlighting how neural cells regulate homeostasis. Next, it examines iron's physiological roles, particularly in neurogenesis and neurodevelopment. Finally, it explores iron's involvement in neurodegenerative diseases, emphasizing neuroinflammation as a primary mechanism of iron toxicity.
    Keywords:  iron; neurodegenerative disorders; neurodevelopment; neurogenesis; neuroinflammation
    DOI:  https://doi.org/10.3390/cells15110999
  28. Cells. 2026 May 22. pii: 962. [Epub ahead of print]15(11):
    Polypharmacology of Pathway Crosstalk in Neurodegenerative Diseases: Chemical Modulation of Interconnected Signaling Networks.
    Muhammad Sohail Khan, Imran Zafar, Muhammad Noman, Gabsik Yang, Ki Sung Kang, Jean C Bopassa.
      Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), arise from highly interconnected molecular and cellular abnormalities that progressively lead to neuronal dysfunction, synaptic failure, and cell death. This review provides a unified framework to understand the interrelated molecular mechanisms driving these diseases, with a focus on identifying key disease-specific intervention nodes. Core contributors include oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and emerging roles of peroxisomal dysfunction in redox imbalance, lipid dysregulation, and inflammatory amplification. Single-target therapies often show limited efficacy due to the complex, interconnected nature of these pathways. In contrast, polypharmacology, which targets multiple disease-relevant mechanisms simultaneously, offers a more promising therapeutic strategy. This review critically examines how pathway crosstalk drives neurodegenerative progression, with particular emphasis on mitochondrial-ROS-inflammatory signaling, aggregation-proteostasis failure, synaptic-neuroimmune dysfunction, and gut-brain communication. It evaluates various multi-node intervention strategies, including multi-target-directed ligands (MTDLs), molecular hybrids, natural products, drug repurposing, and nanocarrier-based delivery systems. Advances in network pharmacology, artificial intelligence (AI), bioinformatics, and multi-omics have enhanced the identification of actionable therapeutic nodes, candidate compounds, and brain-targeted delivery platforms. Notably, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathways-play distinct roles in neuroinflammation, amplifying neuronal damage by releasing inflammatory cytokines and inducing mitochondrial dysfunction. However, successful translation into clinical practice remains constrained by challenges such as blood-brain barrier penetration, patient heterogeneity, and biomarker limitations. The review advocates for a shift towards mechanism-informed, patient-stratified polypharmacological strategies to better address the network pathology of neurodegeneration, despite significant translational hurdles.
    Keywords:  multi-target drugs; network pharmacology; neurodegeneration; pathway crosstalk; polypharmacology; systems biology
    DOI:  https://doi.org/10.3390/cells15110962
  29. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00025-6. [Epub ahead of print]105 1-39
    Toward non-invasive CNS delivery: The emergence of brain shuttle peptides.
    Macarena Sánchez-Navarro, Benjamí Oller-Salvia.
      The blood-brain barrier (BBB) is a highly specialized interface that preserves neural homeostasis but severely limits the entry of therapeutic agents, posing a major challenge for central nervous system (CNS) drug development. While invasive approaches such as intracerebral injection and focused ultrasound can transiently bypass the barrier, their complexity and safety concerns restrict clinical applicability, particularly in chronic conditions. Non-invasive strategies that exploit endogenous transport mechanisms-carrier-mediated uptake, adsorptive-mediated transcytosis (AMT), and receptor-mediated transcytosis (RMT)-may offer a safer solution. Within this framework, brain shuttles have emerged as molecular vectors designed to cooperate with endothelial biology rather than disrupt it. These include antibodies, proteins, small molecules, and peptides, each with distinct advantages and limitations. Among them, peptides stand out for their versatility, manufacturability, and chemical tunability. Advances in solid-phase synthesis, non-natural modifications, and rational design have enabled peptides to achieve a balance between uptake efficiency and release beyond the endothelium. Their modular nature supports conjugation to diverse payloads, including small molecules, proteins, nucleic acids, and nanoparticles, while maintaining functional integrity. Peptide shuttles also offer broader receptor targeting and compatibility with multiple administration routes, positioning them as a cornerstone of future CNS delivery platforms. This chapter provides a mechanistic overview of the BBB, reviews invasive and non-invasive delivery strategies, and introduces the concept and evolution of brain shuttle peptides. It sets the stage for subsequent discussions on discovery methodologies, chemical optimization, validation models, and translational pathways, highlighting the promise of peptide-enabled systems to transform therapeutic access to the brain.
    Keywords:  blood-brain barrier; brain delivery; brain shuttle peptides; drug delivery
    DOI:  https://doi.org/10.1016/bs.apha.2026.03.001
  30. Muscle Nerve. 2026 Jun 12.
    Optimizing Research Operations and Resource Utilization in ALS Care: Insights From the Tofersen Antisense Oligonucleotide Expanded Access Protocol.
    Alison Wheeler, Kush Mehta, Danica Sanders, Cathy Chin, Hannah Zivalic, Judith Carey, Alexandra McCaffrey, Pravin Pant, Carl Lewenhaupt, Sarah Luppino, Gabriel Jacobs, Shea Golden, Ryan Gifford, Erica Scirocco, Mackenzie Keegan, Munaf Hatem, Taravat Yazdanian, Sanem P Uysal, Natalie Susco, Shauna Schwartzman, Karen Branch, Kathryn E Hall, Joanna Barnas, Jenny Lam, Jennifer Hagar, Carol Ann Hannan, Sabrina Paganoni, James D Berry, Mark Garret, Jennifer Scalia, Suma Babu.
       INTRODUCTION/AIMS: Tofersen is a gene-targeted therapy for individuals with superoxide dismutase 1 (SOD1) (+) amyotrophic lateral sclerosis (ALS). Prior to U.S. Food and Drug Administration (FDA) approval, tofersen was made available through expanded access protocol. This study describes the clinical and operational experience of administering tofersen through expanded access protocols at a single academic medical center in the U.S.
    METHODS: Individuals with symptomatic SOD1(+) ALS (≥ 18 years), who were ineligible for traditional ALS clinical trials, received tofersen via bedside lumbar punctures at Massachusetts General Hospital. Treatment was provided through single-patient and intermediate-sized expanded access protocols prior to FDA approval. Demographic and clinical characteristics, referral-to-treatment timelines, safety outcomes, and operational costs were collected.
    RESULTS: Eleven individuals with SOD1(+) ALS received monthly intrathecal tofersen over a two-year period (July 2021 to July 2023). Most participants were female, and 81.8% had leg-onset ALS. The mean (SD) referral-to-first dose duration was 36 (22.4) days. A total of 120 doses were administered over a two-year period. Tofersen was safe and well tolerated, with no treatment-related serious adverse events. Operational costs totaled $336,620, supported by philanthropy and insurance. The company provided the drug for free.
    DISCUSSION: This experience demonstrates the feasibility of implementing a resource-intensive expanded access protocol within an academic medical center using a mixed funding model to facilitate early access to emerging ALS therapies.
    Keywords:   SOD1 ; amyotrophic lateral sclerosis; expanded access; motor neuron disease; tofersen
    DOI:  https://doi.org/10.1002/mus.70310
  31. Int J Biol Macromol. 2026 Jun 05. pii: S0141-8130(26)02849-7. [Epub ahead of print]370 152922
    Inhibitory effect of silymarin on amyloid formation in ALS-associated hSOD1 P66R mutant.
    Zahra Hosseinpoor, Bagher Seyedalipour, Nasrin Keivan Behjou, Saman Hosseinkhani, Payam Baziyar.
      The aberrant aggregation of human superoxide dismutase 1 (hSOD1) into β-sheet-rich amyloid fibrils is a crucial process in the pathogenesis of amyotrophic lateral sclerosis (ALS), enhancing motor neuron degeneration and disease progression. The P66R mutation in SOD1 destabilizes local structure and promotes β-sheet-driven fibrillation, which makes it a suitable model for exploring approaches for reducing pathogenic aggregation. Here, we evaluate silymarin, a polyphenolic compound with known antioxidant and neuroprotective properties, for its potential to inhibit P66R-hSOD1 aggregation. ThT fluorescence and transmission electron microscopy analyses demonstrate a significant decrease in amyloid fibril formation in the presence of silymarin; in addition, FTIR spectroscopy confirms the suppression of β-sheet formation. Fluorescence quenching and ANS binding assays indicate a moderate-affinity binding between silymarin and the mutant protein, along with a reduction in surface hydrophobicity. Hemolysis assays confirm its protective effect against membrane damage induced by aggregates, while molecular docking and dynamic simulations indicate that silymarin stabilizes aggregation-prone areas with hydrogen bonding and hydrophobic interactions, thereby promoting compact conformations and reducing solvent-exposed surfaces. The findings identified silymarin as an effective anti-amyloidogenic agent that reduces β-sheet accumulation and fibril formation while also decreasing cytotoxicity, highlighting its potential as a therapeutic candidate for ALS.
    Keywords:  ALS; Amyloid inhibition; Loop IV; P66R mutation; Protein aggregation; Silymarin
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152922
  32. Front Immunol. 2026 ;17 1827437
    The tango of immune and neural cells: orchestrating neuroinflammation mediated brain disorders.
    Yimao Wu, Weiqi Lyu, Xiaofei Xie, Xiao Fu, Liao Zhang, Junfu Pan.
      The bidirectional interaction between immune cells and neural cells is the core effector unit of neuroinflammation, determining whether the central nervous system (CNS) maintains homeostasis or develops disease. Under physiological conditions, this interaction supports CNS homeostasis through microglial surveillance, astrocytic metabolic support (including the astrocyte-neuron lactate shuttle and glutamate reuptake), and blood-brain barrier (BBB) integrity. Under pathological states, dysregulated immune-neural crosstalk drives neuroinflammation. Damaged neurons activate microglia and astrocytes, which in turn secrete proinflammatory factors that impair neurons, reduce neurotrophic support, and disrupt BBB integrity. This interaction operates through cell surface receptor-ligand systems and soluble signals. Representative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), depression, and schizophrenia share common inflammatory features such as glial cell activation, BBB damage, and synaptic dysfunction, while exhibiting disease-specific pathological mechanisms. Clinical translation progress has been made in developing biomarkers for diagnosis, targeting immune cells and neural cells for therapy, and exploring emerging interventions like immunometabolic regulation and cell therapy. However, gaps remain in understanding cell type specificity, spatiotemporal dynamics, and achieving precise clinical application. Future interdisciplinary research will further advance the role of immune-neural interaction as a key target for preventing and treating neurological diseases, providing more precise diagnostic and therapeutic strategies.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; clinical translation; immune cell-neural cell interaction; molecular mediators; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1827437
  33. Chin J Nat Med. 2026 Jul;pii: S1875-5364(26)61099-0. [Epub ahead of print]24(7): 769-790
    Battle of the wall for aromatic "orifice-opening" agents: defending and breaching the blood-brain barrier.
    Xiaoman Yang, Jing Zhang, Hao Yu, Yulei Zhao, Guanqun Hou, Shijun Wang, Bingbing Han.
      The brain is the most stringently safeguarded organ in the human body. The 7-mm-thick cranial vault shields the central nervous system (CNS) from external damage, while the blood-brain barrier (BBB) functions as a specific physiological barrier, successfully safeguarding it from circulating toxins and pathogens. BBB disruption is closely linked to the emergence and development of various CNS disorders, and the strong constraints of BBB on substance exchange present a considerable obstacle to medicine administration for the treatment of neurological diseases. Aromatic orifice-opening agents (AOOAs), a specific class of traditional Chinese medicine (TCM), exhibit a unique bidirectional interaction with BBB. Such agents can loosen the BBB junctions, transiently enhance its permeability, and ease the passage of medications into the brain, a phenomenon referred to as the "permeability-promoting" effect on BBB. In contrast, under pathological conditions, AOOAs can preserve BBB integrity and exert a "permeability-restricting" effect by reducing inflammatory responses and alleviating oxidative stress. This review systematically analyzes the regulatory factors affecting BBB permeability, investigates the dual mechanisms by which AOOAs protect and penetrate the BBB, and highlights the innovative opportunities and significant potential these agents present for treating CNS disorders.
    Keywords:  Aromatic “orifice-opening” agents; Blood-brain barrier; Central nervous system
    DOI:  https://doi.org/10.1016/S1875-5364(26)61099-0
  34. Cell Signal. 2026 Jun 06. pii: S0898-6568(26)00309-8. [Epub ahead of print]146 112654
    Phosphodiesterase 8 (PDE8), a novel target for neurodegenerative diseases.
    Xuan Zhao, Yi-Ting Fu, Nian-Zhuang Qiu, Yu-Xuan Pan, Han-Ting Zhang, Hao Wang.
      Phosphodiesterases (PDEs) constitute a superfamily of enzymes comprising 11 distinct families that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), thereby precisely regulating the spatiotemporal dynamics of intracellular cyclic nucleotides. Among these PDEs, PDE8 is distinguished by its high affinity and specificity for cAMP and exerts diverse biological effects. The PDE8 family comprises two genes, Pde8a and Pde8b, which are widely distributed throughout the brain and are expressed in both neuronal and glial cells. The widespread distribution of PDE8 in the brain suggests its involvement in roles of the central nervous system (CNS). In this context, dysregulation of PDE8 has been implicated in the pathogenesis of several CNS diseases, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This review aimed to enhance the understanding of the role of PDE8 in the mechanisms underlying neurodegenerative diseases, while providing a theoretical foundation and potential avenues for developing novel therapeutic strategies.
    Keywords:  Alzheimer's disease; Cyclic adenosine monophosphate (cAMP); Inflammation; Neurodegenerative diseases; Phosphodiesterase 8 (PDE8)
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112654
  35. J Alzheimers Dis. 2026 Jun 12. 13872877261456324
    A mechanistic framework linking the oral microbiome to Alzheimer's disease through neuroinflammation.
    Manon J A P Evers, Bastiaan P Krom, Caroline A de Jongh.
      Alzheimer's disease (AD) is a growing problem in our society and the most common form of dementia. This neurodegenerative disease is characterized by neuroinflammation and the accumulation of amyloid-β (Aβ) and tau. Previous studies have found associations between the oral microbiome and AD. This review aims to elucidate the role of the oral microbiome in AD, through neuroinflammation, and reviews the relationship between AD and bacteria and fungi. Studies have found bacteria (e.g., Porphyromonas gingivalis) and fungi (e.g., Candida albicans) in postmortem AD brains. Moreover, mice models have shown that oral microbes are able to cross the blood-brain barrier (BBB), and were correlated with activated microglia, neuroinflammation, and Aβ load. This review introduces a mechanistic framework that describes how oral microbes cause an inflammatory response resulting in AD pathology. Specifically, oral dysbiosis causes oral pathogens to disseminate into the bloodstream, this triggers an inflammatory response, subsequently activating microglia, ultimately resulting in AD pathology. This process can follow two pathways: First, there is a direct response of the immune system in the brain to oral pathogens that migrate through the bloodstream and cross the BBB, which causes neuroinflammation and activates microglia, leading to AD pathology. Second, an early-life systemic inflammation causes microglia to get into a "hyperactive" state, in which they respond in an exaggerated way to normal stimuli triggering immune responses throughout a person's life that result in AD pathology. This mechanistic framework provides new line of thought for future research on the question of causality of AD.
    Keywords:  Alzheimer's disease; bacteria/microbiome/microbiota; microglia; neuroinflammation; periodontal disease
    DOI:  https://doi.org/10.1177/13872877261456324
  36. Pharmacol Res Perspect. 2026 Jun;14(3): e70280
    The Use of Statins in Parkinson's and Alzheimer's Disease: A 2021-2025 State-of-the-Art Review of Clinical and Preclinical Evidence.
    Luigi Maria Chiatto, Lucia Buccarello, Giuseppe Carota, Rocco Salvatore Calabrò, Carmela Rifici, Emanuela Esposito, Alessio Ardizzone, Giuseppe Caruso.
      Statins, widely prescribed for cardiovascular prevention, have emerged as potential disease-modifying agents in neurodegenerative disorders due to their pleiotropic effects on cholesterol metabolism, neuroinflammation, oxidative stress, and protein aggregation. Over the past decade, growing interest has focused on the potential repurposing of statins for Parkinson's disease (PD) and Alzheimer's disease (AD); however, clinical evidence remains heterogeneous and, in some cases, contradictory. This state-of-the-art review synthesizes clinical and preclinical studies published between 2021 and 2025 to critically evaluate the therapeutic potential and limitations of statins in PD and AD. Recent observational studies and large-scale cohort analyses suggest that long-term statin use may be associated with a reduced risk of incident PD and AD, as well as slower cognitive decline in selected patients' subgroups. However, these associations appear to depend on factors such as statin lipophilicity, treatment duration, and genetic background. Preclinical models provide mechanistic support, showing that statins can attenuate neuroinflammation, modulate microglial activation, reduce α-synuclein aggregation in PD models, and interfere with amyloid-β production and tau phosphorylation in AD models. Nevertheless, randomized controlled trials remain limited in number and often underpowered, and some reports indicate neutral or even adverse neurological outcomes, underscoring the complexity of cholesterol-dependent and cholesterol-independent mechanisms in the central nervous system (CNS). Collectively, the evidence from 2021 to 2025 highlights both the therapeutic promise and the unresolved challenges of statin repurposing in neurodegenerative diseases. Future research should prioritize well-designed clinical trials and biomarker-driven patient stratification to determine whether statins can be effectively leveraged as adjunctive disease-modifying therapies in PD and AD.
    Keywords:  Alzheimer's disease; Parkinson's disease; disease‐modifying therapies; drug repurposing; neurodegeneration; neuroinflammation; neuroprotection; statins
    DOI:  https://doi.org/10.1002/prp2.70280
  37. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00019-0. [Epub ahead of print]105 99-131
    Brain shuttle peptides: From permeability assay toolbox to data-driven discovery.
    Nikolina Mohović, Marko Njirjak, Ena Dražić, Patrizia Janković Bevandić, Daniela Kalafatovic.
      The blood-brain barrier (BBB) is a highly selective transport interface that protects the central nervous system (CNS), but its complex cellular and molecular architecture presents a major challenge for drug delivery to the brain. Peptides have emerged as promising brain shuttles due to their selectivity, ease of synthesis, and ability to engage endogenous transport mechanisms such as receptor- or adsorptive-mediated transcytosis. We provide an overview of in vitro and in vivo models, ranging from artificial membranes, dynamic BBB-on-a-chip systems and mass-based quantification techniques to brain perfusion and molecular imaging. Particular emphasis is placed on how these approaches are selected and combined to assess BBB permeability, transport mechanisms, and brain distribution of peptide shuttles. Recently, machine learning methods have been increasingly used to identify peptide sequences with BBB-crossing potential. By highlighting recent examples and key methodological considerations, this chapter aims to guide researchers in selecting appropriate tools and strategies for studying peptide transport across the BBB.
    Keywords:  BBB assays; Blood-brain barrier; Brain shuttle peptides; Datasets; Machine learning
    DOI:  https://doi.org/10.1016/bs.apha.2026.02.002
  38. Clin Neuroradiol. 2026 Jun 08.
    Clinical Research for the Use of 7 T Magnetic Resonance Imaging for Spinal Pathologies: a Scoping Review.
    Nathan Nguyen, Alexa R Lauinger, Anant Naik, Robert Liu, Yagiz Yolcu, Paul M Arnold.
       PURPOSE: Magnetic resonance imaging (MRI) at 7 T (7T) offers higher signal-to-noise ratio and improved spatial resolution compared to lower magnetic field strengths such as 1.5T and 3T, which may improve lesion detection and anatomical visualization for spinal cord pathology. This review summarizes current techniques and achievements in 7T spinal imaging and outlines associated technical barriers and future directions.
    METHODS: A scoping review in accordance with PRISMA extension for scoping reviews guidelines was performed utilizing PubMed, Scopus, and Web of Science. Only studies related to 7T MRI of human subjects were included, after removing unrelated studies and those of non-human subjects.
    RESULTS: Twenty-nine studies were included. Current literature supports 7T's superior resolution and signal-to-noise ratio in comparison to 1.5T and 3T MRI. These studies reported improved lesion detection and staging in multiple sclerosis (MS), spinal cord injury (SCI), and amyotrophic lateral sclerosis (ALS); however, the implications of results are limited by small sample sizes, technical heterogeneity, and inconsistent outcome measures. Additionally, the use of 7T spinal imaging remains limited by radiofrequency coil design, susceptibility artifacts, physiological noise, lack of FDA-clearance for spinal indications, and an absence of standardized imaging protocols. Future research aims to address these limitations.
    CONCLUSION: Spinal cord imaging at 7T is challenging due to technical constraints and higher susceptibility to artifacts as a result of physiological noise (respiration, swallowing, and bulk movement). However, early studies' results using 7T imaging support improved ability, compared to 3T, to provide enhanced visualization of fine anatomical structures, such as nerve roots, and to improve spinal cord lesion detection.
    Keywords:  7‑tesla; Magnetic resonance imaging; Neurology; Neurosurgery; Safety; Ultra-high field imaging
    DOI:  https://doi.org/10.1007/s00062-026-01669-x
  39. J Neuroinflammation. 2026 Jun 12.
    Circadian gatekeepers of the gut-brain-immune axis: implications for neuroinflammation and neurodegeneration.
    Wai-Yin Cheng, Po-Lam Chan, Man-Ka Chan, Jiaying Xu, Ka-Hing Wong, Raymond Chuen-Chung Chang.
      Circadian rhythms, primarily regulated by light-dark cycles, play a crucial role in maintaining physiological health, including metabolism and immune responses. Evidence shows that circadian rhythms are involved in modulating gut microbiota composition, peripheral and central immune systems, and neurodegenerative disease progression. Recent research has illuminated the complex interplay between circadian rhythms and the gut microbiota-immune-brain axis. This review examines the bidirectional relationship between circadian rhythms and gut microbiota, and explores how this interaction influences brain function through the gut-brain axis, with particular focus on neuroinflammation and neurodegeneration. We aim to provide novel insights that could inform therapeutic strategies to prevent or slow down the progression of neurodegenerative diseases through circadian rhythm modulation.
    Keywords:  Diurnal rhythms; Microglia; Neuroimmune responses; Prebiotics; Systemic inflammation
    DOI:  https://doi.org/10.1186/s12974-026-03899-9
  40. Front Neurol. 2026 ;17 1843630
    Safety evaluation of Tofersen in amyotrophic lateral sclerosis based on the FAERS database.
    Xuefeng Xiao, Gang Hao, Ping Wan, Wenzhuang Hou.
       Background: This study utilizes data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) to conduct a post-marketing safety evaluation of Tofersen.
    Methods: A systematic search of the FAERS database was performed to identify adverse event (AE) reports from Q1 2023 to Q4 2025 was performed. Multi-dimensional disproportionality analyses were conducted using the ROR, PRR, BCPNN, and MGPS method.
    Results: A total of 409 Tofersen-related reports were identified, revealing significant signals across 22 System Organ Class (SOC) categories and 369 Preferred Terms (PTs). At the SOC level, the most prominent safety signals were observed in injury, poisoning and procedural complications, nervous system disorders, and musculoskeletal and connective tissue disorders. In contrast, ear and labyrinth disorders, as well as respiratory, thoracic and mediastinal disorders, were not listed in the current product labeling and may warrant further investigation. At the PT level, neurological procedural complication, CSF red blood cell count positive, CSF white blood cell count increased, and CSF cell count increased exhibited the strongest signals, primarily reflecting cerebrospinal fluid cytological and biochemical abnormalities, as well as procedural-related adverse events such as post-lumbar puncture syndrome, procedural pain, and procedural headache. Although central nervous system-related events (e.g., increased intracranial pressure, peroneal nerve palsy, papilloedema, and facial paralysis) and infectious or inflammatory events (e.g., radiculopathy, myelitis, aspiration pneumonia, and meningitis) were less frequently reported, their relatively high disproportionality signals warrant clinical attention and systematic monitoring. Notably, a newly identified signal of pulmonary embolism suggests a potential thromboembolic risk in specific patient populations.
    Conclusion: These findings provide real-world evidence to inform the balance between the therapeutic potential and safety profile of Tofersen. Future clinical strategies should focus on mitigating central nervous system-related and procedure-related adverse events. Further mechanistic studies are crucial.
    Keywords:  FAERS; Tofersen; adverse events; amyotrophic lateral sclerosis; data mining
    DOI:  https://doi.org/10.3389/fneur.2026.1843630
  41. Front Pharmacol. 2026 ;17 1844585
    Luteolin and neuroinflammation: a multi-target therapeutic strategy for central nervous system disorders.
    Jianting Huang, Miaomiao Yu, Yanan Zou, Lezhen Wang, Yuan Ma, Yue Ma, Xiangyi Kong, Fei Rong.
      Neuroinflammation is a fundamental pathological hallmark driving the initiation and progression of various neurological disorders. Luteolin, a natural flavonoid abundant in medicinal plants, fruits, and vegetables, exerts multifaceted neuroprotective effects across diverse experimental disease models. Its beneficial activities are mediated through complementary mechanisms, including suppression of aberrant microglial activation, modulation of pro-inflammatory signaling pathways, and enhancement of endogenous antioxidant defenses. These integrated actions attenuate inflammatory mediator release, reduce oxidative stress-induced neuronal damage, and inhibit apoptosis, thereby counteracting neuroinflammation-driven pathology. This review synthesizes current knowledge on luteolin's protective roles in central nervous system (CNS) disorders. It elucidates underlying molecular mechanisms, encompassing regulation of key signaling cascades such as NF-κB, MAPK, and Nrf2, as well as its impact on cellular processes including autophagy and mitochondrial function. Critical challenges hindering clinical translation-notably limited oral bioavailability and restricted blood-brain barrier (BBB) permeability-are systematically discussed to guide future research. A comprehensive understanding of luteolin's pleiotropic pharmacological actions will not only enhance knowledge of its therapeutic potential but may also facilitate the development of novel preventive and therapeutic strategies for neuroinflammatory and neurodegenerative diseases.
    Keywords:  blood–brain barrier; luteolin; neuroinflammation; neurological disorders; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphar.2026.1844585
  42. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00024-4. [Epub ahead of print]105 415-456
    Physiological strategies for brain delivery.
    Daniel Gonzalez-Carter.
      The blood-brain barrier (BBB) remains an obstacle to treat neurological diseases, prompting the development of delivery strategies to target therapies to the brain. Receptor-mediated transport has become a major focus of research efforts aiming to exploit innate transport mechanisms. The last decade has seen important innovations ranging from ligand-modified nanocarriers to engineered biologics that harness trafficking pathways. However, such developments have demonstrated brain delivery requires a nuanced engagement of target proteins to ensure efficient internalization and intracellular trafficking. Therefore, much remains to be understood of BBB transport mechanisms to ensure maximal brain delivery of therapeutics. Furthermore, accumulating evidence indicates cell-membrane targets do not necessarily require an innate biological transport function to promote transport across the BBB. These observations open the possibility of expanding our target repertoire beyond transport-related proteins. Novel targets may therefore include structural or signalling proteins which have a more favourable brain-to-periphery expression ratio. In addition, they may include non-protein components of the cell membrane, for instance the glycocalyx covering endothelial surfaces. Such novel targets would therefore allow us to harness more fully the phenotypic specialization of brain endothelial cells. In addition, recent years have witnessed the development of targeting strategies harnessing not only structural differences of brain endothelial cells, but in addition take advantage of the dynamic control of BBB specialization. As such, advances have been made to exploit cell-membrane dynamics; haemodynamic response; vascular segmentation; or pathological modulation. The field of brain delivery is therefore advancing towards exploiting the highly unique physiology of the BBB to achieve a more dynamic approach to BBB targeting and maximize transport into the brain.
    Keywords:  Blood-brain barrier; Cell-membrane targets; Glycocalyx; Intracellular trafficking; Therapeutic carriers; Therapeutic vehicles; Transcytosis; Transport proteins
    DOI:  https://doi.org/10.1016/bs.apha.2026.02.007
  43. Front Aging Neurosci. 2026 ;18 1838306
    Treg-microglia crosstalk in Alzheimer's disease: stage-dependent dynamics, molecular mechanisms, and translational challenge.
    Hua Fu, Jing Yang, Miao Zhang.
      Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) deposition, tau hyperphosphorylation, and chronic neuroinflammation. Emerging evidence from preclinical models suggests that aberrant immune crosstalk between regulatory T cells (Tregs) and microglia may contribute to disease progression, though its precise role in human AD remains to be fully elucidated. In rodent models, Tregs have been shown to cross the blood-brain barrier and, through cell-contact-dependent mechanisms and secretion of pro-resolutive factors such as transforming growth factor-β, appear to promote microglial transitions toward pro-resolutive states and facilitate Aβ phagocytosis. However, these mechanisms have been predominantly demonstrated in transgenic mouse strains with early-onset amyloid pathology, and their relevance to the slow, aging-associated progression of human sporadic AD requires cautious interpretation. In AD animal models, reductions in Treg numbers and suppressive function coincide with microglial dysregulation, with the interaction between these cell types shifting from homeostatic to pro-inflammatory states as pathology advances. It is critical to note that while such findings suggest a potential regulatory axis, they derive largely from simplified animal systems that do not fully recapitulate human immune aging, genetic heterogeneity, or decades-long disease kinetics. Moreover, therapeutic strategies targeting this crosstalk that show efficacy in mice have yielded inconsistent results in early human trials, highlighting significant translational gaps. This review critically assesses the current preclinical evidence, emphasizing that findings from rodent models should be interpreted as hypothesis-generating rather than definitive proof of mechanism in human disease. We underscore the urgent need for validation through human tissue analysis, cerebrospinal fluid biomarkers, and advanced humanized model systems before Treg-microglia interactions can be established as robust therapeutic targets for AD.
    Keywords:  Alzheimer’s disease; immune regulation; microglia; neuroinflammation; regulatory T cells
    DOI:  https://doi.org/10.3389/fnagi.2026.1838306
  44. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00002-5. [Epub ahead of print]105 41-82
    Brain shuttle peptides derived from natural proteins.
    Andrej Nikolić, Toni Todorovski.
      Blood-brain barrier (BBB) is the primary physiological barrier that regulates the movement of substances between the systemic circulation and the brain. Its unique structure, based on specialized endothelial cells, allows tight regulation of central nervous system (CNS) homeostasis and at the same time is the main hurdle in the modern medicine to treat neurological conditions. Many promising in vitro drugs become ineffective in vivo due to BBB restrictive permeability. However, in the last two decades, a variety of molecules, mainly peptide-based and named brain shuttle peptides, were able to ferry various payloads (small molecules, proteins, antibodies etc.) into the brain. Therefore, these shuttles could become key future therapeutics to fight various CNS conditions. Brain shuttle peptides are part of a larger family of cell-penetrating peptides (CPPs) that utilize different modes of membrane transport with predominance of adsorptive-mediated transcytosis (AMT) and receptor-mediated transcytosis (RMT). The discovery and development process of new brain shuttle peptides is mainly guided by using rational design and bioinformatics approaches focusing mostly on proteins from natural sources (viruses, amphibians, reptiles and mammals). In the last years, the virus- and mammal-derived brain shuttle peptides have been gaining increased attention due to their superb translocation capacity, low immunogenicity and toxicity, good stability and ease of preparation. Here, we will focus on the most prominent brain shuttle peptides of viral and animal origin with documented BBB crossing capabilities, discussing their mechanisms of translocation and therapeutic applications. Notably, the two brain shuttle peptides that have successfully progressed to clinical trials thus far originate from a viral source (TAT) and a mammalian source (Angiopep-2).
    Keywords:  Blood-brain barrier; Natural proteins; Peptide shuttles; Rational design; Viruses
    DOI:  https://doi.org/10.1016/bs.apha.2026.01.002
  45. Neurochem Int. 2026 Jun 10. pii: S0197-0186(26)00091-4. [Epub ahead of print] 106200
    Complement System-Mediated Immunomodulation in Epilepsy: From Pathogenesis to Therapeutic Opportunities.
    Linqian Peng, Mengxuan Lu, Mingyue Chen, Rongchuan Liu, Shuang Xia, Guohe Tan.
      Epilepsy is a prevalent neurological disorder characterized by recurrent seizures and aberrant neuronal hyperexcitability. Although several antiseizure medications are clinically available, current treatments are primarily symptomatic and fail to prevent epileptogenesis or disease progression. Moreover, nearly one-third of patients develop resistance to these drugs. The absence of effective disease-modifying therapies underscores the urgent need to identify novel pathogenic mechanisms and therapeutic targets. As a core component of innate immunity, the complement system has recently emerged as a key regulator of injury and repair processes in the central nervous system. Accumulating preclinical evidence indicates that abnormal complement activation contributes to epileptogenesis. This suggests that complement dysregulation is not merely an epiphenomenon of neuroinflammation but rather a potential driver of seizure development and progression. However, clinical evidence remains limited and heterogeneous, and has not yet been systematically integrated. This review summarizes current preclinical and clinical evidence on complement-mediated mechanisms in epilepsy, with a focus on neuroinflammation, synaptic remodeling, glial proliferation, biomarkers, and therapeutic targets. It also discusses the challenges and opportunities associated with developing complement-based disease-modifying strategies for epilepsy.
    Keywords:  Complement system; Epilepsy; Glial cell; Immunomodulation; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.neuint.2026.106200
  46. Mol Neurobiol. 2026 Jun 10. pii: 686. [Epub ahead of print]63(1):
    CRISPR-Based Gene Therapy for Brain Disease.
    Fatemeh Khajouei, Asma Ghaemi, Khalil Abnous, Seyed Mohammad Taghdisi, Mohammad Ramezani, Mona Alibolandi.
      Neurological disorders are complex and often very challenging for patients. Many of these conditions result from mutations in genes that are essential for normal function. Most existing treatments only alleviate symptoms, highlighting the urgent need for more effective therapeutic strategies. In the current drug development landscape, gene therapy offers hope as a promising approach. Specifically, CRISPR-Cas9 technology enables precise gene editing across diverse cell types and organisms. An increasing number of research groups are investigating innovative therapies and the molecular mechanisms behind neurological diseases. This review highlights the use of CRISPR-based gene therapies for various brain diseases, including multiple sclerosis, Alzheimer's, Parkinson's disease, epilepsy, stroke, and brain tumors. It consistently recognizes significant challenges in clinical applications, including overcoming the blood-brain barrier (BBB), managing off-target effects, ensuring efficient delivery, and addressing immunogenicity and ethical concerns.
    Keywords:  CRISPR-Cas9; Gene editing; Neurodegenerative disorders; Neurological disorders
    DOI:  https://doi.org/10.1007/s12035-026-05966-x
  47. Neurodegener Dis Manag. 2026 Jun 12. 1-10
    Association between influenza infection and subsequent Parkinson's disease diagnosis: a systematic review and meta-analysis.
    Alice Halim, Shin Jie Yong, Anood A Alenezy, Maha A Aljumaa, Zainab H Almansour, Hayam A Alrasheed, Ali Hazazi, Nawal A Al Kaabi, Ali A Zaidan, Mashahed Y Almoutawa, Nada N Alshehri, Jumana M Al-Jishi, Mohammed S Almogbel, Rana Abdulrahim Ali Alaeq, Ali A Rabaan.
       INTRODUCTION: As infectious agents may be associated with neurodegenerative diseases, this systematic review and meta-analysis investigated whether prior influenza infection is associated with an increased odds of subsequent Parkinson's disease (PD) diagnosis.
    METHODS: We searched PubMed, Web of Science, and Scopus for observational studies examining influenza infection and later PD diagnosis. Seven studies (comprising eight cohorts) were analyzed using frequentist and Bayesian random-effects meta-analyses. Meta-regression and subgroup analyses were conducted to explore the moderating effect of the time interval between influenza exposure and subsequent PD diagnosis (i.e. exposure window).
    RESULTS: A significant association was observed in both approaches: pooled OR = 1.87 (95% CI: 1.24-2.81) under the frequentist model, and posterior median OR = 1.88 (95% CrI: 1.07-3.36) under the Bayesian model. Meta-regression and subgroup analyses identified the influenza exposure window as a moderator (R2 = 36.6%, p < 0.05), with studies reporting influenza exposure within five years before PD diagnosis showing the strongest associations.
    CONCLUSION: Our findings support a probable and temporally sensitive association between influenza infection and subsequent PD diagnosis. However, these findings should be interpreted cautiously, given the retrospective and heterogeneous nature of the available data.
    Keywords:  Bayesian meta-analysis; Parkinson’s disease; epidemiology; influenza virus; meta-regression; neurodegenerative disease; neuroscience
    DOI:  https://doi.org/10.1080/17582024.2026.2687479
  48. Front Neurosci. 2026 ;20 1815976
    The triple-hit hypothesis of Alzheimer's disease: blood-brain barrier breakdown, infection, and neuroimmune activation as a unified etiological framework.
    Gregor Majdic.
      Studies of Alzheimer's disease (AD) have long been dominated by the amyloid cascade hypothesis, although mounting evidence suggests that amyloid-β (Aβ) deposition might be a late downstream event, rather than the initiating trigger of AD. Here, I propose a unifying Triple-Hit Hypothesis in which AD develops through a sequential interaction among three causative processes that have been individually implicated before in the onset of Alzheimer's disease: (1) early blood-brain barrier (BBB) breakdown, (2) entry or reactivation of microbial agents within the brain, and (3) maladaptive innate immune responses that produce chronic neuroinflammation and Aβ accumulation. Converging data from human imaging, neuropathology, infectious disease studies, genetics, and vascular medicine could suggest that these three processes, which were in some previous studies linked to AD, might not be independent but rather that their temporal synergy could drive disease progression. This new conceptual framework integrates long-standing but fragmented lines of evidence and, if confirmed by experimental studies, offers the possibility for the development of new diagnostic biomarkers, new therapeutic entry points, and prevention strategies for AD. I argue that understanding AD as a disorder of the blood-brain barrier, immunity, and host-pathogen interactions should be taken into account in future research on the etiology and clinical progression of AD.
    Keywords:  Alzheimer’s disease; amyloid beta; blood–brain barrier; brain; neuroinflammation
    DOI:  https://doi.org/10.3389/fnins.2026.1815976
  49. J Headache Pain. 2026 Jun 10.
    Blood-brain barrier integrity and brain entropy in reversible cerebral vasoconstriction syndrome.
    Chia-Hung Wu, Tun-Wei Hsu, Yu-Hsiang Ling, Yen-Feng Wang, Chien-Yuan Lin, Chia-Wei Lee, Jiing-Feng Lirng, Shuu-Jiun Wang, Shih-Pin Chen.
       BACKGROUND: Elucidating functional brain dynamics under different blood-brain barrier (BBB) permeabilities may resolve the enigmatic pathophysiology of reversible cerebral vasoconstriction (RCVS); however, relevant investigations are lacking. We aimed determine the relationship between brain functional dynamics and BBB permeability in patients with RCVS.
    METHODS: We prospectively recruited RCVS patients and healthy controls (HCs) from November 2016 to January 2023 in Headache Center in a tertiary medical center (> 3000 beds) and adjacent communities. RCVS patients who were diagnosed according to the International Headache Society criteria, and age- and sex-matched HCs were enrolled. Normalized entropy, derived from resting-state fMRI (rs-fMRI), was compared at the network and parcel levels between RCVS patients with and without BBB disruption. Dynamic contrast-enhanced MRI (DCE-MRI)-derived Ktrans BBB permeability and ultrasonographic findings were analyzed.
    RESULTS: In total, 188 subjects (100 RCVS + 88 HCs) were enrolled. Compared with the HCs, the RCVS patients had greater entropy (p = 0.014), which was greater in the RCVS patients without than in those with (adjusted p = 0.040) BBB disruption. Compared with HCs, patients without BBB disruption had greater entropy between 60 and 90 days after headache onset (adjusted p = 0.006). No significant differences in entropy were noted between disease stages in BBB-disrupted patients. Parcels within subnetworks of the Default mode network (Default A and C) exhibited higher entropy in patients without BBB disruption. In specific anatomical locations, entropy values were negatively correlated with ultrasonographic Lindegaard index vasoconstriction severity (p = 4.3 × 10- 6; within the Default A network) and DCE-MRI Ktrans BBB permeability (p = 0.005; within the Default C network).
    CONCLUSION: The differential changes in normalized entropy suggest that increased rs-fMRI signal complexity may reflect a compensatory functional response to abrupt vasoconstriction. In contrast, the loss of entropy fluctuations in the context of severe BBB disruption indicates a state of impaired cerebral autoregulation in patients with RCVS. The compensatory capacity decreased as vasoconstriction or BBB disruption exacerbated.
    Keywords:  Blood–brain barrier (BBB); Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI); Reversible cerebral vasoconstriction syndrome (RCVS); Transcranial color-coded sonography (TCCS); resting-state functional magnetic resonance imaging (rs-fMRI)
    DOI:  https://doi.org/10.1186/s10194-026-02409-9
  50. Front Neurol. 2026 ;17 1820238
    Neurofilament light chain reflects motor impairment in myotonic dystrophy type 1.
    Chul Hwi Shin, Incheol Seo, Ye-Ri Kim, Jin-Mo Park, Jin-Sung Park.
       Introduction: Myotonic dystrophy type 1 (DM1) is a genetic disorder caused by CTG trinucleotide repeat expansion in the dystrophia myotonica-protein kinase (DMPK) gene and is characterized by progressive muscle weakness with multisystemic involvement, including the central nervous system (CNS). Neurofilament light chain (NfL) has emerged as a biomarker of neuroaxonal damage in various neurological conditions. This study aimed to evaluate plasma NfL as a biomarker of disease severity by examining its association with motor function in ambulatory patients with DM1.
    Methods: Thirty-three DM1 patients and 31 controls were enrolled. Plasma NfL levels were measured, and clinical variables including age, sex, age at onset, and disease duration were collected. Motor function was assessed using the Muscular Impairment Rating Scale (MIRS) and the 6-min walk test (6MWT). Associations between NfL levels and clinical measures were analyzed using partial correlation based on Kendall's Tau with adjustment for age.
    Results: Age-adjusted analyses demonstrated a significant positive correlation between NfL levels and MIRS scores (τ = 0.387, p = 0.002) and a significant negative correlation with 6MWT performance (τ = -0.344, p = 0.014). Disease duration was also positively associated with age-adjusted NfL levels (τ = 0.334, p = 0.007). Although NfL levels showed a negative correlation with peroneal CMAP amplitudes, this association was not significant after age adjustment.
    Conclusion: Plasma NfL levels were associated with disease duration and motor function severity in DM1. These findings suggest that NfL may serve as a biomarker reflecting not only neuroaxonal damage but also motor impairment in DM1. Larger longitudinal studies are warranted to validate these findings.
    Keywords:  biomarkers; motor impairment; muscular impairment rating scale; myotonic dystrophy type 1; neurofilament light chain
    DOI:  https://doi.org/10.3389/fneur.2026.1820238
  51. Neurochem Int. 2026 Jun 10. pii: S0197-0186(26)00092-6. [Epub ahead of print]198 106201
    Adaptive immune signals shape neural circuit development through CNS Border-Glia pathways.
    Xing Wei, Fuxian Liu, Zhenggang Shi.
      The central nervous system (CNS) has long been considered a relatively immune-privileged site. However, accumulating evidence indicates that CNS border structures, including the meninges, choroid plexus, blood-brain barrier (BBB), and perivascular spaces, are not merely passive barriers but dynamic immune interfaces that enable regulated communication between the peripheral immune system and the brain microenvironment. This review discusses how adaptive immune signals are filtered, integrated, and translated at CNS borders during critical developmental windows, and how these signals subsequently influence neural circuit development through microglia and astrocytes. Meningeal-resident T cells, B cells, plasma cells, and related innate-like lymphocytes can establish cytokine milieus characterized by IL-4, IL-17 A, IFN-γ, and other immune mediators within border niches. Once sensed by glial cells, these signals can regulate complement-dependent synaptic pruning, receptor-mediated phagocytosis, astrocyte-derived synaptic homeostatic factors, and excitatory/inhibitory (E/I) balance. Because glial cells exhibit marked heterogeneity across brain regions and developmental stages, the same immune bias may produce time-window-dependent and region-specific neurodevelopmental consequences. These processes do not usually determine the onset of a specific disease directly; rather, they reshape developmental trajectories of neural circuits and thereby alter susceptibility to neurodevelopmental and neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ). Overall, this review highlights glial cells as pivotal cellular hubs linking adaptive immunity, CNS border microenvironments, and neural circuit development, and provides a mechanistic framework for understanding neuroimmune interactions and their translational relevance.
    Keywords:  Adaptive immunity; Astrocytes; CNS borders; Cytokine bias; Disease susceptibility; Microglia; Neural circuit development
    DOI:  https://doi.org/10.1016/j.neuint.2026.106201
  52. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00020-7. [Epub ahead of print]105 133-170
    Chemically enhanced brain shuttle peptides.
    Cristina Díaz-Perlas.
      The blood-brain barrier (BBB) constitutes a major impediment to central nervous system pharmacotherapy due to its highly selective permeability and enzymatic defense mechanisms. Brain shuttle peptides have emerged as a promising modality for overcoming this barrier, primarily via receptor-mediated transcytosis. To enhance their pharmacokinetic properties and transcytosis efficiency, several structural and chemical optimization strategies have been employed. Cyclization and retro-enantio modifications confer proteolytic resistance while preserving receptor affinity, as demonstrated by engineered peptides such as retro-D-THR, retro-D-T7, and BB4. Venom-derived scaffolds, including MiniAp-4 and MiniCTX3, further exemplify the potential of naturally occurring peptides for BBB penetration. Multivalent presentation, achieved through branched architectures or nanoparticle surface functionalization, significantly increases avidity and cellular uptake, thereby improving transcytosis. Dual-ligand systems, such as THR-TAT conjugates, have shown synergistic effects in glioma models, enhancing both BBB crossing and tumor targeting. While PEGylation is widely utilized in drug delivery to prolong circulation and reduce immunogenicity, its application in brain shuttle systems remains limited due to potential interference with receptor-mediated uptake. Collectively, these advances underscore the versatility of protease-resssistant brain shuttle peptides as targeted delivery vehicles for CNS therapeutics and provide a strong foundation for their translation into clinical applications.
    Keywords:  Blood-brain barrier (BBB); Brain shuttle peptides; Central nervous system (CNS); Cyclic peptides; Multivalency; Receptor-mediated transcytosis (RMT); Retro-enantio peptides; Targeted CNS drug delivery
    DOI:  https://doi.org/10.1016/bs.apha.2026.02.003
  53. Toxicol In Vitro. 2026 Jun 12. pii: S0887-2333(26)00078-0. [Epub ahead of print] 106270
    Preclinical in vitro evaluation of a new nasal formulation combining xylometazoline and hyaluronic acid: Permeability and penetration analysis using an advanced characterized human nasal model.
    Larisa Tratnjek, Laura Simic, Urška Dragin Jerman, Ivan Sušanj, Karina Vukelic, Slavko Kralj, Zdravka Knezevic, Mateja Erdani Kreft.
      A new nasal formulation combining xylometazoline, a well-established nasal decongestant, and hyaluronic acid (HA) at a 3 mg/ml concentration and low-molecular-weight has been developed as a topical product intended for use in viral acute rhinosinusitis, with the aim of relieving nasal congestion and supporting epithelial integrity. HA, a moisturizing component of respiratory secretions, has been shown to promote epithelial integrity, stimulate mucociliary clearance and support wound healing. As part of the drug development process, this study investigated the permeation and penetration properties of xylometazoline, and HA in the new formulation using a human nasal epithelium in vitro model. Results were compared to those of a xylometazoline mono-formulation and a well-established fixed-dose combination of xylometazoline and dexpanthenol. Morphological, ultrastructural and physiological analyses were performed to test nasal cells tolerability on prolonged drug exposure (6 h). HA in this new nasal formulation seems to be a component that exerts its effect mainly on the mucosal surface, which is the favoured site of action for topical products. HA was not detected in the basolateral compartment, consistent with retention at the mucosal surface. The results of our preclinical study do not indicate that the safety profile of xylometazoline would be altered by the addition of HA (or dexpanthenol). The barrier integrity of the in vitro human nasal epithelium was preserved across all tested formulations Nanoparticle endocytosis was absent. These findings, obtained in a healthy in vitro nasal epithelial model, provide a valuable foundation for subsequent evaluation of this formulation in human clinical studies.
    Keywords:  Acute rhinosinusitis; Cytotoxicity; Light and electron microscopy; Nanoparticles; Nasal drug formulations; Nasal in vitro model
    DOI:  https://doi.org/10.1016/j.tiv.2026.106270
  54. Behav Brain Res. 2026 Jun 07. pii: S0166-4328(26)00295-0. [Epub ahead of print]513 116319
    Natural monomer compounds in neurodegenerative diseases: Targeting ferroptosis and neuroinflammation.
    Kexin Zhang, Silin Kong, Yujie Ma, Chengxia Kan, Tianpeng Zheng, Xiaodong Sun.
      Neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss driven by oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Ferroptosis, an iron-dependent and lipid peroxidation-associated form of regulated cell death, has recently been identified as a key contributor to neuronal vulnerability. Emerging evidence demonstrates that purified natural monomer compounds derived from medicinal plants exert potent neuroprotective effects by targeting ferroptosis and neuroinflammatory pathways. Representative agents such as curcumin, baicalin, resveratrol, and ginsenoside Rg1 activate nuclear factor E2-related factor-2 and glutathione peroxidase 4 signaling to preserve redox balance, while suppressing microglia-mediated inflammation through inhibition of toll-like receptor 4 pathways. This review highlights the interplay between ferroptosis and neuroinflammation in NDDs, summarizes the regulatory effects of bioactive herbal monomer compounds, and discusses recent advances in multi-omics profiling, nano-delivery strategies, and translational research. By modulating the ferroptosis-neuroinflammation axis, these compounds may represent promising therapeutic candidates for NDDs.
    Keywords:  Ferroptosis; Natural monomer compounds; Neurodegenerative diseases; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.bbr.2026.116319
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