bims-barned Biomed News
on BBB and Neurodegeneration-ALS
Issue of 2026–06–21
forty-nine papers selected by
Luca Bolliger, lxBio
  1. Focused ultrasound-mediated nanocarrier delivery across the blood-brain barrier for neurodegenerative diseases.
  2. Pathogenic Proteins Driving ALS Pathogenesis: Molecular Mechanisms and Translational Therapeutic Perspectives.
  3. Designing polymer-peptide conjugates to target dipeptide repeat aggregates implicated in amyotrophic lateral sclerosis.
  4. Towards Early Prediction of Amyotrophic Lateral Sclerosis Empowered by Machine Learning and Clinical Big Data.
  5. Amyotrophic Lateral Sclerosis: Therapeutic Innovations and Evolving Regulatory Approaches.
  6. TDP-43 Aggregation: The Healthy-Toxic Balance of the Prion-Like Domain.
  7. Quantitative susceptibility mapping reveals widespread brain iron abnormalities in sporadic patients with early-stage amyotrophic lateral sclerosis.
  8. The lung-brain axis in neurodegeneration: inflammatory, immune, and vascular mechanisms with therapeutic implications.
  9. Brain activity in an end-stage ALS patient suggests the presence of an unresponsive wakefulness syndrome.
  10. Thyroid hormones and energy metabolism in amyotrophic lateral sclerosis.
  11. Whole-body muscle MRI improves diagnostic certainty in amyotrophic lateral sclerosis.
  12. Linking Neurodegeneration and Age-related Macular Degeneration: Unified Pathways and Intervention Strategies.
  13. PML as a neuroprotective guardian: Leveraging nuclear protein quality control to mitigate neurotoxicity of an ALS-associated NEK1 variant.
  14. Novel Compounds as TREM2 Modulators for Treating Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, and Nasu-Hakola Disease.
  15. Amyotrophic lateral sclerosis as a network disease: from metabolic decline to network failure.
  16. Microglia-driven neuroinflammatory signaling in neurodegeneration: mechanisms and therapeutic opportunities.
  17. The Emotional Experiences of Healthcare Professionals Working in Amyotrophic Lateral Sclerosis: A Systematic Review.
  18. Comparison of Consumer Smartwatch and Research-Grade Accelerometer-Derived Step Counts in Amyotrophic Lateral Sclerosis.
  19. Cognitive and Neuroimaging Divergence Between Juvenile and Adult FUS Amyotrophic Lateral Sclerosis.
  20. Efficacy of Sodium Phenylbutyrate-Taurursodiol in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.
  21. Efficacy of Sodium Phenylbutyrate-Taurursodiol in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.
  22. Mechanistic Perspectives of Icariin against Neuroinflammation: Taming Glial Activation.
  23. Limiting neurodegeneration in ALS: A phosphatase paves the way.
  24. Strategic Amyotrophic Lateral Sclerosis Australia-Systems Genomics Consortium (SALSA-SGC): cohort profile.
  25. Co-development of a genetic care pathway for ALS: real-world perspectives from the North of England.
  26. Administration of Pgk1 missense mutation leads to more effective mitigation of neurodegenerative effects observed in ALS mice and transgenic zebrafish.
  27. Mechanisms and therapeutic advances of gut metabolites in the regulation of neuroimmune inflammatory diseases.
  28. The ALS Home Health and Durable Medical Equipment Medical Standard Expert Consensus Guideline.
  29. Integration of Serum Neurofilament Light Chain and Cortical Dysfunction Improves Diagnostic Accuracy in ALS.
  30. Plant-Derived Exosome-Like Nanoparticles in Neurodegenerative Diseases: From Dual Bioactive-Delivery Roles to Translational Challenges.
  31. POLG-associated Parkinson's disease-ALS overlap: A novel variant and first reported use of continuous subcutaneous foslevodopa/foscarbidopa infusion in Brait-Fahn-Schwartz disease.
  32. Plasma proteomic signatures of cellular aging predict human disease.
  33. Glaucoma and Systemic Neurodegenerative Diseases: The Brain-Eye Continuum.
  34. Innate immune signaling as a potential pathomechanistic biomarker for distinct subtypes in amyotrophic lateral sclerosis.
  35. Gerobiotics and neuroprotection: effects on the gut-brain axis in age-related neurodegenerative diseases.
  36. PCSK9 in bridging metabolism and neurodegeneration: a new paradigm for alzheimer's treatment.
  37. Targeting CD4⁺ T cell infiltration: mechanisms and therapeutic insights into CD4⁺ T cell transmigration across the blood-brain barrier in acute ischemic stroke.
  38. Hydrogels in Neurological Disorders: Emerging Diagnostic and Therapeutic Applications.
  39. S-acylation of TDP-43: PALMing down aggregation?
  40. Aberrant immunomodulatory signature in β-propeller protein-associated neurodegeneration patient iPSC-derived microglia.
  41. The Association Between Alzheimer's Disease-Related Biomarkers And Parkinson's Disease Based On Single-Cell Sequencing Analysis Combined With Mendelian Randomization.
  42. Bruton's tyrosine kinase inhibitors: a new class of multiple sclerosis therapeutics.
  43. Structural biology of alpha-synuclein amyloid filaments: Implications in synucleinopathies.
  44. The lactate shuttle in ageing: a metabolic bridge between muscle fatigue and brain resilience.
  45. Increased neurotoxic gliosis and blood-brain barrier dysregulation in canine cognitive dysfunction syndrome (CCD).
  46. Focused Ultrasound Modulation of PGC-1α Pathways in Neurological Disease: Mechanistic Rationale and Translational Opportunities.
  47. Teaching Video NeuroImage: Beyond Cognition: Amyotrophic Lateral Sclerosis-Like Disease in PSEN1 c.1292C>A (Jalisco Founder Effect) Variant.
  48. Neuroprotective effects of traditional Chinese medicine using zebrafish models - a review.
  49. Next-generation intranasal delivery nano-platforms for targeted brain therapy of Alzheimer's disease.
  1. Biomed Pharmacother. 2026 Jun 13. pii: S0753-3322(26)00658-X. [Epub ahead of print]201 119622
    Focused ultrasound-mediated nanocarrier delivery across the blood-brain barrier for neurodegenerative diseases.
    Khojaste Rahimi Jaberi, Maryam Rohani Haghighi, Hadi Aligholi, Sara Takallu, Peyman Asadi, Esmaeil Mirzaei, Abbas Rahimi Jaberi, Ali Sahraian.
      The development of effective therapies for neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis remains a major challenge due to the restrictive nature of the blood-brain barrier (BBB). Conventional systemic drug delivery strategies often fail to achieve sufficient central nervous system (CNS) penetration while avoiding peripheral toxicity. Focused ultrasound (FUS), particularly when combined with microbubbles or nanocarriers, has emerged as a non-invasive approach to transiently and precisely open the BBB, enabling targeted delivery of therapeutics to the brain parenchyma. This review provides a comprehensive overview of the mechanisms by which FUS enhances CNS drug delivery, with a dedicated focus on its integration with nanoparticle-based systems, including liposomes, polymeric nanoparticles, dendrimers, metallic nanoparticles, and exosomes. We discuss how these nanocarriers can be engineered for improved stability, targeting specificity, and stimulus-responsive release upon FUS exposure. Recent advances in ultrasound technology, image guidance (particularly MRI), and therapeutic formulations are summarized, along with preclinical and clinical evidence across key neurodegenerative conditions. Despite promising results, several challenges remain, including long-term BBB stability, regulatory standardization, and scalability for broad clinical application. By integrating principles from acoustics, pharmacology, and nanotechnology, FUS-mediated drug delivery, especially in combination with smart nano systems, represents a significant advancement in precision neurotherapeutics, offering new hope for previously untreatable CNS diseases.
    Keywords:  CNS therapeutics; Focused ultrasound; Nanoparticle drug delivery; Neurodegenerative diseases; Ultrasound-mediated delivery
    DOI:  https://doi.org/10.1016/j.biopha.2026.119622
  2. CNS Neurol Disord Drug Targets. 2026 Apr 01.
    Pathogenic Proteins Driving ALS Pathogenesis: Molecular Mechanisms and Translational Therapeutic Perspectives.
    Harshpreet Kaur, Mandeep Kaur, Gopal Krishna Sethi, Arora Sukhpreet Kaur, Aparna Mishra, Neha Sharma.
      Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive degeneration of motor neurons, with protein aggregation as a central pathological hallmark. Key pathogenic proteins, including TDP-43, SOD1, FUS, and dipeptide repeat proteins (DPRs) from C9orf72 expansions, drive disease progression through diverse but converging mechanisms. TDP-43 proteinopathy, present in nearly all ALS cases, involves cytoplasmic mislocalization, misfolding, and aggregation, disrupting RNA processing, protein transport, and DNA repair. Similarly, SOD1 and FUS mutations promote toxic protein aggregation, impairing cellular homeostasis and contributing to neuronal dysfunction. C9orf72-derived DPRs exert toxicity by interfering with nucleocytoplasmic transport. The propagation of these pathogenic proteins between neurons and glia, often via prion-like mechanisms, underlies the characteristic spread of ALS pathology throughout the nervous system. Cellular protective responses, such as molecular chaperones and the ubiquitin-proteasome system, attempt to mitigate aggregation but are often overwhelmed in disease states. Mitochondrial dysfunction, oxidative stress, and disturbances in calcium homeostasis are also implicated, with evidence showing that SOD1 mutations can alter redox balance and mitochondrial function in both neurons and non-neuronal cells. Impaired DNA repair mechanisms, involving proteins such as TDP-43, FUS, NEK1, and VCP, have emerged as important contributors to ALS pathogenesis, linking protein aggregation to genomic instability. Recent therapeutic strategies focus on directly targeting misfolded proteins using small molecules, peptides, or antisense oligonucleotides to inhibit aggregation or enhance clearance, offering hope for disease modification. Understanding the interplay between protein aggregation, impaired RNA metabolism, and cellular stress responses is crucial for developing effective translational therapies for ALS.
    Keywords:  Amyotrophic lateral sclerosis; C9orf72; FUS; TDP-43; mitochondrial dysfunction; pathogenic proteins.
    DOI:  https://doi.org/10.2174/0118715273440191260226063811
  3. J Mater Chem B. 2026 Jun 15.
    Designing polymer-peptide conjugates to target dipeptide repeat aggregates implicated in amyotrophic lateral sclerosis.
    Vincent P Gray, Zixian Cui, Mackenzie Klepsig, Rachel A Letteri.
      Toxic dipeptide repeats such as the aggregating glycine-alanine (GA)n peptide are implicated in the progression of amyotrophic lateral sclerosis (ALS), a lethal neuromuscular disease with an urgent need for new therapeutics. Here, we report polymer-peptide conjugates that prevent aggregation of (GA)10. Optical density measurements and transmission electron microscopy demonstrate that conjugates prevent aggregation when co-incubated with (GA)10 and disperse pre-aggregated (GA)10. These results represent an important step toward a new generation of therapeutics for ALS and contribute to a growing body of literature demonstrating the potential of polymer-peptide conjugates as therapeutics.
    DOI:  https://doi.org/10.1039/d6tb00210b
  4. AMIA Jt Summits Transl Sci Proc. 2026 ;2026 623-632
    Towards Early Prediction of Amyotrophic Lateral Sclerosis Empowered by Machine Learning and Clinical Big Data.
    Askar Safipour Afshar, Jefferey Statland, Xing Song.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by substantial symptom heterogeneity and overlap with other neurological conditions, often delaying diagnosis. This study developed a consensus-based feature selection framework to identify a stable and parsimonious minimal feature set for early ALS prediction using large-scale observational data. Using multi-year medical claims and multi-site EHRs, we identified 1,716 ALS cases with matched controls. The approach integrated variability across sample, task, and model dimensions to isolate features predictive up to 18 months before diagnosis. Predictive models using LASSO regression and GBT were evaluated with AUROC and classification metrics. The resulting nine-feature set achieved AUROC values above 0.85 across time windows. The GBT model was further evaluated in musculoskeletal, nervous system, and limb or bulbar subgroups, demonstrating reliable discrimination and preserved sensitivity and specificity. These findings highlight the potential of stable minimal feature sets to support earlier ALS identification.
  5. CNS Neurol Disord Drug Targets. 2026 Apr 01.
    Amyotrophic Lateral Sclerosis: Therapeutic Innovations and Evolving Regulatory Approaches.
    Gautam Singh, Samarendra Singh, Atreyee Sarkar, Navjot Kaur Sandhu.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons, leading to muscle weakness, paralysis, and respiratory failure. Despite extensive research, riluzole and edaravone remain the only globally approved disease-modifying therapies, offering modest survival benefits. This review summarizes current understanding of ALS pathogenesis, approved pharmacological treatments, and emerging gene-, RNA-, and cell-based therapeutic strategies. Particular emphasis is placed on regulatory considerations and evolving clinical trial designs in ALS drug development. The accelerated approval and subsequent withdrawal of sodium phenylbutyrate-taurursodiol (AMX0035) are discussed as a critical case study highlighting the challenges of regulatory flexibility in rare, fatal diseases. Advances in biomarker development, especially neurofilament light chain, are examined for their growing role in trial design and therapeutic evaluation. Collectively, these insights underscore a shift toward biomarker- informed and precision-based approaches that may improve future ALS therapeutic development.
    Keywords:  Amyotrophic lateral sclerosis (ALS); RNA therapeutics; complementary and alternative medicine; edaravone; gene therapy; neurodegeneration; neuroprotection.; regulatory considerations; riluzole; stem cell therapy
    DOI:  https://doi.org/10.2174/0118715273438968260318203940
  6. Adv Sci (Weinh). 2026 Jun 15. e76119
    TDP-43 Aggregation: The Healthy-Toxic Balance of the Prion-Like Domain.
    Luca Zangrando, Emanuele Buratti, Francesca Paron.
      TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed RNA-binding protein that plays essential roles in RNA metabolism, including transcription, splicing, transport, and stability. Pathological TDP-43 aggregates have become a defining hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and a large subset of frontotemporal lobar degeneration (FTLD). In the last decade, increasing evidence has challenged the initial thought of TDP-43 condensates as a purely pathological event, highlighting instead the physiological relevance of reversible self-association, polymerization and liquid-liquid phase separation (LLPS) in regulating TDP-43 functions. In this review, we provide an integrated overview of the structural determinants governing TDP-43 two-faced polymerization, with a particular focus on the prion-like domain and its parallelism with prion proteins. Indeed, while physiological assemblies support normal RNA processing, the dysregulation of LLPS by either disease-associated mutations, altered RNA-binding, aberrant post-translational modifications, or proteolytic cleavage can promote the transition toward irreversible, pathogenic aggregates. Finally, we summarize strategies aimed at eliminating TDP-43 aggregates or modulating its phase-separation behavior. Altogether, this review frames TDP-43 polymerization in both healthy and pathological conditions, offering a prion-like centered view of TDP-43 proteinopathies.
    Keywords:  LLPS; TDP‐43; neurodegeneration; prion‐like domain; protein aggregation; therapeutic strategies
    DOI:  https://doi.org/10.1002/advs.76119
  7. Brain Commun. 2026 ;8(3): fcag190
    Quantitative susceptibility mapping reveals widespread brain iron abnormalities in sporadic patients with early-stage amyotrophic lateral sclerosis.
    Mingjie Ma, Bing Zhao, Ninglu Gao, Xiaohan Sun, Kai Shao, Pengfei Lin, Wei Li, Yuying Zhao, Dexin Yu, Chuanzhu Yan, Shuangwu Liu, Yan Yun.
      In the present study, using the novel quantitative susceptibility mapping technique, we aimed to systematically investigate brain iron alterations in a large group of sporadic early-stage amyotrophic lateral sclerosis patients and their correlation with clinical disability. In this study, amyotrophic lateral sclerosis patients at King's stage 1 were defined as early-stage amyotrophic lateral sclerosis patients, and 53 newly diagnosed early-stage amyotrophic lateral sclerosis patients and 50 healthy controls were included. Voxel-based whole-brain quantitative susceptibility mapping analysis was used to explore brain iron alterations. Voxel-based morphometry analysis was also performed. Longitudinal follow-up was performed in amyotrophic lateral sclerosis patients, and the follow-up progression rate was calculated. We found that, compared with healthy controls, early-stage amyotrophic lateral sclerosis patients presented significantly increased susceptibility values, mainly in the motor cortex, prefrontal cortex, hippocampus and cerebellar regions, while volumetric alterations were not detected. Moreover, motor and extra-motor cortex susceptibility values were significantly correlated with upper motor neuron scores and follow-up progression rate (r = 0.452-0.504, P < 0.01) in early-stage amyotrophic lateral sclerosis patients. We demonstrated a clear profile of early motor and extra-motor iron depositions and their important roles in early-stage amyotrophic lateral sclerosis patients. We suggest that quantitative susceptibility mapping is likely a promising neuroimaging approach for assessing early upper motor neuron damage and detecting early extra-motor alterations in amyotrophic lateral sclerosis patients.
    Keywords:  ALS; motor disability; quantitative susceptibility mapping
    DOI:  https://doi.org/10.1093/braincomms/fcag190
  8. Inflammopharmacology. 2026 Jun 16.
    The lung-brain axis in neurodegeneration: inflammatory, immune, and vascular mechanisms with therapeutic implications.
    Ahmed S Al-Shami, Mai M Anwar.
      Neurodegenerative and chronic pulmonary diseases represent major global health challenges and have widely been investigated separately. Emerging evidence indicates the existence of a lung-brain axis, through which pulmonary pathology and environmental exposures can influence neurological health. The current review highlights the mechanistic and clinical evidence linking chronic lung inflammation, air pollution, and immune dysregulation to the onset and progression of Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). A pathway-based framework is presented in which lung inflammation, systemic cytokine release, oxidative stress, blood-brain barrier disruption, immune priming, and protein misfolding mediate lung-to-brain communication. Associations between chronic obstructive pulmonary disease, asthma, particulate matter exposure, and adverse neurological outcomes including cognitive decline, brain atrophy, disease progression, and elevated neurodegenerative risk are emphasized. Specific mechanisms are addressed, including immune-mediated effects in multiple sclerosis, inhalation-driven protein aggregation in Parkinson's disease, and vascular and oxidative injury contributing to dementia and amyotrophic lateral sclerosis. COVID-19 is considered a clinical model of acute lung-brain axis disruption, demonstrating inflammation-driven neurocognitive consequences, and its role in this context was also highlighted. Additionally, potential preventive and therapeutic strategies are discussed, highlighting pulmonary health and environmental exposure reduction as modifiable factors that may help mitigate neurological disease. This integrative review underscores the clinical relevance of the lung-brain axis and calls for interdisciplinary strategies to improve neurological outcomes through pulmonary and environmental interventions.
    Keywords:  Air pollution; Blood–brain barrier; Lung–brain axis; Microglia; Neurodegeneration; Neuroinflammation
    DOI:  https://doi.org/10.1007/s10787-026-02285-4
  9. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jun 17. 1-7
    Brain activity in an end-stage ALS patient suggests the presence of an unresponsive wakefulness syndrome.
    Sandra Frycz, Wiktor Więcławski, Marcin Skotniczny, Marek Binder.
       OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor neurons. It is widely assumed that cortical structures beyond motor neurons are relatively preserved, and patients in the end-stage ALS are regarded as being in complete locked-in syndrome (cLIS). However, emerging evidence suggests substantial heterogeneity in cognitive functioning among ALS patients, indicating possible extra-motor cortical involvement and impaired levels of consciousness. We report a case study assessing electrophysiological markers and auditory system integrity to evaluate the presence of covert consciousness in end-stage ALS.
    METHODS: The patient was a 42-year-old woman with bulbar-onset, end-stage ALS, a six-year disease duration, and no means of communication. She underwent several EEG-based protocols, including resting-state EEG (RS-EEG), a passive auditory oddball paradigm, and 40 Hz auditory steady-state responses (ASSR). Audiological evaluation comprised transient-evoked and distortion-product otoacoustic emissions, as well as auditory brainstem responses (ABR).
    RESULTS: RS-EEG was dominated by prefrontal 1-3 Hz activity resembling frontal intermittent rhythmic delta activity. Power spectra were poorly differentiated and consistent with a 1/f profile. No event-related potentials were observed in the oddball paradigm, and no ASSR responses were detected. Audiological testing revealed absent otoacoustic emissions and ABR indicating severe to profound hearing loss.
    CONCLUSIONS: Our findings indicate severe cortical dysfunction and provide no electrophysiological evidence of covert consciousness. The electrophysiological profile closely resembles that observed in unresponsive wakefulness syndrome. This case supports the hypothesis that advanced ALS following cLIS onset may be more appropriately conceptualized as a disorder of consciousness rather than persistent cLIS.
    Keywords:  Amyotrophic lateral sclerosis; auditory response; covert consciousness; electroencephalography; unresponsive wakefulness syndrome
    DOI:  https://doi.org/10.1080/21678421.2026.2688249
  10. Brain Commun. 2026 ;8(3): fcag198
    Thyroid hormones and energy metabolism in amyotrophic lateral sclerosis.
    Liubov Novikova, Christina Lang, Hayrettin Tumani, Veronika Klose, Jan Kassubek, Jens Dreyhaupt, Luc Dupuis, Martin Wabitsch, Albert Ludolph.
      Weight loss, partially caused by hypermetabolism, represents a well-documented and therapeutically relevant feature of the amyotrophic lateral sclerosis phenotype worldwide. In this study, we retrospectively analysed the association between thyroid function and clinical, prognostic and metabolic parameters in a cohort of patients with amyotrophic lateral sclerosis in an experienced centre in Germany (n = 1754). Specifically, we examined the relationship between thyroid stimulating hormone levels, age, glucose and body mass index and-in subgroups-phosphorylated neurofilament heavy chain levels in CSF. There was no association between thyroid stimulating hormone levels and body mass index in patients with amyotrophic lateral sclerosis (n = 954). In contrast with other cohorts, thyroid stimulating hormone levels decreased with age in patients with amyotrophic lateral sclerosis indicating hypothalamic deficiency in the ageing patients. There was no association between thyroid stimulating hormone and phosphorylated neurofilament heavy chain (prognostic marker) in CSF of a subcohort (n = 646). Thyroid stimulating hormone levels correlated with glucose levels, an effect more pronounced in male patients. In conclusion, our results suggest that thyroid metabolism does not significantly contribute to amyotrophic lateral sclerosis-related weight loss or disease prognosis as estimated by phosphorylated neurofilament heavy chain; thyroid dysfunction is unlikely to be a primary driver of the metabolic dysregulation observed in amyotrophic lateral sclerosis. Most interestingly, thyroid stimulating hormone levels show an unexpected negative relation to age in patients with amyotrophic lateral sclerosis.
    Keywords:  ALS; body mass index; catabolism; neurofilaments; thyroid function
    DOI:  https://doi.org/10.1093/braincomms/fcag198
  11. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jun 15. 1-9
    Whole-body muscle MRI improves diagnostic certainty in amyotrophic lateral sclerosis.
    Vincent Fabry, Marie Faruch-Bilfeld, Rokia El Khalfi, Blandine Acket, Yassine Al Achram, Pascal Cintas.
      Introduction: Early diagnosis of amyotrophic lateral sclerosis (ALS) remains challenging due to the absence of a definitive biomarker and the difficulty of demonstrating widespread lower motor neuron (LMN) involvement. Whole-body muscle MRI (WB-MRI) enables comprehensive assessment of muscle involvement and may improve detection of LMN dysfunction. This study aimed to evaluate whether WB-MRI improves diagnostic certainty in ALS when combined with clinical and electromyography (EMG) assessment. Methods: In this prospective single-center study, 47 patients with ALS underwent clinical examination, EMG, and WB-MRI. Diagnostic classification according to the Awaji criteria was assessed using clinical and EMG data alone and after integration of MRI markers of LMN involvement, including fatty infiltration and muscle edema, or muscle edema alone as a surrogate marker. Results: WB-MRI identified additional LMN-involved regions in 27.7% of patients when both fatty infiltration and muscle edema were considered, and in 42.6% when considering muscle edema alone. This resulted in diagnostic upgrading in 14.9% and 25.5% of patients, respectively. The proportion of definite ALS increased from 8.5% to 17.0% when muscle edema alone was considered. MRI had limited impact on diagnostic classification according to the Gold Coast criteria. Among patients without LMN involvement on clinical and EMG assessment (all with bulbar-onset), 50% were reclassified after MRI. Conclusion: WB-MRI improves detection of LMN involvement and increases diagnostic certainty according to the Awaji criteria, with muscle edema appearing to be the most relevant MRI marker for integration into ALS diagnostic assessment.
    Keywords:  Amyotrophic lateral sclerosis; electromyography; whole-body MRI
    DOI:  https://doi.org/10.1080/21678421.2026.2685160
  12. CNS Neurol Disord Drug Targets. 2026 Jun 12.
    Linking Neurodegeneration and Age-related Macular Degeneration: Unified Pathways and Intervention Strategies.
    Shubhangi Mukherjee, Suman Kumar Ray, Sukhes Mukherjee.
      Age-related macular degeneration (AMD) is caused by the degeneration of photoreceptors and retinal pigment epithelium (RPE) along with drusen deposition and is the leading cause of vision loss in older adults. Both these structures within the central nervous system (CNS) utilize common neuro-inflammatory mechanisms because the retina is an outgrowth of the brain. Like the brain, the eye has its own physical characteristics and surface molecules as well as a tendency towards specific immune reactions. Numerous distinct neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Frontotemporal dementia (FTD) that impact the brain present as eye symptoms, and the conventional diagnosis of these neurodegenerative disorders (NDs) is often preceded by ocular symptoms. Furthermore, several eye-specific disorders have characteristics in common with other CNS disorders. NDs and AMD share common key features, such as tau and amyloid-β deposits, oxidative stress response, chronic inflammation, and dysregulation of microglia and müller glia. Common pathological mechanisms include complement activation, amyloid aggregation, neuroinflammation, vascular impairment, and cell death, providing a basis for a convergent neuroimmune axis between retinal and cerebral degeneration. Comparing these age-related diseases will facilitate the identification of shared risk factors, convergent molecular pathways, and potential cross-applicable therapeutic strategies, such as anti-inflammatory, anti-complementary, anti-apoptotic, and anti-VEGF-based approaches. This knowledge may enhance understanding of neurodegenerative diseases, help identify early biomarker development for diagnosis, and enable the design of targeted therapeutic strategies.
    Keywords:  Age-related macular degeneration (AMD); amyloid β aggregation.; neurodegenerative disorders (NDs); neuroinflammation; pathophysiological mechanism; targeted therapy
    DOI:  https://doi.org/10.2174/0118715273450093260523224914
  13. FEBS J. 2026 Jun 19.
    PML as a neuroprotective guardian: Leveraging nuclear protein quality control to mitigate neurotoxicity of an ALS-associated NEK1 variant.
    Tabea Stark, Stefan Müller.
      Insoluble protein aggregates are a hallmark of neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). The ubiquitin-proteasome system (UPS) serves as a neuroprotective quality control mechanism that clears aggregates. PML nuclear bodies (NBs) were proposed to serve as hubs for SUMO-primed ubiquitylation and degradation of misfolded proteins. Georgiadou et al. provide evidence that an ALS-linked NEK1 truncation mutant is recruited to PML NBs, where it likely undergoes SUMOylation and ubiquitylation. In mice, PML loss exacerbates ALS-like symptoms, while induced PML expression delays disease onset. These findings establish PML as a key regulator of proteostasis and highlight PML induction as a potential therapeutic strategy for ALS and related proteinopathies.
    Keywords:  ALS; NEK1; PML; SUMO; SUMO‐targeted ubiquitylation; ubiquitin
    DOI:  https://doi.org/10.1111/febs.70630
  14. ACS Med Chem Lett. 2026 Jun 11. 17(6): 1236-1237
    Novel Compounds as TREM2 Modulators for Treating Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, and Nasu-Hakola Disease.
    Ram W Sabnis, Anika R Sabnis.
      Provided herein are novel compounds as TREM2 modulators, pharmaceutical compositions, use of such compounds in treating Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Nasu-Hakola disease, and processes for preparing such compounds.
    DOI:  https://doi.org/10.1021/acsmedchemlett.6c00249
  15. Brain. 2026 Jun 18. pii: awag211. [Epub ahead of print]
    Amyotrophic lateral sclerosis as a network disease: from metabolic decline to network failure.
    Raffaele Dubbioso, Sabina Pappatà.
      
    DOI:  https://doi.org/10.1093/brain/awag211
  16. Mol Biol Rep. 2026 Jun 18. pii: 941. [Epub ahead of print]53(1):
    Microglia-driven neuroinflammatory signaling in neurodegeneration: mechanisms and therapeutic opportunities.
    Komal Saini, Preeti Dhiman.
      Neuroinflammation has been identified as a major component to the pathogenesis and progression of many neurodegenerative illnesses, going beyond its traditional role as a protective immune response within central nervous system (CNS). There is growing evidence that persistent activation of peripheral immune pathways, microglia and astrocytes causes progressive neurodegeneration, synaptic loss and progressive neurodegeneration. This review examines the mechanisms of microglia- driven neuroinflammatory signaling and its involvement in major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Key neuroinflammatory mechanisms covered in depth including microglial activation, astrocyte reactivity, peripheral immune cell infiltration, cytokine dysregulation, and blood brain barrier (BBB) disruption. This review also emphasizes the role of neuroinflammation in acute neurological symptoms and mental and cognitive impairments. Glial activation markers, inflammatory cytokines, BBB proteins and kynurenine pathway metabolites are emerging as promising biomarkers for disease diagnosis and monitoring. Additionally, the potential of new mathematical and systems level computational models to describe intricate neuroimmune interactions and forecast the course of disease and treatment results is investigated. Current and emerging therapies targeting neuroinflammation include anti-inflammatory and immunomodulatory drugs, lifestyle interventions, stem cell approaches, gene-editing technologies and nanoparticle-based drug delivery systems. Despite significant progress, translating preclinical findings into effective clinical therapies remains challenging. Future developments in integrative neuroimmune modeling, biomarker-guided therapies and precision medicine may make it possible to create individualized treatments plans targeted at reducing neuroinflammation and enhancing the course of neurodegenerative illnesses.
    Keywords:  Alzheimer's disease; Amyotrophic lateral sclerosis; Astrocytes; Microglia; Multiple sclerosis; Parkinson's disease
    DOI:  https://doi.org/10.1007/s11033-026-12128-8
  17. Muscle Nerve. 2026 Jun 18.
    The Emotional Experiences of Healthcare Professionals Working in Amyotrophic Lateral Sclerosis: A Systematic Review.
    Young Chan, Sarah Creer, Jess Mere, Alys Wyn Griffiths, Charlotte Wright, Esther V Hobson, Christopher J McDermott, Emily J Mayberry.
      Healthcare professionals (HCPs) working with people living with amyotrophic lateral sclerosis (ALS) are often exposed to emotive circumstances including end of life care, trauma, loss, and death. Existing reviews have explored the emotional experiences of people living with ALS and their carers but have largely ignored healthcare staff and the impact of this work on them. This systematic review of qualitative research aims to explore the emotional experiences of and impact on HCPs working with people living with ALS using thematic synthesis (PROSPERO reference: CRD42025631749). Electronic databases were searched for journal articles and gray literature (Medline, Scopus, PsycINFO, Google Scholar, King's Fund Library Database, ProQuest Dissertations, Theses Global) for qualitative or mixed-methods studies exploring the emotional impact on HCPs working in ALS. Twelve studies were included, critically appraised, and analyzed. Four themes were identified. The emotional intensity due to the nature of ALS created challenges for HCPs, while they were also faced with absorbing the emotions of others. HCPs learned to balance their emotional involvement, and HCPs also described positive experiences and coping mechanisms. HCPs working in ALS experience multi-faceted emotional challenges, and they do describe positive emotional experiences within their roles. However, HCPs describe having few coping mechanisms and limited formal support systems in place to process the intense emotions or to guide their emotional involvement. The lack of support for staff may ultimately negatively affect patient care. There is an unmet demand for debriefing, supervision, and further training on how to deal with intense, distressing emotions.
    Keywords:  amyotrophic lateral sclerosis; emotional experiences; healthcare professionals; motor neuron disease; qualitative evidence synthesis
    DOI:  https://doi.org/10.1002/mus.70309
  18. Muscle Nerve. 2026 Jun 19.
    Comparison of Consumer Smartwatch and Research-Grade Accelerometer-Derived Step Counts in Amyotrophic Lateral Sclerosis.
    Gordon Jewett, Reed Ferber, Colin B Josephson, Lawrence Korngut, Joon Lee.
       INTRODUCTION/AIMS: Objective, scalable measures of function are needed in amyotrophic lateral sclerosis (ALS). Research-grade accelerometers are promising but may be difficult to deploy for prolonged remote monitoring, whereas consumer smartwatches offer a practical alternative. We evaluated the feasibility of long-term smartwatch monitoring in ALS and compared smartwatch- and accelerometer-derived daily step counts.
    METHODS: In this single-centre prospective observational study, participants wore a Fitbit Sense (smartwatch) on the wrist longitudinally and an ActiGraph GT9X Link (accelerometer) on the opposite wrist during clinic-aligned assessment periods. Device comparison was restricted to concurrent valid days (≥ 10 h wear) and included paired comparison of mean daily step counts, Pearson correlation, Bland-Altman analysis, and proportional bias assessment.
    RESULTS: Forty participants were enrolled and 39 contributed data across 8093 smartwatch and 915 accelerometer days. Step count comparison included 503 concurrent valid days from 34 participants. Mean daily step counts were 3480 (SD 4365) for smartwatch and 4066 (SD 4797) for accelerometer (p < 0.0001), with strong correlation (r = 0.91, p < 0.0001). Mean bias was -586 steps for smartwatch, with 95% limits of agreement from -4193 to 3021. Among participants with ≥ 6 months of concurrent data, devices showed similar decline over time (interaction p = 0.76).
    DISCUSSION: Long-term remote monitoring using a smartwatch was feasible in ALS. Smartwatch-derived step counts were strongly correlated with accelerometer-derived estimates but were systematically lower and showed wide day-level limits of agreement. Smartwatch-derived step counts may be useful for group-level analyses and longitudinal monitoring, though device-specific bias should be considered in interpretation.
    Keywords:  actigraphy; amyotrophic lateral sclerosis; smartwatch; step count; wearable devices
    DOI:  https://doi.org/10.1002/mus.70323
  19. Ann Clin Transl Neurol. 2026 Jun 15.
    Cognitive and Neuroimaging Divergence Between Juvenile and Adult FUS Amyotrophic Lateral Sclerosis.
    Alexandra V Jürs, Marcel Naumann, Annaliis Lehto, Hanna Schön, Jens Kurth, Johannes Prudlo, Andreas Hermann, Elisabeth Kasper.
       OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron degeneration. Fused in sarcoma (FUS)-associated juvenile ALS (jALS) represents a distinct and aggressive subgroup with rapid deterioration and poor prognosis. Certain FUS mutations have been associated with comorbid intellectual disability, suggesting neurodevelopmental involvement. We compared FUS-jALS with adult-onset FUS-ALS cases (aALS) to evaluate the association between premorbid cognitive impairment, genetic and clinical features incorporating neuroimaging data.
    METHODS: Patients with genetically confirmed FUS-ALS were classified as jALS (onset < 25 years) or aALS (onset ≥ 25 years). Neuropsychological assessment used Mehrfachwahl-Wortschatz-Test (MWT) for verbal IQ, and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), with cognitive impairment classified according to Strong criteria. Volumetric analysis was conducted on structural MRI and FDG-PET data.
    RESULTS: All three jALS (P525L [n = 2], H517_Q519del [n = 1]) showed rapid progression with early severe clinical events. Neuropsychological assessment revealed global cognitive deficits (ALS-ci) with widespread dysfunction beyond typical ALS-specific patterns and reduced verbal IQ, pointing towards premorbid cognitive impairment. aALS demonstrated slower progression and were predominantly cognitively unimpaired (ALS-ni) or showed an ALS-specific impairment. Neuroimaging revealed distinct patterns: jALS cases demonstrated posterior cortical atrophy and hypometabolism on FDG-PET, while aALS showed largely preserved brain volumes and limbic-subcortical hypometabolism.
    INTERPRETATION: Specific FUS mutations (P525L, H517_Q519del) predispose to jALS with severe progression and premorbid cognitive impairments, supporting a genotype-phenotype association. Posterior cortical findings suggest neurodevelopmental delay rather than disease-related neurodegeneration. Genetic FUS screening may be warranted in patients with intellectual disability and motor signs, given emerging targeted therapies.
    Keywords:  FUS; amyotrophic lateral sclerosis; cognitive function; intellectual disability; juvenile‐onset ALS; neuroimaging
    DOI:  https://doi.org/10.1002/acn3.70447
  20. Ann Indian Acad Neurol. 2026 May 01. 29(3): 343-352
    Efficacy of Sodium Phenylbutyrate-Taurursodiol in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.
    Abdulkareem M Jomaa, Haseeba Khalid, Halder J Abozait, Hammad Mudassar, Ravneet Kaur.
       OBJECTIVE: To evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol (PB-TURSO) and its components in slowing disease progression and improving survival in patients with amyotrophic lateral sclerosis (ALS).
    METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies comparing PB-TURSO or its components to placebo or standard of care in adults with ALS were included. The primary outcomes were functional decline (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R]) and survival. Two reviewers independently screened studies, extracted data, and assessed the risk of bias. A random-effects model was used for the meta-analysis, and a narrative synthesis was conducted for Tauroursodeoxycholic Acid (TUDCA) monotherapy and secondary analyses from the CENTAUR trial.
    RESULTS: Two RCTs (n = 801) were included in the meta-analysis. The pooled analysis demonstrated no statistically significant difference in either ALSFRS-R decline (mean difference [MD] 1.51, 95% confidence interval [CI] -1.01 to 4.02; P = 0.24; I² =71%) or survival (hazard ratio [HR] 0.90, 95% CI 0.73-1.11; P = 0.31; I² = 61%). A separate trial of TUDCA monotherapy ( n = 34) demonstrated significant functional benefits. Post hoc analyses of the CENTAUR trial reported a survival benefit of 6.5-10.6 months and delayed progression to major disease milestones. Biomarker analyses suggested anti-inflammatory effects. The risk of bias was moderate to high, and the certainty of evidence was rated very low by GRADE.
    CONCLUSIONS: Based on very low certainty evidence, the available RCT data do not support a definitive conclusion regarding the efficacy of PB-TURSO in ALS. Post hoc exploratory analyses suggest a potential survival benefit, which requires confirmation in adequately powered, prospectively designed trials; current results are hypothesis-generating rather than practice-defining.
    Keywords:  ALS; Amyotrophic lateral sclerosis; phenylbutyrate; taurursodiol; treatment
    DOI:  https://doi.org/10.4103/aian.aian_1101_25
  21. Ann Indian Acad Neurol. 2026 Jun 12.
    Efficacy of Sodium Phenylbutyrate-Taurursodiol in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.
    Abdulkareem M Jomaa, Haseeba Khalid, Halder J Abozait, Hammad Mudassar, Ravneet Kaur.
       OBJECTIVE: To evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol (PB-TURSO) and its components in slowing disease progression and improving survival in patients with amyotrophic lateral sclerosis (ALS).
    METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies comparing PB-TURSO or its components to placebo or standard of care in adults with ALS were included. The primary outcomes were functional decline (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R]) and survival. Two reviewers independently screened studies, extracted data, and assessed the risk of bias. A random-effects model was used for the meta-analysis, and a narrative synthesis was conducted for Tauroursodeoxycholic Acid (TUDCA) monotherapy and secondary analyses from the CENTAUR trial.
    RESULTS: Two RCTs (n = 801) were included in the meta-analysis. The pooled analysis demonstrated no statistically significant difference in either ALSFRS-R decline (mean difference [MD] 1.51, 95% confidence interval [CI] -1.01 to 4.02; P = 0.24; I² =71%) or survival (hazard ratio [HR] 0.90, 95% CI 0.73-1.11; P = 0.31; I² = 61%). A separate trial of TUDCA monotherapy ( n = 34) demonstrated significant functional benefits. Post hoc analyses of the CENTAUR trial reported a survival benefit of 6.5-10.6 months and delayed progression to major disease milestones. Biomarker analyses suggested anti-inflammatory effects. The risk of bias was moderate to high, and the certainty of evidence was rated very low by GRADE.
    CONCLUSIONS: Based on very low certainty evidence, the available RCT data do not support a definitive conclusion regarding the efficacy of PB-TURSO in ALS. Post hoc exploratory analyses suggest a potential survival benefit, which requires confirmation in adequately powered, prospectively designed trials; current results are hypothesis-generating rather than practice-defining.
    Keywords:  ALS; Amyotrophic lateral sclerosis; phenylbutyrate; taurursodiol; treatment
    DOI:  https://doi.org/10.4103/aian.aian_1101_25
  22. Mini Rev Med Chem. 2026 Apr 09.
    Mechanistic Perspectives of Icariin against Neuroinflammation: Taming Glial Activation.
    Niraj Kumar Singh, Ashini Singh.
      Glial-mediated neuroinflammation significantly contributes to major neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Inhibition of glial-mediated neuroinflammation is effective in treating neurodegenerative diseases. Although no permanent cure exists, considerable research aims to identify natural compounds that may slow the disease progression. Icariin is a naturally occurring flavonoid derived from the herb Herba epimedii and has been shown to have several medicinal benefits, including anti-aging, antioxidant, anti-inflammatory, and anti-apoptotic properties. Recent studies have indicated that Icariin, a potent prenylated flavonol glycoside, exhibits neuroprotective effects against glial-mediated neuroinflammation. Icariin attenuates glial pro-inflammatory responses and prevents neurotoxicity in cellular and animal models. Additionally, Icariin is speculated to facilitate neuronal functioning and survival in experimental conditions. The present review highlights the remarkable role of glial cells in neuroinflammatory processes subsequently neurodegeneration, and the potential of icariin to suppress glial-mediated neuroinflammation. We hope that this review will accelerate the pharmacological development of icariin as a potential therapeutic compound against glial-mediated neuroinflammation, which triggers the pathogenesis of several neurodegenerative disorders.
    Keywords:  Flavonoid; astrocytes; icariin; microglia; neurodegenerative disorder.; neuroinflammation
    DOI:  https://doi.org/10.2174/0113895575448388260306051328
  23. Neuron. 2026 Jun 17. pii: S0896-6273(26)00325-9. [Epub ahead of print]114(12): 2073-2075
    Limiting neurodegeneration in ALS: A phosphatase paves the way.
    Elena I Rugarli, Thomas Langer.
      Zheng et al. identify phosphatase PGAM5 as a novel promising target for the treatment of different amyotrophic lateral sclerosis subtypes. PGAM5 dephosphorylates and activates the stress-regulated mitochondrial peptidase OMA1, which elicits a maladaptive mitochondrial integrated stress response in motor neurons.
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.030
  24. BMJ Open. 2026 Jun 18. 16(6): e110906
    Strategic Amyotrophic Lateral Sclerosis Australia-Systems Genomics Consortium (SALSA-SGC): cohort profile.
    Anjali K Henders, Laura Ziser, Fleur C Garton, Lorel Adams, Karalyn Ernst, Sarah Furlong, Judith Anne Heads, Susan Heggie, Ruth Krasniqi, Madhura Bhadravathi Lokeshappa, Srestha Mazumder, Elyshia McNamara, Amanda MacShane, Linda Mekhael, Lorelle Nunn, Bronwen Orden, Julie Ryder, Kathryn Thorpe, Marie Toubia, Leanne M Wallace, Dina Wickremeratne, Emma Windebank, Beben Benyamin, Shyuan Ngo, Garth Nicholson, Roger Pamphlett, Frederik J Steyn, Peter M Visscher, Kelly L Willams, Robert Henderson, Matthew C Kiernan, Nigel Laing, Susan Mathers, Pamela A McCombe, Merrilee Needham, Dominic Rowe, David Schultz, Paul Talman, Steve Vucic, Ian P Blair, Allan F McRae, Naomi R Wray.
       PURPOSE: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative motor neuron disease (MND) with heterogeneity in disease onset, progression and treatment response. The Strategic ALS Australia-Systems Genomics Consortium (SALSA-SGC) was established in recognition of the need for large data sets of clinical data matched with biological samples to enable and foster ALS research and better understanding of aetiology and biological mechanisms. SALSA-SGC brought together the major Australian MND clinics to set up sustainable infrastructure that could facilitate long-term human ALS research and clinical trials nationally and internationally.
    PARTICIPANTS: Between April 2016 and December 2024, SALSA-SGC recruited 1813 participants, including 1386 ALS/MND cases, 388 controls and 39 others (asymptomatic relatives and ALS mimics). Clinical data and biospecimens are available for 1333 and 1189 ALS cases, respectively, with longitudinal data spanning 4442 total clinic visits and 3201 samples. An open-access online data explorer showcases collected datasets.
    FINDINGS TO DATE: Detailed clinical and questionnaire data allow an in-depth description of the cohort, informing clinical and health policy research. Screening for known ALS large-effect risk variants identified 125 mutation carriers (11.5% from N=1059), including 70 with C9orf72 expansions. Single Nucleotide Polymorphism (SNP)-array data (N=1088 cases; N=244 controls) have supported multiple published studies. SALSA-SGC resources are actively used by national and international researchers.
    FUTURE PLANS: Ongoing efforts aim to expand recruitment into regional Australia and enhance sample processing for cell-based studies. The SALSA-SGC resource is accessible by researchers under agreements governed by participant consent, human ethics committee guidelines and agreed use of data and samples.
    Keywords:  GENETICS; Longitudinal studies; Motor neurone disease
    DOI:  https://doi.org/10.1136/bmjopen-2025-110906
  25. Orphanet J Rare Dis. 2026 Jun 17.
    Co-development of a genetic care pathway for ALS: real-world perspectives from the North of England.
    Clementine Wood, Georgia Brown, Kirsten Chalk, Samantha Holden Smith, Hayley Williams, Greg Broadhurst, John Ealing, Hisham Hamdalla, Catherine Breen, Rhona Macleod, Amina Chaouch.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disorder, with a substantial proportion of cases attributed to genetic factors. Recent advances in gene discovery and genomic technologies have transformed ALS care by enabling genomic testing to inform prognosis, assess familial risk, and facilitate access to novel therapies. However, guidance on the delivery of genetic testing and counselling in ALS remains limited, leading to variability in clinical practice. In response, the Manchester Motor Neuron Disease (MND) Care Centre and the Manchester Centre for Genomic Medicine co-developed a structured genetic care pathway for ALS, drawing on real-world data, patient engagement, and multidisciplinary collaboration.
    RESULTS: A retrospective evaluation of 326 ALS patients at the Manchester MND Care Centre identified significant variability in genetic testing uptake, counselling practices, and record-keeping. Patient survey and engagement sessions revealed uncertainty regarding key genetic concepts and inconsistent recall of pre- and post-test discussions. Priorities for improvement included clearer communication, standardised discussions, and enhanced support for families following genetic findings. Consequently, the Greater Manchester ALS Genetic Testing Pathway was developed by a multidisciplinary team, incorporating consensus-based steps for patient identification, pre-test conversations, consent, testing, results disclosure, and post-test support. This pathway integrates genetic testing into routine ALS care, clarifies team responsibilities, and establishes a framework for ongoing evaluation using key performance indicators. Patient and staff feedback is used to support continuous improvement.
    CONCLUSIONS: The co-developed ALS genetic testing pathway provides a scalable model for standardising genomic care in mainstream clinical settings. By establishing clear processes for genetics discussions, consent, and follow-up, the pathway seeks to improve equity, transparency, and person-centred care. Ongoing evaluation and collaboration with patients, clinicians, and genetic services are essential to ensure the pathway remains responsive to scientific advances and evolving patient needs. Wider adoption of structured genetic pathways may facilitate the integration of genomics into care for rare diseases across healthcare systems.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Care pathway; Genomic testing; Motor neuron disease (MND)
    DOI:  https://doi.org/10.1186/s13023-026-04417-z
  26. Biomed Pharmacother. 2026 Jun 19. pii: S0753-3322(26)00710-9. [Epub ahead of print]201 119674
    Administration of Pgk1 missense mutation leads to more effective mitigation of neurodegenerative effects observed in ALS mice and transgenic zebrafish.
    Bing-Chang Lee, Jui-Che Tsai, Wei-Zen Chang, Chun-Cheng Wang, Ai-Ling Hour, Chia-Chuan Wang, Huai-Jen Tsai.
      Amyotrophic lateral sclerosis (ALS) is characterized by progressive degeneration of motor neurons (MNs) with few available therapeutic options. Previous ALS studies demonstrated a decrease in phosphoglycerate kinase 1 (Pgk1) secreted from NogoA-overexpressing muscle cells, thus reducing interaction between extracellular Pgk1 (ePgk1) and neural membranous Enolase 2 (Eno2) with consequent inhibition of neurite outgrowth of MNs (NOMN). The negatively charged 419th aspartic acid of receptor Eno2 (Eno2-D419) is a critical residue interacting with the positively charged 353rd lysine of ligand ePgk1-K353. To strengthen the charge attraction, we mutated ePgk1-K353 to arginine (ePgk1-K353R). Compared to wild-type Pgk1, supplementary mutant Pgk1-K353R proved more effective in increasing NOMN derived from NSC34 neural cells cultured in Sol8-vector condition medium. In vivo, Pgk1-K353R-immersed zebrafish embryos exhibited increased caudal primary MNs branching. Intravenous injection of Pgk1-K353R into ALS-mice exhibited more preservative in innervated neuromuscular junctions in gastrocnemius muscle and diaphragm, increased grip strength, higher rearing frequency, 1.6-fold greater locomotive distance and longer survival. For example, median survival days for the control, Pgk1 and Pgk1-K353R groups were 131, 137.5 and 148, respectively. Collectively, we found a single-amino-acid mutant Pgk1-K353R that exhibits higher efficacy to ameliorate neurodegeneration in ALS-mice by delaying disease progression compared to that driven by wild-type Pgk1. We suggest this outcome might be due to more electrostatic attraction between ePgk1-K353R and Eno2-D419 region predicted by in silico analysis. Therefore, mutant Pgk1-K353R protein should be considered a promising neuroprotective drug for ALS treatment.
    Keywords:  ALS disease; Amino acid charge; Motor neurons; Neurodegeneration; Pgk1; Point mutation
    DOI:  https://doi.org/10.1016/j.biopha.2026.119674
  27. Front Immunol. 2026 ;17 1795042
    Mechanisms and therapeutic advances of gut metabolites in the regulation of neuroimmune inflammatory diseases.
    Xiaodan Shen, Caiji Zheng, Renyong Lin, Juan Wang, Zheng Chen.
      Gut-derived metabolites function as critical signaling intermediaries that translate environmental cues into central nervous system (CNS) responses, playing an indispensable role in the pathogenesis and trajectory of neuroimmune inflammatory disorders. Key metabolites, including short-chain fatty acids (SCFAs) and bile acids, either traverse the blood-brain barrier directly or orchestrate immune modulation peripherally, thereby fine-tuning the dynamic crosstalk between systemic immunity and neural homeostasis. SCFAs exert potent anti-inflammatory effects by promoting regulatory T-cell (Treg) differentiation through activation of G protein-coupled receptors (GPCRs) on immune cells and inhibition of histone deacetylases (HDACs). Within the CNS, they further confer neuroprotection by suppressing the pro-inflammatory activation of microglia and astrocytes. In contrast, bile acids display a context-dependent, "double-edged sword" effect: while certain subtypes activate the anti-inflammatory TGR5 receptor, neurotoxic metabolites (e.g., taurolithocholic acid) can accumulate and directly provoke pro-inflammatory polarization of microglia, thereby fueling neuroinflammation. Dysbiosis of the gut microbiota and consequent metabolite profile alterations are strongly implicated in neuroimmune inflammatory diseases-such as multiple sclerosis (MS), Alzheimer's disease (AD), and neuromyelitis optica spectrum disorders (NMOSD) -which are characterized by both a distinct metabolite imbalance and a pervasive pro-inflammatory immune milieu. Building on this framework, novel therapeutic strategies targeting the "gut-immune-brain axis" are evolving along two complementary avenues: (1) Immune-centric approaches that directly modulate neuroimmune pathways (e.g., by tempering microglial activation or expanding Treg populations); and (2) Microbiota-centric interventions that employ specific probiotics, prebiotics, or metabolite supplements to restore gut ecological balance, systemically recalibrate immunity, and mitigate neuroinflammation. Future research must prioritize elucidating the precise molecular dialogues between metabolites and immune cell subsets, conducting large-scale clinical validation, and advancing personalized, precision-medicine strategies. Such efforts will solidify a novel systemic perspective and strategic paradigm for preventing and treating neuroimmune inflammatory diseases.
    Keywords:  gut metabolites; gut-immune-brain axis; immunomodulation; neuroimmune inflammatory diseases; precision medicine
    DOI:  https://doi.org/10.3389/fimmu.2026.1795042
  28. Muscle Nerve. 2026 May 26.
    The ALS Home Health and Durable Medical Equipment Medical Standard Expert Consensus Guideline.
    AANEM
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with escalating disability and complex care needs. Although most individuals with ALS reside at home, existing US guidelines primarily address clinic-based care and provide limited direction on medically necessary home health services and durable medical equipment (DME). The objective of this task force was to develop expert consensus guidance defining minimum medical standards for home health services and DME for individuals with ALS, with the goal of improving patient outcomes, safety, and quality of life. This guideline was developed by a multidisciplinary task force convened by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM). The process incorporated a scoping literature review, stakeholder engagement (patients, caregivers, and advocacy groups), and iterative expert consensus. Recommendations were informed by clinical expertise, patient-centered priorities, and existing policy frameworks. This guideline outlines stage-responsive home healthcare recommendations spanning nursing, home health aides, physical and occupational therapy, speech-language pathology, respiratory therapy, nutritional support, and social work. It emphasizes proactive, anticipatory care aligned with the predictable trajectory of ALS, rather than being reactive based on functional decline. The document defines medically necessary DME across domains, including mobility, communication, respiratory support, and activities of daily living, advocating for timely access independent of restrictive payer criteria. Key principles include coordinated interdisciplinary care, continuous reassessment, caregiver support, and integration of palliative care. These recommendations establish a foundational standard for ALS home-based care in the United States. Adoption may reduce delays, prevent complications, and support sustained independence and dignity for individuals with ALS.
    DOI:  https://doi.org/10.1002/mus.70290
  29. Ann Clin Transl Neurol. 2026 Jun 16.
    Integration of Serum Neurofilament Light Chain and Cortical Dysfunction Improves Diagnostic Accuracy in ALS.
    Aicee Dawn Calma, Nathan Pavey, Yukiko Tsuji, Amirul Ab Ghapar, Mehdi A J van den Bos, Bronwen Orden, Grace Lee, Linda Mekhael, Julie Ryder, Cláudia Santos Silva, David McDonald, Fakhria Kakar, Con Yiannikas, Matthew C Kiernan, David A Brown, Parvathi Menon, Steve Vucic.
       OBJECTIVE: To determine whether integration of serum neurofilament light chain (NfL) and cortical dysfunction improves diagnostic accuracy in amyotrophic lateral sclerosis (ALS) when applied alongside the Gold Coast criteria (GCC).
    METHODS: In this prospective study, 148 participants with suspected ALS were recruited (101 ALS and 47 with ALS mimicking disorders). Participants taking medications known to influence TMS measures were excluded. Serum NfL levels were quantified using a single-molecule array assay. Cortical function was assessed using threshold tracking transcranial magnetic stimulation, with cortical dysfunction defined by reduced mean short interval intracortical inhibition or motor cortex inexcitability. Diagnostic performance was evaluated using sensitivity, specificity, and diagnostic odds ratios (DOR), with 95% confidence intervals (CI).
    RESULTS: Serum NfL demonstrated excellent discrimination (area under the curve 0.92, p < 0.001), with cut-off ≥ 33.5 pg/mL providing a sensitivity of 0.85 (95% CI 0.77-0.91) and specificity 0.87 (95% CI 0.75-0.94). Cortical dysfunction demonstrated very good diagnostic performance (sensitivity 0.77 [95% CI 0.68-0.84], specificity 0.77 [95% CI 0.63-0.86]). The GCC achieved a sensitivity of 0.89 (95% CI 0.82-0.94) and specificity 0.89 (95% CI 0.77-0.95). Combining GCC with elevated NfL or cortical dysfunction increased the specificity to 0.98 (95% CI 0.89-1.00) while maintaining high sensitivity at 0.87 (95% CI 0.79-0.92), yielding the highest DOR.
    INTERPRETATION: Integration of serum NfL and cortical dysfunction with the Gold Coast criteria improves diagnostic accuracy in ALS, particularly by increasing specificity. This multimodal approach provides a practical framework for earlier and more definitive diagnosis that may facilitate more efficient clinical trial recruitment.
    Keywords:  amyotrophic lateral sclerosis; cortical dysfunction; neurofilament light chain
    DOI:  https://doi.org/10.1002/acn3.70454
  30. Int J Nanomedicine. 2026 ;21 608292
    Plant-Derived Exosome-Like Nanoparticles in Neurodegenerative Diseases: From Dual Bioactive-Delivery Roles to Translational Challenges.
    Yue Sun, Zongqiang Xu, Lianhui Cui, Jianfei Guo, Xiaohui Zhang, Yilei Xiao.
      Neurodegenerative diseases, particularly Alzheimer's disease (AD) and related disorders, remain difficult to treat because of their multifactorial pathogenesis, limited disease-modifying therapies, and insufficient central nervous system exposure of many therapeutic agents. Plant-derived exosome-like nanoparticles (PELNs) are emerging as biogenic nanovesicles that combine intrinsic bioactivity with natural nanocarrier properties. Enriched with lipids, proteins, small RNAs, and phytochemicals, PELNs may exert neuroprotective effects while offering opportunities for gastrointestinal stability, systemic transport, and potential central nervous system delivery. This review critically summarizes the dual bioactive-delivery roles of PELNs in AD and related neurodegenerative disorders. We discuss their potential mechanisms in modulating neuroinflammation, glial cell-mediated immune responses, redox imbalance, mitochondrial dysfunction, pathological protein aggregation, neural repair, and gut-brain axis regulation. We further examine how administration routes, biodistribution patterns, cellular uptake, and blood-brain barrier (BBB) models influence the interpretation of evidence for central nervous system (CNS) targeting. In addition, recent advances in isolation, purification, characterization, cargo loading, and surface engineering strategies are reviewed in the context of improving stability, targeting capacity, and translational feasibility. Despite their promise, the clinical development of PELNs remains constrained by source-dependent heterogeneity, non-standardized isolation methods, insufficiently defined critical quality attributes, inconsistent dosing metrics, limited pharmacokinetic and biodistribution data, and unresolved long-term biosafety concerns. Establishing rigorous Chemistry, Manufacturing, and Controls (CMC) frameworks, reproducible quality-control assays, and evidence-based translational pathways will be essential for advancing PELNs from experimental bioactive vesicles to clinically relevant neurotherapeutic platforms.
    Keywords:  AD; Alzheimer’s disease; BBB; PELNs; bioactive nanocarriers; blood-brain barrier; neurodegenerative diseases; plant-derived exosome-like nanoparticles
    DOI:  https://doi.org/10.2147/IJN.S608292
  31. Parkinsonism Relat Disord. 2026 Jun 18. pii: S1353-8020(26)00225-7. [Epub ahead of print]149 108398
    POLG-associated Parkinson's disease-ALS overlap: A novel variant and first reported use of continuous subcutaneous foslevodopa/foscarbidopa infusion in Brait-Fahn-Schwartz disease.
    Kiran Waqar, Mahmoud Shaqfeh, Shivam Om Mittal.
      A 38-year-old Emirati man developed levodopa-responsive young-onset parkinsonism followed by electrophysiologically confirmed amyotrophic lateral sclerosis consistent with Brait-Fahn-Schwartz disease. Whole-genome sequencing identified a novel heterozygous POLG variant (c.2620T > A; p. Leu874Met). Motor fluctuations on oral therapy prompted escalation to continuous subcutaneous foslevodopa/foscarbidopa infusion, achieving near-complete motor normalization at twelve months. This is the first reported use of device-aided therapy in POLG-associated parkinsonian-ALS overlap.
    DOI:  https://doi.org/10.1016/j.parkreldis.2026.108398
  32. Nat Med. 2026 Jun;32(6): 2060-2072
    Plasma proteomic signatures of cellular aging predict human disease.
    Global Neurodegeneration Proteomics Consortium (GNPC)
      Aging is asynchronous across cells and organs. Here we tested whether plasma proteomics can be used to analyze cell type-specific aging. From analyses of over 7,000 plasma proteins measured in 60,542 individuals, we developed machine learning models to estimate the biological age of over 40 cell types spanning neuronal, immune, glial, endocrine, epithelial and musculoskeletal origins. We observed that 20-25% of individuals exhibited accelerated aging in a single cell type and 1-3% in 10 or more cell types. Cellular aging signatures were associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Individuals with the APOE4 genotype showed older astrocytes but younger macrophages compared to APOE3 carriers, whereas the APOE2 genotype had inverse associations. Moreover, extreme astrocyte aging tripled the risk of incident Alzheimer's Disease in individuals with two APOE4 alleles, while youthful astrocytes reduced risk. Individuals with extremely aged compared to youthful skeletal myocytes exhibited a 12.7-fold higher risk of developing amyotrophic lateral sclerosis. In individuals who smoked, extreme respiratory epithelial cell aging was associated with a 58% higher lung cancer risk compared to smoking alone. Specific cellular vulnerabilities and cumulative cellular aging burden influenced survival, with youthful immune and neuronal cell types conferring protective effects. Finally, we developed a polycellular aging risk score that stratified mortality risk across cohorts and proteomics platforms. These findings establish a framework for quantifying human physiology at cellular resolution, revealing heterogeneous aging trajectories and their impact on disease susceptibility and resilience.
    DOI:  https://doi.org/10.1038/s41591-026-04446-y
  33. J Curr Glaucoma Pract. 2026 Jan-Mar;20(1):20(1): 26-30
    Glaucoma and Systemic Neurodegenerative Diseases: The Brain-Eye Continuum.
    Priti Singh, Samendra Karkhur, Vidhya Verma, Saroj Gupta, Arushi Beri.
      Glaucoma is a chronic, progressive optic neuropathy characterized by retinal ganglion cell (RGC) death and visual field loss. It is the leading cause of irreversible blindness globally, affecting more than 70 million people, and its prevalence is expected to rise with aging populations. Traditionally, glaucoma was defined primarily as a disease of intraocular pressure (IOP) dysregulation, but recent decades have reframed it as a complex neurodegenerative disorder involving multiple systemic and local risk factors. In parallel, systemic neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) pose immense healthcare and socioeconomic burdens. The concept of the "eye as a window to the brain" arises from the fact that the retina and optic nerve are direct extensions of the central nervous system (CNS). This has positioned the eye as a valuable site for studying neurodegenerative processes noninvasively, using advanced imaging modalities such as optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA). Glaucoma is a chronic neurodegenerative optic neuropathy, and the concept of the "eye as a window to the brain" highlights its overlap with systemic diseases such as AD, PD, and MS.
    How to cite this article: Singh P, Karkhur S, Verma V, et al. Glaucoma and Systemic Neurodegenerative Diseases: The Brain-Eye Continuum. J Curr Glaucoma Pract 2026;20(1):26-30.
    Keywords:  Air puff; Alzheimer's disease; Glaucoma; Intraocular pressure; Optical coherence tomography; Parkinson's disease; Retinal imaging
    DOI:  https://doi.org/10.5005/jp-journals-10078-1513
  34. Amyotroph Lateral Scler Frontotemporal Degener. 2026 Jun 15. 1-8
    Innate immune signaling as a potential pathomechanistic biomarker for distinct subtypes in amyotrophic lateral sclerosis.
    Marcel Naumann, Stefanie Kretschmer, Johannes Dorst, Hanna Lapp, Kevin Peikert, Susanne Petri, Burkhard Gess, Christine Wolf, Annekathrin Rödiger, Uta Smesny, Francisco Pan-Montojo, Philippe Kerschen, Torsten Grehl, Johannes Prudlo, Martin Regensburger, Albert Ludolph, René Günther, David Brenner, Min Ae Lee-Kirsch, Andreas Hermann.
      Stimulation of the innate immune system has been implicated in ALS and particularly in distinct monogenic forms of ALS. To address whether this is of diagnostic value, we performed a proof-of concept study using qPCR to assess the Interferon score in blood samples of genetic ALS.
    56.5% of genetic ALS patients showed significant IFN activation, highest in C9orf72HRE patients (77.3%). About half of FUS-ALS (52.2%), but none of SOD1-ALS patients demonstrated pathological IFN scores. The IFN score significantly correlated with the ALSFRS-R slope and inversely with the time to severe event as a survival surrogate in this genetic ALS cohort. IFN + patients were more likely to be male, showed more rapid disease progression and higher neurofilament levels.
    The IFN score might have the potential as a stratification and readout tool for biomarker-guided individualized therapy in ALS.
    Keywords:  C9orf72 hexanucleotide repeat expansion; Pathogen-associated molecular patterns (PAMPs); interferon score (IFN score); interferon type 1; neurofilament heavy chain
    DOI:  https://doi.org/10.1080/21678421.2026.2663910
  35. Front Aging Neurosci. 2026 ;18 1814234
    Gerobiotics and neuroprotection: effects on the gut-brain axis in age-related neurodegenerative diseases.
    Betul Kocaadam-Bozkurt, Serkan Aslan, Osman Bozkurt, Mahmut Bodur, Duygu Agagündüz, Ferenc Budán.
      As the global population ages, effective strategies to attenuate or prevent neurodegenerative processes are becoming increasingly important. Gerobiotics, an emerging class of probiotic strains and their derived postbiotics, are considered promising geroprotective agents because of their potential to target fundamental mechanisms of aging, modulate the gut-brain axis, and attenuate age-related cognitive and functional decline. This review aims to synthesize existing evidence from preclinical and clinical studies on the neuroprotective effects of gerobiotics, with particular emphasis on ageing-related changes in gut microbiota composition, systemic inflammation, and the pathophysiology of neurodegenerative diseases. Preclinical animal studies show that gerobiotics ameliorate memory impairment, preserve synaptic integrity, and attenuate neuroinflammation. Furthermore, clinical results suggest improvements in cognitive performance, mood regulation, and gastrointestinal function, particularly in the early stages of neurodegenerative disorders and among individuals with mild cognitive impairment. The microbiota-gut-brain axis has emerged as a relevant therapeutic target, with gerobiotic supplementation representing a multidimensional approach to support healthy cognitive ageing and counteract neurodegenerative processes. The underlying mechanisms, manifested mostly through modulation of microbial metabolites, include the restoration of intestinal and blood-brain barrier integrity, the reduction of neuroinflammation, the enhancement of neurotrophic factors, and the modulation of immunological pathways. Although current evidence is promising, heterogeneity in probiotic strains, dosages, and study designs indicates the need for further rigorous investigation. Further well-designed, large-scale clinical studies are required to establish efficacy, optimize intervention protocols, and support the translation of gerobiotics into evidence-based clinical practice for the prevention and management of age-related neurodegenerative diseases.
    Keywords:  aging; gerobiotics; gut-brain axis; microbiome; neuroprotection
    DOI:  https://doi.org/10.3389/fnagi.2026.1814234
  36. Metab Brain Dis. 2026 Jun 17. pii: 137. [Epub ahead of print]41(1):
    PCSK9 in bridging metabolism and neurodegeneration: a new paradigm for alzheimer's treatment.
    Shreya Sood, Shareen Singh, Thakur Gurjeet Singh.
      Proprotein convertase subtilisin-kexin type 9 (PCSK9) has recently emerged as a significant mediator that links metabolic dysfunction to neurodegeneration related to Alzheimer's disease (AD). It is a well-known and crucial component involved in cholesterol homeostasis. However, its function in the central nervous system (CNS) is still in its early stages. Normally, it is engaged with the breakdown of cholesterol in the body, but within the brain, PCSK9 has been seen to disrupt the homeostasis of cholesterol and its uptake. Receptors such as LDL receptor-related protein-1 (LRP-1) and low-density lipoprotein receptor (LDLR) are crucial for the survival of neurons, as they are responsible for the clearance of amyloid-β (Aβ) and peripheral lipid control. Elevated PCSK9 activity may promote degradation of these receptors, which eventually leads to deposition of Aβ near synapses along with reduced uptake of cholesterol by neurons, which may contribute to neurotoxicity and neuronal dysfunction. This review aims to explore the effect of elevated PCSK9 levels on the development as well as exacerbation of AD via different molecular mechanisms. Along with cholesterol dyshomeostasis, PCSK9 is found to be involved in glucose dysregulation, mechanistic target of rapamycin (mTOR) dysregulation, increased oxidative stress, neuroinflammation, reduced neurogenesis, affected Wnt-β-catenin signaling, and cholinergic signaling. Together, these mechanisms may contribute to AD progression. Preclinical studies show that pharmacological therapies targeting PCSK9 can give promising results by reducing neuroinflammation, modulating lipid homeostasis, and lowering Aβ accumulation. Therefore, modulation of PCSK9 represents a promising therapeutic strategy that warrants further mechanistic and clinical investigation in AD.
    Keywords:  Alzheimer’s Disease; Cholesterol; Dysregulation; Neurodegeneration; Neurogenesis; Neurotoxicity; PCSK9
    DOI:  https://doi.org/10.1007/s11011-026-01900-1
  37. Fluids Barriers CNS. 2026 Jun 17.
    Targeting CD4⁺ T cell infiltration: mechanisms and therapeutic insights into CD4⁺ T cell transmigration across the blood-brain barrier in acute ischemic stroke.
    Congai Chen, Jialin Cheng, Zehan Zhang, Jun Zhou, Shuling Liu, Ying Liu, Chuxin Zhang, Yuxiao Zheng, Yiping Wu, Qinyuan Zhang, Lu Liu, Changxiang Li, Bin Li.
      The blood-brain barrier (BBB) serves as a physical barrier of the central nervous system, characterized by selective permeability and immune isolation. It plays a critical role in transporting essential nutrients for normal neuronal metabolism while preventing the entry of toxic substances into the brain. Following acute ischemic stroke, the integrity of the BBB is compromised, leading to extensive T-cell infiltration into the brain. These infiltrating T cells influence BBB permeability and can exert either protective or detrimental effects on brain tissue. Current research has largely focused on the subset-specific regulation of T cells after their infiltration or on inhibiting T-cell migration into the brain during ischemic stroke. However, a systematic understanding of the routes and mechanisms underlying T-cell trafficking across the BBB in this context remains limited. In this review, we systematically examine the functional alterations of the BBB induced by different CD4+ T-cell subsets in ischemic stroke and explore the associated molecular mechanisms. Special emphasis is placed on the migratory behavior of CD4+ T cells across the BBB, highlighting the roles of selectins, LFA-1, ICAM, and VCAM in mediating T-cell capture, adhesion, and transmigration. We also provide a detailed discussion of immunosuppressive agents clinically used to inhibit the infiltration of peripheral immune cells into the brain. By synthesizing these insights, this review aims to inform the optimization of therapeutic strategies targeting CD4+ T-cell trafficking and to facilitate the development of adjunct neuroprotective approaches, thereby advancing stroke treatment and improving patient outcomes. Ultimately, this work seeks to deepen the understanding of the mechanisms by which CD4+ T cells influence ischemic stroke and to provide a theoretical foundation for novel immunomodulatory neuroprotective therapies.
    Keywords:  Blood–brain barrier (BBB); CD4⁺ T cell; Ischemic stroke; Neuroinflammation; Transendothelial migration (TEM)
    DOI:  https://doi.org/10.1186/s12987-026-00821-6
  38. Int J Nanomedicine. 2026 ;21 618081
    Hydrogels in Neurological Disorders: Emerging Diagnostic and Therapeutic Applications.
    Nan-Nan Wang, Fei Cao, Da Xu.
      The clinical management of neurological disorders remains a major challenge worldwide, constrained by fundamental limitations in both diagnosis and therapy. Electroencephalography (EEG), the cornerstone of neurological assessment, is limited by low spatial resolution and inconsistent signal quality. Therapeutically, the blood-brain barrier (BBB) restricts drug delivery to the brain, resulting in subtherapeutic intracerebral concentrations. These convergent diagnostic and delivery bottlenecks underscore an urgent imperative for innovative materials and technologies. Hydrogels, characterized by biomimetic three-dimensional (3D) architectures, have emerged as a versatile material platform to bridge this gap. From a diagnostic perspective, hydrogels-based electrodes exhibit exceptional biocompatibility and low interfacial impedance, enabling high-fidelity EEG acquisition while minimizing insult to sensitive neural and skin tissues. From a therapeutic perspective, their 3D architecture provides versatile scaffolds for therapeutic agents, supporting high loading efficiency and programmable release profiles for neurological interventions. In this review, we first outline the physicochemical properties and fabrication techniques of hydrogels. We then discuss their applications, with particular emphasis on neural bio-electrodes, brain-computer interfaces (BCIs), drug delivery, and neuro-bioengineering. Finally, we examine the challenges impeding the clinical translation of hydrogels and outline prospective mitigation strategies. The integration of these functionalities is anticipated to advance closed-loop therapeutic systems for the precise management of complex neurological disorders.
    Keywords:  brain computer interface; drug delivery; flexible electrode; hydrogel; neurological disorders
    DOI:  https://doi.org/10.2147/IJN.S618081
  39. Cell Chem Biol. 2026 Jun 18. pii: S2451-9456(26)00188-1. [Epub ahead of print]33(6): 742-744
    S-acylation of TDP-43: PALMing down aggregation?
    Ruonan Yang, Yanshan Fang.
      S-acylation is well known for regulating protein stability and trafficking. In a recent issue of Molecular Cell, Xu et al.1 reveal a distinct, aggregation-suppressing function of this posttranslational lipid modification: S-acylation of the RNA-binding protein TDP-43 antagonizes poly(ADP-ribose)-driven condensation. Moreover, reduced S-acylation levels are linked to ALS pathogenesis.
    DOI:  https://doi.org/10.1016/j.chembiol.2026.05.009
  40. Sci Rep. 2026 06 15. pii: 18516. [Epub ahead of print]16(1):
    Aberrant immunomodulatory signature in β-propeller protein-associated neurodegeneration patient iPSC-derived microglia.
    Gamze Özata, Rachel M Wise, Aida Cardona-Alberich, Naiyareen F Mayeen, Stephan A Müller, Stefan F Lichtenthaler, Luigi Zecca, Lena F Burbulla.
      Microglia are the brain's resident immune cells, essential for homeostasis and implicated in common neurodegenerative diseases like Alzheimer's and Parkinson's disease (PD), where their early activation and sustained inflammatory mediator release contribute to neuronal loss. However, their role in rare disorders is unclear. β-propeller protein-associated neurodegeneration (BPAN), caused by WDR45 mutations, shares key features with PD, including iron accumulation and dopaminergic neuron loss, but the impact of microglia and mutant WDR45 in BPAN pathophysiology remains unexplored. To address this, we established the first induced pluripotent stem stell (iPSC)-derived microglia model from BPAN patients. Parallel targeted transcriptomic and secretomic profiling revealed a shift from a homeostatic microglial toward a stress-adapted and transcriptionally reprogrammed state characterized by selective remodeling of immune signaling pathways and dysregulation of autophagy and cellular stress responses. Complementary secretomic analysis identified reduced secretion of lysosomal enzymes alongside increased shedding of immune-associated surface proteins, indicating altered lysosomal trafficking and remodeling of microglial immune signaling. These findings identify a distinct microglial phenotype in BPAN and implicate microglial dysfunction as a potential contributor to disease mechanisms, highlighting new avenues for therapeutic strategies targeting neuroimmune pathways.
    DOI:  https://doi.org/10.1038/s41598-026-55648-w
  41. J Mol Neurosci. 2026 Jun 16. pii: 105. [Epub ahead of print]76(3):
    The Association Between Alzheimer's Disease-Related Biomarkers And Parkinson's Disease Based On Single-Cell Sequencing Analysis Combined With Mendelian Randomization.
    Xiaodong Duan, Delong Huang, Haoshu Zhong, Xiaowei Guo, Xingyu Lu, Junhao Wu, Liheng Huang.
      Parkinson's disease (PD) and Alzheimer's disease (AD) are both neurodegenerative disorders sharing overlapping pathological mechanisms. Several studies suggest that AD biomarkers may have diagnostic and predictive value in PD, but causal evidence remains insufficient. This study aimed to explore the association between AD-related biomarkers and PD. Bidirectional two-sample Mendelian randomization (MR) was performed using GWAS summary statistics of AD-related biomarkers and PD to assess causal relationships. Subsequently, single-nucleus RNA sequencing (snRNA-seq) of postmortem midbrain tissues was employed to examine the expression of AD biomarkers in PD patients and to explore underlying cellular signaling pathways. Forward MR revealed a significant causal association between PD and decreased CSF p-tau levels. PD progression showed significant causal associations with decreased CSF Aβ42 and increased CSF total tau. Reverse MR indicated that elevated CSF total tau may increase PD risk. SnRNA-seq analysis demonstrated that MAPT (encoding tau) was predominantly expressed in dopaminergic neurons, with differentially expressed genes enriched in PD- and neurodegeneration-related pathways. Our findings provide preliminary, hypothesis-generating evidence at the genetic level suggesting potential associations between CSF tau, Aβ42, and PD or its progression. Bidirectional MR analyses suggest that CSF total tau may be associated with increased PD risk, while exploratory snRNA-seq analysis indicates that MAPT is predominantly expressed in dopaminergic neurons with enrichment in PD-related pathways. Given the limited number of instrumental variables for several exposures, the small snRNA-seq cohort, and the absence of protein-level validation, these findings should be interpreted with caution. Large-scale prospective clinical studies with protein-level biomarker assessment, tau-PET imaging, and independent multi-cohort transcriptomic validation are warranted before CSF total tau can be considered a candidate biomarker for PD progression.
    Keywords:  Amyloid; Mendelian randomization; Parkinson's disease; Single-cell transcriptome; Tau
    DOI:  https://doi.org/10.1007/s12031-026-02558-1
  42. Lancet Neurol. 2026 Jul;pii: S1474-4422(26)00141-9. [Epub ahead of print]25(7): 673-688
    Bruton's tyrosine kinase inhibitors: a new class of multiple sclerosis therapeutics.
    Jiwon Oh, Amit Bar-Or, Xavier Montalban, Maria Pia Sormani, Martin S Weber, Daniel S Reich.
      Bruton's tyrosine kinase (BTK) is an intracellular enzyme involved in a wide range of cellular functions. BTK inhibitors (BTKIs) are of interest in multiple sclerosis because they modulate various types of immune cells that have key roles in multiple sclerosis pathophysiological processes, including B cells and microglia. Moreover, because BTKIs are small molecules that might cross the blood-brain barrier and potentially modulate relevant cells within the CNS, there is added interest in their use in multiple sclerosis. In the past decade, there has been a flurry of drug development of BTKIs in multiple sclerosis. The BTKIs being evaluated in multiple sclerosis have differences in pharmacological properties that might result in meaningful differences in safety and efficacy. Recently reported phase 2 and phase 3 clinical trials have provided the field with renewed hope that some BTKIs could modulate progressive multiple sclerosis disease mechanisms that current disease-modifying treatments insufficiently address. However, meaningful differences in clinical outcomes and MRI findings have been reported. If the beneficial findings seen with some BTKIs are confirmed, these observations suggest the beginning of a new era of treatment in multiple sclerosis. The results of upcoming clinical trials, real-world studies, and regulatory approval decisions will guide a more nuanced approach to determining the patient populations that will benefit most from this treatment class.
    DOI:  https://doi.org/10.1016/S1474-4422(26)00141-9
  43. J Parkinsons Dis. 2026 Jun 19. 1877718X261461375
    Structural biology of alpha-synuclein amyloid filaments: Implications in synucleinopathies.
    Phelippe do Carmo Gonçalves, Irina Fernández, Claudio O Fernández Outón.
      Synucleinopathies are a group of neurodegenerative disorders characterized pathologically by the presence of neuronal and/or oligodendrocyte inclusions composed of aggregated alpha-synuclein (αS). These disorders can be divided into two major sub-types: Lewy body disease and multiple system atrophy, which have distinct clinical and pathological profiles. As is seen with other neurodegenerative diseases, recent evidences suggest that the conformation and molecular organization of αS amyloid filaments deposited in brains might dictate the distinct pathological and clinical profiles in synucleinopathies. Resolving the structure of disease-specific αS aggregates becomes, therefore, of clinical interest. Until recently, the specific conformations of these aggregates at molecular resolution have remained elusive. This is now possible due to the advent and development of cryo-electron microscopy (cryo-EM) technology. This review aims to cover the recent advances in the structural biology of αS amyloid filaments implicated in synucleinopathies, raising a number of critical questions that continue to be investigated. What can we learn from these structures? What are the main structural differences between experimental systems and human tissue derived protein aggregates? What factors drive these differences? Do the amplified assemblies represent faithfully the seed structures? How these new findings improve our understanding of the molecular mechanisms behind fibril formation in disease? Can this knowledge be exploited for the design of diagnostic and therapeutical strategies? These aspects and the recent advances in the field will be addressed and discussed in this work.
    Keywords:  Amyloid; cryo-EM; disease modeling; polymorphism; therapy
    DOI:  https://doi.org/10.1177/1877718X261461375
  44. Front Physiol. 2026 ;17 1823430
    The lactate shuttle in ageing: a metabolic bridge between muscle fatigue and brain resilience.
    Yu Zhang, Wenyi Yang, Chunlan Tian.
      Traditionally, lactate was considered a glycolytic byproduct that causes muscle fatigue, but now its biological role is undergoing a significant paradigm shift. Emerging evidence suggests that lactate acts as an inter-organ metabolic and signaling mediator linking exercise-induced peripheral metabolic stress to central nervous system adaptation. This review explores how exercise drives lactate pulses and delivers them to the brain through the circulatory system and blood-brain barrier (BBB). Lactate has a dual function in the brain, serving not only as the preferred energy substrate for active neurons but also as a core signaling molecule. Through pathways involving G protein coupled receptor 81 (GPR81) and histone lactylation, lactate regulates neuroplasticity, cerebrovascular function, neuroinflammation, and antioxidant defense, thereby establishing cognitive resilience. During aging, multiple components of this proposed lactate signaling axis may become compromised, including skeletal muscle lactate production, circulatory and blood-brain barrier transport, and cellular responsiveness within the brain. Such multi-level impairment may contribute to neuromuscular co-aging and may increase vulnerability to neurodegenerative disorders, including Alzheimer's disease. Ultimately, we explored the translational potential of restoring the lactate signaling axis through multimodal strategies to promote healthy aging, including precise exercise prescriptions, GPR81 targeted therapy, metabolic interventions, and biomarker development. This review aims to combine metabolic science with evidence of neuroaging, providing a new theoretical framework for determining the primacy of exercise-driven brain health and advancing anti-aging interventions.
    Keywords:  GPR81 receptor; aging; blood-brainbarrier; exercise; histone lactylation; lactate; lactate shuttle; neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fphys.2026.1823430
  45. Front Aging. 2026 ;7 1829442
    Increased neurotoxic gliosis and blood-brain barrier dysregulation in canine cognitive dysfunction syndrome (CCD).
    Sean W Boland, Greta N Coyner, Sydney J Risen, Abdullatif Alsulami, Stephanie McGrath, Julie A Moreno.
       Background: As Alzheimer's Disease (AD) and related dementias (ADRD) prevalence is projected to double by 2050, the urgency for relevant models to study its pathology intensifies. Aging is the primary risk factor for AD development and influenced by a myriad of factors including neurotoxic glial activation and BBB degradation; however, historically AD models consist of transgenic mouse in-vivo and in-vitro methods. While this offers many strengths, it is limited in their ability to mimic aging induced AD pathology. Currently, canine cognitive dysfunction (CCD) syndrome is being investigated as it is a natural and spontaneous disease with similar pathologies to AD and other dementias. Our lab and many others have worked extensively to characterize CCD pathology. However, the role of microglial and astrocytic activation and the interplay between the blood-brain barrier (BBB) have not been investigated. This study aims to fill this gap in knowledge in CCD and in turn its relation to human AD. We hypothesize that CCD-afflicted canines will exhibit increased neurotoxic glial activation and BBB degradation.
    Methods/Results: We utilized immunohistochemistry (IHC), morphological analyses, and immunofluorescence to investigate CCD pathology comparing CCD negative and CCD positive dogs. In this study we see glial morphology consistent with those seen in neurotoxic glia in neurodegenerative disease, increased S100β/C3 astrocyte activation, decreased claudin-5 expression, and region-dependent perivascular AQP4 expression modulation in dogs with CCD, compared to those without CCD.
    Conclusion: Our results further characterize glial and BBB roles in CCD pathogenesis and reinforces the strengths of modeling AD/ADRD in aging dogs.
    Keywords:  astrocytes; blood-brain barrier (BBB); canine cognitive dysfunction; microglia; neuroinflamamation
    DOI:  https://doi.org/10.3389/fragi.2026.1829442
  46. Mol Neurobiol. 2026 Jun 17. pii: 699. [Epub ahead of print]63(1):
    Focused Ultrasound Modulation of PGC-1α Pathways in Neurological Disease: Mechanistic Rationale and Translational Opportunities.
    Yu Ning, Yan Gao.
      The brain's disproportionate energy demand creates an enduring bioenergetic imperative where mitochondrial performance directly determines synaptic resilience and neuronal survival. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) has emerged as a master transcriptional regulator orchestrating mitochondrial biogenesis, antioxidant defenses, proteostasis, and neuroplasticity, with dysregulation of this axis representing a convergent pathogenic mechanism across Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, and neuropsychiatric disorders. Despite compelling preclinical evidence, conventional pharmacological PGC-1α activators confront fundamental translational barriers including poor blood-brain barrier penetration, inadequate bioavailability, and off-target metabolic effects. This review synthesizes mechanistic evidence suggesting that focused ultrasound may provide a noninvasive platform for regionally precise modulation of PGC-1α pathways. In this review, focused ultrasound is presented as a proposed upstream modulator of the PGC-1α axis. Existing studies support its ability to induce membrane tension, engage mechanosensitive channels such as Piezo1 and TRAAK, and trigger downstream kinase signaling, but the full ultrasound → PPARGC1A → neuroprotection chain in brain tissue remains a working hypothesis rather than a demonstrated therapeutic mechanism. Indirect priming through reversible blood-brain barrier opening, hemodynamic augmentation, and glial immunomodulation may further facilitate this model. We integrate emerging concepts including the mitochondrial synapse, PGC-1α isoform diversity, and theranostic architectures combining functional ultrasound mapping with targeted sonication. By defining mechanistic opportunities, disease-specific therapeutic strategies, and the sonogenetics frontier, this review proposes a hypothesis-generating roadmap for ultrasonic modulation of PGC-1α-dependent neuroprotection, a drug-free, focal approach that converts acoustic energy into a testable mitonuclear rescue framework requiring direct experimental validation.
    Keywords:  Focused ultrasound; Mechanotransduction; Mitochondrial biogenesis; Neuroprotection; PGC-1α
    DOI:  https://doi.org/10.1007/s12035-026-06005-5
  47. Neurology. 2026 Jul 28. 107(2): e218247
    Teaching Video NeuroImage: Beyond Cognition: Amyotrophic Lateral Sclerosis-Like Disease in PSEN1 c.1292C>A (Jalisco Founder Effect) Variant.
    Gonzalo Andrés Pacheco-Ortega, Oscar Esquivel-Zapata, Enrique Piña-Rosales, David J Davila-Ortíz de Montellano, Petra Yescas Gomez, Raul Medina-Rioja.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000218247
  48. Front Pharmacol. 2026 ;17 1810881
    Neuroprotective effects of traditional Chinese medicine using zebrafish models - a review.
    Jun Shao, Yun An, Ruicong Ding, Shanshan Wang, Xueke Wang.
      Neurological disorders, including Alzheimer's disease, Parkinson's disease, and stroke, remain major causes of global disability and mortality, with limited neuroprotective therapies available. Traditional Chinese medicine (TCM) offers multi-target therapeutic potential, but its mechanistic complexity requires systematic investigation using appropriate model systems. Zebrafish (Danio rerio) has emerged as a valuable vertebrate platform for TCM neuroprotection research due to its genetic homology with humans, optical transparency, and high-throughput screening compatibility. This review summarizes the application of zebrafish models in studying TCM for Alzheimer's disease, Parkinson's disease, cerebral ischemia, epilepsy, insomnia, depression, and spinal cord injury. Key findings indicate that TCM metabolites exert neuroprotective effects through multiple mechanisms, including anti-oxidative stress, anti-neuroinflammation, anti-apoptosis, neurotransmitter modulation, neurogenesis promotion, and vascular protection. Zebrafish models have proven particularly useful for high-throughput screening of active metabolites, real-time in vivo imaging of neurovascular processes, and rapid safety assessment. However, limitations such as the absence of a layered neocortex, differences in drug metabolism, and the predominantly acute nature of current models must be acknowledged. Addressing these challenges through model standardization, multi-omics integration, and cross-species validation will further enhance the translational relevance of zebrafish-based TCM research. This review provides a practical framework for leveraging zebrafish models to advance the mechanistic understanding and clinical development of neuroprotective TCM therapies.
    Keywords:  Traditional Chinese Medicine; clinical translation; drug screening; neurological disorders; neuroprotection; zebrafish
    DOI:  https://doi.org/10.3389/fphar.2026.1810881
  49. Nanomedicine (Lond). 2026 Jun;21(12): 1775-1795
    Next-generation intranasal delivery nano-platforms for targeted brain therapy of Alzheimer's disease.
    Akanksha Malaiya, Rameshroo Kenwat, Aanjaneya Mamgain, Shivani Rai Paliwal, Kunjbihari Sulakhiya, Sabyasachi Maiti, Rishi Paliwal.
       INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that poses a growing global health burden. Effective drug delivery to the brain is largely constrained by the selective nature of the blood-brain barrier (BBB), which limits therapeutic efficacy of conventional oral medications. Intranasal administration has emerged as a noninvasive and promising route for direct nose-to-brain transport, circumventing BBB restrictions.
    AREA COVERED: This review explores the potential of intranasal drug delivery as an alternative approach for targeted brain therapy in Alzheimer's disease. It comprehensively discusses the mechanisms of nasal absorption, physiological and formulation-related barriers, and the role of advanced nanocarrier platforms in overcoming these limitations. Emphasis is placed on recent innovations involving polymeric, lipid-based, and vesicular carriers, along with the incorporation of mucoadhesive and permeation-enhancing agents.
    EXPERT OPINION: The present focus is enhancing bioavailability, prolonging drug residence time, and minimizing systemic toxicity. Surface modifications of nanocarriers further facilitates mucosal adhesion and enables effective nose-to-brain transport of encapsulated therapeutic agents. However, clinical translation remains challenging due to interindividual variability in nasal physiology, scalability constraints, and regulatory complexities. Future progress will depend on the rational design of multifunctional nanocarriers, integration of mucoadhesive and stimuli-responsive components, and the use of precision-based formulation strategies.
    Keywords:  Alzheimer’s disease; blood brain barrier; brain targeting; nanoparticles; nose-to-brain delivery
    DOI:  https://doi.org/10.1080/17435889.2026.2685131
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