Brain最新文献

{"title":"Decoding inflammatory pathways in spinal muscular atrophy: implications for next-generation therapies.","authors":"Linda Ottoboni,Claudio Bruno,Stefania Corti","doi":"10.1093/brain/awaf392","DOIUrl":"https://doi.org/10.1093/brain/awaf392","url":null,"abstract":"Spinal muscular atrophy (SMA) is a devastating neurodegenerative disorder caused by SMN1 gene mutations that lead to compromised production of survival motor neuron (SMN) protein. The inflammatory footprint of SMA extends beyond neural tissues, leading to significant inflammatory manifestations across multiple body systems. In motor neurons, several molecular pathways contribute to local degeneration: cytokine activation, purinergic signalling, NF-κB pathway stimulation, complement cascade activation, and glutamate excitotoxicity. These mechanisms, which involve reactive glial and immune cells, trigger neuroinflammation and non-cell-autonomous death processes that can affect non-neural organ systems. Biological samples from patients with SMA and model systems of SMA consistently exhibit altered immune patterns, elevated inflammatory markers, and immunocyte and glial dysfunction. Even revolutionary SMN-restoring therapy for SMA may not treat the potential inflammation-related aspects of the disease. Current research has identified both anti-inflammatory and pro-inflammatory effects and outcomes after SMN restoration, with unclear implications. Preclinical investigations targeting inflammation in SMA models have yielded promising findings, although optimal intervention timing requires refinement. Despite these encouraging results, translation to clinical practice remains unrealized. The field requires advanced investigative approaches, particularly single-cell RNA sequencing, to elucidate inflammatory molecular pathways, identify novel biomarkers for early detection, and develop targeted anti-inflammatory agents that complement SMN-augmenting therapies. Understanding the inflammatory mechanisms associated with SMA is crucial for developing effective combination therapies addressing both SMN deficiency and inflammatory processes. Elucidating inflammation timing and mechanisms will inform optimal intervention windows and identify patients most likely to benefit from combined treatment approaches. Future research should prioritize personalized strategies targeting both SMN-dependent and inflammatory pathways.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"12 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PET-MRI biomarkers reveal efficacy of a novel NLRP3 inhibitor in Parkinson's disease models.","authors":"Eduardo A Albornoz,Karine Mardon,Rajiv Bhalla,Vinod Kumar,Damion H R Stimson,Gary Cowin,Cedric S Cui,Mark S Butler,Ruby Pelingon,Richard Gordon,Rebecca C Coll,Kate Schroder,Reena Halai,Angus M MacLeod,Kim Matthews,Avril A B Robertson,Matthew A Cooper,Trent M Woodruff","doi":"10.1093/brain/awaf372","DOIUrl":"https://doi.org/10.1093/brain/awaf372","url":null,"abstract":"Parkinson's disease is one of the fastest-growing neurodegenerative disorders, with no effective treatments to modify its progression. Microglial-driven neuroinflammation, mediated by NLRP3 inflammasome activation, plays a key role in disease onset and progression. The NLRP3 inflammasome is upregulated in microglia from Parkinson's disease patients and activated by oxidative stress and a-synuclein aggregates, triggering the release of pro-inflammatory mediators that contribute to neuroinflammation and neuronal death. MCC950, the first described specific NLRP3 inhibitor, has shown promise in Parkinson's disease models but is limited by suboptimal pharmacokinetics and safety, hindering its clinical development. Here, we developed a novel NLRP3 inflammasome inhibitor, MCC7840 (also known as Inzomelid or Emlenoflast), and utilised clinically relevant PET-MRI imaging biomarkers to assess its therapeutic efficacy in preclinical models of Parkinson's disease. MCC7840 inhibited NLRP3 in human and mouse microglia with nanomolar potency, while demonstrating improved systemic exposure, half-life, brain permeability, and bioavailability compared to MCC950. In a murine NLRP3 gain-of-function model of Muckle-Wells syndrome, MCC7840 effectively inhibited mortality and demonstrated superior potency compared to MCC950. Chronic oral administration of MCC7840 protected against neuroinflammation, motor deficits, and dopamine loss in both 6-hydroxydopamine and preformed α-synuclein fibril mouse models of Parkinson's disease. Radiotracer imaging of multiple PET markers in the same mouse revealed that MCC7840 attenuated neuroinflammation ([18F]DPA-714), preserved dopamine uptake ([18F]FDOPA), mitigated dopamine transporter loss ([18F]FBCTT), and reduced blood-brain barrier leakage (gadolinium contrast MRI). Notably, MCC7840 was effective in a slowly progressing 12-month α-synuclein model, even when administered after symptom onset, 4 months post-α-synuclein injection. These findings highlight the utility of PET/MRI as a non-invasive tool to evaluate drug efficacy and support MCC7840, and other brain-penetrant NLRP3 inhibitors, as promising disease-modifying therapies for Parkinson's disease, warranting future clinical investigation.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"25 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RAB3A variants in ataxia and other neurodegenerative disorders.","authors":"Marco Percetti,Edoardo Monfrini,Roberto Del Bo,Margherita Canesi,Francesco Cavallieri,Giulia Di Rauso,Valentina Fioravanti,Eleonora Del Prete,Daniela Frosini,Giovanni Palermo,Roberto Ceravolo,Giorgio Sacilotto,Alessio Di Fonzo","doi":"10.1093/brain/awaf383","DOIUrl":"https://doi.org/10.1093/brain/awaf383","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"37 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Charcot redux","authors":"A J Lees","doi":"10.1093/brain/awaf386","DOIUrl":"https://doi.org/10.1093/brain/awaf386","url":null,"abstract":"Jean-Martin Charcot was born in Paris on 29 November 1825. To mark the bicentenary of his birth, the International Society for the History of the Neurosciences held a meeting in July 2025 at the Brain Institute in Paris. AJ Lees discusses the event and reflects on how Charcot’s scientific legacy continues to shape neurology today.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"19 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adieu to an aphorism: why nociception is necessary for pain","authors":"Asaf Weisman, John Quintner, Milton Cohen","doi":"10.1093/brain/awaf387","DOIUrl":"https://doi.org/10.1093/brain/awaf387","url":null,"abstract":"An aphorism is a short saying intended to express a general truth. In this paper, the popular aphorism, “nociception is neither necessary nor sufficient for pain,” is critically examined. While the latter part of that aphorism, that nociception is not always associated with pain, is not controversial, the former part, that pain can occur without nociception, poses a major challenge to scientific and clinical understanding. This article traces the origins of this part of the aphorism in the pain-related literature and the empirical evidence upon which it is based. The assertion that nociception is not necessary for pain is found to contradict the definition of pain itself. Furthermore, the observational and experimental evidence drawn upon to support that assertion does not withstand critical examination. It is shown that the assertion that nociception is not necessary for pain is untenable on both logical and biological grounds. It is argued therefore that the aphorism should be discarded in favour of “nociception is necessary but not sufficient for pain. The conceptual, scientific and clinical implications of this signal change in principle are discussed.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"62 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding sensory abnormalities in fibromyalgia through autoantibodies.","authors":"Andreas Themistocleous,Steven J Middleton,John M Dawes","doi":"10.1093/brain/awaf384","DOIUrl":"https://doi.org/10.1093/brain/awaf384","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"52 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compound heterozygous mutations in the SSPOP gene lead to epilepsy and developmental disorders.","authors":"Aojie Cai,Fan Zhang,Jinliang Li,Jingmin Wang,Ye Wu,Yuehua Zhang,Kai Gao,Yuwu Jiang","doi":"10.1093/brain/awaf327","DOIUrl":"https://doi.org/10.1093/brain/awaf327","url":null,"abstract":"The SSPOP gene, currently classified as a pseudogene in the human genome, encodes the SCO-spondin protein, which plays an important role in human neurodevelopment, though its function remains poorly understood. In this study, we used trio-based whole exome sequencing to identify compound heterozygous SSPOP variants in four children from three unrelated families, including one pair of dizygotic twins. These children exhibited variable phenotypes, including variation in age of onset, seizure semiology, and response to antiseizure medications, along with neurodevelopmental disorders. We demonstrated that SSPOP is a functional gene by confirming its expression at both the transcriptional and protein levels. We analysed ten brain tissue samples from seven pediatric patients and brain organoids derived from human iPSCs to confirm its expression via qRT-PCR, immunofluorescence and Western blotting, supporting its biological function during both prenatal and postnatal stages of brain development. In addition, CRISPR-mediated sspo knockout zebrafish demonstrated abnormal neurodevelopment and epileptic discharges in vivo. Together, these findings suggest that SSPOP is a functional gene and a potential contributor to neurodevelopmental disorders and epilepsy.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"136 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Motor learning after stroke: what we’ve learned and what lies ahead","authors":"Ellen T Koch, Sean P Dukelow, Tyler Cluff","doi":"10.1093/brain/awaf388","DOIUrl":"https://doi.org/10.1093/brain/awaf388","url":null,"abstract":"Each year, there are millions of new stroke survivors globally. As many as 75% of stroke survivors will have impairments in moving their upper limb(s) that compromise daily activities like eating and grooming. Stroke rehabilitation practices often rely on motor learning principles to facilitate the recovery of motor function. Many principles applied in a therapy setting have been derived from studies involving healthy adults, even though stroke-related brain damage may alter these processes. Other studies have focused on the chronic stage of stroke recovery (>6 months post-stroke), despite most rehabilitation taking place in the first weeks and months post-stroke. It is unclear how motor learning and the underlying neuroplastic changes differ from early (acute and subacute) to late (chronic) stages of recovery. An evidence-based understanding of how motor learning is affected early after stroke, and how these changes interact with the course of motor recovery may hold promise for improving rehabilitation outcomes. In this review, we focus on two major categories of motor learning: motor skill learning and sensorimotor adaptation. We provide a comprehensive review of studies of stroke survivors, organized around a conceptual framework that examines how motor learning is impaired after stroke, what clinical and demographic factors interact with motor learning capacity, and where in the brain lesions are associated with poorer outcomes. We highlight key priorities for future research, including early post-stroke assessment of motor learning, large-scale longitudinal studies, standardized designs for comparability between studies, and a better understanding of factors like reinforcement and explicit task instruction that may alter learning. We conclude with recommendations to help bridge the gap between motor learning research and stroke rehabilitation practice.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"1 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145295600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KIF2A downregulation links amyloid-β to Tau phosphorylation in Alzheimer's disease","authors":"Nuria Ruiz-Reig, Margaux Virosztek, Georges Chehade, Nuria Suelves, Nathalie Kyalu Ngoie Zola, Yasmine Salman, Olivier Schakman, Pascal Kienlen-Campard, Bernard Hanseeuw, Fadel Tissir","doi":"10.1093/brain/awaf382","DOIUrl":"https://doi.org/10.1093/brain/awaf382","url":null,"abstract":"Microtubules (MT) are essential components of the cytoskeleton. Dysfunctions of MT and MT-associated proteins are prominent features of neurodegenerative disorders. In Alzheimer's disease (AD), changes in MT composition and hyperphosphorylation of Tau are more closely related to neurodegeneration than amyloid plaque formation. However, the accumulation of amyloid beta (Aβ) species is the earliest event in AD pathology and induces Tau toxicity. KIF2A is a microtubule depolarizing kinesin with important roles during cortical development. KIF2A expression is maintained in the mature brain, where it is required for neuronal survival. Here, we used a conditional approach to ablate KIF2A specifically in the adult mouse cortex and hippocampus to assess the impact of KIF2A deletion on neuronal survival and Tau phosphorylation. We found that KIF2A deficiency leads to a reduction of dendritic spine density and maturation associated with cognitive decline, followed by an increase in Tau phosphorylation through ERK1/2 activation. We also studied KIF2A expression in 5xFAD mouse model and post-mortem human brain tissue. We report that Aβ accumulation alters KIF2A expression in neurons and most importantly, KIF2A protein levels are drastically reduced in AD patients but not in patients with other primary Tauopathies. Our results shed light on the relationship between Aβ accumulation, KIF2A deregulation, microtubule dysfunction, and enhanced Tau phosphorylation in the context of AD.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"16 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Folate deficiency in women with epilepsy: a scoping review.","authors":"Ammar T Abdulaziz,Nanya Hao,Terence J O'Brien,Josemir W Sander,Jinmei Li,Dong Zhou","doi":"10.1093/brain/awaf298","DOIUrl":"https://doi.org/10.1093/brain/awaf298","url":null,"abstract":"Folate deficiency is associated with increased risks of adverse maternal and offspring health outcomes. This review aimed to review the available evidence on folate deficiency among women with epilepsy, particularly potential causes and identified predictors of inadequate folic acid (FA) supplement use. We conducted this review using the PRISMA extension for scoping reviews. We searched Medline, Embase, EBM reviews and all Ovid journals for studies reporting on folate status/FA use in women with epilepsy. Of 3778 items reviewed, 105 relevant articles were identified and included. Many reports suggest that folate deficiency is common among women with epilepsy. Common triggers for folate deficiency include poor dietary intake, inadequate FA use, genetic susceptibility, poor fortification policies, antiseizure medications, increased demands, chronic inflammation, lifestyle factors and lack of counselling. The prevalence of FA use among women with epilepsy is low, with more than half not taking supplements before conception. Predictors of inadequate FA use are unplanned pregnancy, low educational achievement, low socio-economic status, being part of an ethnic minority, lack of counselling, young age, no antiseizure medication exposure and concerns about its use. Current practice needs adjustments towards establishing an adequate, rather than minimal, folate concentration in women with epilepsy to prevent adverse outcomes. One-size-fits-all seems inappropriate; folate intake should be individualized and adjusted to achieve adequate folate status based on folate levels and other metabolic biomarkers. Folate deficiency in women with epilepsy may reflect disparities in care and links to several social determinants of health. Despite the potential progress recently achieved in understanding folate deficiency in women with epilepsy, there are still significant gaps in knowledge requiring further work. Folate deficiency is common among women with epilepsy. The causes of folate deficiency are multifactorial, and awareness, early recognition, proper intervention and regular follow-ups are required to maintain adequate folate levels. Establishing an adequate, rather than minimal, folate concentration to prevent adverse outcomes is imperative. More work is needed to understand the mechanisms of folate deficiency in women with epilepsy and to develop the optimal intervention strategies.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"23 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}