Brain最新文献

{"title":"Direct electrical stimulation maps white matter anatomy to function.","authors":"Davide Giampiccolo,Guillaume Herbet,Hugues Duffau","doi":"10.1093/brain/awaf188","DOIUrl":"https://doi.org/10.1093/brain/awaf188","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"9 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144087647","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":"FGF14 repeat length and mosaic interruptions: modifiers of spinocerebellar ataxia 27B?","authors":"Joshua Laß, Mirja Thomsen, Max Borsche, Theresa Lüth, Julia C Prietzsche, Susen Schaake, Andona Milovanović, Hannah Macpherson, Emil K Gustavsson, Paula Saffie Awad, Nataša Dragašević-Mišković, Björn-Hergen Laabs, Inke R König, Ana Westenberger, Christopher E Pearson, Norbert Brüggemann, Christine Klein, Joanne Trinh","doi":"10.1093/brain/awaf183","DOIUrl":"https://doi.org/10.1093/brain/awaf183","url":null,"abstract":"Deep intronic FGF14 repeat expansions have been identified as a frequent genetic cause of late-onset cerebellar ataxias, explaining up to 30% of patients. Interruptions between repeats have previously been identified to impact the penetrance in other repeat expansion disorders. Repeat interruptions within FGF14 have yet to be characterized in detail. We utilized long-range PCR, Sanger sequencing, repeat-primed PCR, Nanopore, and PacBio sequencing to distinguish the repeat motifs, mosaicism, and number of repeat interruptions present in FGF14-related ataxia patients and unaffected individuals. A total of 304 patients with late-onset ataxia and 190 unaffected individuals were previously screened for repeat expansions in the FGF14 gene by long-range PCR, identifying 37 individuals with expanded repeat lengths (≥250 repeats). These, along with three newly identified expansion carriers were included in the present study, and advanced genetic methods were applied to investigate the repeat composition in 27 patients and 13 unaffected individuals. The expansions, based on Nanopore data, ranged from 236 to 486 repeats (SD = 60), with 20 individuals showing repeat interruptions, including complex motifs such as GAG, GAAGGA, GAAGAAAGAA, GAAAAGAAGAAGGAAGAAGGAA, GAAAAGAAGAAGGAA, and GCAGAAGAAGAAGAA. We calculated the longest pure GAA length from the long-read data for all 40 individuals. When comparing the pure GAA tract between patients and unaffected individuals, clusters were apparent based on greater or less than 200 repeats. Five ataxia patients with interruptions still had a remaining pure GAA expansion <200. We observed an association of the pure GAA length with age at onset (p=0.016, R2=0.256). Somatically-incurred mosaic divergent repeat interruptions were discovered that affect motif length and sequence (mDRILS), which varied in number and mosaicism (frequency: 0.37-0.93). The mDRILS correlated with pure GAA length (p=0.022, R2=0.334), with a higher mosaic frequency of interruptions in unaffected individuals compared to patients (unaffected: 0.90; patients: 0.67; p=0.009). We demonstrate that i) long-read sequencing is required to detect complex repeat interruptions accurately; ii) repeat interruptions in FGF14 are mosaic, have various lengths and start positions in the repeat tract, and can thereby be annotated as mDRILS, which iii) enabled us to establish a categorization based on remaining pure GAA repeats quantifying the impact of mDRILS on pathogenicity or age at onset, dependent on the interruption length and position, with high accuracy. Finally, we iv) provide evidence that mosaicism stabilizes pure GAA repeats in interrupted FGF14 repeat expansions.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"18 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066910","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":"Astrocytic mGluR5-dependent calcium hyperactivity promotes amyloid-β pathology and cognitive impairment.","authors":"Tianqi Yang,Dianjun Zhang,Haiwei Huang,Fangyue Liu,Juanli Wu,Xiaolin Ma,Shuangshuang Liu,Man Huang,Yu-Dong Zhou,Yi Shen","doi":"10.1093/brain/awaf186","DOIUrl":"https://doi.org/10.1093/brain/awaf186","url":null,"abstract":"Astrocytic dysfunction is a crucial factor for the pathogenesis of Alzheimer's disease. Metabotropic glutamate receptor 5 (mGluR5) is ubiquitously expressed in the brain and is a key molecule that regulates synaptic transmission and plasticity. It has been shown that mGluR5 is elevated in astrocytes in Alzheimer's disease. However, it remains elusive how astrocytic mGluR5 contributes to the pathogenesis of Alzheimer's disease. Here, we first quantified a high expression level of astrocytic mGluR5 in the hippocampus of Alzheimer's disease brains and demonstrated that the expression of astrocytic mGluR5 was positively correlated with Alzheimer's disease progression in both humans and mice. Upregulating astrocytic mGluR5 in the CA1 area at an early stage accelerated, whereas downregulating these receptors rescued, Aβ pathology and cognitive impairment in Alzheimer's disease mice. Moreover, the activation of mGluR5 led to calcium hyperactivity in astrocytes, causing Aβ pathology progression due to dysregulated Aβ uptake and degradation in astrocytes. Importantly, attenuating astrocytic calcium hyperactivity in the hippocampal CA1 area in the prodromal phase ameliorated Aβ pathology and cognitive defects in Alzheimer's disease mice. Our findings thus reveal a fundamental contribution of astrocytic mGluR5 in presymptomatic Alzheimer's disease that may serve as a potential diagnostic and therapeutic target for early Alzheimer's disease pathogenesis.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"4 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065808","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":"Structural covariance analysis for neurodegenerative and neuroinflammatory brain disorders.","authors":"Neus Mongay-Ochoa,Gabriel Gonzalez-Escamilla,Vinzenz Fleischer,Deborah Pareto,Àlex Rovira,Jaume Sastre-Garriga,Sergiu Groppa","doi":"10.1093/brain/awaf151","DOIUrl":"https://doi.org/10.1093/brain/awaf151","url":null,"abstract":"Structural MRI can robustly assess brain tissue alterations related to neurological diseases and ageing. Traditional morphological MRI metrics, such as cortical volume and thickness, only partially relate to functional impairment and disease trajectories at the individual level. Emerging research has increasingly focused on reconstructing interregional meso- and macro-structural relationships in the brain by analysing covarying morphometric patterns. These patterns suggest that structural variations in specific brain regions tend to covary with deviations in other regions across individuals, a phenomenon termed structural covariance. This concept reflects the idea that physiological and pathological processes follow an anatomically defined spreading pattern. Advanced computational strategies, particularly those within the graph-theoretical framework, yield quantifiable properties at both the whole-brain and regional levels, which correlate more closely with the clinical state or cognitive performance than classical atrophy patterns. This review highlights cutting-edge methods for evaluating morphometric covariance networks on an individual basis, with a focus on their utility in characterizing ageing, central nervous system inflammation and neurodegeneration. Specifically, these methods hold significant potential for quantifying structural alterations in patients with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and multiple sclerosis. By capturing the distinctive morphometric organization of each individual's brain, structural covariance network analyses allow for the tracking and prediction of pathology progression and clinically outcomes, information that can be integrated into clinical decision-making and used as variables in clinical trials. Furthermore, by investigating distinct and cross-diagnostic patterns of structural covariance, these approaches offer insights into shared mechanistic processes that are critical to the understanding of severe neurological disorders and their therapeutic implications. Such advancements pave the way for more precise diagnostic tools and targeted therapeutic strategies.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"124 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065809","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":"Neurological complications of orthopoxvirus infections: neurotropism and neurovirulence","authors":"Hajar Miranzadeh Mahabadi, Ryan S Noyce, David H Evans, Christopher Power","doi":"10.1093/brain/awaf181","DOIUrl":"https://doi.org/10.1093/brain/awaf181","url":null,"abstract":"With the declaration of monkeypox virus (MPXV) infection as a global health emergency in 2022 by the WHO and its ongoing presence, Orthopoxviruses have garnered increasing attention, including their capacity to cause neurological disease. Indeed, the mpox syndrome caused by MPXV infection is recapitulated in humans for several other Orthopoxviruses including variola (VARV, the cause of smallpox), Vaccinia (VACV), camelpox (CMPX), and cowpox (CPXV) viruses, albeit with variable disease severities. In addition to prototypic signs and symptoms of orthopoxvirus infections, such as fever, swollen lymph nodes, malaise, and skin lesions, MPXV-infected individuals also develop neurological syndromes such as headaches, myalgias, seizures, altered consciousness, and encephalopathy/encephalitis. Magnetic resonance imaging (MRI) of the brains of MPXV-infected persons can display hyperintensities consistent with brain edema. Pleocytosis has also been reported in the cerebrospinal fluid (CSF) from persons with MPXV infections, implying active infection of the central nervous system (CNS). Of note, newborn rodents, or animals with severe combined immune deficiency, were found to be susceptible to MPXV infection with evidence that the virus can cross the blood-brain barrier (BBB). In the present review we highlight the current understanding of Orthopoxvirus neuropathogenesis together with germane diagnostic and therapeutic considerations.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"5 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980023","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":"Classifying neurogenic dysphagia as a movement disorder.","authors":"Corinne A Jones,Maggie-Lee Huckabee,Georgia A Malandraki,David Paydarfar","doi":"10.1093/brain/awaf177","DOIUrl":"https://doi.org/10.1093/brain/awaf177","url":null,"abstract":"Swallowing is a complex sensorimotor task critical for maintaining nutrition, hydration, and quality of life. Given the widespread neural involvement and combined volitional and reflexive control, many neurologic conditions can result in swallowing disorders (dysphagia). There is no classification framework for neurogenic dysphagia according to where dysfunction lies within the sensorimotor hierarchy. Thus, underlying neuropathology is not thoroughly considered during dysphagia assessment and rehabilitation. In this review, we explore neurogenic dysphagia through classical sensorimotor hierarchy and movement disorders terminology. We provide comprehensive evidence of dysphagia signs and symptoms in pure cases of movement disorders and discuss nuances related to assessing signs of neuropathology responsible for disordered oropharyngeal swallowing biomechanics. Appreciation of the complexities of dysphagia and investigations into underlying pathologies will advance clinical management of neurogenic dysphagia and inform investigations of dysphagia identification and treatment.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"116 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945552","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":"Medial temporal lobe structural changes when Down syndrome and Alzheimer's disease collide.","authors":"Laura E M Wisse,Renaud La Joie","doi":"10.1093/brain/awaf176","DOIUrl":"https://doi.org/10.1093/brain/awaf176","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"3 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945553","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":"Filamin A in focus: unravelling the multifaceted roles of filamin A in neurodevelopment and neurological disorders.","authors":"Longbo Zhang","doi":"10.1093/brain/awaf180","DOIUrl":"https://doi.org/10.1093/brain/awaf180","url":null,"abstract":"Neurodevelopment is an intricate process encompassing the proliferation, differentiation, migration, and maturation of neural cells. Disruptions in these tightly regulated events can lead to a variety of neurodevelopmental disorders. Filamin A (FLNA), a key actin-binding protein, plays a pivotal role in regulating neuronal migration, morphological development, and synaptic connectivity by modulating actin cytoskeletal dynamics and interacting with various signaling pathways. FLNA mutations are implicated in several neurodevelopmental disorders, such as periventricular nodular heterotopia (PVNH), leading to neurological symptoms such as epilepsy, intellectual disability, and cognitive impairments. In this review, we delve into FLNA's multifaceted role in neurodevelopment, with a particular focus on its contributions to neuronal migration, dendritic and axonal growth, and mechanotransduction. Additionally, we examine how FLNA dysregulation leads to neurodevelopmental abnormalities, providing insights into its potential as a therapeutic target. By elucidating the molecular mechanisms through which FLNA governs neurodevelopment, we aim to advance our understanding of its crucial role in both brain formation and disease pathogenesis.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"27 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945554","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":"Souvenirs of an awake craniotomy","authors":"Camille Bégin","doi":"10.1093/brain/awaf124","DOIUrl":"https://doi.org/10.1093/brain/awaf124","url":null,"abstract":"What do you, a bilingual person, do when a surgeon asks which language you wish to keep as he is about to perform an awake craniotomy to remove your right frontal lobe brain tumour? Winner of the Brain Essay Competition 2024, Camille Bégin shares her personal experience of brain surgery.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"3 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946021","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":"AAV-based TCAP delivery rescues mitochondria dislocation in limb-girdle muscular dystrophy R7.","authors":"Xiaoqing Lv, Shuangwu Liu, Xi Li, He Lv, Kai Shao, Sushan Luo, Dandan Zhao, Chuanzhu Yan, Pengfei Lin","doi":"10.1093/brain/awae351","DOIUrl":"10.1093/brain/awae351","url":null,"abstract":"<p><p>Limb-girdle muscular dystrophy R7 is a rare genetic disease caused by homozygous or compound heterozygous variants in the titin-cap (TCAP) gene that results in the absence of the protein telethonin. The primary pathological features of limb-girdle muscular dystrophy R7 are fibre size variation, nuclear centralization and abnormal mitochondrial distribution. The mechanisms underlying this disease are unclear and there is currently no specific treatment for limb-girdle muscular dystrophy R7. This study established a Tcap-deficient mouse model to explore the disease mechanism of mitochondria dislocation and potential therapeutic strategies. We used methods such as proteomics, immunofluorescence, histopathological staining and western blotting to explore the mechanism of mitochondrial dislocation. Moreover, in the quest for a prospective therapeutic intervention for this disorder, the adeno-associated virus (AAV) serotype 2/9 was employed to deliver the Tcap gene into the muscles of these mice, facilitating preclinical experimentation. After 2 months and 7 months, the muscular phenotype was evaluated and selected mice were humanely euthanized for subsequent molecular and histological analysis. The phenotype of Tcap-/- mice mimicked that observed in individuals diagnosed with limb-girdle muscular dystrophy R7. This study elucidated the mechanism of mitochondrial dislocation in limb-girdle muscular dystrophy R7. Through our in vitro experiments, we discovered that telethonin aids in preserving the integrity of desmin by preventing truncation at the N-terminus. Additionally, telethonin combined with desmin and co-localized at the Z-disc. Research has shown that the Tcap gene plays a crucial role in controlling the desmin cytoskeleton organization. The absence of telethonin leads to a collapsed desmin cytoskeleton. This causes disorganization of the mitochondrial network, leading to mitochondrial dysfunction. In addition, the study investigated the efficacy of AAV-mediated Tcap replacement in Tcap-/- mice. By intramuscular delivery of AAV, we observed dramatic improvements in muscle phenotype, muscle pathology, CK levels, muscle MRI, mitochondrial network organization and mitochondrial function. The results of this study demonstrated that telethonin deficiency led to desmin cytoskeleton collapse that caused mitochondrial dislocation. AAV-mediated replacement therapy could be a promising safe and efficient treatment option for limb-girdle muscular dystrophy R7. The study highlights the potential of AAV-mediated replacement therapy for specific types of limb-girdle muscular dystrophy.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1680-1694"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520989","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}