Brain最新文献

{"title":"We're all in this together: a rejoinder to Masud Husain's (rant) editorial.","authors":"Fritz Sager,Hugues Abriel,Markus Brönnimann,Andrew Chan,Heike Mayer,Virginia Richter","doi":"10.1093/brain/awaf139","DOIUrl":"https://doi.org/10.1093/brain/awaf139","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"4 1","pages":"e43-e44"},"PeriodicalIF":14.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945556","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":"Inferring the 'functions' of tracts: a cautionary note.","authors":"Emiel van den Hoven, Cornelius Weiller, Marco Reisert, Michel Rijntjes","doi":"10.1093/brain/awaf114","DOIUrl":"10.1093/brain/awaf114","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1447-1450"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699588","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":"Parvalbumin neurons mediate neurological phenotypes of anti-NMDAR encephalitis.","authors":"Yi-Fan Feng, Zi-Ke Zeng, You Ni, Yue Hu, Ke-Xin Yang, Fang Cai, Qin-Ming Zhou, Ming Chen, Xiao-Na Zhu, Sheng Chen, Ji Hu","doi":"10.1093/brain/awae374","DOIUrl":"10.1093/brain/awae374","url":null,"abstract":"<p><p>Patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, often present with severe psychiatric symptoms, yet the neuropathological mechanisms underlying their cognitive deficits remain insufficiently understood. In this study, we constructed an animal model using anti-NMDAR IgG purified from the serum of patients with anti-NMDAR encephalitis, and we used IgG obtained from healthy individuals as a control. Daily administration of anti-NMDAR IgG into the medial prefrontal cortex (mPFC) of mice for 7 days resulted in cognitive impairments resembling clinical symptoms, which spontaneously resolved 30 days after discontinuing the injections. Immunohistochemical staining and electrophysiological testing of parvalbumin neurons in the mPFC treated with anti-NMDAR IgG revealed significant cellular morphological damage, reduced excitability, synaptic dysfunction and a loss of NMDAR antagonist-induced gamma oscillations. Application of optogenetic and pharmacogenetic techniques to activate parvalbumin neurons in the mPFC successfully reversed the cognitive impairments observed in the anti-NMDAR-IgG-treated mice. Single-cell sequencing of anti-NMDAR-IgG-treated parvalbumin neurons identified differentially expressed genes and pathways related to synapses and neuronal development, offering potential targets for therapeutic intervention. Additionally, we showed that these alterations in parvalbumin neurons were not confined to the mPFC, as similar changes were detected in the hippocampus after anti-NMDAR IgG injections. In summary, our findings elucidate distinct alterations in parvalbumin neurons during the pathogenesis of anti-NMDAR encephalitis, providing preclinical rationale for exploring approaches to modulate parvalbumin neuronal function to treat anti-NMDAR encephalitis.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1652-1664"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12073974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smaller cingulate grey matter mediates the association between dual-task gait and incident dementia.","authors":"Pauline Ali, Frederico Pieruccini-Faria, Cédric Annweiler, Mickaël Dinomais, Surim Son, Scott K Wilson, Richard Camicioli, Susan Muir-Hunter, Robert Bartha, Manuel Montero-Odasso","doi":"10.1093/brain/awae356","DOIUrl":"10.1093/brain/awae356","url":null,"abstract":"<p><p>Individuals with mild cognitive impairment who have high dual-task gait cost (≥20% slowing in gait speed while performing a cognitive brain-demanding task) are 3-fold more likely to progress to dementia. However, the cortical regions that might explain this association are unknown, which might identify potentially treatable areas. The aim of the present study was to investigate whether brain grey matter volume loss and motor cortex metabolite levels explain the association between dual-task cost and incident dementia in individuals with mild cognitive impairment. We included participants with mild cognitive impairment from the Gait and Brain Study Cohort, who had a baseline MRI and were followed up for 9 years with cognitive and gait assessments every 6 months. Gait performance was investigated in four conditions: usual gait, counting backwards by ones, naming animals and subtracting serial sevens. Dual-task cost was calculated as the percentage change in gait speed in dual-task conditions relative to usual gait speed. Data were collected from July 2007 to June 2023. From the 139 individuals with mild cognitive impairment included at baseline [mean (standard deviation) age, 73 (6) years; 62 (44%) female], 33 (24%) progressed to dementia. Baseline high dual-task cost (≥20%) during counting backwards by ones and naming animals conditions were associated with smaller grey matter volume in several brain structures. A higher ratio of choline to creatine in the primary motor cortex was associated with higher serial sevens dual-task cost. High dual-task cost while counting backwards by ones and naming animals was associated with a 3-fold risk of incident dementia (P = 0.02). Mediation analyses revealed that grey matter volume clusters localized in the right anterior and middle cingulate cortices mediated the association between counting backwards by ones dual-task cost and incident dementia (effect: 48%; P = 0.045) with no mediation observed in grey matter loss in other brain regions or through motor cortex metabolite levels. Smaller grey matter volume of the right anterior and middle cingulate cortices explained the association between high dual-task cost and incident dementia in mild cognitive impairment. This result sheds light on the neural mechanisms of cognitive-motor interaction linked with cognitive decline and dementia in mild cognitive impairment and supports the use of gait under dual-tasking as a motor biomarker of dementia.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1551-1561"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12073990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypometabolic mismatch with atrophy and tau pathology in mixed Alzheimer's and Lewy body disease.","authors":"Michael Tran Duong, Sandhitsu R Das, Pulkit Khandelwal, Xueying Lyu, Long Xie, Emily McGrew, Nadia Dehghani, Corey T McMillan, Edward B Lee, Leslie M Shaw, Paul A Yushkevich, David A Wolk, Ilya M Nasrallah","doi":"10.1093/brain/awae352","DOIUrl":"10.1093/brain/awae352","url":null,"abstract":"<p><p>Polypathology is a major driver of heterogeneity in the clinical presentation and extent of neurodegeneration (N) in patients with Alzheimer's disease (AD). Beyond amyloid (A) and tau (T) pathologies, over half of patients with AD have concomitant pathology such as α-synuclein (S) in mixed AD with Lewy body disease (LBD). Patients with multiple aetiology dementia such as AD + LBD have faster progression and potentially differential responses to targeted treatments, although the diagnosis of AD + LBD can be challenging given the overlapping clinical and imaging features. Development and validation of improved in vivo biomarkers are required to study relationships between N and S and identify imaging patterns reflecting mixed AD + LBD pathologies. We hypothesized that individual proteinopathies, such as T and S, are associated with commensurate levels of N. Thus, we assessed biomarkers of A, T, N and S with PET, MRI and CSF seeding amplification assay (SAA) data to determine molecular presentations of mixed A+S+ versus A+S- cognitively impaired patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Strikingly, A+S+ patients had parieto-occipital 18F-fluorodeoxyglucose hypometabolism (a measure of N) disproportionate to the degree of regional atrophy or T burden, highlighting worse hypometabolism associated with S+ status on SAA. Following up on this hypometabolic mismatch with CSF metabolite and proteome analyses, we found that A+S+ patients exhibited lower CSF levels of dopamine metabolites and synaptic markers like neuronal pentraxin-2 (NPTX2), suggesting that altered neurotransmission and neuron integrity contribute to this dissociation between metabolic PET and MRI. Potential confounders exist when studying relations between N, AD and LBD pathologies, including neuroinflammation and other non-Alzheimer's pathologies in mixed dementia, although our findings imply posterior hypometabolic mismatch is related more to S than vascular or TDP-43 pathology. Overall, A+S+ patients had posterior mismatch with excessive 18F-fluorodeoxyglucose hypometabolism relative to atrophy or T load, possibly reflecting impaired neuronal integrity. Further research must disentangle the impact of multiple proteinopathies and clinicopathologic factors on hypometabolism and atrophy. Cumulatively, patients with mixed AD + LBD aetiologies harbour a unique metabolic PET mismatch signature.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"1577-1587"},"PeriodicalIF":10.6,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12073973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding brain calcification via N-terminal acetylation at the Golgi apparatus","authors":"Anette Siggervåg, Åse K Bekkelund, Jaakko Saraste, Henriette Aksnes","doi":"10.1093/brain/awaf175","DOIUrl":"https://doi.org/10.1093/brain/awaf175","url":null,"abstract":"Primary familial brain calcification (PFBC) provides valuable insights into the mechanisms underlying brain calcification as it singles out the proteins that potentially are involved in the relevant cellular pathways. To date, seven genes have been linked to PFBC, and studying their encoded proteins marks an exciting new era in understanding the disease mechanisms, which may ultimately lead to therapeutic strategies to prevent brain calcification. With each new gene found to be associated with PFBC due to pathogenic variants, an additional level of understanding is achieved. Here, we highlight the most recently discovered PFBC gene, encoding the Golgi-localized N-terminal acetyltransferase NAA60. We explore the novel perspectives gained from the understanding of this enzyme’s molecular, cellular and physiological properties. Interestingly, NAA60 shares a critical role with the most frequent PFBC gene, SLC20A2. Both these proteins seem to be involved in maintaining the structural integrity of the Golgi apparatus, as deficiency in either protein leads to Golgi fragmentation. Altered Golgi morphology is therefore emerging as a new significant topic in PFBC research, and we here discuss this topic in relation to existing knowledge regarding Golgi rearrangements and dysfunction as a factor in neurodegenerative diseases.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"140 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143930864","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":"Functional contribution of astrocytic Kir4.1 channels to spasticity after spinal cord injury","authors":"Tony Barbay, Emilie Pecchi, Jorge Ramirez-Franco, Anton Ivanov, Frédéric Brocard, Nathalie Rouach, Rémi Bos","doi":"10.1093/brain/awaf147","DOIUrl":"https://doi.org/10.1093/brain/awaf147","url":null,"abstract":"Spasticity, a prevalent motor issue characterized by network hyperexcitability, causes pain and discomfort, with existing treatments offering limited relief. While past research has focused on neuronal factors, the role of astrocytes in spasticity has been overlooked. This study explores the potential of restoring astrocytic potassium (K+) uptake to reduce spasticity following spinal cord injury (SCI). Astrocytes buffer extracellular K+ via Kir4.1 channels, preventing neuronal hyperexcitability. Following SCI, Kir4.1 levels decrease at the injury site, though the consequences and mechanisms of this reduction within the motor output area have not been investigated. We here demonstrate that lumbar astrocytes in a juvenile thoracic SCI mouse model switch to a reactive phenotype, displaying morpho-functional and pro-inflammatory changes. These astrocytes also experience NBCe1-mediated intracellular acidosis, leading to Kir4.1 dysfunction and impaired K+ uptake. Enhancing Kir4.1 function reduces spasticity in SCI mice, revealing new therapeutic targets for neurological diseases associated with neuronal hyperexcitability.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"16 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920276","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":"Diagnosing migraine from genome-wide genotype data: a machine learning analysis.","authors":"Antonios Danelakis,Tjaša Kumelj,Bendik S Winsvold,Marte Helene Bjørk,Parashkev Nachev,Manjit Matharu,Dominic Giles,,Erling Tronvik,Helge Langseth,Anker Stubberud","doi":"10.1093/brain/awaf172","DOIUrl":"https://doi.org/10.1093/brain/awaf172","url":null,"abstract":"Migraine has an assumed polygenic basis, but the genetic risk variants identified in genome-wide association studies only explain a proportion of the heritability. We aimed to develop machine learning models, capturing non-additive and interactive effects, to address the missing heritability. This was a cross-sectional population-based study of participants in the second and third Trøndelag Health Study. Individuals underwent genome-wide genotyping and were phenotyped based on validated modified criteria of the International Classification of Headache Disorders. Four datasets of increasing number of genetic variants were created using different thresholds of linkage disequilibrium and univariate genome-wide associated p-values. A series of machine learning and deep learning methods were optimized and evaluated. The genotype tools PLINK and LDPred2 were used for polygenic risk scoring. Models were trained on a partition of the dataset and tested in a hold-out set. The area under the receiver operating characteristics curve was used as the primary scoring metric. Classification by machine learning was statistically compared to that of polygenic risk scoring. Finally, we explored the biological functions of the variants unique to the machine learning approach. 43,197 individuals (51% women), with a mean age of 54.6 years, were included in the modelling. A light gradient boosting machine performed best for the three smallest datasets (108, 7,771 and 7,840 variants), all with hold-out test set area under curve at 0.63. A multinomial naïve Bayes model performed best in the largest dataset (140,467 variants) with a hold-out test set area under curve of 0.62. The models were statistically significantly superior to polygenic risk scoring (area under curve 0.52 to 0.59) for all the datasets (p<0.001 to p=0.02). Machine learning identified many of the same genes and pathways identified in genome-wide association studies, but also several unique pathways, mainly related to signal transduction and neurological function. Interestingly, pathways related to botulinum toxins, and pathways related to the calcitonin gene-related peptide receptor also emerged. This study suggests that migraine may follow a non-additive and interactive genetic causal structure, potentially best captured by complex machine learning models. Such structure may be concealed where the data dimensionality (high number of genetic variants) is insufficiently supported by the scale of available data, leaving a misleading impression of purely additive effects. Future machine learning models using substantially larger sample sizes could harness both the additive and the interactive effects, enhancing precision and offering deeper understanding of genetic interactions underlying migraine.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"26 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914910","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":"Mitochondria as the key to understanding neuroinflammation.","authors":"Tamas Kozicz,Eva Morava","doi":"10.1093/brain/awaf173","DOIUrl":"https://doi.org/10.1093/brain/awaf173","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"43 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914909","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":"The case for targeting latent and lytic Epstein-Barr virus infection in multiple sclerosis.","authors":"Gavin Giovannoni,Louisa James,Adekunle A Adeniran,Julian Gold,Lawrence S Young,David L Selwood,David Baker,Ruth Dobson","doi":"10.1093/brain/awaf170","DOIUrl":"https://doi.org/10.1093/brain/awaf170","url":null,"abstract":"Epstein-Barr virus (EBV) is strongly associated with multiple sclerosis (MS). It is likely to play a causal role in the pathogenesis of MS, possibly via triggering autoimmunity through molecular mimicry, autoantigenic presentation or immune dysregulation. Alternatively, evidence supports a direct role for EBV in driving MS disease activity via latent-lytic infection cycling either within the central nervous system or the periphery. We highlight the recent immunological and virological findings supporting the role of active EBV infection in MS, supporting an evaluation of anti-EBV strategies as potential treatments for MS. Anti-EBV strategies include CNS penetrant small molecule anti-viral agents targeting latent and lytic infection, and immunotherapies. Immunotherapies include EBV-specific autologous or allogeneic cytotoxic T-cells (CTL) and therapeutic EBV vaccines and/or immune checkpoint inhibitors to rejuvenate and boost endogenous EBV-targeted CTL responses. In parallel, several licensed MS disease-modifying therapies may work via mechanisms targeting EBV directly or indirectly. B-cell depleting therapies have been shown to have anti-EBV activity; additionally new strategies to target intrathecal B-cells, plasmablasts and plasma cells are being explored including high-dose anti-CD20 therapy, cladribine, proteasome inhibitors, BTK inhibitors, CNS-penetrant anti-CD20/CD19 monoclonal antibodies and CD19-targeted CAR T-cells. Innovative trial designs for proof-of-concept studies to test EBV antivirals and immunotherapies in MS are needed to catalyse a wave of drug development targeting EBV as a therapeutic strategy to prevent or treat MS.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"67 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915237","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}