Brain最新文献

{"title":"Traumatic brain injury or head impacts from contact sports are associated with tau astrogliopathy.","authors":"John D Arena, William Stewart, Gabor G Kovacs, Edward B Lee, John L Robinson, Virginia M Y Lee, John Q Trojanowski, Andrea L C Schneider, Douglas H Smith, Victoria E Johnson","doi":"10.1093/brain/awaf073","DOIUrl":"10.1093/brain/awaf073","url":null,"abstract":"<p><p>Exposure to traumatic brain injury (TBI) and/or repetitive head impacts (RHI) increase the risk of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy neuropathologic change (CTE-NC). Astrocytic tau pathology reminiscent of ageing-related tau astrogliopathy is a component feature of CTE-NC in many cases. Yet the relationship between TBI/RHI exposure and wider tau astrogliopathy, beyond that of CTE-NC, remains poorly characterized. Autopsy-derived material from 556 individuals was selected to include cases with a history of moderate or severe traumatic brain injury (survival >6 months, n = 77) or a history of participation in contact sports (n = 45), for comparison with uninjured controls with (n = 397) or without (n = 37) neuropathologically confirmed neurodegenerative disease. Representative tissue sections from multiple brain regions were then immunostained for hyperphosphorylated tau (p-tau; PHF-1) and assessed in accordance with the harmonized evaluation criteria for ageing-related tau astrogliopathy. PHF-1-immunoreactive thorn-shaped astrocytes were observed more frequently in contact sports participants (75.6%) versus controls with (32.5%; P < 0.001) and without (8.1%; P < 0.001) neurodegenerative disease. In addition, although the prevalence of thorn-shaped astrocytes following moderate/severe TBI (32.5%) was similar to neurodegenerative disease controls, regression analyses demonstrated increased odds of thorn-shaped astrocytes, when adjusting for age and sex (odds ratio 2.42, 95% confidence interval 1.29-4.54). These findings were observed regardless of whether the pathognomonic lesion of CTE-NC was present in the regions examined. Intriguingly, although subpial thorn-shaped astrocytes at sulcal depths were occasionally observed in aged controls with (3.6%) and without (2.8%) neurodegenerative disease, this pathology was considerably more common following RHI/TBI (42.2%; P < 0.001). These findings support a history of RHI or TBI as an independent risk factor for the development of thorn-shaped tau astrogliopathy, over and above ageing-related tau astrogliopathy observed in ageing and wider neurodegenerative disease. Moreover, trauma might be associated with thorn-shaped astrocytes within specific distributions, including the subpial region of the cortical sulcal depths. The clinical significance of these observations will be important to determine.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"2671-2683"},"PeriodicalIF":11.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762599","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":"Dominant rhabdomyolysis linked to a recurrent ATP2A2 variant reducing SERCA2 function in muscle.","authors":"Sivasankar Malaichamy, Romane Idoux, Kiran Polavarapu, Katarina Šikić, Elisa Holla, Rachel Thompson, Sally Spendiff, Anne Schänzer, Benno Küsters, Emily Freeman, Andreas Hentschel, Daniel O'Neil, Ricardo Carmona-Martinez, Vera Dobelmann, Calvin Tucht, Meyke Schouten, Tobias Ruck, Ulrike Schara-Schmidt, Erik-Jan Kamsteeg, Danijela Petković Ramadža, Antonia Jakovčević, Tamara Žigman, Mislav Čavka, Veronika Karcagi, Agnes Herczegfalvi, Steven Laurie, Leslie Matalonga, Sergi Beltran, Rita Horvath, Nicol Voermans, Andreas Roos, Ivo Barić, Hanns Lochmüller","doi":"10.1093/brain/awaf067","DOIUrl":"10.1093/brain/awaf067","url":null,"abstract":"<p><p>Rhabdomyolysis is an acute failure of cellular homeostasis resulting in muscle breakdown, triggered by trauma, infection, drugs or strenuous exercise. Recurrent rhabdomyolysis is often associated with genetic and metabolic defects of skeletal muscle. The sarcoendoplasmic reticulum Ca2+-ATPase 2 (SERCA2), encoded by the ATP2A2 gene, is an intracellular pump located in the sarcoplasmic and endoplasmic reticulum that is essential for maintaining intracellular calcium (Ca2+) homeostasis and is highly expressed in slow-twitch muscle. Heterozygous loss-of-function variants in ATP2A2 have previously been associated with dominant skin diseases, but not with rhabdomyolysis. In this study, we report a rare novel heterozygous missense variant in the ATP2A2 gene (c.1583G>A, p.R528Q) identified in 14 affected individuals from three unrelated families with recurrent rhabdomyolysis. Muscle biopsy revealed mild myopathic changes with fibre type uniformity, core-like structures and Z-band streaming, but normal levels of SERCA2 protein. Ca2+ imaging showed that sarcoplasmic reticulum Ca2+ reuptake mediated by SERCA was significantly slower in myotubes derived from patient fibroblasts carrying the c.1583G > A variant. We hypothesize that the ATP2A2 variant impairs SERCA2a function in slow-twitch muscle, disrupting SR Ca2+ reuptake and causing cytosolic Ca2+ overload following a trigger, leading to recurrent rhabdomyolysis. Morphant zebrafish embryos with atp2a2a knockdown showed morphological and functional muscle abnormalities, with a reduction in body length and trunk muscle area associated with a reduction in locomotor activity in zebrafish larvae. Co-injection of wild-type human SERCA2a mRNA, but not variant SERCA2a mRNA, resulted in complete rescue of the phenotype. This study reveals a novel association between a heterozygous ATP2A2 variant and autosomal dominant recurrent rhabdomyolysis. Both in vitro and in vivo studies provide evidence that the variant alters SERCA2 function, causing abnormal intracellular Ca2+ homeostasis in skeletal muscle, resulting in rhabdomyolysis. The work not only increases understanding of autosomal dominant rhabdomyolysis but also provides a diagnostic conclusion for three generations of affected individuals across the three families.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"2869-2882"},"PeriodicalIF":11.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456769","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":"De novo and inherited variants in DDX39B cause a novel neurodevelopmental syndrome.","authors":"Kevin T A Booth, Sharayu V Jangam, Martin M C Chui, Kayla Treat, Lorenzo Graziani, Alessia Soldano, Yao Ruan, Jeffrey Wan-Hei Hui, Kerry White, Celanie K Christensen, Ty Lynnes, Shinya Yamamoto, Oguz Kanca, Mandy H Y Tsang, Sally A Lynch, Sureni V Mullegama, Julia Baptista, Daniela Iancu, Shelagh K Joss, Sandra Y Y Wong, Christopher C Y Mak, Anna K Y Kwong, Hugo J Bellen, Erin Conboy, Remo Sanges, Anskar Yu-Hung Leung, Michael F Wangler, Brian H Y Chung, Francesco Vetrini","doi":"10.1093/brain/awaf035","DOIUrl":"10.1093/brain/awaf035","url":null,"abstract":"<p><p>DDX39B is a conserved member of the DEAD-box family of ATP-dependent RNA helicases, critical in mRNA metabolism across eukaryotes. DDX39B is also a core component of the TRanscription-EXport (TREX) super protein complex, and recent studies have highlighted the important role of its subunits in neurodevelopmental disorders. Here, we describe six individuals from five families, four harbouring de novo missense variants in DDX39B and one with an inherited splicing variant, presenting with variable developmental delay, congenital hypotonia, epilepsy, short stature, skeletal abnormalities, dysmorphic features and microcephaly in three patients. 3D molecular modelling predicts these variants would alter protein structure. In vitro studies using overexpression of HA-tagged human DDX39B protein in 293FT cells revealed variants p.(Gly92Asp) and c.433-1G>T impaired interaction with DDX39B and other TREX complex members, while variants p.(Gly37Cys), p.(Ser44Arg) and p.(Arg123Gln) did not affect TREX complex assembly. Blood transcriptomics studies demonstrated significantly elevated aberrant splicing events in individuals carrying the p.(Gly37Cys), p.(Arg123Gln) or c.433-1G>T variant, compared to controls, suggesting a mRNA signature of disrupted mRNA splicing and export. To understand variant effects in vivo, we generated Drosophila transgenic DDX39B-reference and variant flies. Human reference DDX39B, when overexpressed ubiquitously, led to lethality, but the patient variants did not, suggesting that the mutants are loss-of-function alleles. Zebrafish anti-sense morpholino knockdown of DDX39B led to reduced head size and body length consistent with the patient phenotypes, and these effects were mitigated by synthesized mRNA, indicating a loss-of-function effect of DDX39B. Collectively, our human genetic data, coupled with in silico, in vitro and in vivo data, support DDX39B as a novel candidate gene in a potential group of disorders called TREX-complex-related neurodevelopmental syndrome.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"2658-2670"},"PeriodicalIF":11.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363624","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":"Reply: Why the threat of psychosocial reductionism to patients in psychiatry and medicine is rather ignored.","authors":"Thomas A Pollak","doi":"10.1093/brain/awaf092","DOIUrl":"10.1093/brain/awaf092","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"e66-e68"},"PeriodicalIF":11.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595753","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 network-specific effect of extreme capsule stimulation for drug-resistant focal epilepsy.","authors":"Yueyang Cheng, Di Wang, Xiaohua Zhang, Guangyuan Jin, Di Wu, Qiao Wang, Jialin Du, Lei Qi, Cuiping Xu, Zichen Qiao, Xiaopeng Wang, Junliang Ge, Siyi Wang, Hao Yan, Xueyuan Wang, Huaqiang Zhang, Tao Yu, Yuping Wang, Fang-Cheng Yeh, Guoguang Zhao, Liankun Ren","doi":"10.1093/brain/awaf097","DOIUrl":"10.1093/brain/awaf097","url":null,"abstract":"<p><p>Treatment for drug-resistant epilepsy in poor candidates for resection surgeries remains challenging. The prevailing deep brain stimulation of subcortical nuclei is effective but exhibits heterogeneous efficacy and unpredictable side effects. Therefore, the investigation of novel deep brain stimulation targets is of paramount importance. Here, we focused on the unique structure known as the extreme capsule (EC), which is a 'butterfly'-like structure passing through the uncinate fasciculus, the inferior fronto-occipital fasciculus and the convergence of the short association fibres connecting to the insula. We investigated the modulatory effect of EC stimulation in 11 drug-resistant epilepsy patients (mean age, 28 years; eight males and three females) who underwent stereo-electroencephalography as part of presurgical evaluation. One electrode was extended to the EC ipsilateral to the presumed seizure onset zone. Structural connectivity to the EC derived from structural human connectome data (n = 1065) was estimated to compare with the effective connectivity to the EC using single-pulse stimulation at 1 Hz during the resting state. To assess the modulatory effect of EC stimulation, we used stepwise incremental stimulation ranging from 5 to 145 Hz in a cyclical pattern. We evaluated how neural activity across distributed cortical areas synchronized with EC stimulation frequencies, in addition to the changes in interictal epileptiform discharges and ripples during the stimulation period compared with the baseline. Moreover, 1 Hz burst stimulation mode was applied to refine the stimulation protocol further. We showed that the EC effective connectivity aligned well with the EC structural network. We also observed that the synchronized and desynchronized modulatory effect of EC stimulation was frequency specific across all the patients. Most importantly, we found that the modulatory effect of EC stimulation was constrained by its structural connectivity. Specifically, high-frequency stimulation of the EC significantly suppressed the epileptic discharges in the ipsilateral orbitofrontal lobe, occipital gyrus, inferior frontal gyrus, insula and temporal pole, which were inside the EC structural network rather than outside it (P < 0.001). Of note, EC 1 Hz burst stimulation demonstrated a comparable inhibitory efficacy to conventional high-frequency stimulation (ANOVA, F = 5.331, P < 0.001). This proof-of-concept study demonstrates that the EC is a promising deep brain stimulation target for treating substantial focal epilepsy with seizure originating from EC structurally connected cortex. It also demonstrates the feasibility of transforming knowledge of white matter node stimulation for seizures originating from its physically connected cortex and offers a promising therapeutic approach using alternative stimulation methods.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"2920-2934"},"PeriodicalIF":11.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673314","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":"Novel modelling approaches to elucidate the genetic architecture of resilience to Alzheimer's disease.","authors":"Jared M Phillips, Logan C Dumitrescu, Derek B Archer, Alexandra N Regelson, Shubhabrata Mukherjee, Michael L Lee, Seo-Eun Choi, Phoebe Scollard, Emily H Trittschuh, Walter A Kukull, Sarah Biber, Jesse Mez, Emily R Mahoney, Michelle Clifton, Julia B Libby, Skylar Walters, William S Bush, Corinne D Engelman, Qiongshi Lu, David W Fardo, Keith F Widaman, Rachel F Buckley, Elizabeth C Mormino, R Elizabeth Sanders, Lindsay R Clark, Katherine A Gifford, Badri Vardarajan, Michael L Cuccaro, Margaret A Pericak-Vance, Lindsay A Farrer, Li-San Wang, Gerard D Schellenberg, Jonathan L Haines, Angela L Jefferson, Sterling C Johnson, Marilyn S Albert, C Dirk Keene, Andrew J Saykin, Shannon L Risacher, Eric B Larson, Reisa A Sperling, Richard Mayeux, Alison M Goate, Alan E Renton, Edoardo Marcora, Brian Fulton-Howard, Tulsi Patel, David A Bennett, Julie A Schneider, Lisa L Barnes, Carlos Cruchaga, Jason Hassenstab, Michael E Belloy, Shea J Andrews, Susan M Resnick, Murat Bilgel, Yang An, Lori L Beason-Held, Keenan A Walker, Michael R Duggan, Brandon S Klinedinst, Paul K Crane, Timothy J Hohman","doi":"10.1093/brain/awaf106","DOIUrl":"10.1093/brain/awaf106","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Up to 30% of older adults meet pathological criteria for a diagnosis of Alzheimer's disease at autopsy yet never show signs of cognitive impairment. Recent work has highlighted genetic drivers of this resilience, or better-than-expected cognitive performance given a level of neuropathology, that allow the aged brain to protect itself from the downstream consequences of amyloid and tau deposition. However, models of resilience have been constrained by reliance on measures of neuropathology, substantially limiting the number of participants available for analysis. We sought to determine whether new approaches using APOE allele status, age and other demographic variables as a proxy for neuropathology could still effectively quantify resilience and uncover novel genetic drivers associated with better-than-expected cognitive performance while vastly expanding sample size and statistical power. Leveraging 20 513 participants from eight well-characterized cohort studies of ageing, we determined the effects of genetic variants on resilience metrics using mixed-effects regressions. The outcome of interest was residual cognitive resilience, quantified from residuals in three cognitive domains (memory, executive function and language) and built within two frameworks: 'silver' models, which obviate the requirement for neuropathological data (n = 17 241), and 'gold' models, which include post-mortem neuropathological assessments (n = 3272). We then performed cross-ancestry genome-wide association studies (European ancestry, n = 18 269; African ancestry, n = 2244), gene- and pathway-based tests and genetic correlation analyses. All analyses were conducted across all participants and repeated when restricted to those with unimpaired cognition at baseline. Despite different modelling approaches, the silver and gold phenotypes were highly correlated (R = 0.77-0.88) and displayed comparable performance in quantifying better- or worse-than-expected cognition, enabling silver-gold meta-analyses. Genetic correlation analyses highlighted associations of resilience with multiple neuropsychiatric and cardiovascular traits [false discovery rate-corrected P (PFDR) values &lt; 5.0 × 10-2]. In pathway-level tests, we observed three significant associations with resilience: metabolism of amino acids and derivatives (PFDR = 4.1 × 10-2), negative regulation of transforming growth factor beta (TGF-β) production (PFDR = 1.9 × 10-2) and severe acute respiratory syndrome (PFDR = 3.9 × 10-4). Finally, in single-variant analyses, we identified a locus on chromosome 17 approaching genome-wide significance among cognitively unimpaired participants (index single nucleotide polymorphism: rs757022, minor allele frequency = 0.18, β=0.08, P = 1.1 × 10-7). The top variant at this locus (rs757022) was significantly associated with expression of numerous ATP-binding cassette genes in brain. Overall, through validating a novel modelling approach, we demonstrate the utility of silver models ","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"2714-2729"},"PeriodicalIF":11.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12295682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668674","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":"Mapping the peripheral immune landscape of Parkinson's disease patients with single-cell sequencing.","authors":"Gael Moquin-Beaudry, Lovatiana Andriamboavonjy, Sebastien Audet, Laura K Hamilton, Antoine Duquette, Sylvain Chouinard, Michel Panisset, Martine Tetreault","doi":"10.1093/brain/awaf066","DOIUrl":"10.1093/brain/awaf066","url":null,"abstract":"<p><p>Parkinson's disease is most recognized for its impact on the CNS. However, recent breakthroughs underscore the crucial role of interactions between central and peripheral systems in Parkinson's disease pathogenesis. The spotlight is now shifting as we explore beyond the CNS, discovering that peripheral changes such as inflammatory dysfunctions may predict the rate of disease progression and severity. Despite more than 200 years of research on Parkinson's disease, reliable diagnostic or progression biomarkers and effective disease-modifying treatments are still lacking. Additionally, the cellular mechanisms that drive changes in immunity are largely unknown. Thus, understanding peripheral immune signatures could lead to earlier diagnosis and more effective treatments for Parkinson's disease. Here, we sought to define the transcriptomic alterations of the complete peripheral immune cell compartment by single-cell RNA and T-cell-receptor sequencing with hopes of uncovering Parkinson's disease signatures and potential peripheral blood biomarkers. Following transcriptional profiling of 78 876 cells from 10 healthy controls and 14 Parkinson's disease donors, we observed all expected major classes of immune cells; the myeloid (monocytes, dendritic cells) and lymphoid (T lymphocytes, B lymphocytes, natural killer) compartments were further analysed through bioinformatics re-clustering to obtain the final 38 cellular subtypes. Comparing immune cell subtypes and phenotypes between patients with Parkinson's disease and healthy control subjects revealed notable features of Parkinson's disease: (i) a significant shift of classical CD14+ monocytes towards an activated CD14+/CD83+ state; (ii) changes in lymphocyte subtype abundance, including a significant decrease in CD4+ naive and mucosal-associated invariant T-cell subtypes, along with an increase in CD56+ natural killer cells; (iii) the identification of several specific T-cell clones shared between multiple patients, suggesting the implication of common epitopes in Parkinson's disease pathogenesis; and (iv) a notable increase in the expression of activation signature genes, including the AP-1 stress-response transcription factor complex, across all Parkinson's disease cell types. This signal was not present in atypical parkinsonism patients with multiple system atrophy or progressive supranuclear palsy. Overall, we present a comprehensive atlas of peripheral blood mononuclear cells from healthy and Parkinson's disease donors which should serve as a tool to improve our understanding of the role the immune cell landscape plays in Parkinson's disease pathogenesis.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"2847-2860"},"PeriodicalIF":11.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141430","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":"Alzheimer and cardiovascular genetic scores and cognition: the FINGER randomized controlled trial.","authors":"Gazi Saadmaan,Maria Carolina Dalmasso,Maleeha Maria,Jenni Lehtisalo,Mikko Hiltunen,Minna U Kaikkonen,Esko Levälahti,Francesca Mangialasche,Markus Perola,Alfredo Ramirez,Ruth Stephen,Tiia Ngandu,Miia Kivipelto,Alina Solomon","doi":"10.1093/brain/awaf277","DOIUrl":"https://doi.org/10.1093/brain/awaf277","url":null,"abstract":"Alzheimer's disease and coronary artery disease are common late-life chronic conditions and share multiple risk factors, including Apolipoprotein E (APOE) ε4 allele. A meta-analysis of two multidomain lifestyle intervention trials indicated more cognitive benefit in APOE4 carriers compared with non-carriers. This study investigated the impact of genetic risk scores for Alzheimer's disease and coronary artery disease (AD-GRS, CAD-GRS) on cognition in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) randomized controlled trial. FINGER included 1259 at-risk individuals without dementia from the general population, aged 60-77 years. Participants were randomized 1:1 to 2-year multidomain lifestyle intervention or regular health advice. Primary outcome was change in cognition based on a modified Neuropsychological Test Battery (14 tests). Previous comprehensive AD-GRS and CAD-GRS were calculated using GWAS data (1,177 participants with 585 in control and 592 in intervention group, exploratory analysis). The intervention-control difference in annual overall cognition change (95% CI) for participants with AD-GRS above/below the median (i.e., higher/lower risk) was 0·032 (0·002-0·063) versus 0·017 (-0·011- 0·045), and for CAD-GRS above/below the median was 0·031 (0·002-0·059) versus 0·016 (-0·012-0·044). AD-GRS or CAD-GRS were not significantly related to the intervention effect overall (p>0·46), but for AD-GRS there were differences between women and men (p=0·024). The intervention-control difference in annual overall score change was 0·045 (0·004-0·087) for higher-risk women, 0·003 (-0·040-0·047) for lower-risk women, 0·019 (-0·026-0·064) for higher-risk men, and 0·027 (-0·009-0·064) for lower-risk men. People with genetic susceptibility for Alzheimer's disease/dementia or coronary artery disease can benefit from multidomain lifestyle interventions. Although the findings for AD-GRS and CAD-GRS risk groups were similar to APOE4 carrier status, with additional gender differences for AD-GRS, these exploratory findings need to be verified across several multidomain lifestyle trials to ensure adequate statistical power and inclusion of genetically diverse populations.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"27 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756304","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":"CD21lo B-cell subsets are recruited to the central nervous system in acute neuromyelitis optica.","authors":"Ryusei Nishigori, Mio Hamatani, Hiroyuki Yoshitomi, Kimitoshi Kimura, Masaki Takata, Shinji Ashida, Chihiro Fujii, Hirofumi Ochi, Ryosuke Takahashi, Takayuki Kondo, Hideki Ueno","doi":"10.1093/brain/awaf086","DOIUrl":"10.1093/brain/awaf086","url":null,"abstract":"<p><p>Neuromyelitis optica (NMO) is an acute inflammatory demyelinating disease of the CNS. The presence of astrocyte-targeted AQP4-immunoglobulin G (IgG) in peripheral blood is a major factor in its diagnosis. Previous studies show that AQP4-IgG contributes directly to CNS inflammation and that B cells play a central pathogenic role in NMO. However, where and how the B-cell response is altered remains controversial. In this study, we used high-parameter flow cytometry to carry out a comprehensive analysis of the immune cell populations in the CSF samples obtained from first-episode acute-phase NMO patients, compared with those from patients with acute-phase multiple sclerosis and other neurological diseases. Among 10 immune cell populations defined in the analysis, the frequency only of B cells and antibody-secreting cells (ASC) was higher in the CSF of acute-phase NMO compared with other neurological diseases. Detailed assessments of B-cell and ASC subsets in the CSF revealed differences in the dominant subsets between NMO and multiple sclerosis. In NMO, a series of CD21lo B-cell subsets, including 'activated' naïve B, double-negative and switched memory subsets, considered as ASC precursors, were dominant. A majority of these CD21lo B-cell subsets expressed CD69 and CXCR3, suggesting their CNS residency. An increase of CD21lo B-cell subsets was also observed in the CSF of treatment-refractory NMO patients. Furthermore, two B-helper T-cell subsets, T peripheral helper type 1 and T follicular helper type 1 cells, both highly expressing CD69 and CXCR3, were enriched in the CSF of NMO patients, suggesting their interactions with ASC precursors in the CNS. In vitro culture experiments using blood samples from patients with NMO showed that CD21lo B cells included AQP4-IgG-producing cells and displayed a high propensity to differentiate into ASCs. We also found that CD21lo B-cell subsets in NMO upregulated the expression of C5a receptors, and C5a signals promoted their differentiation into ASCs. ASCs derived from CD21lo B cells expressed high levels of CXCR3 and CD138. The increase in CD21lo B-cell subsets was significantly correlated with the annual relapse rate. Collectively, our study strongly suggests that the mechanism to promote the generation of CD21lo B cells, probably via the extrafollicular pathway, becomes activated during the acute phase of NMO and that the generated CD21lo B-cell subsets contribute to the pathogenesis. Targeting CD21lo B-cell subsets might be useful for the development of novel therapeutic approaches.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"2995-3010"},"PeriodicalIF":11.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555861","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":"Heterozygous RAB3A variants cause cerebellar ataxia by a partial loss-of-function mechanism.","authors":"Holger Hengel, Shabab B Hannan, Selina Reich, Danique Beijer, Johanna Roller, Bernd K Gilsbach, Christian Johannes Gloeckner, Daniel Greene, Dagmar Timmann, Christel Depienne, Andrew Mumford, Mary O'Driscoll, Andrea H Nemeth, Julie Lundberg, Lance H Rodan, Ange-Line Bruel, Julian Delanne, Tine Deconinck, Jonathan Baets, Ziv Gan-Or, Guy Rouleau, Oksana Suchowersky, Mehrdad A Estiar, Stephen Reich, Camilo Toro, Stephan Züchner, Jamilé Hazan, Hjörvar Pétursson, Florian Harmuth, Claudia Bauer, Peter Bauer, Ernest Turro, David Lambright, Ludger Schöls, Matthis Synofzik","doi":"10.1093/brain/awaf111","DOIUrl":"10.1093/brain/awaf111","url":null,"abstract":"<p><p>RAB3A encodes a small GTP-binding protein that is abundant in brain synaptic vesicles and crucial for the release of neurotransmitters and synaptic plasticity. Here, we identified RAB3A as a candidate gene for autosomal dominant cerebellar ataxia by two independent approaches: linkage in a large dominant ataxia family and, in parallel, an untargeted computational genetic association approach, analysing the 100 000 Genomes Project datasets. To validate the role of RAB3A in ataxia, we next screened large rare disease databases for rare heterozygous RAB3A variants in probands with ataxia features. In total, we identified 18 individuals from 10 unrelated families all sharing a cerebellar ataxia phenotype. Notably, 9 of the 10 families carried a recurrent variant in RAB3A, p.Arg83Trp, including one de novo occurrence. In addition, our screening revealed three families with a neurodevelopmental phenotype and three unique RAB3A variants, which were either de novo or loss-of-function variants. In line with the different RAB3A variant types, protein domains and predicted functional consequences, a comprehensive set of complementary methods was used to characterize the identified variants functionally. As expected, GTPase-activating protein (GAP)-dependent GTP hydrolysis was reduced for those two missense variants located in the GAP-binding domain of RAB3A (Arg83Trp and Tyr91Cys). In a Drosophila Rab3 loss-of-function model, these two missense variants also failed to rescue a synaptic phenotype. Overexpression of Rab3 variants in Drosophila wild-type background did not cause an obvious phenotype, making a dominant negative effect of these variants unlikely. Lastly, exploring interactors of RAB3A variants by using co-immunoprecipitation and mass spectrometry showed differential changes in variant-specific interactions with known RAB3A key regulatory and effector proteins. In sum, our results establish RAB3A as a neurological disease gene. It represents an autosomal dominant gene for cerebellar ataxia with different variants associated with disease, including the frequent reoccurring variant p.Arg83Trp. Our study sheds light on the variant-specific interactome of RAB3A. Finally, we suggest an association of RAB3A with a neurodevelopmental phenotype, as reported for variants in several RAB3A interaction partners and as seen in Rab3A-deficent mice, although this possible association warrants further investigation by future studies.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":"2812-2826"},"PeriodicalIF":11.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751067","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}