Brain最新文献

{"title":"Anatomical progression of genetic frontotemporal lobar degeneration across the lifespan.","authors":"Vincent Planche, Boris Mansencal, Vladimir Fonov, José V Manjon, Thomas Tourdias, Arabella Bouzigues, Lucy L Russell, Phoebe H Foster, Eve Ferry-Bolder, John C van Swieten, Lize C Jiskoot, Harro Seelaar, Raquel Sanchez-Valle, Robert Laforce, Caroline Graff, Daniela Galimberti, Rik Vandenberghe, Alexandre de Mendonça, Pietro Tiraboschi, Isabel Santana, Alexander Gerhard, Johannes Levin, Sandro Sorbi, Markus Otto, Maxime Bertoux, Thibaud Lebouvier, Chris R Butler, Isabelle Le Ber, Elizabeth Finger, Maria Carmela Tartaglia, Mario Masellis, James B Rowe, Matthis Synofzik, Fermin Moreno, Barbara Borroni, Jonathan D Rohrer, D Louis Collins, Simon Ducharme, Pierrick Coupé","doi":"10.1093/brain/awaf195","DOIUrl":"10.1093/brain/awaf195","url":null,"abstract":"<p><p>The recent development of brain charts for the human lifespan offers an ideal modeling framework for pathologies such as genetic frontotemporal lobar degeneration (FTLD) which likely involve both neurodevelopmental and neurodegenerative processes over a lifetime. We have therefore combined this new methodological approach with MRI data from asymptomatic and symptomatic subjects, carrying C9orf72, MAPT or GRN mutations from the GENFI and ALLFTD cohorts. We analyzed 37,532 MRIs from control subjects covering the entire lifespan and a total of 1,341 MRIs from subjects with a pathogenic FTLD mutation, aged from 18 to 86 years old. We detected the first significant regional brain volume differences on average at 27 years old in C9orf72 and MAPT mutation carriers, and at 42 years old in GRN mutation carriers. The delay between the onset of anatomical changes and the average age of symptom onset (i.e. the presymptomatic phase) was 13 years for MAPT, 17 years for GRN, and 34 years for C9orf72 mutation carriers. In terms of effect size, cumulative atrophy over the lifespan was twice as severe in affected brain regions in MAPT than in GRN or C9orf72 mutation carriers. However, the neurodegenerative process was spatially more extensive in C9orf72 (35 brain regions affected out of the 61 tested) compared to GRN or MAPT mutations carriers (25 and 18 regions, respectively). Schematically, the chronological staging of atrophy progression showed an initial involvement of the thalamus in C9orf72 expansion carriers, followed by the fronto-temporo-insular regions, the striatum and the amygdala. In GRN mutation carriers, atrophy began in fronto-insular areas, before progressing toward subcortical structures. In MAPT mutation carriers, atrophy affected the anterior temporal pole with the amygdala and hippocampus, before progressing to fronto-insular regions and the striatum. Our results using brain charts for the human lifespan show that C9orf72 is the most diffuse but also the slowest to emerge among genetic FTLD. MAPT FTLD is more aggressive and focal, while GRN FTLD is also rapidly progressive but with a later onset of the presymptomatic phase. Beyond quantification of the anatomical progression of genetic FTLD over the lifespan, these results may help determine the best timing to model and test disease-modifying strategies in FTLD, and monitor their effect in future clinical trials.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155926","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":"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":"https://doi.org/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":""},"PeriodicalIF":10.6,"publicationDate":"2025-05-26","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":"Cholinergic basal forebrain degeneration in isolated REM sleep behaviour disorder","authors":"Ryul Kim, Bora Jin, Heejung Kim, Kyung Ah Woo, Eun Jin Yoon, Seoyeon Kim, Jung Hwan Shin, Hyunwoo Nam, Yu Kyeong Kim, Beomseok Jeon, Jee-Young Lee","doi":"10.1093/brain/awaf196","DOIUrl":"https://doi.org/10.1093/brain/awaf196","url":null,"abstract":"Although growing evidence suggests that cholinergic basal forebrain degeneration is linked to cognitive impairment and axial motor symptoms in Lewy body disorders (LBDs), the cholinergic contribution to their prodromal phase remains largely unknown. Herein, we aimed to address three important yet unresolved questions focusing on prodromal LBDs: (1) to examine whether and where basal forebrain degeneration begins; (2) to determine how such alterations are related to other brain morphometric changes and monoaminergic deficits; and (3) to investigate the extent to which basal forebrain atrophy contributes to the clinical picture. We included 93 patients with polysomnography-confirmed isolated REM sleep behavior disorder (iRBD), 33 with de novo Parkinson’s disease (PD) with a premorbid history of RBD (dnPDRBD), and 36 healthy controls. Participants underwent baseline assessments including volumetric MRI, 18F-FP-CIT PET scan, the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, and neuropsychological evaluations. Regional volumes of cholinergic nuclei 1, 2, and 3 (Ch1–3) and cholinergic nucleus 4 (Ch4) were extracted using probabilistic maps, and voxel-based and surface-based morphometric analyses were applied to identify basal forebrain atrophy-associated cortical and subcortical regions. Subgroups of patients with iRBD underwent repeated motor and cognitive assessments (38 and 34 patients for 2 and 4 years, respectively). Among the basal forebrain complex, Ch4 volumes, but not Ch1–3 volumes, were significantly reduced in patients with iRBD. This reduction positively correlated with limbic regions, including the amygdala and cingulate cortex, and, to a lesser extent, with the neocortical regions, particularly the frontal and temporal cortices. With respect to clinical symptoms, both Ch1–3 and Ch4 volume reductions were modestly associated with severe axial motor symptoms. Additionally, Ch1–3 volume reduction was associated with higher incidence of dementia and faster progression of memory impairment, whereas Ch4 volume reduction was associated with faster progression of limb bradykinesia. Using a multimodal imaging approach, we found that iRBD patients who later converted to PD showed predominant monoaminergic deficits but variable cholinergic involvement, and these patterns were similar to those observed in the dnPDRBD group. Conversely, iRBD patients who later converted to dementia with Lewy bodies showed predominant cholinergic deficits but variable monoaminergic involvement. This comprehensive analysis provides important implications for understanding how cholinergic basal forebrain degeneration is associated with brain morphometric changes, clinical outcomes, and monoaminergic degeneration during the prodromal phase of LBDs.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"25 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136758","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":"SLC35A2 loss-of-function variants affect glycomic signatures, neuronal fate and network dynamics","authors":"Dulcie Lai, Paulina Sosicka, Damian J Williams, MaryAnn E Bowyer, Andrew K Ressler, Sarah E Kohrt, Savannah J Muron, Peter B Crino, Hudson H Freeze, Michael J Boland, Erin L Heinzen","doi":"10.1093/brain/awaf198","DOIUrl":"https://doi.org/10.1093/brain/awaf198","url":null,"abstract":"SLC35A2 encodes a UDP-galactose transporter essential for glycosylation of proteins and galactosylation of lipids and glycosaminoglycans. Germline genetic SLC35A2 variants have been identified in congenital disorders of glycosylation and somatic SLC35A2 variants have been linked to intractable epilepsy associated with malformations of cortical development. However, the functional consequences of these pathogenic variants on brain development and network integrity remain unknown. In this study, we use an isogenic human induced pluripotent stem cell-derived neuron model to comprehensively interrogate the functional impact of loss of function variants in SLC35A2 through the integration of cellular and molecular biology, protein glycosylation analysis, neural network dynamics, and single cell electrophysiology. We show that loss of function variants in SLC35A2 result in disrupted glycomic signatures and precocious neurodevelopment, yielding hypoactive, asynchronous neural networks. This aberrant network activity is attributed to an inhibitory/excitatory imbalance as characterization of neural composition revealed preferential differentiation of SLC35A2 loss of function variants towards the GABAergic fate. Furthermore, electrophysiological recordings of synaptic activity and gene expression differences suggest network phenotypes are driven by changes occurring at the synapse. Our study is the first to provide mechanistic insight regarding the early development and functional connectivity of SLC35A2 loss-of-function variant harboring human neurons, providing important groundwork for future exploration of potential therapeutic interventions.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"23 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145792","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":"Oligoadenylate synthetase 1a suppresses prion infection through binding to cellular prion protein.","authors":"Takujiro Homma,Takehiro Nakagaki,Takuya Nishinakagawa,Yurie Morita,Ryuichiro Atarashi,Shigeru Kakuta,Yoichiro Iwakura,Noriyuki Nishida,Daisuke Ishibashi","doi":"10.1093/brain/awaf193","DOIUrl":"https://doi.org/10.1093/brain/awaf193","url":null,"abstract":"Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein (PrPC) into its infectious β-sheet-rich isoform (PrPSc). Conventionally, prions were thought to be incapable of eliciting robust immune responses because PrPC and PrPSc share an identical primary structure. However, recent evidence highlights the critical involvement of type I interferon (I-IFN) signaling in host defense against prion propagation. Although we have previously shown that I-IFN, activated by interferon regulatory factor 3 (IRF3), plays an essential role in limiting prion invasion, the precise mechanisms underlying its protective effects remain unclear. Here, using in vivo and ex vivo prion infection models, we discovered that 2'-5' oligoadenylate synthetase 1a (Oas1a), an interferon-stimulated gene downstream of the I-IFN receptor, inhibits prion invasion at an early stage. Using Oas1a-knockout mice, we show that loss of Oas1a significantly accelerates prion disease progression and shortens survival, demonstrating its protective role in vivo. Consistent with this, mouse embryonic fibroblasts from Oas1a-knockout mice exhibited significantly increased susceptibility to 22L prion infection, effectively abrogating the anti-prion effects of I-IFN treatment. In addition, we found that recombinant Oas1a, when applied extracellularly, inhibited prion propagation without activating conventional RNase L pathways. Mechanistically, Oas1a directly binds PrPC, preventing its conversion to PrPSc and thus limiting PrPSc accumulation in vitro. These findings highlight the critical role of the IFN-Oas1a axis in limiting prion propagation and underscore its potential as a novel therapeutic target for prion diseases.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"44 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122188","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":"Models of autoantibody mediated diseases: actively nearing the human gold standard.","authors":"Sarosh R Irani","doi":"10.1093/brain/awaf160","DOIUrl":"https://doi.org/10.1093/brain/awaf160","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"31 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122189","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":"Neural substrates of the link between dual-task gait and dementia: an intermediary step in which direction?","authors":"A Charlotte Menart,M Arfan Ikram,Frank J Wolters","doi":"10.1093/brain/awaf187","DOIUrl":"https://doi.org/10.1093/brain/awaf187","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"136 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114085","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":"Correction to: Sex-specific modulation of amyloid-β on tau phosphorylation underlies faster tangle accumulation in females.","authors":"","doi":"10.1093/brain/awaf174","DOIUrl":"https://doi.org/10.1093/brain/awaf174","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"25 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103698","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: Neural substrates of the link between dual-task gait and dementia: an intermediary step in which direction?","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/awaf192","DOIUrl":"https://doi.org/10.1093/brain/awaf192","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"51 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114117","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":"Pure autonomic failure: a natural history study of the Queen Square cohort","authors":"Giacomo Chiaro, Ekawat Vichayanrat, Shiwen Koay, Antoine Rogeau, Gordon T Ingle, Patricia McNamara, Laura Watson, Jamshed Bomanji, Christopher J Mathias, Valeria Iodice","doi":"10.1093/brain/awaf191","DOIUrl":"https://doi.org/10.1093/brain/awaf191","url":null,"abstract":"The current research challenge in pure autonomic failure (PAF) lies in identifying specific biomarkers that can differentiate it from the other Lewy body disorders (Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies) and multiple system atrophy in the early stages and predict phenoconversion trajectories to more widespread impairment. In this study, we described the natural history of our cohort of PAF patients over five decades and validated a cluster of clinical, autonomic, and neuroimaging biomarkers that help identify clinical profiles susceptible to further neurodegeneration, working towards a biological definition of PAF. Consecutive patients with an initial diagnosis of PAF were recruited and monitored through key milestones (disease onset, first and repeat autonomic assessment, phenoconversion, and death/final contact). A subset underwent brain magnetic resonance imaging and DaTSCAN. Uni- and multivariate regression analyses explored the associations among different factors, survival times, and phenoconversion, and were used to predict the probability of phenoconversion. 281 PAF patients were followed for a median of 10 years. Of these, 33% (91) converted to a more widespread synucleinopathy, and 41% (115) died during follow-up, of whom 53% (61) retained a PAF phenotype. Baseline cardiovascular autonomic biomarkers were key in differentiating disease trajectories and repeat testing indicated worsening of autonomic failure during the disease course. Median survival of PAF patients was 15 years from orthostatic symptoms onset and was mostly influenced by age and the severity of orthostatic hypotension. 39% of patients had abnormal DaTSCAN results up to 7 years before phenoconversion, with 84% of these patients progressing to more widespread synucleinopathy. Male sex, older age, dream enactment behaviour, and supine noradrenaline levels &amp;gt;200 pg/mL were correlated with the risk of phenoconversion to Lewy body disorders, whereas younger age, bladder dysfunction, catheter use, and dream enactment behaviour were associated with phenoconversion to multiple system atrophy. Our natural history study involves the largest single-centre longitudinal cohort of patients with an initial diagnosis of PAF and identifies robust clinical, autonomic, and neuroimaging biomarkers that, when used together, could serve as a novel and sensitive screening tool for early identification and stratification of patients at risk of phenoconversion to more widespread synucleinopathy.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"32 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113831","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}