Brain最新文献

{"title":"Low β predicts motor output and cell degeneration in the A53T Parkinson's disease rat model","authors":"Katarina Hofman, Jia Zhi Chen, Tanmoy Sil, Franziska Pellegrini, Stefan Haufe, Nicolo Pozzi, Chiara Palmisano, Ioannis Isaias, James B Koprich, Jonathan M Brotchie, Andrea A Kühn, Cordula Matthies, Martin M Reich, Muthuraman Muthuraman, Jens Volkmann, Chi Wang Ip","doi":"10.1093/brain/awaf063","DOIUrl":"https://doi.org/10.1093/brain/awaf063","url":null,"abstract":"Elevated beta (β; 13-30 Hz) synchronization within the subthalamic nucleus (STN) characterizes bradykinesia in Parkinson’s disease (PD). β oscillations may serve as biomarkers for off-period motor symptoms and control signals for adaptive, closed-loop deep brain stimulation (DBS) in PD. However, their relation to striatal dopaminergic denervation and PD progression remains uncertain. Research on β oscillations is limited to advanced PD stages undergoing DBS, prohibiting insights into early-stage progression and compensatory mechanisms. We therefore investigated β dynamics, correlation with motor performance, and nigrostriatal neurodegeneration in a progressive PD rat model overexpressing AAV1/2-A53T α-synuclein, mimicking PD pathology. Over eight weeks, we longitudinally conducted behavioral assessments using the cylinder test and recorded local field potentials (LFP) from the STN and motor cortex (MCx) in the AAV-A53T-αSyn PD rat model. Increased β power and burst parameters accompanied early motor deficits in the AAV-A53T-αSyn PD rat model. Changes were observed in the STN and MCx versus empty vector controls; alterations intensified with pathology progression. Increased high β power and burst parameters (e.g. long burst probability in the STN but not MCx) were associated with motor impairment and nigrostriatal dopaminergic neurodegeneration. Multivariate analyses from these rat-derived data demonstrated that combined β parameters in the cortico-subthalamic pathway and striatal dopaminergic fiber density predicted motor performance and neurodegeneration. Additional multivariate analyses confirmed the translational relevance of the A53T PD model, linking β activity and dopamine uptake to motor impairment (UPDRS III Med-OFF) in human PD patients. Our data support the pathophysiological significance of β oscillations as a progression marker of PD for motor symptoms and neurodegeneration. Our predictive models carry translational relevance, with the prospect of monitoring disease progression and neuroprotective outcomes in PD based on LFP recordings.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"1 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443447","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: Age at onset of genetic disease and genetic dependent stage: evidence from cases with SCN1A variants.","authors":"Andreas Brunklaus","doi":"10.1093/brain/awaf065","DOIUrl":"10.1093/brain/awaf065","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424966","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":"Genotype and phenotype spectrum of Charcot-Marie-Tooth disease due to mutations in SORD.","authors":"Andrea Cortese, Maike F Dohrn, Riccardo Curro, Sara Negri, Petra Lassuthova, Chiara Pisciotta, Stefano Tozza, Abdullah Al-Ajmi, Changyoung Feng, Pedro J Tomaselli, Gorka Fernandez-Eulate, Saif Haddad, Matilde Laurà, Alexander M Rossor, Elisa Vegezzi, Stefano Facchini, James N Sleigh, Adriana Rebelo, Danique Beijer, Jacquelyn Raposo, Mario Saporta, Barbora Lauerova, Helena F Pernice, Pascal Achenbach, Ulrike Schöne, Tayir Alon, Marcus Deschauer, Isabell Cordts, Carolin D Obermaier, Natalie Winter, Peter D Creigh, Janet E Sowden, Tyler Rehbein, Stefania Magri, Alessandro Bertini, Paola Saveri, Paolo Ripellino, Jingyu Huang, Aleksandra Nadaj-Pakleza, Alison Ross, James K L Holt, Kathryn M Brennan, Rivka Sukenik-Halevy, Varoona Bizaoui, Yesim Parman, Esra Battaloglu, Arman Cakar, Hadil Alrohaif, Simon Hammans, Kishore R Kumar, Marina L Kennerson, Hülya Kayserili, Defne A Amado, Katrin Hahn, Paola Valentino, Francesca Cavalcanti, Carlo Gaetano, Franco Taroni, Geir J Braathen, Henry Houlden, Tanya Stojkovic, Stojan Peric, Alessandra Bolino, Stefano C Previtali, Yi-Chung Lee, Ayşe N Başak, Sherifa A Hamed, Ricardo Rojas-Garcia, Kristl G Claeys, Wilson Marques, Teresa Sevilla, Beate Schlotter-Weigel, Fiore Manganelli, Ruxu Zhang, David N Herrmann, Steven S Scherer, Pavel Seeman, Davide Pareyson, Mary M Reilly, Michael E Shy, Stephan Züchner","doi":"10.1093/brain/awaf021","DOIUrl":"https://doi.org/10.1093/brain/awaf021","url":null,"abstract":"<p><p>Biallelic loss-of-function mutations in the sorbitol dehydrogenase (SORD) gene cause the most common recessive type of Charcot-Marie-Tooth disease (CMT), CMT-SORD. However, the full genotype-phenotype spectrum and progression of the disease remain to be defined. Notably, a multicenter phase 2/3 study to test the efficacy of govorestat (NCT05397665), a new aldose reductase inhibitor, is currently ongoing. Diagnosing CMT-SORD will become imperative when disease-modifying therapies become available. In this cross-sectional multicentre study, we identified 144 patients from 126 families, including 99 males (69%) and 45 females (31%). Patients represented multiple ancestries, including European, Hispanic, Chinese, Near Eastern, and Northern African. We confirmed c.757delG (p.Ala253GlnfsTer27) as the most common pathogenic allele, followed by c.458C>A (p.Ala153Asp), while other variants were identified mostly in single cases. The average sorbitol level in CMT-SORD patients was significantly higher compared to controls and heterozygous carriers, independently from serum storage duration, sex, or variant type. Two-thirds of cases were diagnosed with CMT2 while one-third had distal hereditary motor neuropathy (dHMN). Disease onset was usually in the second decade of life. Although foot dorsiflexion was the most affected muscle group, dorsal and plantar flexion had a similar degree of weakness in most cases (difference of Medical Research Council score ≤ 1). One fourth of patients used ankle foot orthoses, usually in their 30s, but most patients maintained independent ambulation later in life. Nerve conduction studies (NCS) were suggestive of a motor predominant axonal neuropathy, with reduced conduction velocities in the intermediate range in one fourth of the cases. Sensory conductions in the upper limbs appeared more frequently affected than in the lower limbs. Foot dorsiflexion and plantar flexion decreased significantly with age. Male sex was significantly associated with the severity of distal lower limb weakness (plantar flexion) and a larger change over time (dorsiflexion). In conclusion, CMT-SORD is a frequent recessive form of axonal, motor predominant CMT, with prominent foot dorsiflexion and plantar flexion involvement. Fasting serum sorbitol is a reliable biomarker of the condition that can be utilized for pathogenicity assessment of identified rare SORD variants.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405687","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":"Combined genomics and proteomics unveils elusive variants and vast aetiologic heterogeneity in dystonia","authors":"Michael Zech, Ivana Dzinovic, Matej Skorvanek, Philip Harrer, Jan Necpal, Robert Kopajtich, Volker Kittke, Erik Tilch, Chen Zhao, Eugenia Tsoma, Ugo Sorrentino, Elisabetta Indelicato, Antonia Stehr, Alice Saparov, Lucia Abela, Miriam Adamovicova, Alexandra Afenjar, Birgit Assmann, Janette Baloghova, Matthias Baumann, Riccardo Berutti, Zuzana Brezna, Melanie Brugger, Theresa Brunet, Benjamin Cogne, Isabel Colangelo, Erin Conboy, Felix Distelmaier, Matthias Eckenweiler, Barbara Garavaglia, Arie Geerlof, Elisabeth Graf, Annette Hackenberg, Denisa Harvanova, Bernhard Haslinger, Petra Havrankova, Georg F Hoffmann, Wibke G Janzarik, Boris Keren, Miriam Kolnikova, Konstantinos Kolokotronis, Zuzana Kosutzka, Anne Koy, Martin Krenn, Magdalena Krygier, Katarina Kusikova, Oliver Maier, Thomas Meitinger, Christian Mertes, Ivan Milenkovic, Edoardo Monfrini, Andre Santos Dias Mourao, Thomas Musacchio, Mathilde Nizon, Miriam Ostrozovicova, Martin Pavlov, Iva Prihodova, Irena Rektorova, Luigi M Romito, Barbora Rybanska, Ariane Sadr-Nabavi, Susanne Schwenger, Ali Shoeibi, Alexandra Sitzberger, Dmitrii Smirnov, Jana Svantnerova, Raushana Tautanova, Sandra P Toelle, Olga Ulmanova, Francesco Vetrini, Katharina Vill, Matias Wagner, David Weise, Giovanna Zorzi, Alessio Di Fonzo, Konrad Oexle, Steffen Berweck, Volker Mall, Sylvia Boesch, Barbara Schormair, Holger Prokisch, Robert Jech, Juliane Winkelmann","doi":"10.1093/brain/awaf059","DOIUrl":"https://doi.org/10.1093/brain/awaf059","url":null,"abstract":"Dystonia is a rare-disease trait for which large-scale genomic investigations are still underrepresented. Genetic heterogeneity among patients with unexplained dystonia warrants interrogation of entire genome sequences, but this has not yet been systematically evaluated. To significantly enhance our understanding of the genetic contribution to dystonia, we (re)analyzed 2,874 whole-exome sequencing (WES), 564 whole-genome sequencing (WGS), as well as 80 fibroblast-derived proteomics datasets, representing the output of high-throughput analyses in 1,990 patients and 973 unaffected relatives from 1,877 families. Recruitment and precision-phenotyping procedures were driven by long-term collaborations of international experts with access to overlooked populations. By exploring WES data, we found that continuous scaling of sample sizes resulted in steady gains in the number of associated disease genes without plateauing. On average, every second diagnosis involved a gene not previously implicated in our cohort. Second-line WGS focused on a subcohort of undiagnosed individuals with high likelihood of having monogenic forms of dystonia, comprising large proportions of patients with early onset (81.3%), generalized symptom distribution (50.8%) and/or coexisting features (68.9%). We undertook extensive searches for variants in nuclear and mitochondrial genomes to uncover 38 (ultra)rare diagnostic-grade findings in 37 of 305 index patients (12.1%), many of which had remained undetected due to methodological inferiority of WES or pipeline limitations. WGS-identified elusive variations included alterations in exons poorly covered by WES, RNA-gene variants, mitochondrial-DNA mutations, small copy-number variants, complex rearranged genome structure, and short tandem repeats. For improved variant interpretation in WGS-inconclusive cases, we employed systematic integration of quantitative proteomics. This aided in verifying diagnoses related to technically challenging variants and in upgrading a variant of uncertain significance (3 of 70 WGS-inconclusive index patients, 4.3%). Further, unsupervised proteomic outlier-analysis supplemented with transcriptome sequencing revealed pathological gene underexpression induced by transcript disruptions in three more index patients with underlying (deep) intronic variants (3/70, 4.3%), highlighting the potential for targeted antisense-oligonucleotide therapy development. Finally, trio-WGS prioritized a de-novo missense change in the candidate PRMT1, encoding a histone-methyltransferase. Data-sharing strategies supported the discovery of three distinct PRMT1 de-novo variants in four phenotypically similar patients, associated with loss-of-function effects in in-vitro assays. This work underscores the importance of continually expanding sequencing cohorts to characterize the extensive spectrum of gene aberrations in dystonia. We show that a pool of unresolved cases is amenable to WGS and complementary multi-omic studies, dir","PeriodicalId":9063,"journal":{"name":"Brain","volume":"27 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401330","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":"Behavioural changes in frontotemporal dementia and their cognitive and neuroanatomical correlates","authors":"Matthew A Rouse, Masud Husain, Peter Garrard, Karalyn Patterson, James B Rowe, Matthew A Lambon Ralph","doi":"10.1093/brain/awaf061","DOIUrl":"https://doi.org/10.1093/brain/awaf061","url":null,"abstract":"Behavioural changes are a central feature of frontotemporal dementia (FTD); they occur in both behavioural-variant (bvFTD) and semantic dementia (SD)/semantic-variant primary progressive aphasia subtypes. In this study, we addressed two current clinical knowledge gaps; (i) are there qualitative or clear distinctions between behavioural profiles in bvFTD and SD, and (ii) what are the precise roles of the prefrontal cortex and anterior temporal lobes in supporting social behaviour? Resolving these conundrums is crucial for improving diagnostic accuracy and for the development of targeted interventions to treat challenging behaviours in FTD. Informant questionnaires to assess behavioural changes included the Cambridge Behavioural Inventory-Revised and two targeted measures of apathy and impulsivity. Participants completed a detailed neuropsychological battery to permit investigation of the relationship between cognitive status (including social-semantic knowledge, general semantic knowledge and executive function) with behaviour change in FTD. To explore changes in regional grey matter volume, a subset of patients had structural MRI. Diagnosis-based group comparisons were supplemented by a transdiagnostic approach which encompassed the spectrum of bvFTD, SD and “mixed” or intermediate cases. Such an approach is sensitive to the systematic graded variation in FTD and allows the neurobiological underpinnings of behaviour change to be explored across an FTD spectrum. We found a wide range of behavioural changes across FTD. Although quantitatively more severe on average in bvFTD, as expected, the item-level analyses found no evidence for qualitative differences in behavioural profiles or “behavioural double dissociations” between bvFTD and SD. Comparisons of self and informant ratings revealed strong discrepancies in the perspective of the caregiver versus patient. Logistic regression revealed that neuropsychological measures had better discriminative accuracy for bvFTD versus SD than caregiver-reported behavioural measures. A principal component analysis of all informant questionnaire domains extracted three components, interpreted as reflecting: (1) apathy, (2) challenging behaviours and (3) activities of daily living. More severe apathy in both FTD subtypes was associated with (a) increased levels of impaired executive function and (b) anterior cingulate cortex atrophy. Questionnaire ratings of impaired behaviour did not correlate with either anterior temporal lobe atrophy or degraded social-semantic knowledge. Together, these findings highlight the presence of a wide range of behavioural changes in both bvFTD and SD, which vary by degree rather than quality. We recommend a transdiagnostic approach for future studies of the neuropsychological and neuroanatomical underpinnings of behavioural deficits in FTD.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"65 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401331","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 inferior fronto-occipital fasciculus: bridging phylogeny, ontogeny and functional anatomy","authors":"Davide Giampiccolo, Guillaume Herbet, Hugues Duffau","doi":"10.1093/brain/awaf055","DOIUrl":"https://doi.org/10.1093/brain/awaf055","url":null,"abstract":"The inferior-fronto-occipital fasciculus is a long-range white matter tract that connects the prefrontal cortex with parietal, posterior temporal and occipital cortices. First identified in the nineteenth century through the pioneering studies of Mayo and Meynert using blunt dissection, its anatomy and function remain contentious topics. Structurally, its projections are well-documented in human blunt dissection and tractography literature, yet its existence has been questioned by tract-tracing studies in macaques. Functionally, while traditional results from direct white matter stimulation during awake surgery suggested a contribution to language, recent evidence from stimulation and lesion data may indicate a broader role in executive control, extending to attention, motor cognition, memory, reading, emotion recognition, and theory of mind. This review begins by examining anatomical evidence suggesting that the inferior fronto-occipital fasciculus evolved in non-human primates to connect temporal and occipital cortices to prefrontal regions involved in context-dependent selection of visual features for action. We then integrate developmental, electrophysiological, functional and anatomical evidence for the human inferior fronto-occipital fasciculus to propose it has a similar role in manipulation of visual features in our species—particularly when inhibition of overriding but task-irrelevant stimuli is required to prioritize a second, task-relevant stimulus. Next, we introduce a graded model in which dorsal (orbitofrontal, superior and middle frontal to precuneal, angular and supero-occipital projections) and ventral (inferior frontal to posterotemporal, basal temporal and infero-occipital) projections of the inferior fronto-occipital fasciculus support perceptual or conceptual control of visual representations for action, respectively. Leveraging this model, we address controversies in the current literature regarding language, motor cognition, attention and emotion under the unifying view of cognitive control. Finally, we discuss surgical implications for this model and its impact on predicting and preventing neurological deficits in neurosurgery.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"22 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393360","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: Threshold of somatic mosaicism leading to brain dysfunction with focal epilepsy.","authors":"","doi":"10.1093/brain/awaf041","DOIUrl":"https://doi.org/10.1093/brain/awaf041","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397828","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":"Interleukin-17B is a new biomarker of human muscle regeneration in dystrophinopathies","authors":"Chang Liu, Zhihao Xie, Qingyue Yuan, Yanyu Lu, Jianwen Deng, Zhaoxia Wang, Lingchao Meng, Yun Yuan, Zhiying Xie","doi":"10.1093/brain/awaf058","DOIUrl":"https://doi.org/10.1093/brain/awaf058","url":null,"abstract":"We aimed to identify novel biomarkers of muscle pathological changes via a large-scale histopathology-based multi-omics study of dystrophinopathies. We performed a comparative pathological analysis of 121 Duchenne muscular dystrophy (DMD) and 114 Becker muscular dystrophy (BMD) patients to determine muscle pathological similarities and differences between DMD and BMD that have not been systematically investigated. Customized bioinformatic analyses of bulk muscle RNA-sequencing data derived from 35 DMD patients, 39 BMD patients, and 21 controls were performed to identify gene signatures associated with pathological changes. Validation experiments, including single-nucleus RNA-sequencing, RNAscope in situ hybridization, and immunofluorescence staining, were performed in a subset of DMD and BMD patients, as well as 27 patients with other acquired and inherited myopathies. Systematic pathological analyses revealed that the percentages of necrotic, regenerating, and hypercontractive myofibers and the degree of muscle fibrosis were greater in DMD patients than in BMD patients. In both DMD and BMD patients, the percentages of necrotic, regenerating, and hypercontractive myofibers respectively increased in the early-stage and decreased in later disease stages, whereas muscle fibrosis progressively worsened with disease progression. Comparative transcriptomic analysis indicated that inflammatory responses were significantly activated in DMD patients compared to BMD patients, which was confirmed by immunohistochemistry analyses. Our customized bioinformatic analyses identified the gene set of MYH3, MYH8, IL17B, TNNT2, MYMK, and TDO2 as the most associated gene signature for muscle necrosis and regeneration. Muscle quantitative reverse transcription-polymerase chain reaction analyses confirmed significantly increased levels of IL17B and TNNT2 mRNA expression in both DMD and BMD patients compared to controls. Muscle IL17B mRNA expression was significantly correlated with histological muscle regeneration and negatively correlated with the age of patients with dystrophinopathy. Single-nucleus RNA-sequencing and RNAscope in situ hybridization demonstrated that IL17B mRNA was expressed in regenerating myofibers of patients with DMD and BMD, as well as in various acquired and inherited myopathies. Immunofluorescence staining further confirmed that interleukin-17B was expressed in regenerating myofibers of DMD and BMD patients. Our study provides evidence that interleukin-17B is a new biomarker of muscle regeneration in dystrophinopathies.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"13 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393917","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":"Single-nucleus transcriptome atlas of the basal forebrain reveals diverse ageing-related pathways","authors":"Jiale Chen, Qianqian Li, Bingqing Ji, Ke Zhang, Miao Ren, Anan Li, Hui Gong, Jian Wang, Gang Cao, Qingming Luo, Xiangning Li","doi":"10.1093/brain/awaf060","DOIUrl":"https://doi.org/10.1093/brain/awaf060","url":null,"abstract":"The basal forebrain is a critical brain region involved in various neurobiological processes, including learning, memory, and attention. Basal forebrain cells undergo structural and functional changes during ageing, increasing their vulnerability to neurodegenerative diseases. To reveal the molecular landscape of distinct cell types during developmental and early ageing, we constructed a comprehensive single-nucleus transcriptomic atlas spanning postnatal day 4 (P4), postnatal day 14 (P14), 3 month (3M), 9 months (9M) and 15 months (15M). Distinct molecular regulatory patterns of basal forebrain subclasses and ageing-related pathways were unveiled. The transcriptional regulation analysis and pseudo-time analysis revealed the dynamic regulatory network of cholinergic neurons during postnatal development. To gain insights into the relationship between ageing and Alzheimer's disease (AD), we conducted an integrative analysis. We identified four potential regulatory networks involved in cholesterol/lipid metabolism, DNA damage repair, and death receptor signal in 5×FAD mice. The cholinergic subtype CN-2 exhibited heightened activity of regulons associated with Srebf2 and Zmiz1, which, in turn, target hub genes implicated in these networks. Meanwhile, CN-2 is the main cholinergic subtype contributing to the alteration of the NRXN signalling pathway. This study offers a significant data source to elucidate the molecular underpinnings of ageing-related and pathological changes in the basal forebrain, paving the way for future research and therapeutic interventions that target specific basal forebrain subclasses and signalling pathways.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"16 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393357","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":"From heart to head: glymphatic disruption as a new pathway in heart failure","authors":"Ian F Harrison","doi":"10.1093/brain/awaf054","DOIUrl":"https://doi.org/10.1093/brain/awaf054","url":null,"abstract":"This scientific commentary refers to ‘Loss of glymphatic homeostasis in heart failure’ by Kritsilis et al. (https://doi.org/10.1093/brain/awae411).","PeriodicalId":9063,"journal":{"name":"Brain","volume":"50 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393358","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}