Brain最新文献

{"title":"Associative learning impairments in unipolar and bipolar depression","authors":"Erdem Pulcu","doi":"10.1093/brain/awaf338","DOIUrl":"https://doi.org/10.1093/brain/awaf338","url":null,"abstract":"This scientific commentary refers to ‘Treatment resistant recurrent unipolar and bipolar depression: associative learning abnormalities’ by Suveges et al. (https://doi.org/10.1093/brain/awaf280).","PeriodicalId":9063,"journal":{"name":"Brain","volume":"90 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089470","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":"Surgical white matter disruption leads to downstream atrophy in the non-resected human brain","authors":"Philip Pruckner, Remika Mito, David Vaughan, Graeme Jackson, Florian Fischmeister, Karl-Heinz Nenning, Marc Berger, Ekaterina Pataraia, Christoph Baumgartner, Christian Dorfer, Karl Rössler, Thomas Czech, Gregor Kasprian, Silvia Bonelli, Robert Smith","doi":"10.1093/brain/awaf344","DOIUrl":"https://doi.org/10.1093/brain/awaf344","url":null,"abstract":"Resective neurosurgery is a cornerstone treatment for many neurological conditions. Although traditionally viewed as localised procedure, increasing evidence from advanced magnetic resonance imaging (MRI) shows that also non-resected anatomy can degenerate following surgery. The relationship between local tissue removal and these postoperative changes remains thus far speculative. Here, we investigate the hypothesis that degenerative changes to surgically preserved grey and white matter are mediated by transneuronal degeneration, a deterioration of intact neuronal populations due to lost axonal input. Using a robust diffusion-weighted and T1-weighted MRI framework specifically tailored for longitudinal analysis of surgical image data, we evaluated evidence to support this mechanism in a series of patients undergoing resective surgery for epilepsy; namely anterior temporal lobectomy (ATL, n=31) or selective amygdalohippocampectomy (SAHE, n=28). We mapped three key aspects of transneuronal degeneration for anatomical regions: 1) loss of surgically resected white matter; 2) longitudinal change in cortical thickness; 3) longitudinal atrophy of non-resected white matter. Using mixed effects models, we explored the evidence in support of a sequential progression of degeneration, where loss of resected white matter leads to downstream atrophy of connected grey matter and the white matter connections thereof. Both ATL and SAHE resulted in extensive resection-related white matter losses, predominately connecting to ipsilateral regions close to resection. We also found pronounced cortical thickness decreases in these regions, as well as extensive white matter atrophy across the ipsilateral hemisphere. These postsurgical alterations were closely associated with resection-related white matter losses, with every 10-fold loss of connections leading to a 3.4% decrease in cortical thickness and a 7.2% decrease in density of downstream pathways. Beyond degenerative effects, we also demonstrate how failure to properly tailor longitudinal image processing to such data can yield misleading evidence for extensive structural network reorganisation, with our more robust approach indicating limited capacity for macroscale plasticity post-resection.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"37 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089522","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":"Targeting lipid droplets in FUS-linked amyotrophic lateral sclerosis mitigates neuronal and astrocytic lipotoxicity","authors":"Laetitia Marcadet, Mari Carmen Pelaez, Antoine Desmeules, Jeanne Serrano, Zhan Cheng, Sahara Khademullah, Elahe Parham, Jaimee Kennedy, Claire Troakes, Caroline Vance, Jorge Soliz, Heather D Durham, Liang Li, Paul A Dutchak, Chantelle F Sephton","doi":"10.1093/brain/awaf328","DOIUrl":"https://doi.org/10.1093/brain/awaf328","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, muscle atrophy, and systemic energy imbalance. Increasing evidence suggests a metabolic shift in ALS from glucose metabolism toward fatty acid utilization; however, the downstream consequences of this reprogramming on disease progression and neuropathology remain poorly defined. We investigated neurometabolic changes in ALS using in vitro and in vivo models of familial ALS expressing the human fused in sarcoma variant R521G (hFUSR521G), along with post-mortem spinal cord tissue from ALS-FUS cases. A combination of unbiased quantitative metabolomic profiling, immunolabeling, and biochemical and molecular approaches were employed. Mass spectrometry of cortical tissue from hFUSR521G mice and littermates revealed a significant increase in acylcarnitine moieties, key substrates used in mitochondrial β-oxidation and cellular energy production. Complementary cytohistological analyses in hFUSR521G mice demonstrated increased lipid droplets (LDs) and peroxidized lipids in both neurons and astrocytes, consistent with our post-mortem findings in spinal cords of individuals carrying FUS R495X or K510E mutations. Arimoclomol, previously shown to ameliorate behavioral phenotypes in this ALS mouse model, was found to enhance lipid metabolism and reduce lipotoxicity in hFUSR521G mice and in cultured neurons and astrocytes expressing FUS R521G. Mechanistically, arimoclomol enhanced LD-mitochondrial contacts and stimulated mitochondrial β-oxidation-dependent lipid catabolism under both basal and pro-inflammatory conditions. This effect was abrogated by etomoxir, an irreversible inhibitor of CPT1, the rate-limiting enzyme of the carnitine shuttle, highlighting a CPT1-dependent mechanism for lipid mobilization. Together, these findings reveal a previously unrecognized role for mitochondrial lipid metabolism in ALS pathogenesis and identify a therapeutic pathway for mitigating the cytotoxic consequences of lipid and acylcarnitine accumulation in FUS-associated ALS.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"3 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089468","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":"Principal axis of primate basal ganglia in processing cognitive flexibility and habitual stability","authors":"Hyoung F Kim","doi":"10.1093/brain/awaf299","DOIUrl":"https://doi.org/10.1093/brain/awaf299","url":null,"abstract":"Cognitive flexibility and habitual stability are essential for survival, enabling adaptation to dynamic environments while ensuring efficiency in stable conditions. A key question is how the brain reconciles these seemingly conflicting properties of flexibility and stability, given that they are unlikely to be mediated by a single neuron or system. In primates, the expanded rostral-caudal axis of the brain provides distinct basal ganglia regions specialised for these functions. Specifically, the rostral and caudal regions of the caudate have been shown to process cognitive flexibility and habitual stability, respectively. This discovery revealed key insights into basal ganglia organisation and established the principle of rostral-caudal functional organisation. This principle demonstrates that basal ganglia structures are functionally organised: rostral regions mediate flexible, updatable goal-directed behaviours, while caudal regions support stable, sustained habitual actions—a framework now recognised across most basal ganglia regions. It offers a cohesive framework for understanding how the primate brain learns, retains, and executes two opposing behavioural strategies through a parallel cortico-basal ganglia system. Parallel processing along the rostral-caudal axis not only provides a unifying framework for basal ganglia function, but also elucidates the mechanisms underlying decision-making at the circuit level and the pathophysiology of basal ganglia-related disorders.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"4 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089521","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":"What is a neurological disease? Definition is not as simple as it might seem","authors":"Simon Shorvon","doi":"10.1093/brain/awaf337","DOIUrl":"https://doi.org/10.1093/brain/awaf337","url":null,"abstract":"Defining neurological disease is less objective than often assumed. Simon Shorvon considers how confusion between symptoms and disease, shifting criteria, unstable classifications, and complex aetiology can undermine the medical model, while labels can have profound social and personal implications the model tends to ignore.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"80 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089469","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":"Staging Alzheimer's disease through amyloid and tau PET.","authors":"Derek R Johnson,Heather J Wiste,Val Lowe,Christopher G Schwarz,David S Knopman,Prashanthi Vemuri,Kejal Kantarci,Bradley F Boeve,Jonathan Graff-Radford,Petrice M Cogswell,Matthew C Senjem,Terry M Therneau,Michael E Griswold,Mingzhao Hu,Ronald C Petersen,Clifford R Jack","doi":"10.1093/brain/awaf346","DOIUrl":"https://doi.org/10.1093/brain/awaf346","url":null,"abstract":"A workgroup assembled by the Alzheimer's Association recently described a conceptual framework for Alzheimer's disease biological staging based on amyloid and tau positron emission tomography (PET) imaging. However, specific tau PET cut points were left to be determined, a step necessary prior to clinical application. We sought to operationalize and evaluate Alzheimer's disease biological staging by identifying meaningful tau PET cut points to define the four biological stages in a well-characterized participant cohort and describe the features of individuals placed into the different biological stages. The primary analysis included 896 participants in the Mayo Clinic Study of Aging or the Mayo Clinic Alzheimer's Disease Research Center longitudinal cohorts. A validation cohort consisted of 328 participants in the Alzheimer's Disease Neuroimaging Initiative. Both cognitively normal and impaired individuals with positive amyloid PET and evaluable tau PET imaging were included. Tau PET cut points were identified with Gaussian Mixture Models to characterize Alzheimer's disease biological stage in study participants with different clinical diagnoses and objective degrees of cognitive impairment as measured by Mini-Mental State Examination. A tau PET cut point in the medial temporal region and two cut points in the temporoparietal region were identified to collectively produce the four Alzheimer's disease biological stages described in the revised criteria. Increasing stage was associated with greater likelihood of mild cognitive impairment and dementia diagnosis and worsening cognitive performance on Mini-Mental State Examination and Clinical Dementia Rating Sum of Boxes, a result that was reproduced in the independent Alzheimer's Disease Neuroimaging Initiative cohort. This study provided empiric validation for the concept of using amyloid PET and tau PET to separate subjects with biomarker-proven Alzheimer's disease into four biological stages with distinct characteristics.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"162 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089905","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 intuitive guesswork to useful data for better clinical decisions.","authors":"Stephen D Auger,Gregory Scott","doi":"10.1093/brain/awaf343","DOIUrl":"https://doi.org/10.1093/brain/awaf343","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"16 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089908","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":"That which we call cortisol awakening response, by any other word would smell as sweet.","authors":"Carmine M Pariante","doi":"10.1093/brain/awaf341","DOIUrl":"https://doi.org/10.1093/brain/awaf341","url":null,"abstract":"","PeriodicalId":9063,"journal":{"name":"Brain","volume":"38 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083361","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":"Cortical tau deposition promotes atrophy in connected white matter regions in Alzheimer's disease.","authors":"Julia Pescoller,Anna Dewenter,Amir Dehsarvi,Anna Steward,Lukas Frontzkowski,Zeyu Zhu,Sebastian N Roemer-Cassiano,Carla Palleis,Fabian Hirsch,Fabian Wagner,Hannah de Bruin,Boris Rauchmann,Robert Perneczky,Johannes Gnörich,Maura Malpetti,Rik Ossenkoppele,Michael Schöll,Johannes Levin,Günter Höglinger,Matthias Brendel,Nicolai Franzmeier","doi":"10.1093/brain/awaf339","DOIUrl":"https://doi.org/10.1093/brain/awaf339","url":null,"abstract":"In Alzheimer's disease (AD), fibrillar tau pathology is a key driver of neurodegeneration and cortical atrophy. Yet, emerging evidence suggests that tau aggregates also contribute to white matter (WM) damage. Specifically, physiological tau stabilizes intra-axonal microtubules, while hyperphosphorylated tau disrupts microtubule integrity, ensuing intraneuronal tau aggregation, neuronal disconnection, and axonal degeneration. Therefore, we investigated whether cortical tau promotes atrophy in connected WM regions in AD. To this end, we included 186 amyloid-positive (Aβ+) patients across the AD spectrum and 102 cognitively normal (CN) amyloid-negative (Aβ-) participants from ADNI, with baseline amyloid-PET, tau-PET, and T1-weighted MRI. Longitudinal tau-PET and MRI (∼2-years) were available for a subset of 138 participants, to further assess the relationship between tau accumulation and WM atrophy over time. For replication, we included 378/60 CN Aβ+/Aβ- participants from the A4/LEARN cohort with baseline amyloid-PET, tau-PET, and T1-weighted MRI, where a subset of 141/4 CN Aβ+/Aβ- subjects had ∼5-year longitudinal tau-PET and MRI. Cortical tau-PET Standardized Uptake Value Ratios were extracted from 210 cortical regions of the Brainnetome Atlas. In addition, we used a diffusion MRI-based tractography template to determine WM volumes of fiber tracts connected to cortical regions using segmented T1-weighted MRI. Using linear regression, we tested whether higher cortical tau-PET at baseline was associated with (i) lower baseline WM volume and (ii) faster WM volume loss over time, and (iii) whether faster longitudinal tau-PET increases paralleled faster WM loss. Testing the reverse model examined whether baseline WM atrophy predicted faster subsequent tau-PET increase in connected regions. Models were adjusted for age, sex, intracranial volume, WM hyperintensity volume, ApoE4 status and global amyloid-PET. In ADNI, elevated baseline cortical tau-PET in temporal regions was associated with lower baseline WM volume in adjacent regions, with more pronounced effects in patients across the AD spectrum and with weaker associations in the preclinical A4/LEARN sample. In both samples, higher baseline temporo-parietal tau-PET as well as faster tau-PET increase over time were significantly linked to accelerated volume loss in connected WM regions, which was especially pronounced in individuals on the AD spectrum. Importantly, baseline WM volume did not predict subsequent tau-PET change rates in adjacent cortical regions, suggesting a unidirectional relationship between fibrillar tau and subsequent WM degeneration. Together, our findings suggest that cortical tau accumulation promotes atrophy in adjacent WM regions in AD, highlighting that tau-induced axonal degeneration and potentially neuronal disconnection may play a pivotal role in disease progression.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"6 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083404","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":"Cerebellar pathology contributes to neurodevelopmental deficits in spinal muscular atrophy.","authors":"Florian Gerstner, Sandra Wittig, Christian Menedo, Sayan Ruwald, Maria J Carlini, Adela Vankova, Leonie Sowoidnich, Gerardo Martín-López, Vanessa Dreilich, Andrea Alonso Collado, John G Pagiazitis, Oumayma Aousji, Chloe Grzyb, Amy K Smith, Mu Yang, Francesco Roselli, George Z Mentis, Charlotte J Sumner, Livio Pellizzoni, Christian M Simon","doi":"10.1093/brain/awaf336","DOIUrl":"10.1093/brain/awaf336","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by ubiquitous SMN deficiency and loss of motor neurons. The persistence of motor and communication impairments, together with emerging cognitive and social deficits in severe Type I SMA patients treated early with SMN-restoring therapies, suggests a broader dysfunction involving neural circuits of the brain. To explore the potential supraspinal contributions to these emerging phenotypes, we investigated the cerebellum, a brain region critical for both motor and cognitive behaviors. Here, we identify cerebellar pathology in both post-mortem tissue from Type I SMA patients and a severe mouse model, which is characterized by lobule-specific Purkinje cell (PC) death driven by cell-autonomous, non-apoptotic p53-dependent mechanisms. Loss and dysfunction of excitatory parallel fiber synapses onto PC further contribute to cerebellar circuit disruption and altered PC firing. Furthermore, we identified impaired ultrasonic vocalization (USV) in a severe SMA mouse model-a proxy for early-developing social communication skills that depend on cerebellar function. Cell-specific rescue experiments demonstrate that intrinsic cerebellar pathology contributes to motor and social communication impairments independently of spinal motor circuit abnormalities. Together, these findings establish cerebellar dysfunction as a pathogenic driver of neurodevelopmental motor and social defects, providing mechanistic insight into the persisting and emerging phenotypes of SMA.</p>","PeriodicalId":9063,"journal":{"name":"Brain","volume":" ","pages":""},"PeriodicalIF":11.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085073","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}