Annals of Neurology最新文献

{"title":"Reframing the Gut-Brain Axis: The Gut Wall as a Neural Immune Interface in Multiple Sclerosis and Autoimmune Neurological Diseases.","authors":"Federico Montini, Sean J Pittock, Laura Cacciaguerra, Howard L Weiner, Luke A Schwerdtfeger","doi":"10.1002/ana.78380","DOIUrl":"https://doi.org/10.1002/ana.78380","url":null,"abstract":"<p><p>Gut wall physiology in multiple sclerosis (MS) and autoimmune neurologic diseases remains underexplored. This review examines gut wall dysfunctions' contribution to MS and autoimmune neurological disorder pathogenesis and progression. We discuss 3 inter-related aspects of gut physiology: intestinal barrier, enteric nervous system (ENS), and mucosal immunity. We highlight the ENS as a putative target of immune injury in selected antibody-mediated and T cell-associated neurologic diseases. Finally, we propose a unifying framework in which the gut functions as a site of immune priming and target of autoimmune injury, bridging microbiome-driven mechanisms in MS with ENS-directed autoimmunity across neurologic diseases. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149056646","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":"An Introduction to the Special Issue from the Editors.","authors":"Kenneth Tyler, Deborah Hall, Kathleen L Poston, Kenneth Marek, Thomas F Tropea","doi":"10.1002/ana.78356","DOIUrl":"https://doi.org/10.1002/ana.78356","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035724","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":"Association Between Genetic Ancestry and Multiple Sclerosis Severity.","authors":"Benjamin M Jacobs, Emily Tregaskis-Daniels, Luisa Schalk, Jakub Nagrodski, Michelle Peter, Rashmi Kaimal, Roxanne Murray, Sadid Hoque, Terri-Louise Brown, Ghaniah Hassan-Smith, Helen L Ford, Bruno Gran, Karim L Kreft, Cord Spilker, Outi Quinn, David Rog, Miriam Mattoscio, Elisa Visentin, Ramya Shamji, Grace Fawehinmi, Katila George, Maria Papachatzaki, Katharine Harding, Rod Middleton, Tarunya Arun, Waqar Rashid, Adil Harroud, Huw R Morris, Eli Silber, Gavin Giovannoni, Alastair J Noyce, Ruth Dobson","doi":"10.1002/ana.78350","DOIUrl":"https://doi.org/10.1002/ana.78350","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study was to determine whether genetic ancestry is associated with differences in the clinical course of multiple sclerosis (MS).</p><p><strong>Methods: </strong>Participants with MS living in the United Kingdom >18 years old were recruited from 2021 to 2025 and genotyped from saliva using a commercial array. Genetic ancestry was inferred using a random forest classifier trained on a diverse reference dataset. Participant-reported MS characteristics including the Age-Related Multiple Sclerosis Severity Score (ARMSS) and age at MS diagnosis were ascertained at recruitment.</p><p><strong>Results: </strong>We analyzed data from 816 people with MS (pwMS), comprising 260 people of South Asian ancestry (31.9%), 163 of African ancestry (20.0%), 316 of European ancestry (38.7%), and 77 participants from other backgrounds. The included cohort was predominantly female (72.3% women), diagnosed with MS at a median age of 32 years (interquartile range [IQR] = 14.0) and recruited at a median age of 44.6 years (IQR = 18.2). Neither South Asian nor African ancestry was consistently associated with higher MS severity compared with European-ancestry participants. No genetic variants were associated with MS severity at genomewide statistical significance.</p><p><strong>Interpretation: </strong>In this cross-sectional, diverse, UK cohort, neither South Asian nor African ancestry is associated with greater MS-related disability. These findings argue against a genetic basis for the previously observed differences between MS outcomes when contrasting ethnic groups. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035712","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":"Sensitivity of Non-contrast Computed Tomography Net Water Uptake Versus FLAIR-MRI, with MR-DWI Reference Standard, for Early Detection and Physiological Characterization of Ischemic Edema in Hyperacute Stroke.","authors":"Gabriel Broocks, Andre Kemmling, Rene Werner, Thilo Sentker, Robert W Regenhardt, Tobias Faizy, Anthony Kam, Rajiv Gupta, Helge Kniep, Lukas Meyer, Jens Fiehler, Karsten Alfke, Michael H Lev","doi":"10.1002/ana.78369","DOIUrl":"https://doi.org/10.1002/ana.78369","url":null,"abstract":"<p><strong>Objective: </strong>On non-contrast computed tomography (NCCT), progressive hypoattenuation can be quantified as percent net water uptake (%NWU), whereas relative fluid attenuated inversion recovery (rFLAIR)-magnetic resonance imaging hyperintensity marks later-stage vasogenic edema and blood-brain-barrier disruption. We compared the degree and rate of %NWU versus rFLAIR development and characterized 4 ischemic edema imaging profiles relative to a magnetic resonance (MR)-diffusion-weighted-imaging (MR-DWI) reference standard.</p><p><strong>Methods: </strong>NCCT and fluid attenuated inversion recovery (FLAIR) images from MR-DWI-positive hyperacute stroke patients were visually rated positive (+) or negative (-) for ischemic hypodensity/hyperintensity and sulcal-effacement (SE), defining 4 edema imaging profiles: (I) NWU-/FLAIR-/SE-, (II) NWU+/FLAIR-/SE-, (III) NWU+/FLAIR+/SE-, and (IV) NWU+/FLAIR+/SE+. %NWU, rFLAIR, and relative apparent diffusion coefficient (rADC) were quantified within the DWI/apparent diffusion coefficient-defined core region-of-interest, normalized to the contralateral mirror region, and compared between groups.</p><p><strong>Results: </strong>Of 53 DWI+ patients, n = 5/17/13/17 were in groups I to IV, with mean onset-to-CT times of 2.4 ± 1.2/2.5 ± 1.6/3.2 ± 1.9/5.0 ± 1.6 hours (p < 0.01), and baseline characteristics were comparable (all p ≥ 0.12). Mean %NWU differed between all groups (1.4 ± 0.3/4.3 ± 4.2/8.0 ± 4.1/13.6 ± 4.3; all pairwise p < 0.012), rADC did not (p = 0.21), and rFLAIR differed only between groups II and III versus group IV (p = 0.02, p = 0.04). %NWU and rFLAIR were uncorrelated (R² = 0.02, p = 0.48). Fitted %NWU increased monotonically and near-linearly within 4.5 hours post-ictus, whereas rFLAIR rose abruptly only in the late transition to group IV.</p><p><strong>Interpretation: </strong>Quantitative %NWU-CT was more sensitive than rFLAIR for detecting the earliest edematous stages of hyperacute stroke, discriminating early, intermediate, late, and late-severe (SE) stages; rFLAIR increased only in the latest stage. %NWU may, therefore, provide a practical, quantitative CT marker of edema progression, supporting acute triage and risk phenotyping in CT-first pathways, pending prospective validation. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149023288","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":"Growth Differentiation Factor 15 as a Cerebrospinal Fluid Biomarker for the Diagnosis and Prognosis of Leptomeningeal Metastasis.","authors":"Haoyu Ruan, Jie Li, Fuhai Wang, Lei Zhang, Jie Luo, Yuan Mu, Ting Wang, Yuqing Wu, Jingping Liu, Yunyun Ning, Xuan Deng, Ming Guan, Jian Xu","doi":"10.1002/ana.78353","DOIUrl":"https://doi.org/10.1002/ana.78353","url":null,"abstract":"<p><strong>Objective: </strong>As leptomeningeal metastasis (LM) has a poor prognosis, reliable cerebrospinal fluid (CSF) diagnostic biomarkers are urgently needed. This study evaluated the diagnostic value of CSF growth differentiation factor 15 (GDF15) in LM from lung adenocarcinoma (LUAD) and breast cancer (BC).</p><p><strong>Methods: </strong>A cohort of 726 CSF samples, including those from patients with LUAD LM, LUAD without LM (LUAD Non-LM; comprising LUAD without brain metastasis and LUAD with parenchymal brain metastasis), neurological controls, and patients with primary intracranial solid tumors, as well as a BC cohort of 83 CSF samples from BC LM and BC Non-LM patients, were enrolled in the study. The GDF15 and carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) levels were measured by the chemiluminescence method.</p><p><strong>Results: </strong>CSF GDF15 levels were elevated >25-fold in LUAD LM compared with Non-LM and neurological controls. CSF GDF15 excellently discriminated LUAD LM from Non-LM (AUC 0.959 and 0.912) and neurological controls (AUC 0.975 and 0.929) in 2 independent cohorts. CSF GDF15 levels effectively distinguished LUAD LM from parenchymal brain metastasis (AUC 0.954) and primary intracranial solid tumors (AUC 0.950). High CSF GDF15 levels were associated with shorter overall survival in LUAD LM patients. CSF CEACAM6 similarly differentiated LUAD LM from parenchymal brain metastasis (AUC 0.956) and primary intracranial solid tumors (AUC 0.970). In the BC cohort, GDF15 (AUC 0.899) and CEACAM6 (AUC 0.869) both performed well in distinguishing LM from Non-LM. The combination of GDF15 and CEACAM6 outperformed either biomarker alone in diagnosis of LUAD LM and BC LM.</p><p><strong>Interpretation: </strong>CSF GDF15 is a high-performance diagnostic biomarker for LUAD LM and BC LM. ANN NEUROL 2026 ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149014854","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":"Genetic Resilience and Resistance in Alzheimer's Disease Diagnosis and Pathology.","authors":"Ganna Leonenko, Kalliopi Mavromati, Lynne Hughes, Jonas S Sundarakumar, Keeley Brookes, Kevin Morgan, Terry Quinn, Valentina Escott-Price","doi":"10.1002/ana.78367","DOIUrl":"https://doi.org/10.1002/ana.78367","url":null,"abstract":"<p><strong>Objective: </strong>Some individuals avoid Alzheimer's disease (AD) pathology as they age, or retain cognition despite substantial pathology, suggesting mechanisms of resistance or resilience to neurodegeneration. Educational attainment (EA) is associated with reduced risk of cognitive decline, although the underlying mechanisms remain unclear. We investigated whether genome-wide polygenic scores (GPS) based on cognitive and non-cognitive components of EA, reflecting intelligence and behavioral/social traits, respectively, show differential associations with AD diagnosis and neuropathology.</p><p><strong>Methods: </strong>Associations between GPS for cognitive and non-cognitive components of EA and AD outcomes were examined across four cohorts: two cohorts included living participants with biomarker assessments (BioHermes-1, n = 770; Alzheimer's Disease Neuroimaging Initiative [ADNI], n = 1,361), and two included postmortem neuropathological evaluations (Religious Orders Study and Rush Memory and Aging Project [ROSMAP], n = 841; Brain for Dementia Research [BDR], n = 511). Outcomes included clinical diagnosis, amyloid status, plasma neurodegenerative biomarkers, and neuropathological measurements.</p><p><strong>Results: </strong>We found a significant negative association between cognitive EA GPS and clinical diagnosis of AD across all four cohorts and with Braak stage in ROSMAP and BDR cohorts. In contrast, the GPS for non-cognitive component of EA showed no significant association with AD diagnosis, neurodegenerative plasma biomarkers or amyloid positron emission tomography (PET) status and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores.</p><p><strong>Interpretation: </strong>These results suggest a brain maintenance mechanism that supports the brain's ability to resist to changes in neuronal integrity. This indicates that interventions focused on increasing EA solely by additional years of schooling are unlikely to affect AD incidence, whereas alternative approaches targeting the cognitive component of EA (intelligence) may offer greater potential for prevention. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149014900","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":"Mechanical Thrombectomy Versus Medical Management for Large Ischemic Core Stroke Identified before Inter-Hospital Transfer: A Post Hoc Analysis of the LASTE Trial.","authors":"Pierre Seners, Adrien Ter Schiphorst, Julien Labreuche, Bertrand Lapergue, Hilde Henon, Nasreddine Nouri, Benjamin Gory, Sébastien Richard, Jean-François Albucher, Christophe Cognard, Liesjet E H van Dokkum, David S Liebeskind, Tudor G Jovin, Vincent Costalat, Caroline Arquizan","doi":"10.1002/ana.78363","DOIUrl":"https://doi.org/10.1002/ana.78363","url":null,"abstract":"<p><strong>Objective: </strong>This study assessed the efficacy of thrombectomy in acute ischemic stroke because of large-vessel occlusion (AIS-LVO) initially admitted to primary stroke centers (PSC) and subsequently transferred to a comprehensive stroke center (CSC), with a large ischemic core identified before transfer.</p><p><strong>Methods: </strong>We performed a post hoc analysis of the Large Stroke Therapy Evaluation (LASTE) randomized controlled trial, which compared medical management (MM) plus thrombectomy and MM alone in anterior circulation AIS-LVO patients with a large core (Alberta Stroke Program Early Computed Tomography Score [ASPECTS], 0-5) treated within 6.5 hours of last seen well. This analysis included patients whose baseline imaging was obtained at a PSC and already demonstrated an ASPECTS of 0 to 5, before inter-hospital transfer. The primary outcome was a 90-day functional outcome, assessed using the modified Rankin Scale (mRS).</p><p><strong>Results: </strong>Among the 324 patients enrolled in LASTE, 157 were included in this analysis, 80 received MM alone, and 77 underwent thrombectomy plus MM. Median age was 73 years, National Institutes of Health Stroke Scale score was 20, last seen well-to-PSC imaging time 120 minutes and ASPECTS on PSC imaging was 0 to 2 in 56% and 3 to 5 in 44%. Thrombectomy resulted in better functional outcomes than MM alone (generalized odds ratio, 1.71; 95% confidence interval [CI], 1.21-2.41; p = 0.002), without heterogeneity across ASPECTS strata. Mortality at 90 days was numerically lower in the thrombectomy group (relative risk = 0.73; 95% CI = 0.50-1.05), whereas symptomatic intracranial hemorrhage was numerically more frequent (relative risk = 1.85; 95% CI = 0.64-5.26).</p><p><strong>Interpretation: </strong>These findings support consideration of inter-hospital transfer for EVT in AIS-LVO patients with large ischemic cores (including ASPECT, 0-2) admitted to PSCs who can reach the CSC in the early time-window. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149014924","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":"Deep Inspiration Clarifies a Web-Like Vertebral Artery Defect.","authors":"Ying Tan, Ning Ma","doi":"10.1002/ana.78379","DOIUrl":"https://doi.org/10.1002/ana.78379","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149014908","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":"An Investigation of Sleep Macro- and Microarchitecture by APOE Genotype.","authors":"Gawon Cho, Anne Chen, Eunyoung Choi, Orfeu M Buxton, Daniel Kay, Adam Mecca, Brienne Miner","doi":"10.1002/ana.78312","DOIUrl":"10.1002/ana.78312","url":null,"abstract":"<p><strong>Objectives: </strong>Apolipoprotein E ε4 (APOE ε4), a robust genetic risk factor for Alzheimer's disease (AD) is associated with functional connectivity deficits and amyloid pathology in brain regions involved in sleep regulation. Thus, alterations in sleep architecture may be one pathway through which ε4 contributes to Alzheimer's disease vulnerability. However, sleep architecture characteristics associated with APOE ε4 remain poorly characterized.</p><p><strong>Methods: </strong>This cross-sectional study examined associations between APOE genotype and sleep architecture among adults aged 50-85 years enrolled in the Sleep Heart Health Study (N = 3,081). APOE genotype was classified into ε4 heterozygotes, ε4 homozygotes, ε2 carriers, and ε3 homozygotes (reference group). Sleep architecture was defined using macro-level traits (percentage of time spent in in each sleep stage and wake after sleep onset) and micro-level traits (spindle characteristics [power, density, and frequency], odds ratio product [ORP], and arousal index). Associations between APOE genotype and each sleep metric was evaluated using linear regression.</p><p><strong>Results: </strong>Macroarchitecture was largely comparable across genotypes. However, substantial differences in micro-level traits were identified, including lower spindle power among ε4 homozygotes (β = -2.14, p = 0.02) and a dose-response decrease in spindle frequency at peak power with each ε4 count (β_{ε4 heterozygotes} = -0.04, p = 0.04; β_{ε4 homozygote} = -0.12, p = 0.065). Both ORP and arousal index decreased in a dose-response pattern with each ε4 count (ORP, β_{ε4-heterozygosity} = -0.03, β_{ε4-homozygosity} = -0.07, all p < 0.01; arousal index, β_{ε4-heterozygosity} = -1.02, p = 0.006, β_{ε4-homozygosity} = -1.78, p = 0.07). Between-genotype differences in ORP widened with age. Associations did not vary by sex, race, cognitive status, pTau181, or Aβ42:40 ratio.</p><p><strong>Interpretation: </strong>Abnormal spindle activity observed among ε4 carriers may contribute to their elevated Alzheimer's disease risk. ε4 carriers also showed less sleep fragmentation, which may reflect diminished arousability or electroencephalogram slowing due to neurodegenerative changes. ANN NEUROL 2026 ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149014836","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":"Dysregulated Cerebellar-Subcortical-Cortical Interactions in Cluster Headache: Evidence From Edge Analysis Across Three Independent Datasets.","authors":"Wei Dai, Mingjie Zhang, Shuhua Zhang, Hui Su, Yun Chen, Yuhan Wu, Yun-Xia Wang, Yueqi Guo, Xiangbing Bian, Xiao Zang, Xinbo Xing, Chenghui Pi, Xiting Nie, Zhe Yu, Guoen Yao, Catherine D Chong, Anders Hougaard, Lixia Tian, Xin Lou, Shengyuan Yu, Zhao Dong","doi":"10.1002/ana.78361","DOIUrl":"https://doi.org/10.1002/ana.78361","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study was to apply edge-centric functional connectivity and motif analyses to capture co-fluctuation communication patterns and test whether altered dynamic network integration underlies clinical manifestations of cluster headache (CH).</p><p><strong>Methods: </strong>This cross-sectional study included 100 participants with episodic CH imaged during the in-bout period outside acute attacks and 116 healthy controls (HCs) using functional magnetic resonance imaging (MRI). Robustness of the findings was assessed via pooled and separate analyses of 3 independent datasets using brain parcellation, edge graph construction, k-means clustering, community entropy calculations, motif, and clinical correlation analyses.</p><p><strong>Results: </strong>Participants with CH showed lower entropy in the cerebellar vermis (β = -0.493, 95% confidence interval [CI] = -0.683 to -0.302, p false discovery rate [p_FDR] = 3.02 × 10^-6) and cerebellar network (mean difference = -0.043, 95% CI = -0.068 to -0.018, t = -3.361, p_FDR = 0.009) compared with HCs. In individuals with CH, longer disease duration was accompanied by a greater reduction in entropy of the cerebellar vermis (r = -0.390, 95% CI = -0.550 to -0.196, p_FDR = 0.004). Motif analysis revealed that participants with CH exhibited (i) higher fractions of forked triads with vermis coordinating subcortical and cortical nodes belonging to sensorimotor, visual, default-mode, and cerebellar networks; and (ii) lower fractions of diverse triads linking vermis to both sensorimotor and cognitive- control networks and to both sensorimotor and default-mode networks (all p_FDR < 0.05).</p><p><strong>Interpretation: </strong>We identified reorganization of the cerebellar-subcortical-cortical network in CH. The cerebellar vermis exhibited a paradoxical pattern: retaining hub-like connectivity while losing flexible network integration. This pattern worsened with disease duration, supporting its role in symptomatology and potential as a candidate region for future neuromodulation studies. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149011655","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}