Annals of Neurology最新文献

{"title":"Microneurography Reveals Unmyelinated Small Nerve Fiber Dysfunction in Long COVID.","authors":"Ana Ribeiro, Shahrzad Hadavi, Nick Gall, Robert D M Hadden, Jordi Serra","doi":"10.1002/ana.78045","DOIUrl":"https://doi.org/10.1002/ana.78045","url":null,"abstract":"<p><strong>Objective: </strong>To review the microneurography findings of long coronavirus disease 2019 (COVID) patients who presented to the clinic with multisystem involvement affecting neurological, cardiovascular, gastrointestinal, genitourinary, pulmonary, and immunological domains.</p><p><strong>Methods: </strong>We analyzed 36 consecutive long COVID patients using microneurography. We evaluated abnormalities in C nociceptors, including spontaneous activity, peripheral sensitization, multiple spikes, conduction failure, and alterations in activity-dependent slowing of conduction velocity. Sympathetic nerve fiber function was assessed using the recovery cycle of excitability. Results were compared with a large normative database.</p><p><strong>Results: </strong>The mean age was 40.9 ± 9.2 years (range 17-60 years), with a female predominance (30/36, 83.3%). Patients were seen from 15 to 61 months after onset of symptoms (35.7 ± 11.3 months). All patients presented with neuropathic symptoms, mainly pain and orthostatic intolerance. A total of 32 patients (88.9%) had objective electrophysiological abnormalities in peripheral C fibers, including spontaneous nociceptor activity (61.1%), peripheral sensitization (27.8%), and multiple spikes (11.1%). Long COVID patients also showed a significant shift in C nociceptor populations, with a higher prevalence of type 1B mechano-insensitive C nociceptors compared with healthy controls. Changes in activity-dependent slowing of conduction velocity differed in opposite directions between mechano-sensitive and mechano-insensitive C nociceptors. Postganglionic sympathetic fibers also showed abnormal recovery cycles with a lack of supernormality, suggesting impaired neuronal homeostasis.</p><p><strong>Interpretation: </strong>This study provides novel electrophysiological evidence linking small nerve fiber dysfunction to long COVID. These findings align with previous histological evidence of small nerve fiber loss, reinforcing the hypothesis that peripheral nerve dysfunction contributes to the multisystem symptoms of long COVID. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111615","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":"Clinical-Radiological Spectrum of Cerebral Amyloid Angiopathy-Related Inflammation.","authors":"Larysa Panteleienko, Gargi Banerjee, Dermot Mallon, Kitti Thiankhaw, Rupert Oliver, Victoria Harvey, Gareth Ambler, Michael Zandi, Hans Rolf Jäger, David J Werring","doi":"10.1002/ana.78029","DOIUrl":"https://doi.org/10.1002/ana.78029","url":null,"abstract":"<p><strong>Objective: </strong>To identify clinical and radiological features of cerebral amyloid angiopathy-related inflammation (CAA-ri), and compare these features with those of sporadic CAA, to improve the understanding, diagnosis, and clinical care of CAA-ri.</p><p><strong>Methods: </strong>We retrospectively reviewed routine clinical data from 37 patients with CAA-ri and 158 patients with sporadic CAA, including conventional vascular risk factors and comorbidities. We assessed brain magnetic resonance imaging for: radiological markers of CAA; features of amyloid-related imaging abnormalities with edema/effusion (ARIA-E) including parenchymal white matter hyperintensities, sulcal hyperintensities, and gyral swelling; and evidence of neurodegeneration (medial temporal atrophy and global cortical atrophy).</p><p><strong>Results: </strong>Compared with patients with sporadic CAA, patients with CAA-ri had more numerous lobar cerebral microbleeds (median 207[IQR 33-811] vs 19[IQR 7-58], p < 0.001), and higher rates of medial temporal and global cortical atrophy. In comparison with sporadic CAA, all ARIA-E features were much more common in patients with CAA-ri (parenchymal hyperintensities 89% vs 3%, sulcal hyperintensities 78% vs 9%, and gyral swelling 86% vs 0.6%), as were conventional vascular risk factors (hypertension, dyslipidemia) and long-term comorbidities (inflammatory and infectious disorders, autoimmune or connective tissue disorders, or malignancies).</p><p><strong>Interpretation: </strong>Features of ARIA-E (parenchymal white matter hyperintensities, sulcal hyperintensities, and gyral swelling) are more common in CAA-ri in comparison with \"non-inflammatory\" sporadic CAA, suggesting shared mechanisms with Alzheimer's disease immunotherapy and a potential role in improving diagnostic accuracy for CAA-ri. The high prevalence of atrophy and lobar cerebral microbleeds suggests a potential mechanistic role for capillary CAA, Alzheimer's disease, or both, in CAA-ri. Cardiovascular risk factors and other long-term comorbidities may also be relevant to the underlying mechanisms of CAA-ri. ANN NEUROL 2025 ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084801","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":"Letter to the Editor: \"Disease Characteristics and Treatments Associated with Outcome in Primary Angiitis of the Central Nervous System-A Multicenter Cohort Study in 163 Patients\".","authors":"Muhammad Owais, Muhammad Huzaifa Sabir, Muhammad Nouman Javed","doi":"10.1002/ana.70017","DOIUrl":"https://doi.org/10.1002/ana.70017","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084811","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":"Fasting Mimicking Diets Reverse Accelerated Biological Aging in Multiple Sclerosis.","authors":"Fatemeh Siavoshi, Matthew D Smith, Sandra Cassard, G Brett Moreau, J Nicholas Brenton, Ellen M Mowry, Kathryn C Fitzgerald, Pavan Bhargava","doi":"10.1002/ana.78044","DOIUrl":"https://doi.org/10.1002/ana.78044","url":null,"abstract":"<p><p>Reversing the aging process may yield significant benefits in people with multiple sclerosis (PwMS), as accelerated biological aging is observed in this population. Secondary analyses of 2 previously conducted dietary interventions including a 6-month modified ketogenic diet in 39 participants and an 8-week randomized comparison of intermittent and daily calorie restriction versus a weight-stable regimen in 36 participants demonstrated significant decreases in metabolomic age (mAge) following the ketogenic diet (p = 0.009) and intermittent calorie restriction (p = 0.04), whereas daily calorie reduction had no effect. These findings indicate that fasting-mimicking diets (FMDs) can reverse accelerated metabolomic aging in PwMS. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084866","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":"Buried Treasure? Overlooked and Newly Discovered Evolutionary Contributions to Human Brain Diseases.","authors":"Nico J Diederich, Martin Brüne, John S Allen, Nicole Bender, Emiliano Bruner, Jean-Pierre Changeux, Cali Corrado, Olga Dolgova, Anne Grünewald, Geneviève Konopka, Peng Jin, Roger Lemon, Gilberto Levy, Pierre Magistretti, Markus J Rantala, Kathleen S Rockland, Roger Sullivan, Annie Swanepoel, Toshiki Uchihara, Katrin Amunts, Christopher G Goetz","doi":"10.1002/ana.78030","DOIUrl":"https://doi.org/10.1002/ana.78030","url":null,"abstract":"<p><p>Clinical neuroscience focuses on the mechanisms of brain function, but this approach falls short of insights into how the central nervous system (CNS) evolved, both in health and disease. Here, we discuss evolutionary concepts relevant to understanding human brain diseases, on the genetic, subcellular, cellular, connectomic, behavioral, and cultural levels. By revisiting common neurological diseases, we discuss evolved residues from our ancestors, mechanisms of exaptation, antagonistic pleiotropy, and human longevity with the consequent outpacing of biological evolution by cultural evolution. An evolution-based conceptual framework can propel transdisciplinary research targeting the constraints imposed by and compensatory adaptations involved in human-specific neurological diseases. ANN NEUROL 2025 ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079158","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":"A Digital Measure of Eye Movements During Reading Sensitively Captures Oculomotor and Speech Dysfunction, Early Changes, and Disease Progression in Ataxias.","authors":"Brandon Oubre, Faye Yang, Anna C Luddy, Rohin Manohar, Nancy N Soja, Christopher D Stephen, Jeremy D Schmahmann, Divya Kulkarni, Lawrence White, Siddharth Patel, Anoopum S Gupta","doi":"10.1002/ana.78039","DOIUrl":"10.1002/ana.78039","url":null,"abstract":"<p><strong>Objective: </strong>Sensitive behavioral measures are needed for clinical trials in ataxias and other neurodegenerative diseases. We hypothesized that quantitative analysis of eye movements during a natural multi-component task (passage reading) could produce a measure capable of capturing subclinical signs and disease progression.</p><p><strong>Methods: </strong>Binocular gaze sampled at 1000 hertz (Hz) was collected from 102 individuals with ataxia (including 36 spinocerebellar ataxias, 12 Friedreich's ataxia, and 5 multiple system atrophy) and 70 healthy controls. Longitudinal data were available for 26 participants with ataxia in the ongoing Neurobooth natural history study. The Reading Eye Abnormality Digital (READ) score was developed by training a regression model to aggregate saccade and fixation kinematics.</p><p><strong>Results: </strong>Mean displacement of fixations, the number and frequency of saccades, and the proportion of regressive saccades were related to oculomotor dysfunction, speech dysfunction, and overall ataxia severity. The READ score was reliable (intraclass correlation coefficient [ICC] = 0.96, p < 0.001) and correlated with Brief Ataxia Rating Scale (BARS) total score (r = 0.82, p < 0.001), oculomotor (r = 0.52, p < 0.001), and speech (r = 0.73, p < 0.001) subscores, and patient reports of function including patient-reported outcome measures (PROM)-Ataxia (r = 0.51, p < 0.001) and the Dysarthria Impact Scale (DIS; r = 0.53, p < 0.001). The READ score detected subclinical oculomotor (area under the curve [AUC] = 0.69, p = 0.02) and speech signs (AUC = 0.72, p < 0.001) and disease progression (d = 0.36, p = 0.03). The BARS total did not reach statistical significance in capturing progression between study visits in this cohort (d = 0.27, p = 0.08).</p><p><strong>Interpretation: </strong>Digital measures of eye movements are a promising approach for sensitively measuring ataxia in clinical trials (including early-stage disease) and may have utility in other neurodegenerative diseases affecting speech or ocular control. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079131","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":"AAV9-DARS2 Gene Therapy Rescues Phenotype in Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation Patient Cells and Neuronal Dars2 Deficient Mice.","authors":"I Garofolo, B Lindsay, Y Liang, B Ratajczak, M Janowski, P Walczak, A Fatemi, C L Nemeth","doi":"10.1002/ana.78037","DOIUrl":"https://doi.org/10.1002/ana.78037","url":null,"abstract":"<p><strong>Objective: </strong>Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare, autosomal recessive disorder caused by variants in the gene DARS2. DARS2 is an essential and ubiquitously expressed enzyme that catalyzes the attachment of aspartate to its cognate tRNA for mitochondrial protein translation. LBSL is clinically characterized by progressive spasticity, ataxia, and dorsal column dysfunction, and is considered a primary axonopathy with secondary demyelination.</p><p><strong>Methods: </strong>Herein, we tested the efficacy of gene supplementation, using adeno-associated virus, serotype 9 (AAV9)-DARS2 in LBSL patient cells, as well as in an LBSL mouse phenolog in which Dars2 was deleted in CamKIIα-expressing neurons of the hippocampus and cortex.</p><p><strong>Results: </strong>In vitro, patient neurons treated with AAV9-DARS2 showed increased gene expression of the gene mirrored by improved mitochondrial function, axonal growth, and reduced lactate release, despite variation in impairment across lines. Knockout mice showed improved behavior and reduced cortical neurodegeneration 6 months after a single intracerebroventricular injection of AAV9-DARS2.</p><p><strong>Interpretation: </strong>Together, this work provides proof-of-concept data that gene supplementation can improve cell function and survival for an extended period of time. AAV9 therapy has proven especially useful for loss of function monogenetic disorders, and these data may support further investigation into therapies for LBSL. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145062900","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":"Clinical and Molecular Genetic Characterization of Landau Kleffner Syndrome: An Observational Cohort and Experimental Study.","authors":"Adeline Ngoh, Maria Clark, Rebecca Greenaway, Xiumin Chen, Kimberley M Reid, Katy Barwick, Esther Meyer, Dale Moulding, Natalie Trump, J Helen Cross, Sean D Fraser, Lachlan de Hayr, Dimitri M Kullmann, Joseph W Lynch, Robert J Harvey, Manju A Kurian","doi":"10.1002/ana.27306","DOIUrl":"https://doi.org/10.1002/ana.27306","url":null,"abstract":"<p><strong>Objective: </strong>Landau-Kleffner syndrome (LKS), is a rare, poorly-understood epileptic encephalopathy with spike-wave activation in sleep associated with mutations in GRIN2A, encoding the N-Methyl-D-Aspartate receptor (NMDAR) GluN2A subunit. Physicians rely on empirical treatments, with scarce information on treatment efficacy and outcomes. This study aims to improve the understanding and clinical management of LKS.</p><p><strong>Methods: </strong>Fifty-two patients with LKS were recruited via one quaternary referral center. Case-notes review delineated clinical features, long-term outcomes, and prognostic factors. Generalized estimating equations were used to determine the longitudinal association among electroencephalogram abnormalities, steroid therapy, and neuropsychological findings. After genetic screening, the impact of identified GRIN2A missense variants on NMDAR function was assessed using homology modeling, cell-surface trafficking assays, and electrophysiology in artificial synapses. Whole exome/genome sequencing was performed on GRIN2A-negative patients to identify novel gene associations.</p><p><strong>Results: </strong>LKS is complex with significant clinical and genetic heterogeneity. Besides speech and language impairment, many patients had other co-morbidities and almost half have long-term disability. Early age at disease onset was associated with worse outcomes. There was no reliable correlation between electroencephalogram findings and developmental scores. Steroid therapy improved language outcomes independently of electroencephalogram findings. GRIN2A mutations were identified in 15.5% of the cohort. Likely pathogenic variants in GABBR2, SCN1A, TRPC1, ERRFI1, CTXN3, IRX6, and IQCA1 were identified in 7 GRIN2A-negative individuals.</p><p><strong>Interpretation: </strong>For LKS, early intervention is important for long-term outcomes. Furthermore, management should not be based solely on electroencephalogram findings. Genetic and functional investigations offer insights into disease pathophysiology and facilitate development of future targeted therapies. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051333","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":"Pleiotropy and the Increasing Complexity of Parkinson's Disease Genetics.","authors":"Jonggeol Kim, Joshua M Shulman","doi":"10.1002/ana.78036","DOIUrl":"https://doi.org/10.1002/ana.78036","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051446","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":"Behavior Decoding Delineates Seizure Microfeatures and Associated Sudden Death Risks in Mouse Models of Epilepsy.","authors":"Yuyan Shen, Jaden Thomas, Xianhui Chen, Jaden Zelidon, Mariam Najeeb, Abigayle Hahn, Ping Zhang, Aaron Sathyanesan, Bin Gu","doi":"10.1002/ana.78032","DOIUrl":"10.1002/ana.78032","url":null,"abstract":"<p><strong>Objective: </strong>Behavior and motor manifestations are distinctive yet often overlooked features of epileptic seizures. Seizures can result in transient disruptions in motor control, often organized into specific behavioral sequences that can inform seizure types, onset zones, and outcomes. However, refined analysis of behaviors in epilepsy remains challenging. Current manual video inspection approaches are subjective, time-consuming, and often overlook the intricate behavioral dynamics and action kinematics. This study investigates whether artificial intelligence (AI)-aided tools can unravel complex behavior repertoire that can delineate seizure outcomes in a data-driven manner.</p><p><strong>Methods: </strong>We utilized two AI-aided tools, DeepLabCut (DLC) and Behavioral Segmentation of Open Field in DLC (B-SOiD), to decode underexplored behavior and action domains of induced seizures in a population of 32 inbred mouse strains that mimic human genetic diversity and a mouse model of Angelman syndrome.</p><p><strong>Results: </strong>Our automated behavior classification tool identified 63 interpretable behavior groups. Analysis of these behavior groups demonstrates significant differential behavior usage and complexity that can delineate distinct seizure states, unravel intrinsic seizure progression over time, and inform mouse sex, strain backgrounds, and specific pathogenic mutations. We also identified seizure behavior transition dynamics and action/subaction kinematics, like hindlimb motions, that can determine the risks of sudden unexpected death in epilepsy (SUDEP).</p><p><strong>Interpretation: </strong>These behavior microfeatures can facilitate preclinical mechanistic studies and antiseizure medication screening at scales. These findings also underscore the translational potential of video-based seizure behavior decoding in both inpatient and outpatient settings, including analyzing videos captured by home surveillance devices and ubiquitous smartphones. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051292","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}