Annals of Neurology最新文献

{"title":"HCN2-Associated Neurodevelopmental Disorders: Data from Patients and Xenopus Cell Models.","authors":"Clara Houdayer, A Marie Phillips, Marie Chabbert, Jennifer Bourreau, Reza Maroofian, Henry Houlden, Kay Richards, Nebal Waill Saadi, Eliška Dad'ová, Patrick Van Bogaert, Mailys Rupin, Boris Keren, Perrine Charles, Thomas Smol, Audrey Riquet, Lynn Pais, Anne O'Donnell-Luria, Grace E VanNoy, Allan Bayat, Rikke S Møller, Kern Olofsson, Rami Abou Jamra, Steffen Syrbe, Majed Dasouki, Laurie H Seaver, Jennifer A Sullivan, Vandana Shashi, Fowzan S Alkuraya, Alexis F Poss, J Edward Spence, Rhonda E Schnur, Ian C Forster, Chaseley E Mckenzie, Cas Simons, Min Wang, Penny Snell, Kavitha Kothur, Michael Buckley, Tony Roscioli, Noha Elserafy, Benjamin Dauriat, Vincent Procaccio, Daniel Henrion, Guy Lenaers, Estelle Colin, Nienke E Verbeek, Koen L Van Gassen, Claire Legendre, Dominique Bonneau, Christopher A Reid, Katherine B Howell, Alban Ziegler, Christian Legros","doi":"10.1002/ana.27277","DOIUrl":"10.1002/ana.27277","url":null,"abstract":"<p><strong>Objective: </strong>We aimed to characterize the phenotypic spectrum and functional consequences associated with variants in HCN2, encoding for the hyperpolarization-activated cyclic nucleotide (HCN) gated channel 2.</p><p><strong>Methods: </strong>GeneMatcher facilitated the recruitment of 21 individuals with HCN2 variants from 15 unrelated families, carrying HCN2 variants. In vitro functional studies were performed by electrophysiology with Xenopus laevis oocytes and membrane trafficking was investigated in HEK cells by confocal imaging. Structural 3D-analysis of the HCN2 variants was performed.</p><p><strong>Results: </strong>The phenotypic spectrum included developmental delay/intellectual disability (DD/ID, 17/21), epilepsy (10/21), language disorders (16/21), movement disorders (12/21), and axial hypotonia (10/21). Thirteen pathogenic variants (12 new and 1 already described) were identified: 11 missense (8 monoallelic and 3 biallelic), 1 recurrent inframe deletion (monoallelic), and 1 frameshift (biallelic). Functional analysis of p.(Arg324His) variant showed a strong increase of HCN2 conductance, whereas p.(Ala363Val) and p.(Met374Leu) exhibited dominant negative effects. The p.(Leu377His), p.(Pro493Leu), and p.(Gly587Asp) variants rendered HCN2 electrophysiologically silent and impaired membrane trafficking. Structural 3D-analysis revealed that, except for p.(Arg324His), all variants altered HCN2 stability.</p><p><strong>Interpretation: </strong>Our findings broadened the HCN2 disease clinical spectrum to include DD/ID with or without epilepsy. Functional analysis in cellular models reveal that pathogenic HCN2 variants can cause either loss-of-function or gain-of-function, providing critical information for the development of targeted therapies for HCN2-related disorders. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12226820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autosomal Recessive Cerebellar Ataxias: Translating Genes to Therapies.","authors":"Brent L Fogel, Thomas Klopstock, David R Lynch, Francesca Maltecca, Mayank Verma, Berge A Minassian, Frances M Platt, Débora Farina Gonçalves, Hélène Puccio, Andreas Roos, Matthis Synofzik","doi":"10.1002/ana.27271","DOIUrl":"https://doi.org/10.1002/ana.27271","url":null,"abstract":"<p><p>Autosomal recessive cerebellar ataxias (ARCAs) represent over 200 clinically heterogeneous genetic conditions involving degeneration of the cerebellum and associated tracts with resultant impairment of balance and coordination. Advancements in genomic testing have enabled rapid identification of the majority of known recessive disorders, shifting research focus to the development of targeted mechanistic treatments addressing underlying physiological pathways. Molecular classification allows recognition of cellular, biochemical, and genetic targets for high-effect precision therapy development. ARCAs represent a significant global health burden, requiring establishment of a robust pathway for novel therapeutic discovery through modification of mechanisms of disease pathogenesis and subsequent clinical trial development. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214462","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":"Longitudinal Analysis of Neuroradiological Biomarkers for Fragile X-Associated Tremor/Ataxia Syndrome and Implications for Clinical Trials.","authors":"David Hessl, Jun Yi Wang, Glenda Espinal, Ellery Santos, Flora Tassone, Randi J Hagerman, Susan M Rivera","doi":"10.1002/ana.27267","DOIUrl":"https://doi.org/10.1002/ana.27267","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study was to show the capacity of structural brain magnetic resonance imaging (MRI) measures to serve as monitoring biomarkers for Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).</p><p><strong>Methods: </strong>From 2 longitudinal studies of male FMR1 premutation carriers, 2 brain MRI scans were selected from each participant, collected within a period of 2 years (12 healthy controls, 17 carriers without FXTAS, and 51 carriers with FXTAS; all men, ages 40 to 80 years), along with clinical measurements and FMR1 cytosine-guanine-guanine (CGG) repeat numbers. Candidate MRI biomarkers included whole brain white matter hyperintensity (WMH) and cerebellar, brainstem, and whole brain volumes.</p><p><strong>Results: </strong>In the FXTAS group, mixed-effects models demonstrated significant volume loss across an average interval of 1.32 years for the whole brain, cerebellum and brain stem volumes, and significant increases in WMH, with large magnitude effects for whole brain and WMH volumes. All MRI measures showed deterioration with advancing FXTAS stage, with the strongest pattern shown in WMH volume. CGG repeat number showed significant nonlinear associations with all 4 brain MRI metrics, with mid-range CGG repeat carriers evidencing the worst brain atrophy and WMHs.</p><p><strong>Interpretation: </strong>Structural brain MRI measurements, especially those capturing white matter deterioration, are correlated with FMR1 premutation size of CGG repeat length and sensitive to FXTAS disease progression across a relatively short interval of less than 2 years, making them potentially suitable as surrogate end points for clinical trials. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207253","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":"Optical Coherence Tomography for Cervical Artery Dissection.","authors":"Guangxun Shen, Jingmin Zhao, Ying Mao, Guangxian Nan","doi":"10.1002/ana.27276","DOIUrl":"https://doi.org/10.1002/ana.27276","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191301","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":"Severely Coiled Internal Carotid Artery.","authors":"Ying Yu, Guofeng Ma, Jiabao Yang, Mingyao Li, Ning Ma","doi":"10.1002/ana.27274","DOIUrl":"https://doi.org/10.1002/ana.27274","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186106","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":"Machine Learning Models of Voxel-Level [18F] Fluorodeoxyglucose Positron Emission Tomography Data Excel at Predicting Progressive Supranuclear Palsy Pathology","authors":"Addison S. Braun BS,&nbsp;Ryota Satoh PhD,&nbsp;Nha Trang Thu Pham BS,&nbsp;Neha Singh-Reilly PhD,&nbsp;Farwa Ali MD,&nbsp;Dennis W. Dickson MD,&nbsp;Val J. Lowe MD,&nbsp;Jennifer L. Whitwell PhD,&nbsp;Keith A. Josephs MD, MST, MSc","doi":"10.1002/ana.27265","DOIUrl":"10.1002/ana.27265","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To determine whether a machine learning model of voxel level [¹⁸f]fluorodeoxyglucose positron emission tomography (PET) data could predict progressive supranuclear palsy (PSP) pathology, as well as outperform currently available biomarkers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>One hundred and thirty-seven autopsied patients with PSP (n = 42) and other neurodegenerative diseases (n = 95) who underwent antemortem [¹⁸f]fluorodeoxyglucose PET and 3.0 Tesla magnetic resonance imaging (MRI) scans were analyzed. A linear support vector machine was applied to differentiate pathological groups with sensitivity analyses performed to assess the influence of voxel size and region removal. A radial basis function was also prepared to create a secondary model using the most important voxels. The models were optimized on the main dataset (n = 104), and their performance was compared with the magnetic resonance parkinsonism index measured on MRI in the independent test dataset (n = 33).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The model had the highest accuracy (0.91) and F-score (0.86) when voxel size was 6mm. In this optimized model, important voxels for differentiating the groups were observed in the thalamus, midbrain, and cerebellar dentate. The secondary models found the combination of thalamus and dentate to have the highest accuracy (0.89) and F-score (0.81). The optimized secondary model showed the highest accuracy (0.91) and F-scores (0.86) in the test dataset and outperformed the magnetic resonance parkinsonism index (0.81 and 0.70, respectively).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The results suggest that glucose hypometabolism in the thalamus and cerebellar dentate have the highest potential for predicting PSP pathology. Our optimized machine learning model outperformed the best currently available biomarker to predict PSP pathology. ANN NEUROL 2025;98:410–420</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 2","pages":"410-420"},"PeriodicalIF":8.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179568","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":"Intracranial Intra-Aneurysm Thrombi Vegetation After Flow Diverter Implantation","authors":"Jiabao Yang MD,&nbsp;Ning Ma MD","doi":"10.1002/ana.27269","DOIUrl":"10.1002/ana.27269","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 2","pages":"270-272"},"PeriodicalIF":8.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186105","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":"AI in Neurology: Everything, Everywhere, all at Once PART 2: Speech, Sentience, Scruples, and Service.","authors":"Matthew Rizzo","doi":"10.1002/ana.27229","DOIUrl":"https://doi.org/10.1002/ana.27229","url":null,"abstract":"<p><p>Artificial intelligence (AI) applications are finding use in real-world neurological settings. Whereas part 1 of this 3-part review series focused on the birth of AI and its foundational principles, this part 2 review shifts gears to explore more practical aspects of neurological care. The review details how large language models, generative AI, and robotics are supporting diagnostic accuracy, patient interaction, and treatment personalization. Special attention is given to ethical and philosophical facets of AI that nonetheless impact practical aspects of care and patient safety, such as accountability for AI-driven decisions and the \"black box\" nature of many algorithms. We will discuss whether AI systems can develop sentience, and the implications for human-AI collaboration. By examining human-robot interactions in neurology, this part 2 review highlights the profound impact AI could have on patient care and, as covered in the ensuing part 3, on global health care delivery and data analytics, while maintaining ethical oversight and human control. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148880","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":"Crossed Facial Muscle Atrophy in Facioscapulohumeral Muscular Dystrophy","authors":"Masayuki Ohira MD,&nbsp;Masaki Takao MD,&nbsp;Ichizo Nishino MD, PhD","doi":"10.1002/ana.27264","DOIUrl":"10.1002/ana.27264","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 1","pages":"199-200"},"PeriodicalIF":8.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148886","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":"Cognitive Outcome in Young Adults after Resolution of Epilepsy in Childhood","authors":"Jacob Megreli MD, MPH,&nbsp;Leo Arkush MBBS, BSc (Hons),&nbsp;Estela Derazne MSc,&nbsp;Arnon Afek MD,&nbsp;Gilad Twig MD, PhD,&nbsp;Bruria Ben-Zeev MD,&nbsp;Jaana Ahonniska Assa PhD,&nbsp;Gali Heimer MD, PhD","doi":"10.1002/ana.27258","DOIUrl":"10.1002/ana.27258","url":null,"abstract":"<p>Self-limited epilepsies of childhood are common and were considered benign. We aim to determine whether cognitive function in young adults who experienced epilepsy as children and are subsequently seizure-free and unmedicated differ from the general population. We report on a cross-sectional population-based study including 2,124,871 men and women aged 16–19 years. Participants &gt; 5 years following the last seizure and &gt; 2 years without anti-seizure medication (n = 3,452) had an odds ratio (OR) of having low cognitive function of 1.44 (95% confidence interval [CI] = 1.24–1.68, <i>p</i> &lt; 0.001) using a multinominal regression model. Our results underscore the need to avoid the term “benign” in the classification of childhood epilepsies. ANN NEUROL 2025;98:62–66</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 1","pages":"62-66"},"PeriodicalIF":8.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27258","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}