Annals of Neurology最新文献

{"title":"Elevated α-Synuclein Aggregate Levels in the Urine of Patients with Isolated REM Sleep Behavior Disorder and Parkinson's Disease.","authors":"Laura Müller, Pelin Özdüzenciler, Charlotte Schedlich-Teufer, Aline Seger, Hannah Jergas, Gereon R Fink, Dieter Willbold, Michael Sommerauer, Michael T Barbe, Gültekin Tamgüney","doi":"10.1002/ana.27250","DOIUrl":"https://doi.org/10.1002/ana.27250","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disorder characterized by α-synuclein aggregation in neurons. Recent advances suggest α-synuclein aggregates could serve as a biomarker for PD and related synucleinopathies. This study used surface-based fluorescence intensity distribution analysis (sFIDA) to measure α-synuclein aggregates in urine. Patients with PD and isolated rapid eye movement sleep behavior disorder, a precursor to PD, had elevated concentrations compared with healthy controls. Sensitivity and specificity were 83% and 65% for PD versus controls and 89% and 62% for isolated rapid eye movement sleep behavior disorder versus controls. The findings highlight sFIDA's potential for diagnosing synucleinopathies. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956431","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":"Phosphatemia is an Independent Prognostic Factor in Amyotrophic Lateral Sclerosis.","authors":"Rosario Vasta, Emanuele Koumantakis, Antonio Canosa, Umberto Manera, Maurizio Grassano, Francesca Palumbo, Sara Cabras, Enrico Matteoni, Francesca Di Pede, Filippo De Mattei, Filippo Vergnano, Jessica Mandrioli, Cecilia Simonini, Ilaria Martinelli, Fabiola De Marchi, Letizia Mazzini, Cristina Moglia, Andrea Calvo, Adriano Chiò","doi":"10.1002/ana.27252","DOIUrl":"https://doi.org/10.1002/ana.27252","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study was to evaluate the prognostic value of several muscle damage biomarkers.</p><p><strong>Methods: </strong>Data from Piemonte and Valle d'Aosta Amyotrophic Lateral Sclerosis (PARALS) were considered for this study. Survival was defined as the time from diagnosis to death, tracheostomy, or the censoring date. Blood levels of potassium, creatinine, creatine kinase, phosphorus, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) diagnosis were evaluated as potential prognostic biomarkers. A Cox model was developed for each biomarker and adjusted for sex, onset age, onset site, and diagnostic delay. Significant findings from PARALS were evaluated in the Pooled Resource Open-Access Amyotrophic Lateral Sclerosis Clinical Trials (PRO-ACT) database. Additionally, a joint model was constructed to evaluate the prognostic role of phosphatemia slope over time using longitudinal data from PRO-ACT.</p><p><strong>Results: </strong>A total of 1,444 and 1,023 patients were included in the PARALS and PRO-ACT cohorts, respectively. Only creatinine (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.50-0.85) and phosphorus (HR = 1.14, 95% CI = 1.04-1.24) showed a significant association with survival in the PARALS cohort. These findings were further validated in the PRO-ACT cohort (creatinine HR = 0.21, 95% CI = 0.13-0.35, p < 0.0001; phosphorus HR = 2.35, 95% CI = 1.13-4.88, p = 0.02). Longitudinal data from the PRO-ACT database showed that an increase of 0.1 mmol/l per month in phosphate levels was also associated with a HR of 8.26 (95% CI = 1.07-96.6, p = 0.044).</p><p><strong>Interpretation: </strong>Creatininemia was confirmed as a prognostic marker in amyotrophic lateral sclerosis (ALS). Additionally, both phosphatemia levels at diagnosis and its rate of change over time were identified as a potential prognostic marker for ALS. As with other blood biomarkers, phosphate levels are cost-effective and minimally invasive to measure, supporting their potential use in clinical trials. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953759","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":"Detecting New Lesions Using a Large Language Model: Applications in Real-World Multiple Sclerosis Datasets.","authors":"Shane Poole, Nikki Sisodia, Kanishka Koshal, Kyra Henderson, Jaeleene Wijangco, Danelvis Paredes, Chelsea Chen, William Rowles, Amit Akula, Jens Wuerfel, Vishakha Sharma, Andreas M Rauschecker, Roland G Henry, Riley Bove","doi":"10.1002/ana.27251","DOIUrl":"https://doi.org/10.1002/ana.27251","url":null,"abstract":"<p><strong>Objective: </strong>Neuroimaging is routinely utilized to identify new inflammatory activity in multiple sclerosis (MS). A large language model to classify narrative magnetic resonance imaging reports in the electronic health record (EHR) as discrete data could provide significant benefits for MS research. The objectives of the current study were to develop such a prompt and to illustrate its research applications through a common clinical scenario: monitoring response to B-cell depleting therapy (BCDT).</p><p><strong>Methods: </strong>An institutional ecosystem that securely connects healthcare data with ChatGPT4 was applied to clinical MS magnetic resonance imaging reports in a single institutional EHR (2000-2022). A prompt (msLesionprompt) was developed and iteratively refined to classify the presence or absence of new T2-weighted lesions (newT2w) and contrast-enhancing lesions (CEL). The multistep validation included evaluating efficiency (time and cost), comparison with manually annotated reports using standard confusion matrix, and application to identifying predictors of newT2w/CEL after BCDT start.</p><p><strong>Results: </strong>Accuracy of msLesionprompt was high for detection of newT2w (97%) and CEL (96.8%). All 14,888 available reports were categorized in 4.13 hours ($28); 79% showed no newT2w or CEL. Data extracted showed expected suppression of new activity by BCDT (>97% monitoring magnetic resonance images after an initial \"rebaseline\" scan). Neighborhood poverty (Area Deprivation Index) was identified as a predictor of inflammatory activity (newT2w: OR 1.69, 95% CI 1.10-2.59, p = 0.017; CEL: OR 1.54, 95% CI 1.01-2.34, p = 0.046).</p><p><strong>Interpretation: </strong>Extracting discrete information from narrative imaging reports using an large language model is feasible and efficient. This approach could augment many real-world analyses of MS disease evolution and treatment response. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955956","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":"Nitrilase 1 Associated Cerebrovascular Small Vessel Disease.","authors":"Seby John, Praveen Kesav, Syed Irteza Hussain","doi":"10.1002/ana.27249","DOIUrl":"https://doi.org/10.1002/ana.27249","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954190","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 Vascular NOTCH3 Aggregation and Disease Severity in a CADASIL Cohort - Implications for NOTCH3 Variant-Specific Disease Prediction.","authors":"Minne N Cerfontaine, Gido Gravesteijn, Remco J Hack, Kyra L Dijkstra, Mar Rodríguez-Girondo, Benno Gesierich, Marie-Noëlle W Witjes-Ané, Remco van Doorn, Marco Duering, Julie W Rutten, Saskia A J Lesnik Oberstein","doi":"10.1002/ana.27240","DOIUrl":"https://doi.org/10.1002/ana.27240","url":null,"abstract":"<p><strong>Objective: </strong>Vascular NOTCH3 protein ectodomain aggregation is a pathological hallmark of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease typically caused by cysteine-altering variants in NOTCH3. Given their high population frequency, these NOTCH3 variants are an important genetic contributor to stroke and vascular dementia worldwide. Disease severity in CADASIL is highly variable and is mainly determined by the position of the pathogenic NOTCH3 variant in the NOTCH3 ectodomain. Here, we aimed to investigate the association between NOTCH3 aggregation load in skin vessels, cysteine-altering NOTCH3 variants, and disease severity in a prospective cohort study of 212 patients with CADASIL with 39 distinct cysteine-altering NOTCH3 variants.</p><p><strong>Methods: </strong>NOTCH3 aggregation load in skin vessels was determined by calculating the NOTCH3 score; the fraction of skin vessel wall area positive for NOTCH3 staining. Variant-specific NOTCH3 scores were calculated for variants present in 10 or more participants, by averaging the NOTCH3 scores of individuals with that distinct variant. The associations between the NOTCH3 score, NOTCH3 variants, and neuroimaging and clinical outcomes were investigated using multivariable linear mixed models, Cox regression, and mediation analyses.</p><p><strong>Results: </strong>The NOTCH3 score was significantly associated with lifetime stroke probability and small vessel disease neuroimaging outcomes, but not with age. Variant-specific NOTCH3 scores reflected differences in disease severity associated with distinct NOTCH3 variants.</p><p><strong>Interpretation: </strong>These findings suggest that differences in NOTCH3 aggregation propensity underlie the differences in disease severity associated with NOTCH3 cysteine-altering variants, and show that NOTCH3-variant specific NOTCH3 scores can contribute to improved individualized disease prediction in CADASIL. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951543","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":"Pragmatic Clinical Trials in Neurology","authors":"Adnan I. Qureshi MD,&nbsp;Gillian Bartlett-Esquilant PhD,&nbsp;Alexandra Brown PhD,&nbsp;James McClay MD, MS,&nbsp;Mamatha Pasnoor MD,&nbsp;Richard J. Barohn MD","doi":"10.1002/ana.27244","DOIUrl":"10.1002/ana.27244","url":null,"abstract":"<p>The need for pragmatic clinical trials evaluating therapeutic interventions in patients with neurological disease is continually increasing due to availability of multiple therapeutic interventions (comparative effectiveness), multifaceted approaches (multiple concurrent synergistic therapeutic interventions), and gaps in trial-specific and real-world population outcomes. Several designs for pragmatic trials are available, including individual randomized trials with pragmatic characteristics, cluster-randomized and non-randomized trials, and observational prospective cohort studies. Cluster trials may have parallel cluster and crossover (unidirectional, bidirectional, and alternating crossover) designs. There are unique aspects of consenting and data collection leveraging existing registries, electronic health records (EHRs), and claims data that make pragmatic trials most suited to study the effectiveness of therapeutic interventions in patients with neurological diseases in real-world settings. ANN NEUROL 2025;97:1022–1037</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 6","pages":"1022-1037"},"PeriodicalIF":8.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955751","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":"Annals of Neurology: Volume 97, Number 5, May 2025","authors":"","doi":"10.1002/ana.26981","DOIUrl":"https://doi.org/10.1002/ana.26981","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 5","pages":"C1"},"PeriodicalIF":8.1,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26981","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143852857","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":"Effectiveness of Autologous Hematopoietic Stem Cell Transplantation versus Alemtuzumab and Ocrelizumab in Relapsing Multiple Sclerosis: A Single Center Cohort Study.","authors":"Paolo Antonio Muraro, Antonio Zito, Alessio Signori, Maria Pia Sormani, Eleonora Rigoni, Federica Pollidoro, Roberto Bergamaschi, Alice Mariottini, Omar Malik, Ashwini Nandoskar, Victoria Singh-Curry, Varun Mehra, Majid Kazmi, Ian Gabriel, Eli Silber, Richard Nicholas, Antonio Scalfari","doi":"10.1002/ana.27247","DOIUrl":"https://doi.org/10.1002/ana.27247","url":null,"abstract":"<p><strong>Objective: </strong>To compare clinical and radiological outcomes among relapsing multiple sclerosis patients treated with autologous hematopoietic stem cell transplantation (AHSCT), alemtuzumab (ATZ), and ocrelizumab (OCR).</p><p><strong>Methods: </strong>From a London (UK) hospital-based observational cohort, modeled data were obtained from 621 relapsing-remitting multiple sclerosis patients, who were treated with AHSCT (n = 103), ATZ (n = 204), and OCR (n = 314), and were followed up for 43, 43, and 32 median months, respectively. The annualized relapse rate, new magnetic resonance imaging (MRI) lesions, and disability progression on Expanded Disability Status Scale were assessed.</p><p><strong>Results: </strong>AHSCT showed superior efficacy compared with ATZ and OCR. After 5-year follow up, the mean annualized relapse rate (0.026 vs 0.087; p < 0.001), the risk of relapses (HR 0.29, 95% CI 0.13-0.63; p = 0.002), and of MRI activity (HR 0.33, 95% CI 0.15-0.72; p = 0.006) were significantly lower in AHSCT versus ATZ group. Compared with OCR, after 3-year follow-up AHSCT showed a significantly lower annualized relapse rate (0.028 vs 0.073; p = 0.02) and a trend to reduced risk of relapse (HR 0.45, 95% CI 0.18-1.14; p = 0.09), but similar low rates (6%) of new MRI activity (HR 0.86, 95% CI 0.28-2.67; p = 0.80). In addition, there was a similar risk of Expanded Disability Status Scale progression in AHSCT, and both ATZ (HR 1.19, 95% CI 0.71-2.00; p = 0.50) and OCR (HR 1.08, 95% CI 0.57-2.04; p = 0.82) groups.</p><p><strong>Interpretation: </strong>AHSCT was followed by greater prevention of relapses compared with ATZ and OCR, and suppressed more profoundly MRI activity than ATZ, but similarly to OCR, albeit with shorter follow up. The risk of accumulating disability was similar among the treated groups. Studies with larger sample sizes and longer follow up may enable confirmation of these findings or detection of any additional differential effects. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954072","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 to “Gender Differences and Vascular Risk: Unveiling New Pathways for Dementia Prevention”","authors":"Jing Yuan MD, MPH,&nbsp;Qiushan Tao MD, MS,&nbsp;Rhoda Au PhD","doi":"10.1002/ana.27238","DOIUrl":"10.1002/ana.27238","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 6","pages":"1224-1225"},"PeriodicalIF":8.1,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951885","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":"Cholinergic Degeneration and Cognitive Function in Early GBA1-Related Parkinson's Disease.","authors":"Sofie Slingerland, Sygrid van der Zee, Giulia Carli, Anne C Slomp, Emile d'Angremont, Jeffrey M Boertien, Teus van Laar","doi":"10.1002/ana.27248","DOIUrl":"https://doi.org/10.1002/ana.27248","url":null,"abstract":"<p><strong>Objective: </strong>The phenotype of patients with Parkinson's disease carrying GBA1 variants (GBA-PD) suggest similarities to symptomatology associated with early cholinergic system degeneration. Therefore, this study aims to investigate the clinical features and the cholinergic innervation pattern in patients with early GBA-PD versus those without the GBA1 mutation (non-GBA-PD).</p><p><strong>Methods: </strong>A total of 46 GBA-PD and 104 non-GBA-PD subjects were included. Clinical assessments included motor and non-motor evaluation, as well as a comprehensive neuropsychological examination. Cholinergic system integrity was assessed using ¹ ⁸F-Fluoroethoxybenzovesamicol (¹⁸F-FEOBV) positron emission tomography (PET) to investigate the differences between GBA-PD and non-GBA-PD. Given the higher prevalence of females in GBA-PD, analyses were repeated when stratified by sex. Additionally, we examined the association between cognitive domains and whole-brain cholinergic binding in both groups. Exploratory analyses examined clinical and ¹⁸F-FEOBV binding differences among GBA1 variants.</p><p><strong>Results: </strong>GBA-PD patients exhibited a higher burden of non-motor symptoms and lower cognitive performance on executive functions and attention. We observed a more pronounced cholinergic denervation in GBA-PD, compared to non-GBA-PD, primarily in the anterior, central, and limbic regions. However, the distribution of cholinergic loss and its association with attention and executive dysfunction was comparable between GBA-PD and non-GBA-PD. In addition, the clinical presentation and cholinergic binding differed significantly between sexes.</p><p><strong>Interpretation: </strong>These results suggest an important role of early cholinergic denervation in GBA-PD patients, which is related to more severe cognitive dysfunction. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955256","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}