Pub Date : 2026-02-01DOI: 10.1001/jamaneurol.2025.5280
James P Ho, David Y Hwang, Amy Brodtmann
{"title":"Endovascular Therapy for Basilar Occlusions-The ATTENTION Trial.","authors":"James P Ho, David Y Hwang, Amy Brodtmann","doi":"10.1001/jamaneurol.2025.5280","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.5280","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"83 2","pages":"101-102"},"PeriodicalIF":21.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142404","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}
Pub Date : 2026-02-01DOI: 10.1001/jamaneurol.2025.4946
Timothy M Miller, Merit E Cudkowicz, Pamela J Shaw, Angela Genge, Gen Sobue, Robert C Bucelli, Adriano Chiò, Philip Van Damme, Albert C Ludolph, Jonathan D Glass, Jinsy A Andrews, Suma Babu, Michael Benatar, Christopher J McDermott, François Salachas, Gaëlle Bruneteau, Ammar Al-Chalabi, Matthew Amorin, Ivan Nestorov, Danielle Graham, Luan Lin, Peng Sun, Manjit McNeill, Sohail Malek, Jennifer Inra, Steve Garafalo, Stephanie Fradette
<p><strong>Importance: </strong>Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are attributable to a pathogenic variant in the superoxide dismutase 1 (SOD1) gene. Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene.</p><p><strong>Objective: </strong>To evaluate the long-term effects of tofersen in adults with SOD1-ALS.</p><p><strong>Design, setting, and participants: </strong>The phase 3, randomized, double-blind, placebo-controlled VALOR trial (A Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tofersen in SOD1-ALS; conducted from March 2019 to July 2021) evaluated tofersen use over 28 weeks in adults (18 years and older) with weaknesses attributable to ALS and a confirmed SOD1 pathogenic variant at 32 sites in 10 countries; participants could then enroll in an open-label extension (OLE; completed August 2024).</p><p><strong>Intervention and exposure: </strong>Adults with SOD1-ALS were randomly assigned 2:1 to receive tofersen (100 mg) or placebo over a 24-week period in the VALOR study. All participants in the OLE were treated with tofersen.</p><p><strong>Main outcomes and measures: </strong>Integrated analysis of VALOR and the OLE study aimed to compare early start vs placebo/delayed start (approximately 6 months later) treatment with tofersen. Key efficacy end points included measures of axonal injury and neurodegeneration (neurofilament), function and strength, quality of life, and survival.</p><p><strong>Results: </strong>VALOR enrolled 108 participants with 42 unique SOD1 pathogenic variants (mean [SD] age: placebo/delayed-start group 51.2 [11.6] [n = 36]; early-start group: 48.1 [12.6] [n = 72]) with 19 (53%) and 43 (60%) of participants being male in the placebo/delayed- and early-start groups, respectively. Overall, 95/108 participants (88%) enrolled in the OLE, and 46 participants completed the OLE (early-start group, 34 [47%]; placebo/delayed-start group, 12 [33%]). At OLE completion, participants could have accumulated 3.5 years or more (range, 192-276 weeks) of follow-up from the start of VALOR. Over 148 weeks, earlier initiation of tofersen (compared to later initiation) was associated with numerically less decline in measures of clinical function (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, -9.9 vs -13.5 points), respiratory function (slow vital capacity, -13.8% vs -18.1%), muscle strength (handheld dynamometry megascore, -0.38 vs -0.43 points), and quality of life (Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 score, 17.0 vs 22.5 points; EuroQol 5 Dimension, 5 Level Questionnaire score, -0.1 vs -0.2 points). Tofersen prolonged survival relative to the expected natural history of SOD1-ALS. Most adverse events were consistent with ALS progression or known procedural adverse effects. All seri
重要性：大约2%的肌萎缩性侧索硬化症（ALS）病例可归因于超氧化物歧化酶1 （SOD1）基因的致病变异。Tofersen是一种鞘内反义寡核苷酸，旨在减少SOD1蛋白的合成，是首个也是唯一被批准用于治疗SOD1基因变异的成人ALS的药物。目的：评价托佛素治疗成人SOD1-ALS的远期疗效。设计、环境和参与者：3期随机、双盲、安慰剂对照VALOR试验（一项评估Tofersen治疗SOD1-ALS的疗效、安全性、耐受性、药代动力学和药效学的研究，于2019年3月至2021年7月进行）评估了Tofersen在10个国家32个地点的成年人（18岁及以上）28周内的使用情况，这些成年人的弱点可归因于ALS，并证实SOD1致病性变异；然后，参与者可以注册开放标签扩展（OLE； 2024年8月完成）。干预和暴露：在VALOR研究中，患有SOD1-ALS的成年人被随机分配为2:1，在24周的时间内接受托佛森（100mg）或安慰剂。所有OLE参与者均接受托佛森治疗。主要结局和测量：VALOR和OLE研究的综合分析旨在比较tofersen早期开始与安慰剂/延迟开始（大约6个月后）治疗。主要疗效终点包括轴突损伤和神经退行性变（神经丝）、功能和强度、生活质量和生存率。结果：VALOR纳入了108名具有42种独特SOD1致病变异的参与者（平均[SD]年龄：安慰剂/延迟启动组51.2 [11.6][n = 36]；早启动组48.1 [12.6][n = 72]），安慰剂/延迟启动组和早启动组分别有19名（53%）和43名（60%）参与者为男性。总体而言，95/108名参与者（88%）参加了OLE， 46名参与者完成了OLE（早开始组，34名[47%]；安慰剂/延迟开始组，12名[33%]）。在OLE完成时，参与者可以从VALOR开始累积3.5年或更长时间（范围，192-276周）的随访。148周后，较早开始使用tofersen（与较晚开始使用相比）与临床功能（肌萎缩性侧索硬化症功能评定量表-修订评分，-9.9 vs -13.5分）、呼吸功能（慢肺活量，-13.8% vs -18.1%）、肌肉力量（手持式动力测量megascore， -0.38 vs -0.43分）和生活质量(肌萎缩性侧索硬化症评估问卷5分，17.0 vs 22.5分；EuroQol 5维度，5级问卷得分，-0.1 vs -0.2分)。相对于SOD1-ALS的预期自然史，Tofersen延长了生存期。大多数不良事件与ALS进展或已知的程序性不良反应一致。所有严重的神经系统不良事件都是可逆的；很少有导致停药的。结论和相关性：VALOR和OLE的最终数据证明了托佛素治疗SOD1-ALS的益处，并为在该人群中使用托佛素提供了明确的理由。试验注册：ClinicalTrials.gov标识符：VALOR NCT02623699；OLE NCT03070119。
{"title":"Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis.","authors":"Timothy M Miller, Merit E Cudkowicz, Pamela J Shaw, Angela Genge, Gen Sobue, Robert C Bucelli, Adriano Chiò, Philip Van Damme, Albert C Ludolph, Jonathan D Glass, Jinsy A Andrews, Suma Babu, Michael Benatar, Christopher J McDermott, François Salachas, Gaëlle Bruneteau, Ammar Al-Chalabi, Matthew Amorin, Ivan Nestorov, Danielle Graham, Luan Lin, Peng Sun, Manjit McNeill, Sohail Malek, Jennifer Inra, Steve Garafalo, Stephanie Fradette","doi":"10.1001/jamaneurol.2025.4946","DOIUrl":"10.1001/jamaneurol.2025.4946","url":null,"abstract":"<p><strong>Importance: </strong>Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are attributable to a pathogenic variant in the superoxide dismutase 1 (SOD1) gene. Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene.</p><p><strong>Objective: </strong>To evaluate the long-term effects of tofersen in adults with SOD1-ALS.</p><p><strong>Design, setting, and participants: </strong>The phase 3, randomized, double-blind, placebo-controlled VALOR trial (A Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tofersen in SOD1-ALS; conducted from March 2019 to July 2021) evaluated tofersen use over 28 weeks in adults (18 years and older) with weaknesses attributable to ALS and a confirmed SOD1 pathogenic variant at 32 sites in 10 countries; participants could then enroll in an open-label extension (OLE; completed August 2024).</p><p><strong>Intervention and exposure: </strong>Adults with SOD1-ALS were randomly assigned 2:1 to receive tofersen (100 mg) or placebo over a 24-week period in the VALOR study. All participants in the OLE were treated with tofersen.</p><p><strong>Main outcomes and measures: </strong>Integrated analysis of VALOR and the OLE study aimed to compare early start vs placebo/delayed start (approximately 6 months later) treatment with tofersen. Key efficacy end points included measures of axonal injury and neurodegeneration (neurofilament), function and strength, quality of life, and survival.</p><p><strong>Results: </strong>VALOR enrolled 108 participants with 42 unique SOD1 pathogenic variants (mean [SD] age: placebo/delayed-start group 51.2 [11.6] [n = 36]; early-start group: 48.1 [12.6] [n = 72]) with 19 (53%) and 43 (60%) of participants being male in the placebo/delayed- and early-start groups, respectively. Overall, 95/108 participants (88%) enrolled in the OLE, and 46 participants completed the OLE (early-start group, 34 [47%]; placebo/delayed-start group, 12 [33%]). At OLE completion, participants could have accumulated 3.5 years or more (range, 192-276 weeks) of follow-up from the start of VALOR. Over 148 weeks, earlier initiation of tofersen (compared to later initiation) was associated with numerically less decline in measures of clinical function (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, -9.9 vs -13.5 points), respiratory function (slow vital capacity, -13.8% vs -18.1%), muscle strength (handheld dynamometry megascore, -0.38 vs -0.43 points), and quality of life (Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 score, 17.0 vs 22.5 points; EuroQol 5 Dimension, 5 Level Questionnaire score, -0.1 vs -0.2 points). Tofersen prolonged survival relative to the expected natural history of SOD1-ALS. Most adverse events were consistent with ALS progression or known procedural adverse effects. All seri","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"83 2","pages":"115-125"},"PeriodicalIF":21.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12723595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142435","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}
Pub Date : 2026-01-26DOI: 10.1001/jamaneurol.2025.5446
Jeffrey L. Saver, David M. Kent, Scott E. Kasner, Benjamin Koethe, John D. Carroll, Gilles Chatellier, Anthony J. Furlan, Howard C. Herrmann, Peter Jüni, Jong S. Kim, Pil Hyung Lee, Benedicte Lefebvre, Jason Nelson, Jean-Louis Mas, Heinrich P. Mattle, Bernhard Meier, Mark Reisman, Richard W. Smalling, Lars Sondergaard, Jae-Kwan Song, David E. Thaler
Importance Patent foramen ovale (PFO) closure decreases recurrent stroke but increases atrial fibrillation (AF). Careful selection of patients in whom PFO is more likely to be the cause of stroke may improve outcomes by avoiding closure in patients unlikely to benefit. Objective To determine whether the PFO-Associated Stroke Causal Likelihood (PASCAL) classification system identifies who will experience net benefit and net harm from PFO closure. Design, Setting, and Participants This meta-analysis was a secondary analysis of individual participant-level data from the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) consortium meta-analysis, including all 6 randomized trials of transcatheter PFO closure vs antithrombotic therapy alone. Participants were young and middle-aged adults (mean [SD] age, 45 [10] years) with a PFO and an otherwise cryptogenic stroke. The trials were conducted in hospitals in North America, Europe, Australia, Brazil, and South Korea from 2000 to 2017. The current analysis, involving all trial participants, was performed from January to August 2025. Interventions Transcatheter PFO closure plus antithrombotic therapy vs antithrombotic therapy alone. Main Outcomes and Measures The primary efficacy end point was recurrent ischemic stroke. The primary safety end point was first-ever detection of AF beyond the periprocedural period (&gt;45 days after randomization). Results The 6 trials enrolled 3740 patients (1889 who had PFO closure, 1851 who had medical therapy); 2058 patients (55.0%) were male, and 1682 (45.0%) were female. Among patients in all 6 trials, PASCAL classified PFO relatedness to the index stroke as probable in 1382 patients (37.0%), possible in 1811 (48.4%), and unlikely in 547 (14.6%); among the 2967 patients in the 4 trials with broad entry criteria, PASCAL classified PFO relatedness as probable in 860 patients (29.0%), possible in 1565 (52.7%), and unlikely in 543 (18.3%). The reduction in the absolute rate of recurrent ischemic strokes over 5 years was greater than the increase in first-ever detection of AF in the postperiprocedural period as follows: in the probable group, fewer strokes, −2.5% (95% CI, −4.2% to −1.3%) vs more late AF, 1.3% (95% CI, 0.0% to 2.5%), and in the possible group, fewer strokes −3.4% (95% CI, −5.4% to −1.3%) vs more late AF, 1.1% (95% CI, −0.5% to 2.6%). Reduction in recurrent ischemic strokes was not observed and increase in first-ever detected postperiprocedural AF was magnified in the unlikely group (more strokes, 0.4%; 95% CI, −4.0% to 4.8%, vs more late AF, 4.6%; 95% CI, 0.3% to 8.9%). Conclusion and Relevance Among young and middle-aged patients with PFO and otherwise cryptogenic stroke, the PASCAL classification algorithm distinguished the 4 of every 5 patients in the probable and possible groups with net benefit and the 1 of every 5 patients in the unlikely group with net harm from closure.
{"title":"Patent Foramen Ovale Closure in Stroke and the PASCAL Classification System","authors":"Jeffrey L. Saver, David M. Kent, Scott E. Kasner, Benjamin Koethe, John D. Carroll, Gilles Chatellier, Anthony J. Furlan, Howard C. Herrmann, Peter Jüni, Jong S. Kim, Pil Hyung Lee, Benedicte Lefebvre, Jason Nelson, Jean-Louis Mas, Heinrich P. Mattle, Bernhard Meier, Mark Reisman, Richard W. Smalling, Lars Sondergaard, Jae-Kwan Song, David E. Thaler","doi":"10.1001/jamaneurol.2025.5446","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.5446","url":null,"abstract":"Importance Patent foramen ovale (PFO) closure decreases recurrent stroke but increases atrial fibrillation (AF). Careful selection of patients in whom PFO is more likely to be the cause of stroke may improve outcomes by avoiding closure in patients unlikely to benefit. Objective To determine whether the PFO-Associated Stroke Causal Likelihood (PASCAL) classification system identifies who will experience net benefit and net harm from PFO closure. Design, Setting, and Participants This meta-analysis was a secondary analysis of individual participant-level data from the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) consortium meta-analysis, including all 6 randomized trials of transcatheter PFO closure vs antithrombotic therapy alone. Participants were young and middle-aged adults (mean [SD] age, 45 [10] years) with a PFO and an otherwise cryptogenic stroke. The trials were conducted in hospitals in North America, Europe, Australia, Brazil, and South Korea from 2000 to 2017. The current analysis, involving all trial participants, was performed from January to August 2025. Interventions Transcatheter PFO closure plus antithrombotic therapy vs antithrombotic therapy alone. Main Outcomes and Measures The primary efficacy end point was recurrent ischemic stroke. The primary safety end point was first-ever detection of AF beyond the periprocedural period (&amp;gt;45 days after randomization). Results The 6 trials enrolled 3740 patients (1889 who had PFO closure, 1851 who had medical therapy); 2058 patients (55.0%) were male, and 1682 (45.0%) were female. Among patients in all 6 trials, PASCAL classified PFO relatedness to the index stroke as probable in 1382 patients (37.0%), possible in 1811 (48.4%), and unlikely in 547 (14.6%); among the 2967 patients in the 4 trials with broad entry criteria, PASCAL classified PFO relatedness as probable in 860 patients (29.0%), possible in 1565 (52.7%), and unlikely in 543 (18.3%). The reduction in the absolute rate of recurrent ischemic strokes over 5 years was greater than the increase in first-ever detection of AF in the postperiprocedural period as follows: in the probable group, fewer strokes, −2.5% (95% CI, −4.2% to −1.3%) vs more late AF, 1.3% (95% CI, 0.0% to 2.5%), and in the possible group, fewer strokes −3.4% (95% CI, −5.4% to −1.3%) vs more late AF, 1.1% (95% CI, −0.5% to 2.6%). Reduction in recurrent ischemic strokes was not observed and increase in first-ever detected postperiprocedural AF was magnified in the unlikely group (more strokes, 0.4%; 95% CI, −4.0% to 4.8%, vs more late AF, 4.6%; 95% CI, 0.3% to 8.9%). Conclusion and Relevance Among young and middle-aged patients with PFO and otherwise cryptogenic stroke, the PASCAL classification algorithm distinguished the 4 of every 5 patients in the probable and possible groups with net benefit and the 1 of every 5 patients in the unlikely group with net harm from closure.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"143 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048259","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}
Pub Date : 2026-01-26DOI: 10.1001/jamaneurol.2025.5394
Timothy Reynold Lim, Suradech Suthiphosuwan, María Inés Gaitán, Mariano Marrodán, Elizabeth A. Horwath, Melanie Guenette, Aditya Bharatha, Pascal Sati, Martina Absinta, Jorge Correale, Russell T. Shinohara, Daniel S. Reich, Jiwon Oh
Importance Most people with radiologically isolated syndrome (RIS) have high proportions of white matter lesions (WMLs) demonstrating the central vein sign (ie, central vein sign–positive lesion [CVS+L]) and at least 1 paramagnetic rim lesion (PRL), representing perivenular lesion development and chronic active demyelination, respectively. Whether these imaging measures predict developing clinical multiple sclerosis (MS) in people with RIS is not yet known. Objective To determine the prognostic value of various magnetic resonance imaging (MRI) measures, particularly PRLs and CVS+L, in predicting clinical MS in people with RIS. Design, Setting, and Participants This was a multicenter prospective cohort study conducted from 2011 and 2024. Participants older than 18 years and fulfilling published RIS criteria were consecutively recruited from 3 large academic MS centers. Exposures Participants underwent 3-T MRI including brain and spinal cord (SC) sequences and longitudinal clinical assessments. MRIs were evaluated for the total WML, PRL, and SC lesion (SCL) counts as well as the proportion of CVS+L. Main Outcomes and Measures The primary outcome was the development of clinical symptoms of MS. Time-varying Cox regression assessed the association between PRLs and symptom onset. Elastic net regression identified key predictors, incorporating PRLs, age, sex, and SCL. Results A total of 79 eligible people with RIS were included (36 [46%] in the discovery cohort [DC], 43 [54%] in the validation cohort [VC]). Of the initial 46 DC participants, 10 withdrew or were lost to follow-up, whereas all VC participants completed follow-up. In the DC (median [IQR] age, 40 [31-51] years; 25 female [70%]; median [IQR] follow-up, 6.4 [5.0-9.1] years), 9 of 36 people with RIS (25%) developed MS (median [IQR] time, 5.2 [5.0-6.8] years). In the VC (median [IQR] age, 43 [36-51] years; 23 female [53%]; median [IQR] follow-up, 4.4 [2.5-7.9] years), 9 of 43 people with RIS (21%) developed MS (median [IQR] time, 4.4 [2.5-4.7] years). Higher PRL count was associated with earlier symptom onset between 5 and 30 years after initial RIS diagnosis (hazard ratio [HR], 1.15; 95% CI, 1.05-1.26; <jats:italic toggle="yes">P</jats:italic> = .004) in the DC, replicated in the VC (HR, 1.51; 95% CI, 1.00-2.27; <jats:italic toggle="yes">P</jats:italic> = .04). In the DC, having 4 or more PRLs (odds ratio [OR], 14.64; 95% CI, 2.00-207.23; <jats:italic toggle="yes">P</jats:italic> = .02) and higher PRL count (OR, 1.15; 95% CI, 1.03-1.32; <jats:italic toggle="yes">P</jats:italic> = .02) predicted clinical MS. In the VC, having any PRL was significantly associated with developing clinical MS (OR, 20.90; 95% CI, 2.35-533.30; <jats:italic toggle="yes">P</jats:italic> = .02). Conclusions and Relevance Study findings suggest that accrual of nonresolving chronic inflammation in WML portends development of clinical MS in people with RIS, which may have clinical utility in guiding treatment decisions ac
大多数放射孤立综合征（RIS）患者有高比例的白质病变（WMLs）表现为中心静脉征象（即中心静脉征象阳性病变[CVS+L]）和至少1个顺磁边缘病变（PRL），分别代表静脉周围病变发展和慢性活动性脱髓鞘。这些影像学指标是否能预测RIS患者的临床多发性硬化症（MS）发展尚不清楚。目的探讨磁共振成像（MRI）各项指标，尤其是prl和CVS+L对RIS患者临床MS的预测价值。设计、环境和参与者这是一项从2011年到2024年进行的多中心前瞻性队列研究。年龄大于18岁且符合已公布的RIS标准的参与者从3个大型学术多发性硬化症中心连续招募。参与者接受了3-T MRI，包括脑和脊髓（SC）序列和纵向临床评估。mri评估WML、PRL和SC病变（SCL）总数以及CVS+L的比例。主要结局和测量主要结局是ms临床症状的发展，时变Cox回归评估prl与症状发作之间的关系。弹性网回归确定了关键的预测因子，包括prl、年龄、性别和SCL。结果共纳入79例符合条件的RIS患者（发现队列[DC] 36例[46%]，验证队列[VC] 43例[54%]）。在最初的46名DC参与者中，10名退出或失去了随访，而所有VC参与者都完成了随访。在DC中（中位[IQR]年龄40[31-51]岁，女性25[70%]，中位[IQR]随访6.4[5.0-9.1]年），36例RIS患者中有9例（25%）发展为MS（中位[IQR]时间5.2[5.0-6.8]年）。在VC中（中位[IQR]年龄43[36-51]岁，女性23[53%]，中位[IQR]随访4.4[2.5-7.9]年），43例RIS患者中有9例（21%）发展为MS（中位[IQR]时间4.4[2.5-4.7]年）。PRL计数较高与首发RIS诊断后5- 30年间症状发作较早相关（风险比[HR]， 1.15; 95% CI, 1.05-1.26; P = 0.004），风险比（HR, 1.51; 95% CI, 1.00-2.27; P = 0.04）。在DC中，有4个或更多PRL（比值比[or]， 14.64; 95% CI, 2.00-207.23; P = 0.02）和较高PRL计数（or, 1.15; 95% CI, 1.03-1.32; P = 0.02）预测临床MS。在VC中，有PRL与发生临床MS显著相关（or, 20.90; 95% CI, 2.35-533.30; P = 0.02）。研究结果表明，WML中非消退性慢性炎症的积累预示着RIS患者临床MS的发展，这可能在指导MS谱的治疗决策方面具有临床应用价值，并加强了将无症状MS纳入诊断标准的案例。越来越多的人认识到，大多数慢性神经系统疾病的早期检测对于预防或减少未来的残疾至关重要，这些发现是这一原则在实践中如何运作的一个具体例子。
{"title":"Paramagnetic Rim Lesions and Development of Clinical MS in Radiologically Isolated Syndrome","authors":"Timothy Reynold Lim, Suradech Suthiphosuwan, María Inés Gaitán, Mariano Marrodán, Elizabeth A. Horwath, Melanie Guenette, Aditya Bharatha, Pascal Sati, Martina Absinta, Jorge Correale, Russell T. Shinohara, Daniel S. Reich, Jiwon Oh","doi":"10.1001/jamaneurol.2025.5394","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.5394","url":null,"abstract":"Importance Most people with radiologically isolated syndrome (RIS) have high proportions of white matter lesions (WMLs) demonstrating the central vein sign (ie, central vein sign–positive lesion [CVS+L]) and at least 1 paramagnetic rim lesion (PRL), representing perivenular lesion development and chronic active demyelination, respectively. Whether these imaging measures predict developing clinical multiple sclerosis (MS) in people with RIS is not yet known. Objective To determine the prognostic value of various magnetic resonance imaging (MRI) measures, particularly PRLs and CVS+L, in predicting clinical MS in people with RIS. Design, Setting, and Participants This was a multicenter prospective cohort study conducted from 2011 and 2024. Participants older than 18 years and fulfilling published RIS criteria were consecutively recruited from 3 large academic MS centers. Exposures Participants underwent 3-T MRI including brain and spinal cord (SC) sequences and longitudinal clinical assessments. MRIs were evaluated for the total WML, PRL, and SC lesion (SCL) counts as well as the proportion of CVS+L. Main Outcomes and Measures The primary outcome was the development of clinical symptoms of MS. Time-varying Cox regression assessed the association between PRLs and symptom onset. Elastic net regression identified key predictors, incorporating PRLs, age, sex, and SCL. Results A total of 79 eligible people with RIS were included (36 [46%] in the discovery cohort [DC], 43 [54%] in the validation cohort [VC]). Of the initial 46 DC participants, 10 withdrew or were lost to follow-up, whereas all VC participants completed follow-up. In the DC (median [IQR] age, 40 [31-51] years; 25 female [70%]; median [IQR] follow-up, 6.4 [5.0-9.1] years), 9 of 36 people with RIS (25%) developed MS (median [IQR] time, 5.2 [5.0-6.8] years). In the VC (median [IQR] age, 43 [36-51] years; 23 female [53%]; median [IQR] follow-up, 4.4 [2.5-7.9] years), 9 of 43 people with RIS (21%) developed MS (median [IQR] time, 4.4 [2.5-4.7] years). Higher PRL count was associated with earlier symptom onset between 5 and 30 years after initial RIS diagnosis (hazard ratio [HR], 1.15; 95% CI, 1.05-1.26; <jats:italic toggle=\"yes\">P</jats:italic> = .004) in the DC, replicated in the VC (HR, 1.51; 95% CI, 1.00-2.27; <jats:italic toggle=\"yes\">P</jats:italic> = .04). In the DC, having 4 or more PRLs (odds ratio [OR], 14.64; 95% CI, 2.00-207.23; <jats:italic toggle=\"yes\">P</jats:italic> = .02) and higher PRL count (OR, 1.15; 95% CI, 1.03-1.32; <jats:italic toggle=\"yes\">P</jats:italic> = .02) predicted clinical MS. In the VC, having any PRL was significantly associated with developing clinical MS (OR, 20.90; 95% CI, 2.35-533.30; <jats:italic toggle=\"yes\">P</jats:italic> = .02). Conclusions and Relevance Study findings suggest that accrual of nonresolving chronic inflammation in WML portends development of clinical MS in people with RIS, which may have clinical utility in guiding treatment decisions ac","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"7 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048283","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}
Pub Date : 2026-01-26DOI: 10.1001/jamaneurol.2025.5558
Hooman Kamel, S. Andrew Josephson
This Viewpoint describes trials of revascularization with medical therapy vs medical therapy alone to prevent stroke in patients with asymptomatic carotid stenosis.
本观点描述了在无症状颈动脉狭窄患者中，联合药物治疗与单独药物治疗预防卒中的试验。
{"title":"Asymptomatic Carotid Stenosis—Is Medical Therapy Enough?","authors":"Hooman Kamel, S. Andrew Josephson","doi":"10.1001/jamaneurol.2025.5558","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.5558","url":null,"abstract":"This Viewpoint describes trials of revascularization with medical therapy vs medical therapy alone to prevent stroke in patients with asymptomatic carotid stenosis.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"42 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048284","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}
Pub Date : 2026-01-26DOI: 10.1001/jamaneurol.2025.5421
Hidetomo Tanaka,Lauren E Black,Shelley L Forrest,Krisztina Danics,Nusrat Sadia,Mozhgan Khodadadi,Charles Tator,Douglas H Smith,Maria Carmela Tartaglia,William Stewart,Gabor G Kovacs
ImportanceExposure to repetitive head impacts (RHI) is associated with increased risk of a range of neurodegenerative diseases, including Alzheimer disease and amyotrophic lateral sclerosis. However, while the protein pathologies in the brains of individuals with the RHI-associated pathology of chronic traumatic encephalopathy (CTE) are well described, the spinal cord pathology in at-risk individuals remains poorly understood.ObjectiveTo evaluate spinal cord pathologies associated with RHI exposure or CTE neuropathologic change (CTE-NC) in the brain.Design, Setting, and ParticipantsThis case-control study of a retrospective autopsy series (June 2019 to August 2025) was performed among autopsied individuals who served as RHI-exposed cases or controls in a multicenter brain bank collaboration. Data analysis was performed from January 2024 to November 2025.ExposuresRHI history and CTE-NC presence.Main Outcomes and MeasuresInformant-reported clinical history as well as symptoms and immunohistochemistry for phosphorylated tau (p-tau), phosphorylated TAR DNA-binding protein 43 (p-TDP-43), α-synuclein, and amyloid-β (Aβ), as well as amyloid precursor protein and human leukocyte antigen DR.ResultsOf 70 autopsied individuals (62 male, 8 female; mean [SD] age, 64.40 [13.94] years), 20 showed CTE-NC in the brain. All cases with CTE-NC exhibited spinal cord p-tau deposits, especially in cases aged 65 years or older with prior RHI (n = 14), often showing extensive spinal tau pathology as both neuronal (all 14 cases) and astrocytic (12 of 14 cases [86%]) p-tau deposits. Spinal p-tau pathology was associated with microglial activation and motor symptoms. Notably, among the individuals with CTE-NC and prior RHI who were aged 65 years or older, additional spinal protein pathologies were present, comprising p-TDP-43 inclusions (9 of 14 cases [64%]), Aβ deposits (13 of 14 cases [93%]), and α-synuclein deposits (7 of 14 cases [50%]), with all 4 of these pathologies present in 4 individuals (29%). In total, across all 20 CTE-NC cases, p-TDP-43 inclusions were confined to the spinal cord in 5 of the 10 individuals with spinal p-TDP-43 pathology. In contrast, among 50 individuals without CTE-NC, typically sparse p-tau deposits were seen in only 27 (54%). Among the 23 confirmed cases with a history of RHI, 16 (70%) exhibited CTE-NC, while 7 (30%) did not. Spinal tau pathology was more severe in those with CTE-NC; however, astrocytic tau pathology was also present in the group without CTE-NC, unlike in controls without RHI or CTE.Conclusions and RelevanceThis case-control study provides autopsy evidence of a high prevalence of complex spinal pathology in individuals with CTE-NC, supporting the concept of trauma-related encephalomyelopathy. The frequent co-occurrence of p-TDP-43, Aβ, and α-synuclein pathologies in individuals aged 65 years or older with CTE-NC suggests that cumulative trauma might contribute to widespread misfolded protein aggregation.
{"title":"Spinal Cord Tau and Protein Copathologies Associated With Chronic Traumatic Encephalopathy.","authors":"Hidetomo Tanaka,Lauren E Black,Shelley L Forrest,Krisztina Danics,Nusrat Sadia,Mozhgan Khodadadi,Charles Tator,Douglas H Smith,Maria Carmela Tartaglia,William Stewart,Gabor G Kovacs","doi":"10.1001/jamaneurol.2025.5421","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.5421","url":null,"abstract":"ImportanceExposure to repetitive head impacts (RHI) is associated with increased risk of a range of neurodegenerative diseases, including Alzheimer disease and amyotrophic lateral sclerosis. However, while the protein pathologies in the brains of individuals with the RHI-associated pathology of chronic traumatic encephalopathy (CTE) are well described, the spinal cord pathology in at-risk individuals remains poorly understood.ObjectiveTo evaluate spinal cord pathologies associated with RHI exposure or CTE neuropathologic change (CTE-NC) in the brain.Design, Setting, and ParticipantsThis case-control study of a retrospective autopsy series (June 2019 to August 2025) was performed among autopsied individuals who served as RHI-exposed cases or controls in a multicenter brain bank collaboration. Data analysis was performed from January 2024 to November 2025.ExposuresRHI history and CTE-NC presence.Main Outcomes and MeasuresInformant-reported clinical history as well as symptoms and immunohistochemistry for phosphorylated tau (p-tau), phosphorylated TAR DNA-binding protein 43 (p-TDP-43), α-synuclein, and amyloid-β (Aβ), as well as amyloid precursor protein and human leukocyte antigen DR.ResultsOf 70 autopsied individuals (62 male, 8 female; mean [SD] age, 64.40 [13.94] years), 20 showed CTE-NC in the brain. All cases with CTE-NC exhibited spinal cord p-tau deposits, especially in cases aged 65 years or older with prior RHI (n = 14), often showing extensive spinal tau pathology as both neuronal (all 14 cases) and astrocytic (12 of 14 cases [86%]) p-tau deposits. Spinal p-tau pathology was associated with microglial activation and motor symptoms. Notably, among the individuals with CTE-NC and prior RHI who were aged 65 years or older, additional spinal protein pathologies were present, comprising p-TDP-43 inclusions (9 of 14 cases [64%]), Aβ deposits (13 of 14 cases [93%]), and α-synuclein deposits (7 of 14 cases [50%]), with all 4 of these pathologies present in 4 individuals (29%). In total, across all 20 CTE-NC cases, p-TDP-43 inclusions were confined to the spinal cord in 5 of the 10 individuals with spinal p-TDP-43 pathology. In contrast, among 50 individuals without CTE-NC, typically sparse p-tau deposits were seen in only 27 (54%). Among the 23 confirmed cases with a history of RHI, 16 (70%) exhibited CTE-NC, while 7 (30%) did not. Spinal tau pathology was more severe in those with CTE-NC; however, astrocytic tau pathology was also present in the group without CTE-NC, unlike in controls without RHI or CTE.Conclusions and RelevanceThis case-control study provides autopsy evidence of a high prevalence of complex spinal pathology in individuals with CTE-NC, supporting the concept of trauma-related encephalomyelopathy. The frequent co-occurrence of p-TDP-43, Aβ, and α-synuclein pathologies in individuals aged 65 years or older with CTE-NC suggests that cumulative trauma might contribute to widespread misfolded protein aggregation.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"65 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044613","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":"Abdominal Clonus in the Setting of a T5 Spinal Cord Injury.","authors":"Yoshimitsu Shimatani,Yoshikatsu Noda,Hiroyuki Ishihara","doi":"10.1001/jamaneurol.2025.5371","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.5371","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"87 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005073","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}
ImportanceAir pollution exposure has been associated with an increased risk of neurodegenerative diseases; however, evidence is limited for motor neuron disease (MND), especially regarding disease progression.ObjectiveTo determine whether long-term exposure to air pollution is associated with the risk and prognosis of MND.Design, Setting, and ParticipantsThis population-based, nested case-control study used Swedish health register data of incident MND cases diagnosed between 2015 and 2023 with up to 8 years of follow-up. Participants included patients with MND, 5 age- and sex-matched population controls without MND per patient with MND, and full siblings of the patients with MND. Data were analyzed between November 6, 2024, and November 4, 2025.ExposuresMean yearly concentrations of particulate matters of 2.5 µm or less, 10 µm or less, or 2.5 to 10 µm in diameter (PM2.5, PM10, PM2.5-10) and nitrogen dioxide (NO2) were assessed at the residential address using a spatiotemporal model to approximate accumulated air pollution exposure.Main Outcome and MeasuresAssociation between air pollution and risk of MND was assessed by comparing cases to both population and sibling controls. Flexible parametric survival models estimated the association between air pollution exposure and the risk of mortality (or use of invasive ventilation) after MND diagnosis (case-only analyses). Based on the rate of decline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score and its subscores after diagnosis, patients were classified into fast (upper 25th percentile) or slow (lower 75th percentile) progression. Logistic regression was used to assess air pollution exposure and the risk of fast progression.ResultsThe study included 1463 patients with MND, 7310 population controls, and 1768 sibling controls. The mean (SD) age for all patients with MND was 67.3 (11.7) years, and 814 (55.6) were male. In the population comparison, long-term air pollution was associated with an increased risk of MND; per IQR increase in the 10-year average level, the odds ratio was 1.21 (95% CI, 1.09-1.34) for PM2.5, 1.30 (95% CI, 1.19-1.42) for PM2.5-10, 1.29 (95% CI, 1.18-1.42) for PM10, and 1.20 (95% CI, 1.12-1.29) for NO2. A higher level of PM10 or NO2 was associated with a higher hazard of mortality, whereas a higher level of all PMs was associated with faster functional decline, particularly motor and respiratory functions, after MND diagnosis.Conclusions and RelevanceThe findings of this case-control study suggest that air pollution, even at relatively low levels typical of Sweden, may contribute both to the risk of developing MND and disease prognosis after MND diagnosis.
{"title":"Long-Term Exposure to Air Pollution and Risk and Prognosis of Motor Neuron Disease.","authors":"Jing Wu,Andrei Pyko,Charilaos Chourpiliadis,Yihan Hu,Can Hou,Susanna Brauner,Fredrik Piehl,Petter Ljungman,Caroline Ingre,Fang Fang","doi":"10.1001/jamaneurol.2025.5379","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.5379","url":null,"abstract":"ImportanceAir pollution exposure has been associated with an increased risk of neurodegenerative diseases; however, evidence is limited for motor neuron disease (MND), especially regarding disease progression.ObjectiveTo determine whether long-term exposure to air pollution is associated with the risk and prognosis of MND.Design, Setting, and ParticipantsThis population-based, nested case-control study used Swedish health register data of incident MND cases diagnosed between 2015 and 2023 with up to 8 years of follow-up. Participants included patients with MND, 5 age- and sex-matched population controls without MND per patient with MND, and full siblings of the patients with MND. Data were analyzed between November 6, 2024, and November 4, 2025.ExposuresMean yearly concentrations of particulate matters of 2.5 µm or less, 10 µm or less, or 2.5 to 10 µm in diameter (PM2.5, PM10, PM2.5-10) and nitrogen dioxide (NO2) were assessed at the residential address using a spatiotemporal model to approximate accumulated air pollution exposure.Main Outcome and MeasuresAssociation between air pollution and risk of MND was assessed by comparing cases to both population and sibling controls. Flexible parametric survival models estimated the association between air pollution exposure and the risk of mortality (or use of invasive ventilation) after MND diagnosis (case-only analyses). Based on the rate of decline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score and its subscores after diagnosis, patients were classified into fast (upper 25th percentile) or slow (lower 75th percentile) progression. Logistic regression was used to assess air pollution exposure and the risk of fast progression.ResultsThe study included 1463 patients with MND, 7310 population controls, and 1768 sibling controls. The mean (SD) age for all patients with MND was 67.3 (11.7) years, and 814 (55.6) were male. In the population comparison, long-term air pollution was associated with an increased risk of MND; per IQR increase in the 10-year average level, the odds ratio was 1.21 (95% CI, 1.09-1.34) for PM2.5, 1.30 (95% CI, 1.19-1.42) for PM2.5-10, 1.29 (95% CI, 1.18-1.42) for PM10, and 1.20 (95% CI, 1.12-1.29) for NO2. A higher level of PM10 or NO2 was associated with a higher hazard of mortality, whereas a higher level of all PMs was associated with faster functional decline, particularly motor and respiratory functions, after MND diagnosis.Conclusions and RelevanceThe findings of this case-control study suggest that air pollution, even at relatively low levels typical of Sweden, may contribute both to the risk of developing MND and disease prognosis after MND diagnosis.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"49 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005015","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}
Pub Date : 2026-01-20DOI: 10.1001/jamaneurol.2025.5329
Casey R Vanderlip, Daniel L Gillen, Craig E L Stark, Joshua D Grill
{"title":"Uniform Amyloid Thresholds Across Populations.","authors":"Casey R Vanderlip, Daniel L Gillen, Craig E L Stark, Joshua D Grill","doi":"10.1001/jamaneurol.2025.5329","DOIUrl":"10.1001/jamaneurol.2025.5329","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12820775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010134","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}
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