Pub Date : 2026-02-02DOI: 10.1001/jamaneurol.2025.5530
Jihwan Yun, Jungah Lee, Daeun Shin, Eun Hye Lee, Jun Pyo Kim, Hongki Ham, Yuna Gu, Min Young Chun, Sung Hoon Kang, Hee Jin Kim, Duk L Na, Ko Woon Kim, Si Eun Kim, Yeshin Kim, Jaeho Kim, Na-Yeon Jung, Yeo Jin Kim, Soo Hyun Cho, Jin San Lee, Seonghyeon Kim, Henrik Zetterberg, Kaj Blennow, Fernando Gonzalez-Ortiz, Nicholas J Ashton, Joel B Braunstein, Philip B Verghese, Tim West, Matthew R Meyer, Sang Won Seo, Hyemin Jang
<p><strong>Importance: </strong>Plasma phosphorylated p-tau 217 levels vary with biological factors such as kidney dysfunction, body mass index (BMI), and anemia. It remains unclear whether a biological subgroup-specific optimal cutoff or a double-cutoff strategy could enhance diagnostic accuracy and cost efficiency beyond the standard single cutoff.</p><p><strong>Objective: </strong>To compare the diagnostic and economic performance of 3 plasma p-tau217 classification strategies for detecting amyloid-β (Aβ) positivity: standard single cutoff, subgroup-specific optimal cutoff, and double cutoff.</p><p><strong>Design, setting, and participants: </strong>This cohort study was a multicenter cross-sectional study conducted from 2016 to 2023; analyses were completed in 2025. Participants were recruited from multiple memory clinics and community-based cohorts. All participants had amyloid positron emission tomography (PET) imaging, clinical evaluation, and p-tau217 testing with measures of estimated glomerular filtration rate (eGFR), BMI, and hemoglobin. Measurements of p-tau217 were made using UGOT Simoa and Roche Elecsys, and the %p-tau217 ratio was assessed using a tau multianalyte assay (C2N Diagnostics LLC).</p><p><strong>Exposures: </strong>Kidney function (chronic kidney disease [CKD], eGFR <60 mL/min/1.73 m2; advanced CKD, eGFR <45 mL/min/1.73 m2), underweight (BMI <18.5), obesity (BMI ≥27.5), and anemia (hemoglobin <12 g/dL in women, <13 g/dL in men).</p><p><strong>Main outcomes and measures: </strong>Plasma p-tau217 concentration; standard single cutoff, optimal cutoffs, and double cutoff for Aβ positivity (Centiloid ≥25.5); accuracy; and cost-effectiveness estimated from false-positive, false-negative, and confirmatory imaging costs.</p><p><strong>Results: </strong>A total of 2571 participants were analyzed with UGOT, 1578 with Roche, and 304 with the C2N %p-tau217 ratio. The mean (SD) age was similar across cohorts (71.3 [8.6] years in the UGOT cohort, 71.3 [8.5] years in the Roche cohort, and 71.8 [7.8] years in the C2N cohort); there were 1633 (63.5%), 1006 (63.8%), and 191 (62.8%) women and 938 (36.5%), 572 (36.2%), and 113 (37.2%) men, respectively. In the UGOT cohort, the optimal cutoff improved diagnostic accuracy compared with the standard single cutoff, particularly in CKD and anemia (CKD: from 0.65; 95% CI, 0.57-0.72; to 0.83; 95% CI, 0.76-0.89; anemia: from 0.80; 95% CI, 0.76-0.84; to 0.86; 95% CI, 0.82-0.90), with consistent findings in the Roche cohort. In all biological subgroups, the double-cutoff strategy also increased accuracy relative to the single cutoff and reduced false classifications but yielded 12% to 39% intermediate results. When compared directly, the optimal cutoff provided higher accuracy than the double cutoff for CKD while lowering total diagnostic costs. For anemia, the double cutoff showed slightly higher accuracy but required confirmatory PET in up to 25% of cases, offsetting its economic advantage. In obes
{"title":"Plasma Phosphorylated Tau 217 Cutoffs for Amyloid Pathology and Kidney Function, Body Mass Index, and Anemia.","authors":"Jihwan Yun, Jungah Lee, Daeun Shin, Eun Hye Lee, Jun Pyo Kim, Hongki Ham, Yuna Gu, Min Young Chun, Sung Hoon Kang, Hee Jin Kim, Duk L Na, Ko Woon Kim, Si Eun Kim, Yeshin Kim, Jaeho Kim, Na-Yeon Jung, Yeo Jin Kim, Soo Hyun Cho, Jin San Lee, Seonghyeon Kim, Henrik Zetterberg, Kaj Blennow, Fernando Gonzalez-Ortiz, Nicholas J Ashton, Joel B Braunstein, Philip B Verghese, Tim West, Matthew R Meyer, Sang Won Seo, Hyemin Jang","doi":"10.1001/jamaneurol.2025.5530","DOIUrl":"10.1001/jamaneurol.2025.5530","url":null,"abstract":"<p><strong>Importance: </strong>Plasma phosphorylated p-tau 217 levels vary with biological factors such as kidney dysfunction, body mass index (BMI), and anemia. It remains unclear whether a biological subgroup-specific optimal cutoff or a double-cutoff strategy could enhance diagnostic accuracy and cost efficiency beyond the standard single cutoff.</p><p><strong>Objective: </strong>To compare the diagnostic and economic performance of 3 plasma p-tau217 classification strategies for detecting amyloid-β (Aβ) positivity: standard single cutoff, subgroup-specific optimal cutoff, and double cutoff.</p><p><strong>Design, setting, and participants: </strong>This cohort study was a multicenter cross-sectional study conducted from 2016 to 2023; analyses were completed in 2025. Participants were recruited from multiple memory clinics and community-based cohorts. All participants had amyloid positron emission tomography (PET) imaging, clinical evaluation, and p-tau217 testing with measures of estimated glomerular filtration rate (eGFR), BMI, and hemoglobin. Measurements of p-tau217 were made using UGOT Simoa and Roche Elecsys, and the %p-tau217 ratio was assessed using a tau multianalyte assay (C2N Diagnostics LLC).</p><p><strong>Exposures: </strong>Kidney function (chronic kidney disease [CKD], eGFR <60 mL/min/1.73 m2; advanced CKD, eGFR <45 mL/min/1.73 m2), underweight (BMI <18.5), obesity (BMI ≥27.5), and anemia (hemoglobin <12 g/dL in women, <13 g/dL in men).</p><p><strong>Main outcomes and measures: </strong>Plasma p-tau217 concentration; standard single cutoff, optimal cutoffs, and double cutoff for Aβ positivity (Centiloid ≥25.5); accuracy; and cost-effectiveness estimated from false-positive, false-negative, and confirmatory imaging costs.</p><p><strong>Results: </strong>A total of 2571 participants were analyzed with UGOT, 1578 with Roche, and 304 with the C2N %p-tau217 ratio. The mean (SD) age was similar across cohorts (71.3 [8.6] years in the UGOT cohort, 71.3 [8.5] years in the Roche cohort, and 71.8 [7.8] years in the C2N cohort); there were 1633 (63.5%), 1006 (63.8%), and 191 (62.8%) women and 938 (36.5%), 572 (36.2%), and 113 (37.2%) men, respectively. In the UGOT cohort, the optimal cutoff improved diagnostic accuracy compared with the standard single cutoff, particularly in CKD and anemia (CKD: from 0.65; 95% CI, 0.57-0.72; to 0.83; 95% CI, 0.76-0.89; anemia: from 0.80; 95% CI, 0.76-0.84; to 0.86; 95% CI, 0.82-0.90), with consistent findings in the Roche cohort. In all biological subgroups, the double-cutoff strategy also increased accuracy relative to the single cutoff and reduced false classifications but yielded 12% to 39% intermediate results. When compared directly, the optimal cutoff provided higher accuracy than the double cutoff for CKD while lowering total diagnostic costs. For anemia, the double cutoff showed slightly higher accuracy but required confirmatory PET in up to 25% of cases, offsetting its economic advantage. In obes","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":""},"PeriodicalIF":21.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12865699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146105505","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 : 2026-02-02DOI: 10.1001/jamaneurol.2025.5496
Candice Maenza, Carolee J. Winstein, Terrence E. Murphy, Nick M. Kitchen, Jennifer Tanaka, Jisung Yuk, Rini Varghese, Robert L. Sainburg
Importance Ipsilesional upper-limb motor deficits after stroke are functionally important yet largely neglected in rehabilitation. Remediation may improve motor outcomes in individuals with severe contralesional arm hemiparesis. Objective To determine whether training of the ipsilesional arm improves motor performance in chronic stroke with severe contralesional impairment and significant ipsilesional arm motor deficits. Design, Setting, and Participants This 2-site, parallel-group randomized clinical trial with blinded outcome assessment was conducted from February 2019 to August 2024, with follow-up through 6 months posttreatment. Data analysis was performed from August 2024 through August 2025. The trial was conducted at outpatient research laboratories at Penn State College of Medicine and the University of Southern California among adults with radiologically confirmed unilateral middle cerebral artery stroke, severe contralesional upper-extremity impairment (Fugl-Meyer score ≤28), and ipsilesional motor deficits. Participants were randomly assigned with equal probability to 2 treatment groups and stratified by sex. Interventions Participants were randomized to a 5-week, 15-session intervention focused on either the ipsilesional (n = 25) or contralesional (n = 28) upper limb. The ipsilesional group received ipsilesional virtual reality and manipulation training; the contralesional group received dose-matched, best practice contralesional arm therapy. Main Outcomes and Measures The primary outcomes were ipsilesional motor performance (Jebsen-Taylor Hand Function Test [excluding writing]), functional independence (Barthel Index), contralesional impairment severity (Fugl-Meyer Assessment [Upper Extremity]), and perceived manual ability (ABILHAND-Stroke). Results Of 100 adults screened, 58 were included, and 53 participants (91%) completed both baseline and immediate posttreatment assessments. Of the 53 participants who completed the study, mean (SD) age was 59 (11) years, and 17 participants (32%) were female. In this modified intent-to-treat analysis, the ipsilesional treatment group showed significant improvement in Jebsen-Taylor Hand Function Test performance (mean difference, −5.87 seconds; 95% CI, −8.89 to −2.85 seconds; <jats:italic>P</jats:italic> = .003), representing a 12% reduction in time to completion. Relative to its own baseline, this improvement was sustained at the 3-week and 6-month follow-up times within the ipsilesional treatment group only. No significant effects were observed for the remaining outcomes. Conclusions and Relevance In this parallel-group randomized clinical trial, targeted ipsilesional arm training significantly improved ipsilesional motor performance in patients with chronic stroke with severe paresis. This approach may enhance functional capacity in patients who rely on the ipsilesional arm for daily activities. Trial Registration ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink="http://www.w3.org/19
卒中后同侧性上肢运动障碍在功能上很重要，但在康复中却被忽视。补救措施可以改善严重对侧性肢体偏瘫患者的运动预后。目的探讨同侧臂训练是否能改善慢性脑卒中伴严重对侧损伤和显著同侧臂运动障碍患者的运动能力。设计、环境和参与者本研究于2019年2月至2024年8月进行双中心、平行组随机临床试验，并进行盲法结局评估，治疗后随访6个月。数据分析从2024年8月到2025年8月进行。该试验在宾夕法尼亚州立医学院和南加州大学的门诊研究实验室进行，研究对象为影像学证实的单侧大脑中动脉卒中、严重对位性上肢损伤（fugel - meyer评分≤28）和同侧运动缺陷的成年人。参与者以等概率随机分为两个治疗组，并按性别分层。干预措施参与者被随机分配到一个5周，15个疗程的干预，重点是同侧上肢（n = 25）或对侧上肢（n = 28）。裸眼组接受裸眼虚拟现实及操作训练；对侧组接受剂量匹配、最佳做法的对侧臂治疗。主要结果和测量主要结果为同侧运动表现（Jebsen-Taylor手功能测试[不包括书写]）、功能独立性（Barthel指数）、对侧损伤严重程度（Fugl-Meyer评估[上肢]）和感知手能力（ABILHAND-Stroke）。结果在100名被筛选的成年人中，58名被纳入，53名参与者（91%）完成了基线和治疗后立即评估。在完成研究的53名参与者中，平均（SD）年龄为59（11）岁，17名参与者（32%）为女性。在这一改进的意向治疗分析中，同切除治疗组在捷成-泰勒手功能测试（Jebsen-Taylor Hand Function Test）方面表现出显著改善（平均差值为- 5.87秒；95% CI为- 8.89至- 2.85秒；P = 0.003），完成时间减少了12%。相对于自己的基线，这种改善仅在同切治疗组的3周和6个月随访时间内持续。其余结果未观察到显著影响。结论与意义在这项平行组随机临床试验中，有针对性的同侧手臂训练可显著改善慢性脑卒中伴重度瘫患者的同侧运动能力。这种方法可以提高依赖同侧臂进行日常活动的患者的功能能力。临床试验注册：ClinicalTrials.gov标识符：NCT03634397
{"title":"Targeted Remediation of the Ipsilesional Arm in Chronic Stroke","authors":"Candice Maenza, Carolee J. Winstein, Terrence E. Murphy, Nick M. Kitchen, Jennifer Tanaka, Jisung Yuk, Rini Varghese, Robert L. Sainburg","doi":"10.1001/jamaneurol.2025.5496","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.5496","url":null,"abstract":"Importance Ipsilesional upper-limb motor deficits after stroke are functionally important yet largely neglected in rehabilitation. Remediation may improve motor outcomes in individuals with severe contralesional arm hemiparesis. Objective To determine whether training of the ipsilesional arm improves motor performance in chronic stroke with severe contralesional impairment and significant ipsilesional arm motor deficits. Design, Setting, and Participants This 2-site, parallel-group randomized clinical trial with blinded outcome assessment was conducted from February 2019 to August 2024, with follow-up through 6 months posttreatment. Data analysis was performed from August 2024 through August 2025. The trial was conducted at outpatient research laboratories at Penn State College of Medicine and the University of Southern California among adults with radiologically confirmed unilateral middle cerebral artery stroke, severe contralesional upper-extremity impairment (Fugl-Meyer score ≤28), and ipsilesional motor deficits. Participants were randomly assigned with equal probability to 2 treatment groups and stratified by sex. Interventions Participants were randomized to a 5-week, 15-session intervention focused on either the ipsilesional (n = 25) or contralesional (n = 28) upper limb. The ipsilesional group received ipsilesional virtual reality and manipulation training; the contralesional group received dose-matched, best practice contralesional arm therapy. Main Outcomes and Measures The primary outcomes were ipsilesional motor performance (Jebsen-Taylor Hand Function Test [excluding writing]), functional independence (Barthel Index), contralesional impairment severity (Fugl-Meyer Assessment [Upper Extremity]), and perceived manual ability (ABILHAND-Stroke). Results Of 100 adults screened, 58 were included, and 53 participants (91%) completed both baseline and immediate posttreatment assessments. Of the 53 participants who completed the study, mean (SD) age was 59 (11) years, and 17 participants (32%) were female. In this modified intent-to-treat analysis, the ipsilesional treatment group showed significant improvement in Jebsen-Taylor Hand Function Test performance (mean difference, −5.87 seconds; 95% CI, −8.89 to −2.85 seconds; <jats:italic>P</jats:italic> = .003), representing a 12% reduction in time to completion. Relative to its own baseline, this improvement was sustained at the 3-week and 6-month follow-up times within the ipsilesional treatment group only. No significant effects were observed for the remaining outcomes. Conclusions and Relevance In this parallel-group randomized clinical trial, targeted ipsilesional arm training significantly improved ipsilesional motor performance in patients with chronic stroke with severe paresis. This approach may enhance functional capacity in patients who rely on the ipsilesional arm for daily activities. Trial Registration ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\"http://www.w3.org/19","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"291 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101444","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 : 2026-02-02DOI: 10.1001/jamaneurol.2025.5412
Michael A. Williams, Mark G. Luciano, Jan Malm, Mark G. Hamilton
This Viewpoint describes the diagnosis and treatment history of normal pressure hydrocephalus and then highlights recent trial results that may serve as a catalyst for renewed scientific and clinical efforts.
{"title":"The Next Era of Idiopathic Normal Pressure Hydrocephalus","authors":"Michael A. Williams, Mark G. Luciano, Jan Malm, Mark G. Hamilton","doi":"10.1001/jamaneurol.2025.5412","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.5412","url":null,"abstract":"This Viewpoint describes the diagnosis and treatment history of normal pressure hydrocephalus and then highlights recent trial results that may serve as a catalyst for renewed scientific and clinical efforts.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"36 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101451","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.2025.4445
Kevin N Sheth, E Ray Dorsey, Michael S Okun
{"title":"Preventive Neurology Isn't a Pill; It's a Plan.","authors":"Kevin N Sheth, E Ray Dorsey, Michael S Okun","doi":"10.1001/jamaneurol.2025.4445","DOIUrl":"10.1001/jamaneurol.2025.4445","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"97-98"},"PeriodicalIF":21.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145540748","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.2025.5077
Wei Hu, Chunrong Tao, Rui Li, Zhongjun Chen, Wenhuo Chen, Tingyu Yi, Hao Wang, Peiyang Zhou, Zhihua Cao, Guoyong Zeng, Tao Cui, Junfeng Su, Li Chen, Guoping Wang, Jun Sun, Yuyou Zhu, Li Wang, Chao Zhang, Tianlong Liu, Jianlong Song, Xiaozhong Jing, Anmo Wang, Jinjing Wang, Pengfei Xu, Cong Luo, Adnan I Qureshi, Mohamad AbdalKader, Thanh N Nguyen, Jeffrey L Saver, Raul G Nogueira, Xinfeng Liu
<p><strong>Importance: </strong>Endovascular thrombectomy (EVT) has been established as an effective treatment for acute basilar artery occlusion (BAO) in the short term. However, the durability of these benefits over the long term has not been well characterized.</p><p><strong>Objective: </strong>To determine whether the clinical benefits of EVT for acute BAO are sustained at 3 years, with a primary focus on functional outcomes and mortality compared with best medical management alone.</p><p><strong>Design, setting, and participants: </strong>This study is a 3-year follow-up extension of a multicenter randomized clinical trial conducted between February 2021 and January 2022, with follow-up data collected through January 2025. The study was designed as an open-label, assessor-blinded trial to evaluate the long-term efficacy of EVT. The trial was conducted at 36 comprehensive stroke centers across China, representing a diverse, population-based setting that enhances the generalizability of the results. A total of 340 patients with acute BAO within 12 hours of estimated symptom onset were randomly assigned to the thrombectomy or control group. Eligible participants were adults with imaging-confirmed BAO and without contraindications to endovascular therapy. Of the randomized patients, 307 (90.3%) completed 3-year follow-up-203 in the thrombectomy group and 104 in the control group.</p><p><strong>Interventions: </strong>Participants in the thrombectomy group received EVT in combination with best medical management, while the control group received best medical management alone. EVT procedures were performed according to institutional protocols using stent retrievers, aspiration devices, balloon angioplasty, stent deployment, intra-arterial thrombolysis, or combinations of these approaches that were left to the discretion of the treating team.</p><p><strong>Main outcomes and measures: </strong>The primary outcome was a modified Rankin Scale (mRS) score of 0 to 3 at 3 years, representing the ability to walk and perform self-care. Secondary outcomes included a mRS score of 0 to 2, distribution across the mRS score categories, and quality of life. These outcomes were prespecified prior to data analysis.</p><p><strong>Results: </strong>Among 307 patients (median [IQR] age, 68 [59-75]; 211 [69%] male) with available data, an mRS score of 0 to 3 at 3 years was observed in 78 patients (38.4%) in the thrombectomy group and in 19 patients (18.3%) in the control group (adjusted risk ratio, 2.05; 95% CI, 1.35-3.11; P = .001). The distribution of mRS scores favored the thrombectomy group over the control group (adjusted common odds ratio, 2.60; 95% CI, 1.53-4.43). The cumulative 3-year mortality increased from 36.7% (n = 83) at 90 days to 55.7% (n = 113) in the thrombectomy group and 55.3% (n = 63) to 73.1% (n = 76) in the control group (adjusted risk ratio, 0.76; 95% CI, 0.65-0.89). On prespecified subgroup analysis, benefit was observed in patients younger th
{"title":"Endovascular vs Medical Treatment of Basilar Artery Occlusion: 3-Year Outcomes of the ATTENTION Randomized Clinical Trial.","authors":"Wei Hu, Chunrong Tao, Rui Li, Zhongjun Chen, Wenhuo Chen, Tingyu Yi, Hao Wang, Peiyang Zhou, Zhihua Cao, Guoyong Zeng, Tao Cui, Junfeng Su, Li Chen, Guoping Wang, Jun Sun, Yuyou Zhu, Li Wang, Chao Zhang, Tianlong Liu, Jianlong Song, Xiaozhong Jing, Anmo Wang, Jinjing Wang, Pengfei Xu, Cong Luo, Adnan I Qureshi, Mohamad AbdalKader, Thanh N Nguyen, Jeffrey L Saver, Raul G Nogueira, Xinfeng Liu","doi":"10.1001/jamaneurol.2025.5077","DOIUrl":"10.1001/jamaneurol.2025.5077","url":null,"abstract":"<p><strong>Importance: </strong>Endovascular thrombectomy (EVT) has been established as an effective treatment for acute basilar artery occlusion (BAO) in the short term. However, the durability of these benefits over the long term has not been well characterized.</p><p><strong>Objective: </strong>To determine whether the clinical benefits of EVT for acute BAO are sustained at 3 years, with a primary focus on functional outcomes and mortality compared with best medical management alone.</p><p><strong>Design, setting, and participants: </strong>This study is a 3-year follow-up extension of a multicenter randomized clinical trial conducted between February 2021 and January 2022, with follow-up data collected through January 2025. The study was designed as an open-label, assessor-blinded trial to evaluate the long-term efficacy of EVT. The trial was conducted at 36 comprehensive stroke centers across China, representing a diverse, population-based setting that enhances the generalizability of the results. A total of 340 patients with acute BAO within 12 hours of estimated symptom onset were randomly assigned to the thrombectomy or control group. Eligible participants were adults with imaging-confirmed BAO and without contraindications to endovascular therapy. Of the randomized patients, 307 (90.3%) completed 3-year follow-up-203 in the thrombectomy group and 104 in the control group.</p><p><strong>Interventions: </strong>Participants in the thrombectomy group received EVT in combination with best medical management, while the control group received best medical management alone. EVT procedures were performed according to institutional protocols using stent retrievers, aspiration devices, balloon angioplasty, stent deployment, intra-arterial thrombolysis, or combinations of these approaches that were left to the discretion of the treating team.</p><p><strong>Main outcomes and measures: </strong>The primary outcome was a modified Rankin Scale (mRS) score of 0 to 3 at 3 years, representing the ability to walk and perform self-care. Secondary outcomes included a mRS score of 0 to 2, distribution across the mRS score categories, and quality of life. These outcomes were prespecified prior to data analysis.</p><p><strong>Results: </strong>Among 307 patients (median [IQR] age, 68 [59-75]; 211 [69%] male) with available data, an mRS score of 0 to 3 at 3 years was observed in 78 patients (38.4%) in the thrombectomy group and in 19 patients (18.3%) in the control group (adjusted risk ratio, 2.05; 95% CI, 1.35-3.11; P = .001). The distribution of mRS scores favored the thrombectomy group over the control group (adjusted common odds ratio, 2.60; 95% CI, 1.53-4.43). The cumulative 3-year mortality increased from 36.7% (n = 83) at 90 days to 55.7% (n = 113) in the thrombectomy group and 55.3% (n = 63) to 73.1% (n = 76) in the control group (adjusted risk ratio, 0.76; 95% CI, 0.65-0.89). On prespecified subgroup analysis, benefit was observed in patients younger th","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"107-114"},"PeriodicalIF":21.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12750332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145856499","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 : 2026-02-01DOI: 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}
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