{"title":"Higher Educational Attainment and Accelerated Tau Accumulation in Alzheimer Disease.","authors":"Yue Cai,Lili Fang,Jie Yang,Xin Zhou,Lin Liu,Anqi Li,Pan Sun,Guoyu Lan,Zhengbo He,Yalin Zhu,Laihong Zhang,Mingxing Jiang,Xianfeng Yu,Zhen Liu,Tengfei Guo, ","doi":"10.1001/jamaneurol.2025.1801","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.1801","url":null,"abstract":"ImportanceThe impact of educational attainment (EA) on longitudinal tau accumulation remains largely underexplored.ObjectiveTo investigate the association of EA with tau accumulation in Alzheimer disease (AD).Design, Setting, and ParticipantsThis cohort study used 3 independent samples: the Alzheimer's Disease Neuroimaging Initiative (ADNI; October 2015-July 2022, mean follow-up: 3.0 years), Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease study (A4; 2014-2022, mean follow-up: 4.7 years), and Greater-Bay-Area Healthy Aging Brain Study (GHABS; July 2021-August 2024, mean interval from plasma collection to tau positron emission tomography [PET]: 1.0 years). The ADNI and GHABS represent Northern American and Southern Chinese populations, respectively. A4 is a multicenter trial. Participants with amyloid β (Aβ) and subsequent tau PET were included from ADNI, A4, and GHABS, and a subset had plasma phosphorylated tau (p-tau) 217 (p-tau217) and resting-state functional magnetic resonance imaging (RS-fMRI) data. Data were analyzed from July 2022 to January 2025.ExposuresEA, Aβ-PET, tau-PET, plasma p-tau217, and RS-fMRI.Main Outcomes and MeasuresParticipants were classified as high EA and low EA based on median years of EA. Longitudinal tau changes were compared across Aβ-PET positivity and EA groups. Interactions of EA status with Aβ burden, entorhinal tau, and plasma p-tau217 on tau accumulation were investigated in Aβ-positive (Aβ+) individuals. Connectivity-associated tau spread was compared across different Aβ/EA groups. Whether or not Aβ-targeting treatment attenuated tau accumulation in Aβ+ high-EA individuals was also evaluated.ResultsThis study included 887 participants: 377 from ADNI (mean [SD] age, 73.3 [7.2] years; 191 female [50.7%]), 395 from A4 (mean [SD] age, 71.9 [4.8] years; 223 female [56.5%]), and 115 from GHABS (mean [SD] years, 66.0 [7.4] years; 76 female [66.1%]). In the Aβ-negative group, high-EA individuals exhibited slower tau accumulation than low-EA individuals (right middle temporal gyrus: estimate = -0.002; 95% CI, -0.003 to -0.0002; P = .03). Conversely, higher EA in the Aβ+ group was correlated with accelerated tau accumulation (left middle temporal gyrus: estimate = 0.003; 95% CI, 0.0003-0.005; P = .03) and stronger Aβ-associated (left visual region: estimate = 0.38; 95% CI, 0.11-0.65; P = .006), entorhinal tau-associated (left middle temporal gyrus: estimate = 0.35; 95% CI, 0.08-0.63; P = .01), and plasma p-tau217-associated tau accumulation (left inferior temporal gyrus: estimate = 0.46; 95% CI, 0.02-0.90; P = .04), as well as increased connectivity-associated tau spread compared with lower EA (estimate = 0.33; 95% CI, 0.003-0.67; P = .048). Aβ-targeting treatment appeared to mitigate plasma p-tau217-associated tau accumulation in patients with AD and higher EA (estimate = -0.52; 95% CI, -0.80 to -0.24; P < .001).Conclusions and RelevanceResults of this cohort study suggest that higher EA was associated with fa","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"93 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568377","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}
JAMA neurologyPub Date : 2025-07-05DOI: 10.1001/jamaneurol.2025.2036
Xianhua Hou, Jiacheng Huang, Li Wang, Yuxuan He, Jiaxing Song, Changwei Guo, Shihai Yang, Xiaolei Shi, Lin Chen, Qu Liu, Junfeng Su, Lin Zeng, Maojun Jiang, Boyu Chen, Xiangping Cheng, Shengli Chen, Honghua Pan, Xiaoping Shen, Youlin Wu, Xionglin Tang, Jian Wang, Shibo Han, Tianqiang Pu, Changchuan Wu, Fengguang Li, Lunxue Qu, Zhong Fu, Hua Liu, Yu Li, Bin Mei, Yanbo Cheng, Zicheng Hu, Haochun Zhang, Tao Lv, Min Wu, Ruchuang Xu, Qinglin Ye, Liangbo Kong, Shuai Mi, Junhua Wu, Yu Wang, Zhenxuan Tian, Wenzhe Sun, Jinfu Ma, Xu Xu, Yazhou Wu, Duolao Wang, Raul G. Nogueira, Thanh N. Nguyen, Jeffrey L. Saver, Wenjie Zi, Zhenhua Zhou
{"title":"Intra-Arterial Tenecteplase After Successful Reperfusion in Large Vessel Occlusion Stroke","authors":"Xianhua Hou, Jiacheng Huang, Li Wang, Yuxuan He, Jiaxing Song, Changwei Guo, Shihai Yang, Xiaolei Shi, Lin Chen, Qu Liu, Junfeng Su, Lin Zeng, Maojun Jiang, Boyu Chen, Xiangping Cheng, Shengli Chen, Honghua Pan, Xiaoping Shen, Youlin Wu, Xionglin Tang, Jian Wang, Shibo Han, Tianqiang Pu, Changchuan Wu, Fengguang Li, Lunxue Qu, Zhong Fu, Hua Liu, Yu Li, Bin Mei, Yanbo Cheng, Zicheng Hu, Haochun Zhang, Tao Lv, Min Wu, Ruchuang Xu, Qinglin Ye, Liangbo Kong, Shuai Mi, Junhua Wu, Yu Wang, Zhenxuan Tian, Wenzhe Sun, Jinfu Ma, Xu Xu, Yazhou Wu, Duolao Wang, Raul G. Nogueira, Thanh N. Nguyen, Jeffrey L. Saver, Wenjie Zi, Zhenhua Zhou","doi":"10.1001/jamaneurol.2025.2036","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.2036","url":null,"abstract":"ImportanceThe optimal dose, safety, and efficacy of intra-arterial tenecteplase after successful reperfusion by endovascular thrombectomy for large vessel occlusion (LVO) is unknown.ObjectiveTo evaluate the dose-dependent adverse events and signals of efficacy of intra-arterial tenecteplase in LVO after successful reperfusion with thrombectomy, defined as an Extended Treatment in Cerebral Infarction score of 2b-3.Design, Setting, and ParticipantsThis open-label, blinded-outcome assessment trial, incorporating a 14 + 8 dose-escalation (phase 1b, nonrandomized) and dose-expansion (phase 2a, randomized) design, was conducted in China between 2023 and 2024, with follow-up continuing through November 2024. This was a multicenter clinical trial including patients with LVO and successful reperfusion within 24 hours of last known well.InterventionsIn phase 1b, intra-arterial tenecteplase, 0.0313, 0.0625, 0.1250, 0.1875 mg/kg; in phase 2a, intra-arterial tenecteplase 0.0313 or 0.0625 mg/kg, or control (without intra-arterial thrombolysis).Main Outcomes and MeasuresThe primary outcome in phase 1b was symptomatic intracranial hemorrhage (sICH) within 24 hours. The primary outcome in phase 2a was 90-day no-disability outcome (modified Rankin Scale score 0-1).ResultsA total of 205 patients (phase 1b: 48, phase 2a: 157) were enrolled and analyzed. The median (IQR) age was 71 (60-77) years, and 113 (55.1%) were male. In phase 1b, 1 of 14 and 2 of 22 patients with sICH were observed at dose tiers 0.0313 and 0.0625 mg/kg, respectively. Three of 12 patients had sICH at dose tier 0.1250 mg/kg, exceeding the prespecified safety threshold (<jats:italic>P</jats:italic> = .04). In phase 2a, eligible patients were randomly assigned to receive tenecteplase, 0.0313 mg/kg (n = 46) and 0.0625 mg/kg (n = 46), and 65 patients composed the control group. The primary outcome occurred in 22 of 65 patients (33.8%) in the control group, 17 of 46 patients (37.0%) in the tenecteplase, 0.0313 mg/kg, group (adjusted risk ratio [RR] vs control, 0.85; 95% CI, 0.54-1.35; <jats:italic>P</jats:italic> = .50), and 20 of 46 patients (43.5%) in the tenecteplase, 0.0625 mg/kg, group (adjusted RR, 1.15; 95% CI, 0.73-1.80; <jats:italic>P</jats:italic> = .55). No significant difference in the safety outcomes was observed among the 3 groups.Conclusions and RelevanceResults of this phase 1 and 2 randomized clinical trial reveal that adjunctive intra-arterial tenecteplase dosages of 0.0313 mg/kg or 0.0625 mg/kg after successful reperfusion in patients with anterior circulation LVO showed adequate safety to advance to larger trials to determine the potential therapeutic benefits.Trial RegistrationChiCTR.org.cn Identifier: <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"https://www.chictr.org.cn/showprojEN.html?proj=202219\">ChiCTR2300073787</jats:ext-link> and <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"https://www","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"1 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565680","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}
JAMA neurologyPub Date : 2025-07-01DOI: 10.1001/jamaneurol.2025.1481
Nicolás Fissolo, Sabine Schaedelin, Luisa M Villar, Jan D Lünemann, Jorge Correale, Konrad Rejdak, Nicholas Schwab, Andreu Vilaseca, Friederike Held, Antonio García-Merino, Stefan Bittner, María Trojano, Roberto Furlan, Hayrettin Tumani, Francisco Pérez-Miralles, Igal Rosenstein, Daniela Galimberti, Gary Álvarez-Bravo, Eric Thouvenot, Sara Llufriu, Samia J Khoury, Robert Hoepner, Sergio Martínez-Yélamos, Harald Hegen, Jelena Drulovic, Neus Téllez-Lara, Michael Khalil, Johanna Oechtering, Ángel Pérez-Sempere, Alfredo Rodríguez-Antigüedad, José Enrique-Martínez, Eva Strijbis, Joep Killestein, Sara Eichau, Elena Colombo, Jonas Schaller-Nagengast, Luciana Midaglia, Antonio J Sánchez-López, Enric Monreal, Andrew Chan, Friedemann Paul, Àlex Rovira, Mar Tintoré, Jan Lycke, Frauke Zipp, Bernhard Hemmer, Jens Kuhle, Xavier Montalban, Manuel Comabella, Uwe K Zettl, Simon Falk, Lucía Gutiérrez, Magda Gasior, José Luis Veiga González, Roser Ferrer, Ana Quiroga-Varela, Franziska Bachhuber, Lucienne Costa-Frossard
{"title":"Prognostic Factors for Multiple Sclerosis Symptoms in Radiologically Isolated Syndrome.","authors":"Nicolás Fissolo, Sabine Schaedelin, Luisa M Villar, Jan D Lünemann, Jorge Correale, Konrad Rejdak, Nicholas Schwab, Andreu Vilaseca, Friederike Held, Antonio García-Merino, Stefan Bittner, María Trojano, Roberto Furlan, Hayrettin Tumani, Francisco Pérez-Miralles, Igal Rosenstein, Daniela Galimberti, Gary Álvarez-Bravo, Eric Thouvenot, Sara Llufriu, Samia J Khoury, Robert Hoepner, Sergio Martínez-Yélamos, Harald Hegen, Jelena Drulovic, Neus Téllez-Lara, Michael Khalil, Johanna Oechtering, Ángel Pérez-Sempere, Alfredo Rodríguez-Antigüedad, José Enrique-Martínez, Eva Strijbis, Joep Killestein, Sara Eichau, Elena Colombo, Jonas Schaller-Nagengast, Luciana Midaglia, Antonio J Sánchez-López, Enric Monreal, Andrew Chan, Friedemann Paul, Àlex Rovira, Mar Tintoré, Jan Lycke, Frauke Zipp, Bernhard Hemmer, Jens Kuhle, Xavier Montalban, Manuel Comabella, Uwe K Zettl, Simon Falk, Lucía Gutiérrez, Magda Gasior, José Luis Veiga González, Roser Ferrer, Ana Quiroga-Varela, Franziska Bachhuber, Lucienne Costa-Frossard","doi":"10.1001/jamaneurol.2025.1481","DOIUrl":"10.1001/jamaneurol.2025.1481","url":null,"abstract":"<p><strong>Importance: </strong>Understanding the risk factors for symptom development will allow clinicians to stratify people with radiologically isolated syndrome (pwRIS) more effectively and tailor their management strategies accordingly.</p><p><strong>Objective: </strong>To identify prognostic factors at radiologically isolated syndrome (RIS) diagnosis associated with the development of multiple sclerosis (MS) symptoms.</p><p><strong>Design, setting, and participants: </strong>This cohort study was performed in samples collected between July 2004 and September 2022 and included 33 MS centers. All pwRIS who meet the 2017 McDonald criteria for dissemination in space with a sample collected near the diagnostic magnetic resonance imaging were included. No patients who met eligibility criteria were excluded. The data were analyzed from July 2024 to November 2024.</p><p><strong>Exposure: </strong>Body fluid biomarkers and environmental factors in pwRIS.</p><p><strong>Main outcomes and measures: </strong>The main outcome was the development of MS symptoms. Analyses involved univariable and multivariable Cox proportional hazards models, including age, sex, and treatment following RIS diagnosis, as additional independent variables.</p><p><strong>Results: </strong>The study included 273 pwRIS (mean age, 38.6 [SD 11.6] years; 207 women [75.8%] and 66 men [24.2%]) with a median follow-up of 5.0 [IQR, 2.5-7.7] years. A total of 101 pwRIS developed MS symptoms (37.0%). The presence of immunoglobulin G oligoclonal bands (OBs) (hazard ratio [HR], 5.09; 95% CI, 2.36-10.97; P < .001), immunoglobulin M OBs (HR, 2.58; 95% CI, 1.61-4.14; P < .001), and a κ free light chain index of 6.1 or more (HR, 2.79; 95% CI, 1.37-5.67; P = .005) were associated with MS symptoms. High cerebrospinal fluid neurofilament light chain (NfL) levels (HR, 1.31; 95% CI, 1.18-1.45; P < .001) and high serum NfL z scores (HR, 1.42; 95% CI, 1.16-1.72; P = .005) were also associated with an increased risk of MS symptoms. In contrast, high anti-cytomegalovirus titers (HR, 0.59; 95% CI, 0.38-0.93; P = .02) and high ultraviolet radiation exposure in the year before (HR, 0.52; 95% CI, 0.37-0.74; P < .001) and the year after (HR, 0.54, 95% CI, 0.38-0.75; P < .001) diagnosis reduced the risk of MS symptoms. For all these prognostic factors, the multivariable analysis yielded similar results. The combination of high serum NfL z scores and positive immunoglobulin G OBs conferred a 5-year risk of clinical symptoms of 58.3% (95% CI, 45.9-67.9). This risk increased to 81.6% (95% CI, 60.9-91.4) in pwRIS who were younger and positive for immunoglobulin M OBs.</p><p><strong>Conclusions and relevance: </strong>The study elucidates the prognostic factors that significantly impact the risk of developing MS symptoms in pwRIS at diagnosis, thereby, enhancing the potential for tailored clinical interventions.</p>","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"722-733"},"PeriodicalIF":20.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199061","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}
JAMA neurologyPub Date : 2025-07-01DOI: 10.1001/jamaneurol.2025.0908
Catherine S Hwang
{"title":"Beyond the Cure.","authors":"Catherine S Hwang","doi":"10.1001/jamaneurol.2025.0908","DOIUrl":"10.1001/jamaneurol.2025.0908","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"639-640"},"PeriodicalIF":20.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967428","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}
JAMA neurologyPub Date : 2025-07-01DOI: 10.1001/jamaneurol.2025.1495
Jason R Smith, James Russell Pike, Rebecca F Gottesman, David S Knopman, Pamela L Lutsey, Priya Palta, B Gwen Windham, Elizabeth Selvin, Moyses Szklo, Karen J Bandeen-Roche, Josef Coresh, A Richey Sharrett, Alden L Gross, Jennifer A Deal
{"title":"Contribution of Modifiable Midlife and Late-Life Vascular Risk Factors to Incident Dementia.","authors":"Jason R Smith, James Russell Pike, Rebecca F Gottesman, David S Knopman, Pamela L Lutsey, Priya Palta, B Gwen Windham, Elizabeth Selvin, Moyses Szklo, Karen J Bandeen-Roche, Josef Coresh, A Richey Sharrett, Alden L Gross, Jennifer A Deal","doi":"10.1001/jamaneurol.2025.1495","DOIUrl":"10.1001/jamaneurol.2025.1495","url":null,"abstract":"<p><strong>Importance: </strong>Midlife vascular risk factors are associated with an elevated risk of dementia. However, the total contribution of vascular risk factors in midlife and late life with incident dementia is uncertain.</p><p><strong>Objective: </strong>To quantify the proportion of incident dementia attributable to modifiable vascular risk factors measured in midlife and late life and to examine differences by apolipoprotein ε4 genotype, self-reported race, and sex.</p><p><strong>Design, setting, and participants: </strong>This was a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study using 33 years of follow-up (1987-2020). The setting included ARIC field centers (Jackson, Mississippi; Forsyth County, North Carolina; Minneapolis suburbs, Minnesota; Washington County, Maryland). Study baseline in Black and White participants with complete exposure and covariate data was set by age at risk factor measurement (45-54 years, 55-64 years, and 65-74 years). Data were analyzed from August 2023 to December 2024.</p><p><strong>Exposures: </strong>Hypertension (systolic blood pressure [BP] ≥130 mm Hg, diastolic BP ≥80 mm Hg, or use of medication for BP), diabetes (fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, self-reported physician's diagnosis, or use of any diabetes medication), and current smoking (self-reported).</p><p><strong>Main outcomes and measures: </strong>Incident dementia. Population attributable fractions were estimated by age 80 years, and separately after 80 years, from having at least 1 vascular risk factor by age at risk factor measurement.</p><p><strong>Results: </strong>A total of 7731 participants were included in analysis of risk factors measured at age 45 to 54 years (4494 female [58%]; 2207 Black [29%]; 5524 White [71%]), 12 274 contributed to analysis of risk factors measured at age 55 to 64 years (6698 female [55%]; 2886 Black [24%]; 9388 White [76%]), and 6787 contributed to analysis of risk factors measured at age 65 to 74 years (3764 female [56%], 1375 Black [20%]; 5412 White [80%]). There were 801, 995, and 422 dementia cases by 80 years, respectively. The fraction of dementia by 80 years attributable to at least 1 vascular factor at age 45 to 54 years was 21.8% (95% CI, 14.3%-29.3%), at 55 to 64 years was 26.4% (95% CI, 19.1%-33.6%), and at 65 to 74 years was 44.0% (95% CI, 30.9%-57.2%). Attributable fractions for these factors were higher in apolipoprotein ε4 noncarriers at age 55 years and older (range, 33.3%-61.4%), Black individuals at age 45 years and older (range, 25.5%-52.9%), and female individuals at age 55 years and older (range, 29.2%-51.3%). Only 2% to 8% of dementia cases after 80 years were attributable to these factors.</p><p><strong>Conclusions and relevance: </strong>Results of this cohort study suggest that between 22% and 44% of incident dementia cases by 80 years in the ARIC study were attributed to midlife and late-life vascular risk factors. Assumi","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"644-654"},"PeriodicalIF":20.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199059","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}