JAMA neurology最新文献

{"title":"Intracranial Hemorrhage in Patients With Stroke After Endovascular Treatment With or Without IV Alteplase: An Individual Participant Data Meta-Analysis.","authors":"Yu Zhou,Lei Zhang,Fabiano Cavalcante,Kentaro Suzuki,Kilian M Treurniet,Bernard Yan,Peter Mitchell,Steven Bush,Urs Fischer,Johannes Kaesmacher,Jan Gralla,Daniel Strbian,Roman Rohner,Manon Kappelhof,Yvo Roos,Charles Majoie,Wenjie Zi,Qingwu Yang,Yongwei Zhang,Yuji Matsumaru,Kazumi Kimura,Xiaofei Ye,Pengfei Yang,Jianmin Liu, ","doi":"10.1001/jamaneurol.2025.2610","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.2610","url":null,"abstract":"ImportanceFor patients with acute ischemic stroke due to anterior circulation large vessel occlusion and presenting directly to endovascular treatment (EVT)-capable centers, intravenous thrombolysis (IVT) before EVT raises concerns about intracranial hemorrhage (ICH), but details are not well understood.ObjectiveTo determine the frequency and subtypes of ICH in patients treated with IVT plus EVT vs EVT alone and to determine the association between various ICH subtypes and patient functional outcomes.Data SourcesPubMed and MEDLINE were searched from database inception through March 9, 2023.Study SelectionRandomized clinical trials comparing EVT alone with IVT plus EVT for anterior circulation large vessel occlusion stroke were included.Data Extraction and SynthesisIndividual participant data were extracted following the Preferred Reporting Items for Systematic Review and Meta-Analyses of independent participant data (PRISMA-IPD) reporting guidelines. Data were pooled using a random-effects model. Data were analyzed between April 2024 and February 2025.Main Outcomes and MeasuresThe primary outcomes were ICH and its subtypes according to the Heidelberg Bleeding Classification (hemorrhagic infarction type 1 [HI1], hemorrhagic infarction type 2 [HI2], parenchymal hematoma type 1 [PH1], parenchymal hematoma type 2 [PH2], and others; symptomatic or asymptomatic ICH), which were evaluated using a mixed-model approach with multinomial or binary regression.ResultsThe analysis involved 2313 participants (1160 allocated to the IVT plus EVT group vs 1153 to EVT alone; median [IQR] age, 71 [62-78] years; 1025 female participants [44%]) from 6 studies. Any ICH occurred in 768 of 2261 participants (34%). IVT was associated with an increased rate of any ICH (411 of 1133 [36%] vs 357 of 1128 [32%]; adjusted odds ratio [OR], 1.23; 95% CI, 1.02-1.49; P = .03) and a higher rate of any parenchymal hematoma (PH1 or PH2) (82 of 1133 [7%] vs 61 of 1128 [5%]; adjusted OR, 1.54; 95% CI, 1.02-2.34; P = .04). Compared with participants without ICH, asymptomatic ICH (adjusted common OR, 0.55; 95% CI, 0.46-0.65) and symptomatic ICH (adjusted common OR, 0.08; 95% CI, 0.05-0.13) were both associated with worse functional outcomes, and there was a graded association of ICH radiologic patterns and patient outcomes.Conclusions and RelevanceIn this individual participant data meta-analysis, compared with EVT alone, IVT plus EVT modestly increased the risk of ICH, notably any parenchymal hematoma. Although ICH was associated with worse functional outcomes, this effect may be offset by IVT's benefit in final successful reperfusion and early reperfusion.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"106 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813063","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":"Error in Figure Key.","authors":"","doi":"10.1001/jamaneurol.2025.2990","DOIUrl":"10.1001/jamaneurol.2025.2990","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12340673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Slowly Expanding Lesions in Pediatric-Onset Multiple Sclerosis.","authors":"Valeria Pozzilli,Ferran Prados Carrasco,Neena Kim,Omar Abdel-Mannan,Riccardo Nistri,Philipp Goebl,Cheryl Hemingway,Asthik Biswas,Kshitij Mankad,Sniya Sudhakar,Amitav Parida,Sukhvir Wright,Evangeline Wassmer,Michael Eyre,Ming Lim,Thomas Rossor,Arman Eshaghi,Frederik Barkhof,Ermelinda De Meo,Olga Ciccarelli,Yael Hacohen","doi":"10.1001/jamaneurol.2025.2619","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.2619","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"113 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813059","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":"Sex Differences in Mortality and Health Care Utilization After Dementia Diagnosis.","authors":"Jay B Lusk,Cassie B Ford,Samir Soneji,Beau Blass,Talita D'Aguiar Rosa,Brystana G Kaufman,Sneha Mantri,Fan Li,Brian Mac Grory,Ying Xian,Rashmita Basu,Kim G Johnson,Richard O'Brien,Bradley G Hammill,Emily C O'Brien","doi":"10.1001/jamaneurol.2025.2236","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.2236","url":null,"abstract":"ImportanceSex differences may contribute to disparities in dementia outcomes.ObjectiveTo understand the association between sex and mortality and health care services use after dementia diagnosis.Design, Setting, and ParticipantsThis nationwide cohort study used Medicare enrollment data and took place from 2014 to 2021 with up to 8 years of follow-up. Analysis was performed from April 2024 to April 2025. This study included 5 721 711 patients 65 years or older with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis codes for dementia with at least 1 year of prior fee-for-service Medicare enrollment.ExposuresSex, determined from Medicare enrollment data, derived from Social Security Administration records.Main Outcomes and MeasuresThe primary outcome was hazard of all-cause mortality, estimated with Cox proportional hazard regression. Secondary outcomes included hazards of use of common health care services, such as all-cause hospitalizations, skilled nursing facility stays, receipt of neuroimaging services, and physical/occupational therapy.ResultsA total of 5 721 711 patients (3 302 579 female and 2 419 132 male) with incident dementia between 2014 and 2021 were included in the study. Female patients had lower crude 1-year mortality rates (21.8% vs 27.2% for male patients; P < .001) and lower rates of all-cause hospitalizations (46.9% vs 50.5%; P < .001). The unadjusted hazard of death associated with male sex was 1.30 (95% CI, 1.29-1.31; P < .001). After adjustment for age, race and ethnicity, Medicaid dual eligibility, medical comorbidity burden, and access to health care resources, the association was modestly attenuated (adjusted hazard ratio, 1.24; 95% CI, 1.23-1.26; P < .001). Similarly, the unadjusted hazard ratio of all-cause hospitalization associated with male sex was 1.13 (95% CI, 1.12-1.14; P < .001); the adjusted hazard ratio was 1.08 (95% CI, 1.08-1.09; P < .001). Male patients also had increased hazards of hospice stay, neuroimaging services, and hospitalization for neurodegenerative disease diagnosis or behavioral disturbance.Conclusions and RelevanceIn this study, male patients with dementia had higher mortality rates and higher use of many health care services, especially hospital stays, than comparable female patients. Strategies to slow mortality and decrease health care use among male patients with dementia may be particularly impactful in limiting the burden of dementia. Given higher incidence of dementia among women, a focus on efforts to prevent dementia is necessary to achieve population-level health equity in dementia-attributable mortality by sex.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"10 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813061","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":"It Ain't About You, Kid.","authors":"Mark A Pacult","doi":"10.1001/jamaneurol.2025.2562","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.2562","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775410","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":"Influenza With and Without Oseltamivir Treatment and Neuropsychiatric Events Among Children and Adolescents.","authors":"James W Antoon,Derek J Williams,Jean Bruce,Mert Sekmen,Yuwei Zhu,Carlos G Grijalva","doi":"10.1001/jamaneurol.2025.1995","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.1995","url":null,"abstract":"ImportanceReports of pediatric neuropsychiatric events during influenza treatment with oseltamivir have prompted public concerns. However, whether oseltamivir or influenza infection is associated with increased risk of neuropsychiatric events remains unclear.ObjectiveTo determine the association between influenza, oseltamivir, and serious neuropsychiatric events.Design, Setting, and ParticipantsThis retrospective cohort study was conducted in a population-based ambulatory setting during the 2016 to 2017 and 2019 to 2020 influenza seasons. Follow-up began on the first day of the influenza season and continued through the earliest occurrence of an outcome event, loss of enrollment, death, age 18 years, or end of the season or study. Children aged 5 to 17 years enrolled in Tennessee Medicaid were for eligible for inclusion. Data analysis was completed from July 2023 to March 2025.ExposuresEach person-day of follow-up was assigned to 1 of the following 5 mutually exclusive exposure groups: (1) untreated influenza; (2) treated influenza; (3) posttreatment period (period between oseltamivir completion and end of influenza period); (4) influenza prophylaxis; and (5) no exposure.Main Outcomes and MeasuresThe primary outcome was a neuropsychiatric event requiring hospitalization, and events were identified using a validated algorithm. Poisson regression estimated incidence rate ratios (IRRs) while accounting for relevant covariates measured on each person-day. Sensitivity analyses examined robustness of findings to alternate exposure and outcome definitions, time-varying outcome risk, negative control outcome, and unmeasured confounding.ResultsAmong 692 975 eligible children, a total of 692 295 children (median [IQR] age, 11 [7-14] years; 50.3% female) experienced 1230 serious neuropsychiatric events (898 neurologic and 332 psychiatric) during 19 688 320 person-weeks of follow-up. Among the 151 401 influenza episodes, 66.7% (95% CI, 66.5%-67.0%) were dispensed oseltamivir (60.1% [95% CI, 59.6%-60.6%] among those at high risk for influenza complications). The most common events overall were mood disorders (36.3%) and suicidal or self-harm behaviors (34.2%). Compared with untreated influenza, event rates were lower during oseltamivir-treated influenza periods (IRR, 0.53; 95% CI, 0.33-0.88) and posttreatment periods (IRR, 0.42; 95% CI, 0.24-0.74). Subanalyses suggest that this finding is driven more by a reduction in neurologic events (IRR, 0.45; 95% CI, 0.25-0.82) than psychiatric events (IRR, 0.80; 95% CI, 0.34-1.88). Sensitivity analyses suggest misclassification or unmeasured confounding would not explain these findings.Conclusions and RelevanceIn this cohort study, oseltamivir treatment during influenza episodes was associated with a reduced risk of serious neuropsychiatric events. These findings support oseltamivir use for prevention of these influenza-related complications.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"41 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769659","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":"Emergence of Anti-CD20 Therapies for Individuals With Multiple Sclerosis Planning Pregnancy.","authors":"Kristen M Krysko","doi":"10.1001/jamaneurol.2025.2559","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.2559","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"77 6 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769660","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":"Therapeutic Management During Pregnancy and Relapse Risk in Women With Multiple Sclerosis.","authors":"Antoine Gavoille,Fabien Rollot,Romain Casey,Guillaume Mathey,Emmanuelle Le Page,Jonathan Ciron,Jérôme De Sèze,Aurélie Ruet,Elisabeth Maillart,Pierre Labauge,Hélène Zephir,Arnaud Kwiatkowski,Caroline Papeix,Gilles Defer,Christine Lebrun-Frenay,Thibault Moreau,David-Axel Laplaud,Eric Berger,Anne-Laure Dubessy,Pierre Clavelou,Eric Thouvenot,Olivier Heinzlef,Jean Pelletier,Abdullatif Al-Khedr,Olivier Casez,Bertrand Bourre,Abir Wahab,Laurent Magy,Solène Moulin,Jean-Philippe Camdessanché,Inès Doghri,Mariana Sarov-Riviere,Karolina Hankiewicz,Corinne Pottier,Amélie Dos Santos,Chantal Nifle,Fabien Subtil,Sandra Vukusic, ","doi":"10.1001/jamaneurol.2025.2550","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.2550","url":null,"abstract":"ImportanceIn women with multiple sclerosis (MS), disease-modifying therapy (DMT) management during pregnancy might impact relapse risk.ObjectiveTo estimate the effect of DMT management during pregnancy on MS relapse rate and compare different therapeutic strategies.Design, Setting, and ParticipantsThis was a multicenter retrospective cohort study using data from January 1990 to December 2023. Data were extracted in December 2023 from the French MS registry. Among 52 955 women in the registry, we included pregnancies identified through childbirths in patients with relapsing-onset MS who were monitored for at least 18 months before delivery and 9 months after. Pregnancies occurring less than 18 months apart or with missing month of birth were excluded.ExposuresMediation analysis was used to estimate the total, direct, and indirect (mediated by DMT management) effects of pregnancy. Different therapeutic strategies were compared: DMT interruption, switching to or maintaining interferon β or glatiramer acetate, switching to or maintaining natalizumab until the third trimester, and switching to or maintaining intravenous anti-CD20 and interrupting it 3 months before conception.Main Outcomes and MeasuresThe primary outcome was the annualized relapse rate (ARR) during the preconception, gestation, and postpartum periods. Within a causal inference framework, counterfactual ARRs were estimated using longitudinal g-computation, combining a random forest algorithm for predicting DMTs, and a mixed-effects Poisson model for relapses.ResultsWe included 6341 pregnancies occurring in 4998 women (mean [SD] age at conception, 31.5 [4.5] years). DMT management during pregnancy significantly increased ARR during gestation (causal rate ratio [cRR], 1.13; 95% CI, 1.06-1.22) and postpartum (cRR, 1.08; 95% CI, 1.01-1.16) periods. This led to a deleterious total effect of pregnancy on ARR, particularly in women receiving natalizumab before pregnancy with prolonged interruption (ie, interruption before the second trimester or resumption more than 3 months after delivery; cRR, 2.18; 95% CI, 1.76-2.69), and in women receiving fingolimod (cRR, 2.15; 95% CI, 1.60-2.93). Compared to DMT interruption, anti-CD20 strategy was the most effective (cRR, 0.38; 95% CI, 0.25-0.52), followed by the natalizumab strategy with short interruption (cRR, 0.80; 95% CI, 0.71-0.90), whereas interferon β (cRR, 0.93; 95% CI, 0.86-0.99) and glatiramer acetate strategies (cRR, 0.91; 95% CI, 0.84-0.99) were less effective.ConclusionIn this study, DMT management during pregnancy significantly increased relapse risk, particularly in patients receiving natalizumab with prolonged interruption or fingolimod. The strategy based on the use of anti-CD20 before pregnancy was the most effective to mitigate this risk.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"31 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769658","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":"Early Treatment With Intravenous Immunoglobulins and Outcomes of Patients With Anti-IgLON5 Disease.","authors":"Thomas Grüter,Carles Gaig,Yvette S Crijnen,Maarten J Titulaer,Lidia Sabater,Anna Heidbreder,Justina Dargvainiene,Anja Tietz,Stjepana Kovac,Andre Dik,María Elena Erro,Jan Lewerenz,Andrea Kraft,Frank Seifert,Romana Höftberger,Franziska S Thaler,Lucie de Azevedo,Jonathan Wickel,Juna M de Vries,Agnita J W Boon,Robin W van Steenhoven,Ralf Gold,Klaus-Peter Wandinger,Gregor Kuhlenbäumer,Josep O Dalmau,Frank Leypoldt,Francesc Graus,Ilya Ayzenberg, ","doi":"10.1001/jamaneurol.2025.2574","DOIUrl":"https://doi.org/10.1001/jamaneurol.2025.2574","url":null,"abstract":"ImportanceAnti-IgLON5 disease is an autoimmune encephalopathy that often leads to severe disability or death. The efficacy of immunotherapy remains unknown.ObjectiveTo investigate whether early immunotherapy is associated with disability and death in anti-IgLON5 disease.Design, Setting, and ParticipantsThis retrospective, multicenter cohort study of patients with anti-IgLON5 disease was conducted from 2014 to 2024, with a median (IQR) follow-up of 66 (33-97) months after disease onset. Data from the German Network for Research on Autoimmune Encephalitis Registry, University Hospital Clinic of Barcelona (Spain), and Erasmus University Medical Center (the Netherlands) were analyzed. Eligibility criteria were clinical features consistent with anti-IgLON5 disease and the presence of IgLON5 antibodies in serum or cerebrospinal fluid. Data were collected by treating physicians using a structured questionnaire. Of 121 patients systematically selected from participating centers and registries, 14 patients were excluded due to insufficient clinical information or withdrawal of consent.InterventionInitiation of immunotherapy based on the treating physician's decision.Main Outcomes and MeasuresClinical disability was assessed using the modified Rankin Scale (mRS) at the most recent follow-up visit and the proportion of patients who died.ResultsAmong 107 patients with anti-IgLON5 disease (46 female [43.0%] and 61 male [57.0%]; median [IQR] age at the time of disease onset, 64 [57-70] years), 25 patients (23.4%) received immunotherapy during the first year of disease onset and 57 patients (53.3%) received it later. Among early treated patients, 9 individuals (36.0%) received intravenous immunoglobulins and 13 individuals (52.0%) received rituximab. A total of 44 patients (41.1%) died, and at least two-thirds of these deaths were related to anti-IgLON5 disease (28 patients [63.6%]). Early immunotherapy was the only modifiable independent factor associated with a lower long-term disability (odds ratio, 0.32; 95% CI, 0.13-0.83; P = .02) and survival (odds ratio, 2.70; 95% CI, 0.99-7.69; P = .047). Only intravenous immunoglobulin started within the first year of disease onset was associated with a lower median (IQR) mRS score at the most recent follow-up (2 [1-2.5] vs 3 [2-6]; P = .005; r = 0.55) and a lower proportion of deaths (0 of 9 patients vs 6 of 16 patients [37.5%]; P = .04) compared with other early immunotherapies despite a similar baseline mRS score.Conclusions and RelevanceIn this study, early initiation of intravenous immunoglobulins (within the first year of onset) was associated with favorable long-term outcomes and improved survival in anti-IgLON5 disease. Larger prospective studies are needed to validate this finding.","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":"37 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769657","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":"White Matter Abnormalities and Cognition in Aging and Alzheimer Disease.","authors":"Christopher Peter, Aditi Sathe, Niranjana Shashikumar, Kimberly R Pechman, Abigail W Workmeister, T Bryan Jackson, Yuankai Huo, Shubhabrata Mukherjee, Jesse Mez, Logan C Dumitrescu, Katherine A Gifford, Corey J Bolton, Leslie S Gaynor, Shannon L Risacher, Lori L Beason-Held, Yang An, Konstantinos Arfanakis, Guray Erus, Christos Davatzikos, Duygu Tosun-Turgut, Mohamad Habes, Di Wang, Arthur W Toga, Paul M Thompson, Panpan Zhang, Kurt G Schilling, Marilyn Albert, Walter Kukull, Sarah A Biber, Bennett A Landman, Barbara B Bendlin, Sterling C Johnson, Julie Schneider, Lisa L Barnes, David A Bennett, Angela L Jefferson, Susan M Resnick, Andrew J Saykin, Paul K Crane, Michael L Cuccaro, Timothy J Hohman, Derek B Archer, Dimitrios Zaras, Yisu Yang, Alaina Durant, Praitayini Kanakaraj, Michael E Kim, Chenyu Gao, Nancy R Newlin, Karthik Ramadass, Nazirah Mohd Khairi, Zhiyuan Li, Tianyuan Yao, Seo-Eun Choi, Brandon Klinedinst, Michael L Lee, Phoebe Scollard, Emily H Trittschuh, Elizabeth A Sanders","doi":"10.1001/jamaneurol.2025.1601","DOIUrl":"10.1001/jamaneurol.2025.1601","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;There has yet to be a large-scale study quantifying the association between white matter microstructure and cognitive performance and decline in aging and Alzheimer disease (AD).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To investigate the associations between tract-specific white matter microstructure and cognitive performance and decline in aging and AD-related cognitive impairment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Design setting and participants: &lt;/strong&gt;This prognostic study of aging and AD, a secondary data analysis of multisite cohort studies, acquired data from 9 cohorts between September 2002 and November 2022. Participants were eligible if they had diffusion-weighted magnetic resonance imaging (dMRI) data, domain-specific cognitive composite &lt;i&gt;z&lt;/i&gt; scores, demographic and clinical data, were aged 50 years or older, and passed neuroimaging quality control. Demographic and clinical covariates included age, sex, education, race and ethnicity, &lt;i&gt;APOE&lt;/i&gt; haplotype status (ε2, ε3, ε4), and clinical status. The present study was conducted from June 2024 to February 2025.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Exposures: &lt;/strong&gt;White matter microstructure and cognitive performance and decline.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main outcomes and measures: &lt;/strong&gt;Clinical diagnosis, imaging measures (dMRI, T1-weighted MRI, and amyloid and tau positron emission tomography), and cognitive tests.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Of 4467 participants who underwent 9208 longitudinal cognitive sessions, 2698 (60.4%) were female, and the mean age (SD) was 74.3 (9.2) years; 3213 were cognitively unimpaired, 972 had mild cognitive impairment, and 282 had AD dementia. White matter free water (FW) showed the strongest associations with cross-sectional cognitive performance and longitudinal cognitive decline across all domains, particularly memory. FW in limbic tracts, such as the cingulum, presented the strongest associations with both memory performance (cingulum: β = -0.718; &lt;i&gt;P&lt;/i&gt; &lt; .001; fornix: β = -1.069; &lt;i&gt;P&lt;/i&gt; &lt; .001) and decline (cingulum: β = -0.115; &lt;i&gt;P&lt;/i&gt; &lt; .001; fornix: β = -0.153; &lt;i&gt;P&lt;/i&gt; &lt; .001). White matter FW measures interacted with baseline diagnosis, gray matter atrophy, &lt;i&gt;APOE&lt;/i&gt; ε4 status, and amyloid positivity to predict poorer cognitive performance and accelerated cognitive decline. Noteworthy interactions include fornix FW and hippocampal volume (β = 10.598; &lt;i&gt;P&lt;/i&gt; &lt; .001), cingulum FW and SPARE-AD index (β = -0.532; &lt;i&gt;P&lt;/i&gt; &lt; .001), and inferior temporal gyrus transcallosal tract FW and baseline diagnosis (β = -0.537; &lt;i&gt;P&lt;/i&gt; &lt; .001), all predicting poorer memory performance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions and relevance: &lt;/strong&gt;White matter microstructural changes, particularly FW, play a critical role in cognitive decline in aging and AD-related cognitive impairment. These findings highlight the importance of FW correction in dMRI studies and highlight the limbic system, especially the cingulum and fornix, as key regions associated with cognitive decl","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"825-836"},"PeriodicalIF":21.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289439","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}