Pub Date : 2024-08-01DOI: 10.1001/jamaneurol.2024.1748
Dena B Dubal, Holly C Elser
{"title":"β-Amyloid in Cognitively Unimpaired Individuals-Blame Mom?","authors":"Dena B Dubal, Holly C Elser","doi":"10.1001/jamaneurol.2024.1748","DOIUrl":"10.1001/jamaneurol.2024.1748","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":null,"pages":null},"PeriodicalIF":20.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330983","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 : 2024-08-01DOI: 10.1001/jamaneurol.2024.1892
Mette Foldager Hindsholm, Luis Alberto García Rodríguez, Axel Brandes, Jesper Hallas, Birgit Bjerre Høyer, Sören Möller, Mahmut Edip Gurol, Claus Ziegler Simonsen, David Gaist
Importance: Patients with atrial fibrillation (AF) can have an ischemic stroke (IS) despite oral anticoagulant (OAC) treatment. Knowledge regarding the association between OAC discontinuation and the subsequent risk of recurrent IS in patients with AF is limited.
Objectives: To determine the risk of recurrent IS in patients with AF receiving OAC and to evaluate the association between OAC discontinuation and the risk of recurrent IS.
Design, setting, and participants: This is a nationwide cohort study of patients aged 50 years or older in Denmark who had AF and an IS (entry IS) and were initiating or restarting subsequent OAC treatment after being discharged between January 2014 and December 2021. Patients were followed up for recurrent IS until June 2022. Within this study cohort, a nested case-control analysis was performed in which patients with recurrent IS were matched to patients receiving OAC who had not yet experienced a stroke. Data were analyzed from May 25, 2023, to April 18, 2024.
Exposure: Use of OAC at the time of recurrent IS or the equivalent date in matched controls based on redeemed prescriptions.
Main outcomes and measures: The primary outcome was recurrent IS. Crude and adjusted cumulative incidences of recurrent IS and all-cause mortality were calculated in cohort analyses, and adjusted odds ratios (aORs) were determined for recurrent IS associated with OAC discontinuation in nested case-control analyses.
Results: The study cohort included 8119 patients (4392 [54.1%] male; mean [SD] age, 78.4 [9.6] years; median (IQR) CHA2DS2-VASc score, 4.0 [3.0-5.0]). Over a mean (SD) follow-up of 2.9 (2.2) years, 663 patients had a recurrent IS, of whom 533 (80.4%) were receiving OAC at the time of their recurrent IS. The crude cumulative incidence of recurrent IS at 1 year was 4.3% (95% CI, 5.9%-7.1%), and the crude cumulative incidence of all-cause mortality was 15.4% (95% CI, 14.7%-16.2%). Adjusted analysis showed similar results. Patients who discontinued OACs had a higher risk of recurrent IS (89 cases [13.4%], 180 controls [6.8%]; aOR, 2.13; 95% CI, 1.57-2.89) compared with patients still receiving OAC.
Conclusions and relevance: The risks of recurrent IS and mortality were high in patients with AF despite secondary prevention with OAC, and OAC discontinuation doubled the risk of recurrent IS compared with patients who continued OAC. This finding highlights the importance of OAC continuation and the need for improved secondary stroke prevention in patients with AF.
重要性:尽管接受了口服抗凝剂(OAC)治疗,心房颤动(AF)患者仍可能发生缺血性卒中(IS)。有关停用 OAC 与心房颤动患者随后复发 IS 风险之间关系的知识还很有限:确定接受 OAC 治疗的房颤患者复发 IS 的风险,并评估停用 OAC 与复发 IS 风险之间的关联:这是一项全国性的队列研究,研究对象为丹麦 50 岁或以上的房颤患者,这些患者在 2014 年 1 月至 2021 年 12 月期间患有房颤和 IS(入组 IS),并在出院后开始或重新开始后续的 OAC 治疗。在 2022 年 6 月之前,对复发 IS 的患者进行随访。在该研究队列中进行了嵌套病例对照分析,将复发性 IS 患者与接受 OAC 但尚未发生卒中的患者进行配对。数据分析时间为 2023 年 5 月 25 日至 2024 年 4 月 18 日。暴露:根据兑换的处方,在复发性 IS 发生时或匹配对照的同等日期使用 OAC:主要结果和测量指标:主要结果是复发性 IS。在队列分析中计算复发性IS和全因死亡率的粗略和调整后累积发生率,在嵌套病例对照分析中确定复发性IS与停用OAC相关的调整后几率比(aORs):研究队列包括 8119 名患者(男性 4392 [54.1%];平均 [SD] 年龄 78.4 [9.6] 岁;CHA2DS2-VASc 评分中位数(IQR)4.0 [3.0-5.0])。在平均(标清)2.9(2.2)年的随访期间,663 名患者复发了 IS,其中 533 人(80.4%)在复发 IS 时正在接受 OAC 治疗。1 年后复发 IS 的粗累计发生率为 4.3%(95% CI,5.9%-7.1%),全因死亡率的粗累计发生率为 15.4%(95% CI,14.7%-16.2%)。调整分析显示了类似的结果。与仍在接受 OAC 的患者相比,停用 OAC 的患者复发 IS 的风险更高(89 例 [13.4%],180 例对照 [6.8%];aOR,2.13;95% CI,1.57-2.89):尽管使用 OAC 进行二级预防,但房颤患者复发 IS 和死亡的风险很高,与继续使用 OAC 的患者相比,停用 OAC 会使复发 IS 的风险增加一倍。这一发现强调了继续使用 OAC 的重要性以及改善房颤患者卒中二级预防的必要性。
{"title":"Recurrent Ischemic Stroke in Patients With Atrial Fibrillation While Receiving Oral Anticoagulants.","authors":"Mette Foldager Hindsholm, Luis Alberto García Rodríguez, Axel Brandes, Jesper Hallas, Birgit Bjerre Høyer, Sören Möller, Mahmut Edip Gurol, Claus Ziegler Simonsen, David Gaist","doi":"10.1001/jamaneurol.2024.1892","DOIUrl":"10.1001/jamaneurol.2024.1892","url":null,"abstract":"<p><strong>Importance: </strong>Patients with atrial fibrillation (AF) can have an ischemic stroke (IS) despite oral anticoagulant (OAC) treatment. Knowledge regarding the association between OAC discontinuation and the subsequent risk of recurrent IS in patients with AF is limited.</p><p><strong>Objectives: </strong>To determine the risk of recurrent IS in patients with AF receiving OAC and to evaluate the association between OAC discontinuation and the risk of recurrent IS.</p><p><strong>Design, setting, and participants: </strong>This is a nationwide cohort study of patients aged 50 years or older in Denmark who had AF and an IS (entry IS) and were initiating or restarting subsequent OAC treatment after being discharged between January 2014 and December 2021. Patients were followed up for recurrent IS until June 2022. Within this study cohort, a nested case-control analysis was performed in which patients with recurrent IS were matched to patients receiving OAC who had not yet experienced a stroke. Data were analyzed from May 25, 2023, to April 18, 2024.</p><p><strong>Exposure: </strong>Use of OAC at the time of recurrent IS or the equivalent date in matched controls based on redeemed prescriptions.</p><p><strong>Main outcomes and measures: </strong>The primary outcome was recurrent IS. Crude and adjusted cumulative incidences of recurrent IS and all-cause mortality were calculated in cohort analyses, and adjusted odds ratios (aORs) were determined for recurrent IS associated with OAC discontinuation in nested case-control analyses.</p><p><strong>Results: </strong>The study cohort included 8119 patients (4392 [54.1%] male; mean [SD] age, 78.4 [9.6] years; median (IQR) CHA2DS2-VASc score, 4.0 [3.0-5.0]). Over a mean (SD) follow-up of 2.9 (2.2) years, 663 patients had a recurrent IS, of whom 533 (80.4%) were receiving OAC at the time of their recurrent IS. The crude cumulative incidence of recurrent IS at 1 year was 4.3% (95% CI, 5.9%-7.1%), and the crude cumulative incidence of all-cause mortality was 15.4% (95% CI, 14.7%-16.2%). Adjusted analysis showed similar results. Patients who discontinued OACs had a higher risk of recurrent IS (89 cases [13.4%], 180 controls [6.8%]; aOR, 2.13; 95% CI, 1.57-2.89) compared with patients still receiving OAC.</p><p><strong>Conclusions and relevance: </strong>The risks of recurrent IS and mortality were high in patients with AF despite secondary prevention with OAC, and OAC discontinuation doubled the risk of recurrent IS compared with patients who continued OAC. This finding highlights the importance of OAC continuation and the need for improved secondary stroke prevention in patients with AF.</p>","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":null,"pages":null},"PeriodicalIF":20.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11197012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442679","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 : 2024-08-01DOI: 10.1001/jamaneurol.2024.2195
{"title":"Errors in Table 1 and Figure 2.","authors":"","doi":"10.1001/jamaneurol.2024.2195","DOIUrl":"10.1001/jamaneurol.2024.2195","url":null,"abstract":"","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":null,"pages":null},"PeriodicalIF":20.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11217883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141467953","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 : 2024-08-01DOI: 10.1001/jamaneurol.2024.1612
Colin Groot, Ruben Smith, Lyduine E Collij, Sophie E Mastenbroek, Erik Stomrud, Alexa Pichet Binette, Antoine Leuzy, Sebastian Palmqvist, Niklas Mattsson-Carlgren, Olof Strandberg, Hanna Cho, Chul Hyoung Lyoo, Giovanni B Frisoni, Debora E Peretti, Valentina Garibotto, Renaud La Joie, David N Soleimani-Meigooni, Gil Rabinovici, Rik Ossenkoppele, Oskar Hansson
Importance: An accurate prognosis is especially pertinent in mild cognitive impairment (MCI), when individuals experience considerable uncertainty about future progression.
Objective: To evaluate the prognostic value of tau positron emission tomography (PET) to predict clinical progression from MCI to dementia.
Design, setting, and participants: This was a multicenter cohort study with external validation and a mean (SD) follow-up of 2.0 (1.1) years. Data were collected from centers in South Korea, Sweden, the US, and Switzerland from June 2014 to January 2024. Participant data were retrospectively collected and inclusion criteria were a baseline clinical diagnosis of MCI; longitudinal clinical follow-up; a Mini-Mental State Examination (MMSE) score greater than 22; and available tau PET, amyloid-β (Aβ) PET, and magnetic resonance imaging (MRI) scan less than 1 year from diagnosis. A total of 448 eligible individuals with MCI were included (331 in the discovery cohort and 117 in the validation cohort). None of these participants were excluded over the course of the study.
Exposures: Tau PET, Aβ PET, and MRI.
Main outcomes and measures: Positive results on tau PET (temporal meta-region of interest), Aβ PET (global; expressed in the standardized metric Centiloids), and MRI (Alzheimer disease [AD] signature region) was assessed using quantitative thresholds and visual reads. Clinical progression from MCI to all-cause dementia (regardless of suspected etiology) or to AD dementia (AD as suspected etiology) served as the primary outcomes. The primary analyses were receiver operating characteristics.
Results: In the discovery cohort, the mean (SD) age was 70.9 (8.5) years, 191 (58%) were male, the mean (SD) MMSE score was 27.1 (1.9), and 110 individuals with MCI (33%) converted to dementia (71 to AD dementia). Only the model with tau PET predicted all-cause dementia (area under the receiver operating characteristic curve [AUC], 0.75; 95% CI, 0.70-0.80) better than a base model including age, sex, education, and MMSE score (AUC, 0.71; 95% CI, 0.65-0.77; P = .02), while the models assessing the other neuroimaging markers did not improve prediction. In the validation cohort, tau PET replicated in predicting all-cause dementia. Compared to the base model (AUC, 0.75; 95% CI, 0.69-0.82), prediction of AD dementia in the discovery cohort was significantly improved by including tau PET (AUC, 0.84; 95% CI, 0.79-0.89; P < .001), tau PET visual read (AUC, 0.83; 95% CI, 0.78-0.88; P = .001), and Aβ PET Centiloids (AUC, 0.83; 95% CI, 0.78-0.88; P = .03). In the validation cohort, only the tau PET and the tau PET visual reads replicated in predicting AD dementia.
Conclusions and relevance: In this study, tau-PET showed the best performance as a stand-alone marker to predict progression to dementia among individu
重要性:准确的预后对轻度认知障碍(MCI)患者尤为重要,因为患者对未来的病情发展具有很大的不确定性:评估tau正电子发射断层扫描(PET)的预后价值,以预测从MCI到痴呆的临床进展:这是一项经外部验证的多中心队列研究,平均(标清)随访 2.0 (1.1) 年。数据收集自韩国、瑞典、美国和瑞士的研究中心,时间为 2014 年 6 月至 2024 年 1 月。参与者的数据是回顾性收集的,纳入标准是基线临床诊断为 MCI;纵向临床随访;迷你精神状态检查 (MMSE) 得分大于 22 分;自诊断起不到 1 年的 tau PET、淀粉样蛋白-β (Aβ) PET 和磁共振成像 (MRI) 扫描可用。共纳入了 448 名符合条件的 MCI 患者(其中 331 人属于发现队列,117 人属于验证队列)。在研究过程中,没有一人被排除在外:主要结果和测量指标:采用定量阈值和目测读数评估 tau PET(感兴趣的颞元区)、Aβ PET(全局;以标准化指标 Centiloids 表示)和 MRI(阿尔茨海默病 [AD] 特征区)的阳性结果。从 MCI 到全因痴呆(无论疑似病因)或 AD 痴呆(疑似病因为 AD)的临床进展为主要结果。主要分析是接收器操作特征:在发现队列中,平均(标清)年龄为 70.9 (8.5)岁,191 人(58%)为男性,平均(标清)MMSE 得分为 27.1 (1.9),110 名 MCI 患者(33%)转为痴呆(71 人转为 AD 痴呆)。与包括年龄、性别、教育程度和 MMSE 评分的基础模型(AUC,0.71;95% CI,0.65-0.77;P = .02)相比,只有 tau PET 模型能更好地预测全因痴呆(接收器操作特征曲线下面积 [AUC],0.75;95% CI,0.70-0.80),而评估其他神经影像标记物的模型并不能提高预测效果。在验证队列中,tau PET 也能预测全因痴呆。与基础模型(AUC,0.75;95% CI,0.69-0.82)相比,加入 tau PET 后,发现队列中的 AD 痴呆预测能力显著提高(AUC,0.84;95% CI,0.79-0.89;P 结论和意义:在这项研究中,tau-PET作为预测MCI患者痴呆进展的独立标记物表现最佳。这表明,就 MCI 的预后而言,tau PET 扫描可能是目前最好的神经影像标记物。
{"title":"Tau Positron Emission Tomography for Predicting Dementia in Individuals With Mild Cognitive Impairment.","authors":"Colin Groot, Ruben Smith, Lyduine E Collij, Sophie E Mastenbroek, Erik Stomrud, Alexa Pichet Binette, Antoine Leuzy, Sebastian Palmqvist, Niklas Mattsson-Carlgren, Olof Strandberg, Hanna Cho, Chul Hyoung Lyoo, Giovanni B Frisoni, Debora E Peretti, Valentina Garibotto, Renaud La Joie, David N Soleimani-Meigooni, Gil Rabinovici, Rik Ossenkoppele, Oskar Hansson","doi":"10.1001/jamaneurol.2024.1612","DOIUrl":"10.1001/jamaneurol.2024.1612","url":null,"abstract":"<p><strong>Importance: </strong>An accurate prognosis is especially pertinent in mild cognitive impairment (MCI), when individuals experience considerable uncertainty about future progression.</p><p><strong>Objective: </strong>To evaluate the prognostic value of tau positron emission tomography (PET) to predict clinical progression from MCI to dementia.</p><p><strong>Design, setting, and participants: </strong>This was a multicenter cohort study with external validation and a mean (SD) follow-up of 2.0 (1.1) years. Data were collected from centers in South Korea, Sweden, the US, and Switzerland from June 2014 to January 2024. Participant data were retrospectively collected and inclusion criteria were a baseline clinical diagnosis of MCI; longitudinal clinical follow-up; a Mini-Mental State Examination (MMSE) score greater than 22; and available tau PET, amyloid-β (Aβ) PET, and magnetic resonance imaging (MRI) scan less than 1 year from diagnosis. A total of 448 eligible individuals with MCI were included (331 in the discovery cohort and 117 in the validation cohort). None of these participants were excluded over the course of the study.</p><p><strong>Exposures: </strong>Tau PET, Aβ PET, and MRI.</p><p><strong>Main outcomes and measures: </strong>Positive results on tau PET (temporal meta-region of interest), Aβ PET (global; expressed in the standardized metric Centiloids), and MRI (Alzheimer disease [AD] signature region) was assessed using quantitative thresholds and visual reads. Clinical progression from MCI to all-cause dementia (regardless of suspected etiology) or to AD dementia (AD as suspected etiology) served as the primary outcomes. The primary analyses were receiver operating characteristics.</p><p><strong>Results: </strong>In the discovery cohort, the mean (SD) age was 70.9 (8.5) years, 191 (58%) were male, the mean (SD) MMSE score was 27.1 (1.9), and 110 individuals with MCI (33%) converted to dementia (71 to AD dementia). Only the model with tau PET predicted all-cause dementia (area under the receiver operating characteristic curve [AUC], 0.75; 95% CI, 0.70-0.80) better than a base model including age, sex, education, and MMSE score (AUC, 0.71; 95% CI, 0.65-0.77; P = .02), while the models assessing the other neuroimaging markers did not improve prediction. In the validation cohort, tau PET replicated in predicting all-cause dementia. Compared to the base model (AUC, 0.75; 95% CI, 0.69-0.82), prediction of AD dementia in the discovery cohort was significantly improved by including tau PET (AUC, 0.84; 95% CI, 0.79-0.89; P < .001), tau PET visual read (AUC, 0.83; 95% CI, 0.78-0.88; P = .001), and Aβ PET Centiloids (AUC, 0.83; 95% CI, 0.78-0.88; P = .03). In the validation cohort, only the tau PET and the tau PET visual reads replicated in predicting AD dementia.</p><p><strong>Conclusions and relevance: </strong>In this study, tau-PET showed the best performance as a stand-alone marker to predict progression to dementia among individu","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":null,"pages":null},"PeriodicalIF":20.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11165418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296022","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 : 2024-08-01DOI: 10.1001/jamaneurol.2024.1763
Mabel Seto, Timothy J Hohman, Elizabeth C Mormino, Kathryn V Papp, Rebecca E Amariglio, Dorene M Rentz, Keith A Johnson, Aaron P Schultz, Reisa A Sperling, Rachel F Buckley, Hyun-Sik Yang
<p><strong>Importance: </strong>Studies have suggested that maternal history of late-onset Alzheimer disease, but not paternal, predisposes individuals to higher brain β-amyloid (Aβ) burden, reduced brain metabolism, and lower gray matter volumes.</p><p><strong>Objective: </strong>To characterize maternal vs paternal history of memory impairment in terms of brain Aβ-positron emission tomography (Aβ-PET) and baseline cognition among a large sample of cognitively unimpaired older adults.</p><p><strong>Design, setting, and participants: </strong>This cross-sectional study leveraged data from 4413 individuals who were screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, a randomized clinical trial conducted across 67 sites in the US, Australia, Canada, and Japan aimed at Alzheimer disease prevention. Data were collected between April 2014 and December 2017 and analyzed from December 2022 to June 2023. Participants were cognitively unimpaired adults (Clinical Dementia Rating = 0 and/or Mini-Mental State Examination score ≥25) between the ages of 65 and 85 years who underwent PET imaging to assess cortical Aβ levels for trial eligibility. A total of 4492 participants were screened, and 79 missing data were excluded.</p><p><strong>Main outcomes and measures: </strong>Demographic characteristics (eg, age, sex, education), apolipoprotein E genotyping, participant-reported parental history of memory impairment and parental age at symptom onset were collected as variables. Parental history was assessed in terms of continuous neocortical 18F-florbetapir Aβ-PET and the Preclinical Alzheimer Cognitive Composite.</p><p><strong>Results: </strong>Of 4413 individuals (mean [SD] age, 71.27 [4.66] years, 2617 women [59.3%]), mean Aβ-PET was elevated in individuals with history of memory impairment in both parents (n = 455; mean [SD] standardized uptake value ratio [SUVR] = 1.12 [0.19]; Wilcoxon P = 1.1 × 10-5) and in those with only maternal history (n = 1772; mean [SD] SUVR = 1.10 [0.19]; Wilcoxon P = 2.70 × 10-5) compared with those with only paternal history (n = 632; mean [SD] SUVR = 1.08 [0.18]; Wilcoxon P = 1.1 × 10-5) or no family history (n = 1554; mean [SD] SUVR = 1.08 [0.19]; Wilcoxon P = 1.1 × 10-5). Paternal history of early-onset memory impairment (age <65 years) but not late-onset (age ≥65 years) was associated with elevated participant Aβ-PET (mean [SD] SUVR = 1.19 [0.21]; P = 3.00 × 10-6) in comparison with no paternal history (mean [SD] SUVR = 1.09 [0.19]) whereas maternal history was associated with elevated Aβ in both early-onset and late-onset groups. There was no association with cognition.</p><p><strong>Conclusions and relevance: </strong>In this study, maternal history (at any age) and paternal history of early-onset memory impairment were associated with Aβ burden among asymptomatic older individuals. Sex-specific parental history may help inform clinicians on likelihood of Aβ burden in offspring and help identify hig
{"title":"Parental History of Memory Impairment and β-Amyloid in Cognitively Unimpaired Older Adults.","authors":"Mabel Seto, Timothy J Hohman, Elizabeth C Mormino, Kathryn V Papp, Rebecca E Amariglio, Dorene M Rentz, Keith A Johnson, Aaron P Schultz, Reisa A Sperling, Rachel F Buckley, Hyun-Sik Yang","doi":"10.1001/jamaneurol.2024.1763","DOIUrl":"10.1001/jamaneurol.2024.1763","url":null,"abstract":"<p><strong>Importance: </strong>Studies have suggested that maternal history of late-onset Alzheimer disease, but not paternal, predisposes individuals to higher brain β-amyloid (Aβ) burden, reduced brain metabolism, and lower gray matter volumes.</p><p><strong>Objective: </strong>To characterize maternal vs paternal history of memory impairment in terms of brain Aβ-positron emission tomography (Aβ-PET) and baseline cognition among a large sample of cognitively unimpaired older adults.</p><p><strong>Design, setting, and participants: </strong>This cross-sectional study leveraged data from 4413 individuals who were screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, a randomized clinical trial conducted across 67 sites in the US, Australia, Canada, and Japan aimed at Alzheimer disease prevention. Data were collected between April 2014 and December 2017 and analyzed from December 2022 to June 2023. Participants were cognitively unimpaired adults (Clinical Dementia Rating = 0 and/or Mini-Mental State Examination score ≥25) between the ages of 65 and 85 years who underwent PET imaging to assess cortical Aβ levels for trial eligibility. A total of 4492 participants were screened, and 79 missing data were excluded.</p><p><strong>Main outcomes and measures: </strong>Demographic characteristics (eg, age, sex, education), apolipoprotein E genotyping, participant-reported parental history of memory impairment and parental age at symptom onset were collected as variables. Parental history was assessed in terms of continuous neocortical 18F-florbetapir Aβ-PET and the Preclinical Alzheimer Cognitive Composite.</p><p><strong>Results: </strong>Of 4413 individuals (mean [SD] age, 71.27 [4.66] years, 2617 women [59.3%]), mean Aβ-PET was elevated in individuals with history of memory impairment in both parents (n = 455; mean [SD] standardized uptake value ratio [SUVR] = 1.12 [0.19]; Wilcoxon P = 1.1 × 10-5) and in those with only maternal history (n = 1772; mean [SD] SUVR = 1.10 [0.19]; Wilcoxon P = 2.70 × 10-5) compared with those with only paternal history (n = 632; mean [SD] SUVR = 1.08 [0.18]; Wilcoxon P = 1.1 × 10-5) or no family history (n = 1554; mean [SD] SUVR = 1.08 [0.19]; Wilcoxon P = 1.1 × 10-5). Paternal history of early-onset memory impairment (age <65 years) but not late-onset (age ≥65 years) was associated with elevated participant Aβ-PET (mean [SD] SUVR = 1.19 [0.21]; P = 3.00 × 10-6) in comparison with no paternal history (mean [SD] SUVR = 1.09 [0.19]) whereas maternal history was associated with elevated Aβ in both early-onset and late-onset groups. There was no association with cognition.</p><p><strong>Conclusions and relevance: </strong>In this study, maternal history (at any age) and paternal history of early-onset memory impairment were associated with Aβ burden among asymptomatic older individuals. Sex-specific parental history may help inform clinicians on likelihood of Aβ burden in offspring and help identify hig","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":null,"pages":null},"PeriodicalIF":20.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11184498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330982","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 : 2024-08-01DOI: 10.1001/jamaneurol.2024.2057
Emily K Acton, Sean Hennessy, Michael A Gelfand, Charles E Leonard, Warren B Bilker, Di Shu, Allison W Willis, Scott E Kasner
Importance: Direct-acting oral anticoagulants (DOACs) are commonly prescribed with antiseizure medications (ASMs) due to concurrency of and the association between atrial fibrillation (AF) and epilepsy. However, enzyme-inducing (EI) ASMs may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk.
Objective: To assess the rates of thromboembolic and major bleeding events in adults with AF and epilepsy dispensed DOACs and EI ASMs vs DOACs with non-EI ASMs.
Design, setting, and participants: This active-comparator, new-user cohort study included US health care data from the Clinformatics Data Mart database from October 2010 to September 2021 for a nationally representative population of adults with AF and epilepsy.
Exposure: Evaluations included episodes of contiguous coadministration of DOACs for AF with EI ASMs (exposed) or non-EI ASMs (referent) for epilepsy.
Main outcomes and measures: Thromboembolic events (primary outcome) and major bleeding events (secondary outcome) were identified based on a series of validated, diagnosis-based coding algorithms. Data-adaptive, high-dimensional propensity score matching was used to control for observed confounders and proxies for unobserved confounders. Adjusted hazard ratios (AHRs) were estimated using Cox proportional hazards regression models with robust variance estimators to account for clustering within matched pairs.
Results: This study included 14 078 episodes (median age, 74 [IQR, 67-81]; 52.4% female) and 14 158 episodes (median age, 74 [IQR, 67-81]; 52.4% female) of incident DOAC and ASM use that met eligibility criteria for assessment of thromboembolic and major bleeding outcomes, respectively. Incidence was 88.5 per 1000 person-years for thromboembolic events and 68.3 per 1000 person-years for bleeding events. Compared with use of non-EI ASMs, use of EI ASMs with DOACs was not associated with a difference in risk of thromboembolic events (AHR, 1.10; 95% CI, 0.82-1.46) but was associated with a reduction in risk of major bleeding events (AHR, 0.63; 95% CI, 0.44-0.89).
Conclusions and relevance: In this cohort study, EI ASMs were not associated with alteration in DOAC efficacy. Further research is needed on the reduction in bleeding risk associated with EI ASMs, as this may suggest that pharmacokinetic interactions are associated with lowering DOAC levels without negating therapeutic effects.
重要性:由于心房颤动(AF)和癫痫之间的并发性和关联性,直接作用口服抗凝剂(DOAC)通常与抗癫痫药物(ASM)一起处方。然而,酶诱导型 ASMs 可能会减少 DOACs 的吸收并加速其代谢,从而可能降低 DOAC 的水平并增加血栓栓塞的风险:评估成人房颤和癫痫患者服用DOACs和EI ASMs与服用DOACs和非EI ASMs时的血栓栓塞和大出血事件发生率:这项主动比较者、新用户队列研究纳入了 Clinformatics Data Mart 数据库中 2010 年 10 月至 2021 年 9 月期间具有全国代表性的成人房颤和癫痫患者的美国医疗保健数据。暴露:评估包括连续联合使用治疗房颤的 DOACs 与治疗癫痫的 EI ASMs(暴露)或非 EI ASMs(参照):血栓栓塞事件(主要结果)和大出血事件(次要结果)是根据一系列经过验证的基于诊断的编码算法确定的。采用数据适应性高维倾向评分匹配来控制观察到的混杂因素和未观察到的混杂因素的替代物。使用带有稳健方差估计器的 Cox 比例危险回归模型估算了调整后的危险比(AHR),以考虑匹配对中的聚类情况:该研究纳入了 14 078 例(中位年龄 74 [IQR,67-81];52.4% 为女性)和 14 158 例(中位年龄 74 [IQR,67-81];52.4% 为女性)符合血栓栓塞和大出血结局评估资格标准的 DOAC 和 ASM 使用事件。血栓栓塞事件的发生率为每千人年 88.5 例,出血事件的发生率为每千人年 68.3 例。与使用非 EI ASMs 相比,使用 EI ASMs 和 DOACs 与血栓栓塞事件风险的差异不大(AHR,1.10;95% CI,0.82-1.46),但与大出血事件风险的降低有关(AHR,0.63;95% CI,0.44-0.89):在这项队列研究中,EI ASM 与 DOAC 疗效的改变无关。还需要对 EI ASMs 降低出血风险进行进一步研究,因为这可能表明药代动力学相互作用与降低 DOAC 水平有关,但不会否定治疗效果。
{"title":"Direct-Acting Oral Anticoagulants and Antiseizure Medications for Atrial Fibrillation and Epilepsy and Risk of Thromboembolic Events.","authors":"Emily K Acton, Sean Hennessy, Michael A Gelfand, Charles E Leonard, Warren B Bilker, Di Shu, Allison W Willis, Scott E Kasner","doi":"10.1001/jamaneurol.2024.2057","DOIUrl":"10.1001/jamaneurol.2024.2057","url":null,"abstract":"<p><strong>Importance: </strong>Direct-acting oral anticoagulants (DOACs) are commonly prescribed with antiseizure medications (ASMs) due to concurrency of and the association between atrial fibrillation (AF) and epilepsy. However, enzyme-inducing (EI) ASMs may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk.</p><p><strong>Objective: </strong>To assess the rates of thromboembolic and major bleeding events in adults with AF and epilepsy dispensed DOACs and EI ASMs vs DOACs with non-EI ASMs.</p><p><strong>Design, setting, and participants: </strong>This active-comparator, new-user cohort study included US health care data from the Clinformatics Data Mart database from October 2010 to September 2021 for a nationally representative population of adults with AF and epilepsy.</p><p><strong>Exposure: </strong>Evaluations included episodes of contiguous coadministration of DOACs for AF with EI ASMs (exposed) or non-EI ASMs (referent) for epilepsy.</p><p><strong>Main outcomes and measures: </strong>Thromboembolic events (primary outcome) and major bleeding events (secondary outcome) were identified based on a series of validated, diagnosis-based coding algorithms. Data-adaptive, high-dimensional propensity score matching was used to control for observed confounders and proxies for unobserved confounders. Adjusted hazard ratios (AHRs) were estimated using Cox proportional hazards regression models with robust variance estimators to account for clustering within matched pairs.</p><p><strong>Results: </strong>This study included 14 078 episodes (median age, 74 [IQR, 67-81]; 52.4% female) and 14 158 episodes (median age, 74 [IQR, 67-81]; 52.4% female) of incident DOAC and ASM use that met eligibility criteria for assessment of thromboembolic and major bleeding outcomes, respectively. Incidence was 88.5 per 1000 person-years for thromboembolic events and 68.3 per 1000 person-years for bleeding events. Compared with use of non-EI ASMs, use of EI ASMs with DOACs was not associated with a difference in risk of thromboembolic events (AHR, 1.10; 95% CI, 0.82-1.46) but was associated with a reduction in risk of major bleeding events (AHR, 0.63; 95% CI, 0.44-0.89).</p><p><strong>Conclusions and relevance: </strong>In this cohort study, EI ASMs were not associated with alteration in DOAC efficacy. Further research is needed on the reduction in bleeding risk associated with EI ASMs, as this may suggest that pharmacokinetic interactions are associated with lowering DOAC levels without negating therapeutic effects.</p>","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":null,"pages":null},"PeriodicalIF":20.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11231911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554762","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 : 2024-08-01DOI: 10.1001/jamaneurol.2024.1677
Gretchen L Birbeck, Karl B Seydel, Suzanna Mwanza, Derby Tembo, Moses Chilombe, Arthur Watts, Ifunanya Ume-Ezeoke, Manoj Mathews, Archana A Patel, Musaku Mwenechanya, Paul Pensulo, Michael P McDermott
Importance: A third of children who survive malaria with neurological involvement (central nervous system [CNS] malaria) develop sequelae. A higher maximum temperature (Tmax) and seizures are risk factors for sequelae.
Objective: To compare aggressive antipyretic therapy using scheduled acetaminophen and ibuprofen vs usual care with acetaminophen alone given only for a temperature of 38.5 °C or higher.
Design, setting, and participants: This randomized clinical trial was conducted at inpatient pediatric services of 1 tertiary care and 1 district hospital in Zambia and a tertiary care center in Malawi. Included were children aged 2 to 11 years with CNS malaria (excluding those with creatinine >1.2 mg/dL), who were enrolled from 2019 to 2022. Data analysis took place from December 2022 to April 2023.
Intervention: The aggressive antipyretic group received acetaminophen (30 mg/kg load, then 15 mg/kg) plus ibuprofen, 10 mg/kg, every 6 hours, regardless of clinical temperature for 72 hours. The usual care group received 15 mg/kg of acetaminophen as needed every 6 hours for a temperature of 38.5 °C or higher.
Main outcomes and measures: The primary outcome variable was Tmax over 72 hours, the total duration of follow-up. Secondary outcomes included seizures and parasite clearance.
Results: Five hundred fifty-three patients were screened, 226 (40.9%) were ineligible, and 57 (10.3%) declined. A total 256 participants (n = 128/group) had a mean (SD) age of 4.3 (2.1) years; 115 (45%) were female, and 141 (55%) were male. The aggressive antipyretic group had a lower Tmax, 38.6 vs 39.2 °C (difference, -0.62 °C; 95% CI, -0.82 to -0.42; P < .001) and lower odds of experiencing multiple or prolonged seizures, 10 (8%) vs 34 children (27%) in the usual care group (odds ratio [OR], 0.26; 95% CI, 0.12 to 0.56). No group difference in parasite clearance time was detected. Severe adverse events occurred in 40 children (15%), 25 (20%) in the usual care group and 15 (12%) in the aggressive antipyretic group, including 13 deaths (10 [8%] and 3 [2%], respectively). Increased creatinine resulted in study drug discontinuation in 8 children (6%) in the usual care group and 13 children (10%) in the aggressive antipyretic group (OR, 1.74; 95% CI, 0.63 to 5.07).
Conclusions and relevance: This study found that aggressive antipyretic therapy reduced mean Tmax to temperature levels comparable with the Tmax among children without neurological impairments in prior observational studies and improved acute seizure outcomes with no prolongation of parasitemia.
{"title":"Acetaminophen and Ibuprofen in Pediatric Central Nervous System Malaria: A Randomized Clinical Trial.","authors":"Gretchen L Birbeck, Karl B Seydel, Suzanna Mwanza, Derby Tembo, Moses Chilombe, Arthur Watts, Ifunanya Ume-Ezeoke, Manoj Mathews, Archana A Patel, Musaku Mwenechanya, Paul Pensulo, Michael P McDermott","doi":"10.1001/jamaneurol.2024.1677","DOIUrl":"10.1001/jamaneurol.2024.1677","url":null,"abstract":"<p><strong>Importance: </strong>A third of children who survive malaria with neurological involvement (central nervous system [CNS] malaria) develop sequelae. A higher maximum temperature (Tmax) and seizures are risk factors for sequelae.</p><p><strong>Objective: </strong>To compare aggressive antipyretic therapy using scheduled acetaminophen and ibuprofen vs usual care with acetaminophen alone given only for a temperature of 38.5 °C or higher.</p><p><strong>Design, setting, and participants: </strong>This randomized clinical trial was conducted at inpatient pediatric services of 1 tertiary care and 1 district hospital in Zambia and a tertiary care center in Malawi. Included were children aged 2 to 11 years with CNS malaria (excluding those with creatinine >1.2 mg/dL), who were enrolled from 2019 to 2022. Data analysis took place from December 2022 to April 2023.</p><p><strong>Intervention: </strong>The aggressive antipyretic group received acetaminophen (30 mg/kg load, then 15 mg/kg) plus ibuprofen, 10 mg/kg, every 6 hours, regardless of clinical temperature for 72 hours. The usual care group received 15 mg/kg of acetaminophen as needed every 6 hours for a temperature of 38.5 °C or higher.</p><p><strong>Main outcomes and measures: </strong>The primary outcome variable was Tmax over 72 hours, the total duration of follow-up. Secondary outcomes included seizures and parasite clearance.</p><p><strong>Results: </strong>Five hundred fifty-three patients were screened, 226 (40.9%) were ineligible, and 57 (10.3%) declined. A total 256 participants (n = 128/group) had a mean (SD) age of 4.3 (2.1) years; 115 (45%) were female, and 141 (55%) were male. The aggressive antipyretic group had a lower Tmax, 38.6 vs 39.2 °C (difference, -0.62 °C; 95% CI, -0.82 to -0.42; P < .001) and lower odds of experiencing multiple or prolonged seizures, 10 (8%) vs 34 children (27%) in the usual care group (odds ratio [OR], 0.26; 95% CI, 0.12 to 0.56). No group difference in parasite clearance time was detected. Severe adverse events occurred in 40 children (15%), 25 (20%) in the usual care group and 15 (12%) in the aggressive antipyretic group, including 13 deaths (10 [8%] and 3 [2%], respectively). Increased creatinine resulted in study drug discontinuation in 8 children (6%) in the usual care group and 13 children (10%) in the aggressive antipyretic group (OR, 1.74; 95% CI, 0.63 to 5.07).</p><p><strong>Conclusions and relevance: </strong>This study found that aggressive antipyretic therapy reduced mean Tmax to temperature levels comparable with the Tmax among children without neurological impairments in prior observational studies and improved acute seizure outcomes with no prolongation of parasitemia.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT03399318.</p>","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":null,"pages":null},"PeriodicalIF":20.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11165415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296017","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}