Plasma pTau181 and pTau217 predict asymptomatic amyloid accumulation equally well as amyloid-PET

Steffi De Meyer, Jolien M Schaeverbeke, Emma S Luckett, Mariska Reinartz, Elena R Blujdea, Isabelle Cleynen, Patrick Dupont, Koen Van Laere, Jeroen Vanbrabant, Erik Stoops, Eugeen Vanmechelen, Guglielmo di Molfetta, Henrik Zetterberg, Nicholas J Ashton, Charlotte E Teunissen, Koen Poesen, Rik Vandenberghe
{"title":"Plasma pTau181 and pTau217 predict asymptomatic amyloid accumulation equally well as amyloid-PET","authors":"Steffi De Meyer, Jolien M Schaeverbeke, Emma S Luckett, Mariska Reinartz, Elena R Blujdea, Isabelle Cleynen, Patrick Dupont, Koen Van Laere, Jeroen Vanbrabant, Erik Stoops, Eugeen Vanmechelen, Guglielmo di Molfetta, Henrik Zetterberg, Nicholas J Ashton, Charlotte E Teunissen, Koen Poesen, Rik Vandenberghe","doi":"10.1093/braincomms/fcae162","DOIUrl":null,"url":null,"abstract":"\n The dynamic phase of preclinical Alzheimer’s disease, as characterised by accumulating cortical amyloid-β (Aβ), is a window of opportunity for Aβ lowering therapies to have greater efficacy. Biomarkers that accurately predict Aβ accumulation may be of critical importance for participant inclusion in secondary prevention trials and thus enhance development of early Alzheimer’s disease therapies. We compared the ability of baseline plasma phosphorylated tau at threonine181 (pTau181), pTau217 and Aβ-PET load to predict future Aβ accumulation in asymptomatic elderly.\n In this longitudinal cohort study, baseline plasma pTau181 and pTau217 were quantified using single molecule array (Simoa) assays in cognitively unimpaired elderly selected from the community-recruited Flemish Prevent Alzheimer’s disease Cohort KU Leuven (F-PACK) based on the availability of baseline plasma samples and longitudinal Aβ-PET data (average time interval = 5 years, range 2 - 10 years). The predictive abilities of pTau181, pTau217 and PET-based Aβ measures for PET-based Aβ accumulation were investigated using receiver operating characteristic analyses, correlations and stepwise regression analyses.\n We included 75 F-PACK subjects (mean age = 70 years, 48% female), of which 16 were classified as Aβ accumulators (median [IQR] Centiloid rate of change = 3.42 [1.60] Centiloids/year). Plasma pTau181 (area under the curve (AUC) [95% CI] = 0.72 [0.59–0.86]) distinguished Aβ accumulators from non-accumulators with similar accuracy as pTau217 (AUC [95% CI] = 0.75 [0.62–0.88] and Aβ-PET (AUC [95% CI] = 0.72 [0.56–0.87]). Plasma pTau181 and pTau217 strongly correlated with each other (r = 0.93, PFDR < 0.001) and, together with Aβ-PET, similarly correlated with Aβ rate of change (rpTau181 = 0.33, rpTau217 = 0.36, rAβ-PET = 0.35, all PFDR ≤ 0.01). Addition of either plasma pTau181, plasma pTau217, or Aβ-PET to a linear demographic model including age, sex and APOE-ε4 carriership similarly improved the prediction of Aβ accumulation (ΔAkaike Information Criterion ≤ 4.1). In a multimodal biomarker model including all three biomarkers, each biomarker lost their individual predictive ability.\n These findings indicate that plasma pTau181, plasma pTau217 and Aβ-PET convey overlapping information and therefore predict the dynamic phase of asymptomatic amyloid-β accumulation with comparable performances. In clinical trial recruitment, confirmatory PET scans following blood-based prescreening might thus not provide additional value for detecting participants in these early disease stages who are destined to accumulate cortical Aβ. Given the moderate performances, future studies should investigate whether integrating plasma pTau species with other factors can improve performance and thus enhance clinical and research utility.","PeriodicalId":9318,"journal":{"name":"Brain Communications","volume":"28 17","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain Communications","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/braincomms/fcae162","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

The dynamic phase of preclinical Alzheimer’s disease, as characterised by accumulating cortical amyloid-β (Aβ), is a window of opportunity for Aβ lowering therapies to have greater efficacy. Biomarkers that accurately predict Aβ accumulation may be of critical importance for participant inclusion in secondary prevention trials and thus enhance development of early Alzheimer’s disease therapies. We compared the ability of baseline plasma phosphorylated tau at threonine181 (pTau181), pTau217 and Aβ-PET load to predict future Aβ accumulation in asymptomatic elderly. In this longitudinal cohort study, baseline plasma pTau181 and pTau217 were quantified using single molecule array (Simoa) assays in cognitively unimpaired elderly selected from the community-recruited Flemish Prevent Alzheimer’s disease Cohort KU Leuven (F-PACK) based on the availability of baseline plasma samples and longitudinal Aβ-PET data (average time interval = 5 years, range 2 - 10 years). The predictive abilities of pTau181, pTau217 and PET-based Aβ measures for PET-based Aβ accumulation were investigated using receiver operating characteristic analyses, correlations and stepwise regression analyses. We included 75 F-PACK subjects (mean age = 70 years, 48% female), of which 16 were classified as Aβ accumulators (median [IQR] Centiloid rate of change = 3.42 [1.60] Centiloids/year). Plasma pTau181 (area under the curve (AUC) [95% CI] = 0.72 [0.59–0.86]) distinguished Aβ accumulators from non-accumulators with similar accuracy as pTau217 (AUC [95% CI] = 0.75 [0.62–0.88] and Aβ-PET (AUC [95% CI] = 0.72 [0.56–0.87]). Plasma pTau181 and pTau217 strongly correlated with each other (r = 0.93, PFDR < 0.001) and, together with Aβ-PET, similarly correlated with Aβ rate of change (rpTau181 = 0.33, rpTau217 = 0.36, rAβ-PET = 0.35, all PFDR ≤ 0.01). Addition of either plasma pTau181, plasma pTau217, or Aβ-PET to a linear demographic model including age, sex and APOE-ε4 carriership similarly improved the prediction of Aβ accumulation (ΔAkaike Information Criterion ≤ 4.1). In a multimodal biomarker model including all three biomarkers, each biomarker lost their individual predictive ability. These findings indicate that plasma pTau181, plasma pTau217 and Aβ-PET convey overlapping information and therefore predict the dynamic phase of asymptomatic amyloid-β accumulation with comparable performances. In clinical trial recruitment, confirmatory PET scans following blood-based prescreening might thus not provide additional value for detecting participants in these early disease stages who are destined to accumulate cortical Aβ. Given the moderate performances, future studies should investigate whether integrating plasma pTau species with other factors can improve performance and thus enhance clinical and research utility.
血浆 pTau181 和 pTau217 预测无症状淀粉样蛋白积聚的能力与淀粉样蛋白-PET 预测能力相当
临床前阿尔茨海默病的动态阶段以皮质淀粉样蛋白-β(Aβ)的积累为特征,是降低 Aβ 的疗法发挥更大疗效的机会之窗。能准确预测 Aβ 积累的生物标志物可能对将参与者纳入二级预防试验至关重要,从而促进早期阿尔茨海默病疗法的开发。我们比较了血浆中苏氨酸181磷酸化 tau(pTau181)、pTau217 和 Aβ-PET 负荷基线预测无症状老年人未来 Aβ 累积的能力。在这项纵向队列研究中,根据基线血浆样本和纵向 Aβ-PET 数据(平均时间间隔 = 5 年,范围为 2 - 10 年)的可用性,从社区招募的弗拉芒预防阿尔茨海默病队列鲁汶大学(F-PACK)中挑选了认知功能未受损的老年人,使用单分子阵列(Simoa)测定法对他们的基线血浆 pTau181 和 pTau217 进行了量化。我们使用接收器操作特征分析、相关性分析和逐步回归分析研究了 pTau181、pTau217 和基于 PET 的 Aβ 测量对基于 PET 的 Aβ 累积的预测能力。我们纳入了 75 名 F-PACK 受试者(平均年龄 = 70 岁,48% 为女性),其中 16 人被归类为 Aβ 累积者(中位数 [IQR] 百分位数变化率 = 3.42 [1.60] 百分位数/年)。血浆pTau181(曲线下面积(AUC)[95% CI] = 0.72 [0.59-0.86])可区分Aβ蓄积者和非蓄积者,其准确性与pTau217(AUC [95% CI] = 0.75 [0.62-0.88])和Aβ-PET(AUC [95% CI] = 0.72 [0.56-0.87])相似。血浆 pTau181 和 pTau217 之间存在密切的相关性(r = 0.93,PFDR < 0.001),并且与 Aβ-PET 一起与 Aβ 变化率存在类似的相关性(rpTau181 = 0.33,rpTau217 = 0.36,rAβ-PET = 0.35,所有 PFDR 均小于 0.01)。将血浆 pTau181、血浆 pTau217 或 Aβ-PET 添加到包括年龄、性别和 APOE-ε4 血型的线性人口统计学模型中,同样可以提高对 Aβ 累积的预测(ΔAkaike 信息标准≤ 4.1)。在包括所有三种生物标志物的多模态生物标志物模型中,每种生物标志物都失去了各自的预测能力。这些研究结果表明,血浆 pTau181、血浆 pTau217 和 Aβ-PET 可传递重叠的信息,因此可预测无症状淀粉样蛋白-β积聚的动态阶段,而且性能相当。因此,在临床试验招募中,基于血液的预筛选后的 PET 扫描确认可能无法为检测处于这些疾病早期阶段、注定会积累皮质 Aβ 的参与者提供额外价值。鉴于其性能一般,未来的研究应探讨将血浆 pTau 种类与其他因素结合是否能改善性能,从而提高临床和研究效用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信