Ashton Nicholas J, Keshavan Ashvini, Brum Wagner S, Andreasson Ulf, Arslan Burak, Droescher Mathias, Barghorn Stefan, Vanbrabant Jeroen, Lambrechts Charlotte, Van Loo Maxime, Stoops Erik, Iyengar Shweta, Ji HaYeun, Xu Xiaomei, Forrest-Hay Alex, Zhang Bingqing, Luo Yuling, Jeromin Andreas, Vandijck Manu, Bastard Nathalie Le, Kolb Hartmuth, Triana-Baltzer Gallen, Bali Divya, Janelidze Shorena, Yang Shieh-Yueh, Demos Catherine, Romero Daniel, Sigal George, Wohlstadter Jacob, Malyavantham Kishore, Khare Meenakshi, Jethwa Alexander, Stoeckl Laura, Gobom Johan, Kac Przemysław R, Gonzalez-Ortiz Fernando, Montoliu-Gaya Laia, Hansson Oskar, Rissman Robert A, Carillo Maria C, Shaw Leslie M, Blennow Kaj, Schott Jonathan M, Zetterberg Henrik
Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
King's College London, Institute of Psychiatry, Psychology and Neuroscience Maurice Wohl Institute Clinical Neuroscience Institute London, UK.
medRxiv. 2024 Aug 22:2024.08.22.24312244. doi: 10.1101/2024.08.22.24312244.
Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer's disease (AD) pathology. Multiple p-tau biomarkers on several analytical platforms are poised for clinical use. The Alzheimer's Association Global Biomarker Standardisation Consortium plasma phospho-tau Round Robin study engaged assay developers in a blinded case-control study on plasma p-tau, aiming to learn which assays provide the largest fold-changes in AD compared to non-AD, have the strongest relationship between plasma and cerebrospinal fluid (CSF), and show the most consistent relationships between methods (commutability) in measuring both patient samples and candidate reference materials (CRM).
Thirty-three different p-tau biomarker assays, built on eight different analytical platforms, were used to quantify paired plasma and CSF samples from 40 participants. AD biomarker status was categorised as "AD pathology" (n=25) and "non-AD pathology" (n=15) by CSF Aβ42/Aβ40 (US-FDA; CE-IVDR) and p-tau181 (CE-IVDR) methods. The commutability of four CRM, at three concentrations, was assessed across assays.
Plasma p-tau217 consistently demonstrated higher fold-changes between AD and non-AD pathology groups, compared to other p-tau epitopes. Fujirebio LUMIPULSE G, UGOT IPMS, and Lilly MSD p-tau217 assays provided the highest median fold-changes. In CSF, p-tau217 assays also performed best, and exhibited substantially larger fold-changes than their plasma counterparts, despite similar diagnostic performance. P-tau217 showed the strongest correlations between plasma assays (rho=0.81 to 0.97). Plasma p-tau levels were weakly-to-moderately correlated with CSF p-tau, and correlations were non-significant within the AD group alone. The evaluated CRM were not commutable across assays.
Plasma p-tau217 measures had larger fold-changes and discriminative accuracies for detecting AD pathology, and better agreement across platforms than other plasma p-tau variants. Plasma and CSF markers of p-tau, measured by immunoassays, are not substantially correlated, questioning the interchangeability of their continuous relationship. Further work is warranted to understand the pathophysiology underlying this dissociation, and to develop suitable reference materials facilitating cross-assay standardisation.
Alzheimer's Association (#ADSF-24-1284328-C).
磷酸化tau蛋白（p-tau）是阿尔茨海默病（AD）病理的一种特异性血液生物标志物。多个分析平台上的多种p-tau生物标志物已准备好用于临床。阿尔茨海默病协会全球生物标志物标准化联盟血浆磷酸化tau蛋白循环研究让检测方法开发者参与了一项关于血浆p-tau的盲法病例对照研究，旨在了解哪些检测方法在AD与非AD患者之间提供最大的倍数变化，血浆与脑脊液（CSF）之间的关系最强，以及在测量患者样本和候选参考物质（CRM）时各方法之间显示出最一致的关系（互换性）。
使用基于八个不同分析平台构建的33种不同的p-tau生物标志物检测方法，对40名参与者的配对血浆和脑脊液样本进行定量分析。通过脑脊液Aβ42/Aβ40（美国食品药品监督管理局；欧盟体外诊断医疗器械法规）和p-tau181（欧盟体外诊断医疗器械法规）方法，将AD生物标志物状态分类为“AD病理”（n = 25）和“非AD病理”（n = 15）。评估了四种CRM在三种浓度下在各检测方法间的互换性。
与其他p-tau表位相比，血浆p-tau217在AD和非AD病理组之间始终显示出更高的倍数变化。富士瑞必欧LUMIPULSE G、优利特IPMS和礼来MSD的p-tau217检测方法提供了最高的中位数倍数变化。在脑脊液中，p-tau217检测方法也表现最佳，并且尽管诊断性能相似，但其倍数变化比血浆对应物大得多。P-tau217在血浆检测方法之间显示出最强的相关性（rho = 0.81至0.97）。血浆p-tau水平与脑脊液p-tau呈弱至中度相关，且仅在AD组内相关性不显著。所评估的CRM在各检测方法间不可互换。
血浆p-tau217检测在检测AD病理方面具有更大的倍数变化和鉴别准确性，并且在各平台之间的一致性优于其他血浆p-tau变体。通过免疫测定法测量的血浆和脑脊液p-tau标志物相关性不强，这对它们持续关系的互换性提出了质疑。有必要进一步开展工作，以了解这种解离背后的病理生理学，并开发合适的参考物质以促进跨检测标准化。
阿尔茨海默病协会（#ADSF - 24 - 1284328 - C）。
