Head-to-head comparisons of high-performance plasma phospho-tau epitopes for the detection of Alzheimer's disease

项目概要/摘要 最近的研究表明，血浆测定在苏氨酸231（p-tau 231）、苏氨酸 181（p-tau 181）和苏氨酸217（p-tau 217）与脑淀粉样蛋白β（Ab）和tau蛋白高度相关。 病理学，并以高准确度识别阿尔茨海默病（AD）的谱。这些研究表明 这些简单的tau磷酸化血液检测为AD的诊断提供了前所未有的进步， 绕过了对包括Ab在内的其他生物标志物的需要。血浆p-tau生物标志物有可能成为 作为快速筛查试验纳入临床实践，以确认或排除AD，并指导 有认知症状的患者。此外，该技术可直接用于诊断和 在临床试验中招募，并可作为监测靶向tau蛋白的候选药物的作用的工具 病理然而，初步的证据表明，不同的血浆p-tau表位可能有很大的不同， 检测AD的灵敏度和特异性取决于它们被量化的疾病阶段。因此 测量相同受试者血浆样本中p-tau 231、p-tau 181和p-tau 217表位的把握度良好的研究 具有阐明使用每种等离子体的优点和局限性的潜力 p-tau表位。该研究还可以阐明是否一个以上的血浆p-tau表位的定量可以 提供与单一测定的定量相比的补充信息。理解内在的 检测AD连续体的每个血浆p-tau表位的特征在解释相互矛盾的 使用不同表位的研究结果可能会在未来几年出现。在这里，我们提出一个 测量p-tau 231、p-tau 181和p-tau 217、Ab、神经丝的非随机观察性生物标志物研究 来自AD谱中1，400名个体的储存血浆样本中的轻链和总tau， 正电子发射断层扫描（PET）tau和Ab扫描，参加了成熟的老龄化队列， AD.将在基线、1年和2年随访访视时对所有个体进行评估。在这项研究中，我们的目标是（1） 比较血浆p-tau表位的性能以鉴定Ab和tau蛋白的早期和晚期沉积 通过PET测量。(2)比较血浆p-tau表位诊断AD的性能 江西篇章(3)比较基线血浆p-tau表位浓度的性能，以研究 纵向认知衰退(4)比较血浆纵向变化的性能 用于临床试验的生物标志物及其与PET生物标志物纵向变化的相关性。的 我们的研究结果将对未来几个生物标志物项目的设计产生影响， 关于血浆p-tau 231、p-tau 181和p-tau 217表位在许多应用中的性能， 研究、临床试验和临床实践。

Project Summary/Abstract Recent studies suggest that plasma assays for phosphorylated tau protein at threonine 231 (p-tau231), threonine 181 (p-tau181), and threonine 217 (p-tau217) are highly associated with both brain amyloid-beta (Ab) and tau pathologies and identify the spectrum of Alzheimer’s disease (AD) with high accuracy. These studies suggest that these simple blood tests for tau phosphorylation offer an unprecedented advance for the diagnosis of AD, bypassing the need for additional biomarkers, including Ab. Plasma p-tau biomarkers have the potential to be incorporated in clinical practice as a rapid screening test to confirm or rule out AD and to guide management of patients with cognitive symptoms. Furthermore, this technology has immediate applications for diagnosis and recruitment in clinical trials and may serve as a tool for monitoring the effects of drug candidates targeting tau pathology. However, preliminary evidence suggests that the different plasma p-tau epitopes may differ widely in sensitivity and specificity to detect AD, depending on the disease's stage at which they are quantified. Thus, a well-powered study measuring p-tau231, p-tau181, and p-tau217 epitopes in the same subjects’ plasma samples across the AD spectrum has the potential to elucidate the advantages and limitations of using each of the plasma p-tau epitopes. This study can also clarify whether the quantification of more than one plasma p-tau epitope can provide complementary information compared to the quantification of a single assay. Understanding the inherent characteristics of each plasma p-tau epitope to detect the AD continuum can be crucial in interpreting conflicting results from studies using the different epitopes that will likely emerge in the coming years. Here, we propose a non-randomized observational biomarker study measuring p-tau231, p-tau181, and p-tau217, Ab, neurofilament light chain, and total tau in stored plasma samples from 1,400 individuals across the AD spectrum, characterized with positron emission tomography (PET) tau and Ab scans, enrolled in well-established cohorts of aging and AD. All individuals will be assessed at baseline, 1-year, and 2-year follow-up visits. In this study, we aim (1) to compare the performance of plasma p-tau epitopes to identify early and late depositions of Ab and tau proteins measured by PET. (2) To compare the performance of plasma p-tau epitopes for the diagnosis of the AD spectrum. (3) To compare the performance of baseline plasma p-tau epitopes concentrations to investigate longitudinal cognitive deterioration. (4) To compare the performance of longitudinal changes in plasma biomarkers for use in clinical trials and their associations with longitudinal changes in PET biomarkers. The results generated in our study will have an impact on the design of several future biomarker programs, shedding light on the performance of the plasma p-tau231, p-tau181, and p-tau217 epitopes for numerous applications in research, clinical trials, and clinical practice.