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

项目摘要/摘要 最近的研究表明，血浆中磷酸化tau蛋白的苏氨酸231(p-tau231)， 181(p-tau181)和苏氨酸217(p-tau217)与脑淀粉样β蛋白(Ab)和tau高度相关 高精度地识别阿尔茨海默病(AD)的病理和谱系。这些研究表明 这些简单的tau磷酸化血液测试为AD的诊断提供了前所未有的进步， 不需要额外的生物标记物，包括Ab.血浆p-tau生物标志物有可能成为 作为一种快速筛查试验纳入临床实践，以确认或排除AD并指导治疗 有认知症状的患者。此外，这项技术还可以立即应用于诊断和 临床试验中的招募，并可作为监测靶向tau的候选药物效果的工具 病理学。然而，初步证据表明，不同的血浆p-tau表位在 检测AD的敏感度和特异度取决于疾病的量化阶段。因此，一个 在相同受试者的血浆样本中测量p-tau231、p-tau181和p-tau217表位的有效研究 通过AD光谱有可能阐明使用每种血浆的优势和局限性 P-tau表位。这项研究还可以澄清是否可以量化一个以上的血浆p-tau表位 与单一化验的量化相比，提供补充信息。了解内在的 检测AD连续体的每个血浆p-tau表位的特征在解释冲突中可能是至关重要的 来自使用不同表位的研究结果，这些表位可能会在未来几年出现。在这里，我们提出一种 测量p-tau231，p-tau181和p-tau217，Ab.神经丝的非随机观察性生物标志物研究 轻链和储存的血浆样本中的总tau，来自AD谱的1400人，表征了 通过正电子发射断层扫描(PET)tau和Ab扫描，登记在公认的老龄化和 广告。所有个人都将在基线、1年和2年的后续访问中进行评估。在本研究中，我们的目标是(1) 比较血浆p-tau表位的性能以识别抗体和tau蛋白的早期和晚期沉积 由正电子发射计算机断层扫描测量。(2)比较血浆p-tau表位在AD诊断中的作用 频谱。(3)比较基线血浆p-tau表位浓度的表现，以考察 纵向认知退化。(4)比较血浆纵向变化的表现 临床试验中使用的生物标记物及其与PET生物标记物纵向变化的关系。这个 我们的研究结果将对未来几个生物标记物计划的设计产生影响， 血浆p-tau231、p-tau181和p-tau217表位在多种应用中的性能 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.