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

用于检测阿尔茨海默病的高性能血浆磷酸 tau 表位的头对头比较

• 批准号: 10576363
• 负责人: Tharick Pascoal
• 金额: $ 74.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576363
• 关键词: Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Amyloid beta-Protein; Biological Assay; Biological Markers; Blood; Blood Tests; Brain; Bypass; Cerebrospinal Fluid; Characteristics; Classification; Clinical; Clinical Trials; Cognitive; Collection; Data; Dementia; Deterioration; Diagnosis; Diagnostic; Disease; Disease Progression; Early identification; Enrollment; Epitopes; Functional disorder; Future; Goals; Head; Image; Individual; Light; Measurement; Measures; Monitor; Neurobehavioral Manifestations; Outcome; Participant; Pathology; Patient Care; Patients; Performance; Plasma; Population; Positron-Emission Tomography; Rapid screening; Research; Research Design; Sampling; Scanning; Sensitivity and Specificity; Sum; Technology; Testing; Threonine; Visit; abeta deposition; beta amyloid pathology; clinical practice; cohort; design; drug candidate; drug development; follow-up; head-to-head comparison; large scale data; mild cognitive impairment; neurofilament; novel; programs; recruit; research study; screening; tau Proteins; tau aggregation; tau-1; tool

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.

项目概要/摘要 最近的研究表明，苏氨酸 231 (p-tau231)、苏氨酸磷酸化 tau 蛋白的血浆检测 181 (p-tau181) 和苏氨酸 217 (p-tau217) 与脑淀粉样蛋白-β (Ab) 和 tau 高度相关 病理学并高精度识别阿尔茨海默病 (AD) 谱系。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， 无需额外的生物标志物，包括抗体。血浆 p-tau 生物标志物有潜力成为 作为一种快速筛查测试纳入临床实践，以确认或排除 AD 并指导 AD 的管理 有认知症状的患者。此外，该技术可直接应用于诊断和治疗 临床试验中的招募并可作为监测针对 tau 的候选药物效果的工具 病理。然而，初步证据表明，不同的血浆 p-tau 表位在以下方面可能存在很大差异： 检测 AD 的敏感性和特异性，取决于对其进行量化的疾病阶段。因此，一个 一项强有力的研究，测量同一受试者血浆样本中的 p-tau231、p-tau181 和 p-tau217 表位 整个 AD 谱有可能阐明使用每种等离子体的优点和局限性 p-tau 表位。这项研究还可以阐明多个血浆 p-tau 表位的定量是否可以 与单一测定的量化相比，提供补充信息。了解内在 用于检测 AD 连续体的每个血浆 p-tau 表位的特征对于解释冲突至关重要 使用未来几年可能出现的不同表位的研究结果。在这里，我们提出一个 非随机观察性生物标志物研究，测量 p-tau231、p-tau181 和 p-tau217、Ab、神经丝 来自 1,400 名 AD 谱系个体的储存血浆样本中的轻链和总 tau 蛋白，经过表征 通过正电子发射断层扫描 (PET) tau 和 Ab 扫描，纳入成熟的衰老和 广告。所有个体都将在基线、1 年和 2 年随访时接受评估。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 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表位对AD诊断的性能 光谱。 (3) 比较基线血浆 p-tau 表位浓度的性能以进行研究 纵向认知恶化。 (4)比较等离子体纵向变化的表现 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关联。这 我们研究中产生的结果将对未来几个生物标志物项目的设计产生影响， 阐明血浆 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。