Blood amyloid-beta relationship with amyloid plaques and CSF amyloid-beta

项目总结 淀粉样β蛋白(Aβ)已被证明在阿尔茨海默病(AD)的病理生理学中起关键作用。 建立了脑脊液Aβ和淀粉样蛋白正电子发射断层扫描示踪剂 检测大脑中淀粉样斑块的生物标志物。目前临床试验的筛查，特别是预防 试验受到复杂、昂贵或侵入性程序的阻碍，可获得性有限。我们的总体目标是 人血浆A-β水平与淀粉样斑块的关系 以改善AD试验的筛查，并验证AD血液测试。血液的关系和时间 Aβ相对于淀粉样蛋白的变化斑块和脑脊液Aβ的测量尚不清楚。有几个 以前没有被解决的问题：血液Aβ是在之前、同时还是之后发生变化的 脑脊液或淀粉样蛋白的变化？‘，’什么人口统计学、临床或遗传因素影响血浆A-β？‘。我们 假设血浆A-β异常预示脑脊液A-β和淀粉样蛋白PET异常。在目标1中，我们将 利用来自区域、国家和国际研究的现有血浆和脑脊液样本来测试我们的 在特征良好的研究队列中的假设。我们将使用纵向样本来调查时间 血浆Aβ、脑脊液Aβ和淀粉样蛋白PET的变化顺序以了解AD血浆Aβ处于哪个阶段 变得不正常。我们还将研究几个辅助因素，以确定它们对血浆Aβ测量的影响 脑淀粉样斑块，包括年龄和载脂蛋白ϵ4。在目标2，我们将实施一项横断面临床研究 在不同的社区和以诊所为基础的人群中，使用血液Aβ测试来筛选个人 淀粉样变性，用淀粉样蛋白PET确诊。根据血液淀粉样蛋白测试的结果， 参与者将接受确诊的淀粉样蛋白正电子发射计算机断层扫描，并重复采血和测试。这将允许 美国将血液Aβ测试与目前淀粉样PET扫描的黄金标准进行比较. 拟议的工作建立在先前的开创性方法的基础上，这种方法影响了对 Aβ在阿尔茨海默病的淀粉样假说和病理生理机制中的作用我们已经扩展了这种方法 随着技术的显著改进，并发现了血液中淀粉样斑块的β特征。我们现在 寻求通过不同的观察性研究在现实世界的研究中验证这一测试。这些研究将为 为快速部署以加快AD试验和临床诊断的登记奠定基础。

PROJECT SUMMARY Amyloid-beta (Aβ) has been shown to be critical in the pathophysiology of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) Aβ and amyloid positron emission tomography (PET) tracers are established biomarkers for detecting amyloid plaques in the brain. Current screening for clinical trials, especially prevention trials, are hampered by complex, expensive or invasive procedures, with limited availability. Our overall goal is to determine the relationship between blood plasma Aβ and the presence of amyloid plaques in the human brain to improve screening for AD trials and to validate an AD blood test. The relationship and timing of blood Aβ changes relative to amyloid PET measures of plaques and CSF Aβ are not understood. There are several questions that have not been addressed before: ‘Does blood Aβ change before, at the same time or after changes in CSF or amyloid PET?’, ‘What demographic, clinical, or genetic factors influence plasma Aβ?‘. We hypothesize that abnormal plasma Aβ is predictive of abnormal CSF Aβ and amyloid PET. In Aim 1, we will leverage existing plasma and CSF samples from regional, national and international studies to test our hypothesis in well-characterized research cohorts. We will use longitudinal samples to investigate the temporal sequence of changes of plasma Aβ, CSF Aβ, and amyloid PET to understand at which stage of AD plasma Aβ becomes abnormal. We will also look at several cofactors to determine their impact on plasma Aβ measures of brain amyloid plaques, including age and APOE ϵ4. In Aim 2, we will implement a cross-sectional clinical study in diverse community and clinic-based populations, using the blood Aβ test to screen individuals for amyloidosis with confirmation using amyloid PET. Based on the results of the blood amyloid test, a subset of participants will follow-up with confirmatory amyloid PET and repeat blood collection and tests. This will allow us to compare the blood Aβ test to the current gold standard of amyloid PET scans. The proposed work builds on the prior pioneering approach that has influenced the understanding of the role of Aβ in the amyloid hypothesis and pathophysiological causes of AD. We have extended this approach with significantly improved techniques, and discovery of a blood Aβ signature of amyloid plaques. We now seek to validate the test in a real-world study with a diverse observational study. These studies will lay the groundwork for rapid deployment to accelerate enrollment of AD trials and clinical diagnosis.