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

血液淀粉样蛋白 β 与淀粉样蛋白斑和脑脊液淀粉样蛋白 β 的关系

• 批准号: 10077729
• 负责人: RANDALL J BATEMAN
• 金额: $ 118.08万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077729
• 关键词: Address; Age; Alzheimer disease prevention; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease blood test; Alzheimer' s disease diagnosis; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Apolipoprotein E; Archives; Biological; Biological Markers; Blood; Blood Tests; Blood specimen; Brain; Cerebrospinal Fluid; Clinic; Clinical; Clinical Research; Clinical Trials; Cognitive; Collection; Communities; Complex; Control Groups; Cross-Sectional Studies; Dementia; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Enrollment; Frontotemporal Dementia; Functional disorder; General Population; Genetic; Genotype; Goals; Gold; Human; Individual; International; Kinetics; Lead; Lewy Body Dementia; Longitudinal Studies; Measures; Neuraxis; Neurodegenerative Disorders; Observational Study; Parkinson Disease; Participant; Plasma; Population; Population Heterogeneity; Positron-Emission Tomography; Prevention Research; Prevention trial; Procedures; Protein Isoforms; Proteins; Reproducibility; Research; Role; Sampling; Senile Plaques; Site; Specimen; Stable Isotope Labeling; Symptoms; Techniques; Testing; Therapeutic; Time; Tracer; Work; apolipoprotein E-4; base; cerebral amyloidosis; clinical Diagnosis; cofactor; cognitive performance; cohort; community clinic; effective therapy; follow-up; improved; nervous system disorder; neurodegenerative dementia; population based; recruit; research study; screening; sex

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.

项目摘要 β-淀粉样蛋白（Aβ）在阿尔茨海默病（AD）的病理生理学中起着关键作用。 建立了脑脊液Aβ和淀粉样蛋白正电子发射断层扫描（PET）示踪剂 用于检测大脑中淀粉样斑块的生物标志物。目前的临床试验筛查，特别是预防 由于复杂、昂贵或侵入性的程序，难以进行临床试验，而且可用性有限。我们的总体目标是 以确定血浆Aβ与人类淀粉样蛋白斑块存在之间的关系， 大脑，以改善AD试验的筛查和验证AD血液测试。血液的关系和时间 尚不清楚斑块和CSF Aβ相对于淀粉样蛋白PET测量的Aβ变化。有几 以前没有解决的问题：“血液Aβ在之前，同时或之后发生变化吗？ CSF或淀粉样PET的变化？什么样的人口统计学、临床或遗传因素会影响血浆Aβ？我们 假设异常血浆Aβ预示异常CSF Aβ和淀粉样PET。在目标1中，我们 利用来自区域、国家和国际研究的现有血浆和CSF样本， 假设在良好表征的研究队列。我们将使用纵向样本来调查时间 血浆Aβ、CSF 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。我们还将研究几种辅助因子，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APOE β 4。在目标2中，我们将实施一项横断面临床研究 在不同的社区和诊所为基础的人群中，使用血液Aβ测试筛选个体， 淀粉样变性并使用淀粉样PET确认。根据血液淀粉样蛋白测试的结果， 受试者将进行淀粉样蛋白PET的确认，并重复血液采集和测试。这将允许 我们将血液Aβ测试与目前淀粉样蛋白PET扫描的金标准进行比较。 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在淀粉样蛋白假说和AD病理生理学病因中的作用。我们已经扩展了这种方法 随着技术的显著改进，以及淀粉样斑块的血液Aβ特征的发现。我们现在 寻求在现实世界的研究中通过不同的观察性研究来验证测试。这些研究将奠定 为快速部署奠定基础，以加快AD试验和临床诊断的入组。

项目成果

Investigating the combination of plasma amyloid-beta and geroscience biomarkers on the incidence of clinically meaningful cognitive decline in older adults.

研究血浆β-淀粉样蛋白和老年科学生物标志物的组合对老年人临床意义认知能力下降的发生率的影响。

• DOI: 10.1007/s11357-022-00554-y
• 发表时间: 2022
• 期刊: GeroScience
• 影响因子: 5.6
• 作者: Lu,Wan-Hsuan;Giudici,KellyVirecoulon;Morley,JohnE;Guyonnet,Sophie;Parini,Angelo;Aggarwal,Geetika;Nguyen,AndrewD;Li,Yan;Bateman,RandallJ;Vellas,Bruno;deSoutoBarreto,Philipe;MAPT/DSAGroup
• 通讯作者: MAPT/DSAGroup