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Blood Biomarker Development and Validation in Chronic Traumatic Encephalopathy and Alzheimer's Disease and Alzheimer's Disease Related Dementias

慢性创伤性脑病、阿尔茨海默病和阿尔茨海默病相关痴呆的血液生物标记物开发和验证

基本信息

批准号：
10662752
负责人：
Michael Alosco
金额：
$ 194.07万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

项目摘要

Each year, millions of people are exposed to repetitive head impacts (RHI) through contact sports, military service, and physical violence. These impacts can confer risk for Alzheimer’s disease (AD) and related dementias (ADRD) including chronic traumatic encephalopathy (CTE). The unique pathological lesion of CTE includes phosphorylated tau (p-tau) in neurons around small blood vessels at the sulci. CTE still cannot be diagnosed during life. Research diagnostic criteria for the clinical syndrome of CTE were developed by our team, known as traumatic encephalopathy syndrome (TES). The TES criteria are non-specific and were developed without biomarkers. To date, efforts on biomarkers for CTE have focused on those with low scalability and poor accessibility (e.g., PET). It is now possible to detect AD/ADRD proteins in the blood, representing an accessible alternative for disease detection. Research on plasma-brain associations in AD/ADRD is still in its infancy. The literature on plasma biomarkers for CTE is even more nascent and plasma-to-autopsy studies are scarce, which are vital for biomarker development and validation. This R01 will examine the ability of plasma biomarkers of p- tau, Aβ, and neurodegeneration to detect CTE and its clinical syndrome (TES), and predict AD/ADRD pathology in the brain. We will leverage the Brain Donation Registry (BDR) that is hosted online by the Concussion Legacy Foundation (CLF). BDR individuals pledge their brain to research and are funneled to the Veteran Affairs-Boston University (BU)-CLF brain bank—the largest repository of RHI tissue in the world (>1250 donors). We will ask BDR individuals (n=1000; 800 RHI, 200 non-RHI; all 40+ years) to have a phlebotomy at a Quest lab for banking at BioSEND. They will complete the UCSF-BU internet-based Brain Health Registry-Head Impact & Trauma Surveillance Study for clinical characterization. The sample of 1000 will facilitate our long-term infrastructure goal of large-scale blood banking on people at risk for CTE and AD/ADRD who agree to brain donation and are clinically characterized. To test the R01 aims, plasma biomarker analyses will be done on 300 of the 1000: 200 RHI and 100 matched people without RHI. We will measure six p-tau epitopes (181+199+202+205+217+231), Aβ40/42, total tau, glial fibrillary acidic protein, and neurofilament light. Of the 1000, we expect 100 brain donations during the grant and the same analytes will be measured in blood and brain. 120 brain donors from our BU ADRC bank have these plasma biomarkers available and will be used for autopsy-proven AD and non- AD comparators. Aim 1 will compare plasma biomarkers between the 200 RHI and 100 non-RHI and test plasma biomarker and clinical associations. Aim 2 will include plasma-to-autopsy studies using the 100 brain donations enriched for CTE (people from the BDR) and the 120 BU ADRC donors with autopsy-proven AD and non-AD. Aim 3 will test RHI and plasma biomarker associations. This R01 will lead to unprecedented data to develop and validate plasma biomarkers for CTE. Large-scale blood banking from people across diverse exposures to RHI who agreed to brain donation will create a unique resource to address unmet needs in AD/ADRD including CTE.

每年，数百万人通过接触性运动、军事和体育运动暴露于重复性头部撞击（RHI）。服务和身体暴力这些影响可能会导致阿尔茨海默病（AD）和相关疾病的风险。痴呆（ADRD），包括慢性创伤性脑病（CTE）。CTE的独特病理损害包括脑沟处小血管周围神经元中的磷酸化tau（p-tau）。CTE仍然不能在生活中诊断。CTE临床综合征的研究诊断标准由我们的团队开发，创伤性脑病综合征（TES）工商业污水附加费标准并不具体，没有生物标志物。到目前为止，CTE生物标志物的努力集中在那些具有低可扩展性和差的生物标志物上。可访问性（例如，PET）。现在可以检测血液中的AD/ADRD蛋白，这代表了一种可获得的疾病检测的替代方案。AD/ADRD的血浆-脑关联研究尚处于起步阶段。的关于CTE的血浆生物标志物的文献甚至更是新生的，血浆到尸检的研究也很少，对于生物标志物的开发和验证至关重要。本R 01将检查血浆中p- tau蛋白、Aβ和神经退行性变检测CTE及其临床综合征（TES），并预测AD/ADRD病理在大脑中。我们将利用脑震荡遗产在线托管的脑捐赠注册表（BDR）基金会（CLF）。BDR个人承诺他们的大脑用于研究，并被输送到退伍军人事务-波士顿大学（BU）-CLF脑库-世界上最大的RHI组织库（>1250名供体）。我们会要求 BDR个体（n=1000; 800例RHI，200例非RHI;均为40岁以上）在Quest实验室进行静脉切开术，用于银行业务在BioSEND。他们将完成UCSF-BU基于互联网的脑健康登记-头部撞击和创伤临床表征的监测研究。1000个样本将有助于我们的长期基础设施大规模血库的目标是对有CTE和AD/ADRD风险的人，他们同意捐献大脑，临床特征。为了测试R 01 aim，将对1000：200中的300例进行血浆生物标志物分析 RHI和100个匹配的没有RHI的人。我们将测量六个p-tau表位（181+199+202+205+217+231）， Aβ40/42、总tau、胶质细胞酸性蛋白和神经丝轻。在这1000人中，我们预计有100人是有头脑的捐赠期间，将在血液和大脑中测量相同的分析物。120名大脑捐赠者，我们的BU ADRC库有这些可用的血浆生物标志物，并将用于尸检证实的AD和非AD。 AD比较器。目的1将比较200例RHI和100例非RHI和试验血浆之间的血浆生物标志物生物标志物和临床关联。目标2将包括使用100个大脑捐赠的血浆到尸检研究富集CTE（来自BDR的人）和120名具有尸检证实的AD和非AD的BU ADRC供体。目标3将测试RHI和血浆生物标志物的关联。R 01将带来前所未有的数据开发，验证CTE的血浆生物标志物。来自不同RHI暴露人群的大规模血库同意捐赠大脑的人将创建一个独特的资源，以解决AD/ADRD（包括CTE）中未满足的需求。