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，数以百万计的人通过接触运动，军事接触重复的头部影响（RHI）服务和身体暴力。这些影响可能会导致阿尔茨海默氏病（AD）及相关的风险痴呆症（ADRD），包括慢性创伤性脑病（CTE）。 CTE的独特病理病变包括在沟的小血管周围神经元中的磷酸化tau（p-tau）。 CTE仍然不能在生命中被诊断出。 CTE临床综合征的研究诊断标准是由我们的团队开发的称为创伤性脑病综合征（TES）。 TES标准是非特异性的，并且是开发的没有生物标志物。迄今为止，CTE生物标志物的努力集中在可伸缩性低和差的人上可访问性（例如宠物）。现在可以检测到血液中的AD/ADRD蛋白，代表可访问的疾病检测的替代方法。 AD/ADRD中血浆 - 脑关联的研究仍处于起步阶段。这有关CTE血浆生物标志物的文献甚至更新生，血浆到自动研究的研究稀缺，这是稀缺的对于生物标志物的发展和验证至关重要。该R01将检查P-血浆生物标志物的能力 tau，aβ和神经退行性变化，以检测CTE及其临床综合征（TES），并预测AD/ADRD病理我们将利用脑震荡遗产在线托管的大脑捐赠注册表（BDR）基金会（CLF）。 BDR个人保证自己的大脑进行研究，并向波士顿退伍军人事务 University（BU）-CLF Brain Bank - 世界上最大的RHI组织存储库（> 1250个捐助者）。我们会问的 BDR个体（n = 1000; 800 RHI，200个非RHI；全40多年）在Quest Lab for Banking实验在Biosend。他们将完成基于UCSF-BU的互联网脑健康注册表的影响和创伤临床表征的监视研究。 1000的样本将有助于我们的长期基础设施大规模血液银行业务的目标是对CTE和AD/ADRD有风险的人，他们同意大脑捐赠并且是临床表征。为了测试R01的目标，血浆生物标志物分析将在1000：200的300个。 RHI和100个没有RHI的人。我们将测量六个P-TAU表位（181+199+202+205+205+217+231）， Aβ40/42，总tau，神经胶质原纤维酸性蛋白和神经丝光。在1000中，我们期望100个大脑赠款期间的捐赠和相同的分析物将在血液和大脑中衡量。 120个大脑供体来自我们的BU ADRC银行提供这些等离子生物标志物，可用于尸检广告和非 - 广告比较器。 AIM 1将比较200 RHI和100非RHI和测试等离子体之间的等离子体生物标志物生物标志物和临床协会。 AIM 2将包括使用100次脑捐赠的等离子体到自动剖宫大研究富含CTE（来自BDR的人）和120个具有尸检广告和非AD的BU ADRC捐赠者。 AIM 3将测试RHI和血浆生物标志物关联。该R01将导致前所未有的数据开发和验证CTE的血浆生物标志物。来自潜水员暴露于RHI的人的大规模血液库同意大脑捐赠的人将创建一个独特的资源，以满足包括CTE在内的广告/ADRD的未满足需求。