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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，数以百万计的人通过接触性运动、军事活动暴露在重复的头部撞击(RHI)中服务和身体暴力。这些影响可能会增加患阿尔茨海默病(AD)和相关疾病的风险痴呆(ADRD)，包括慢性创伤性脑病(CTE)。CTE独特的病理改变包括脑沟小血管周围神经元中的磷酸化tau(p-tau)。CTE仍然不能在生活中被诊断出来。CTE临床证候诊断标准的研究由本课题组制定，称为创伤性脑病综合征(TES)。工商业污水附加费标准是非特定的，是由没有生物标记物。到目前为止，CTE的生物标记物的努力主要集中在那些可伸缩性较低和较差的人可访问性(例如，PET)。现在可以检测血液中的AD/ADRD蛋白，代表着一种可访问的疾病检测的替代方案。对AD/ADRD中血浆-脑关联的研究仍处于初级阶段。这个关于CTE的血浆生物标记物的文献甚至更新，血浆到身体解剖的研究很少，这对于生物标记物的开发和验证是至关重要的。本R01将检测血浆生物标记物的能力-p- Tau、Aβ和神经变性检测CTE及其临床综合征(TES)，并预测AD/ADRD的病理在大脑里。我们将利用由Conussion Legacy在线托管的大脑捐赠注册中心(BDR) 基金会(CLF)。BDR个人承诺将他们的大脑用于研究，并被输送到退伍军人事务部-波士顿大学(BU)-CLF脑库-世界上最大的RHI组织储存库(&gt；1250名捐赠者)。我们会问 BDR个人(n=1000；800 RHI，200非RHI；全部40岁以上)在Quest银行实验室进行静脉抽血在BioSend。他们将完成加州大学旧金山分校基于互联网的脑健康注册-Head Impact&Trauma 临床特征的监测研究。1,000个样本将促进我们的长期基础设施为CTE和AD/ADRD的高危人群建立大规模血库的目标，这些高危人群同意脑捐赠，并具有临床特征的。为了测试R01 AIMS，将对1000：200中的300进行血浆生物标志物分析 RHI和100名匹配的没有RHI的人。我们将测量6个p-tau表位(181+199+202+205+217+231)， Aβ40/42，总tau，胶质纤维酸性蛋白，神经丝光。在1000个人中，我们预计有100个大脑捐赠期间的捐款和相同的分析物将通过血液和大脑进行测量。120名脑捐赠者来自我们BU ADRC银行有这些血浆生物标志物可用，并将用于尸检证实的AD和非 AD比较器。AIM 1将比较200个RHI和100个非RHI的血浆生物标志物，并测试血浆生物标记物与临床的关系。AIM 2将包括使用100个大脑捐赠进行血浆到身体解剖的研究为CTE(来自BDR的人)和120名尸检证实的AD和非AD的BU ADRC捐赠者提供了丰富的资金。 AIM 3将测试RHI和血浆生物标记物的相关性。这款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。不同RHI暴露人群的大规模血库世卫组织同意捐赠大脑将创造一种独特的资源，以解决AD/ADRD中未得到满足的需求，包括CTE。