The ARIC-PET Amyloid Imaging Study

项目摘要 阿尔茨海默病（AD）的成功预防和治疗策略的确定仍然是 难以捉摸，部分原因是AD的临床症状在疾病发展中具有晚期表现，但也 因为没有明确的与AD神经病理学直接相关的靶点， available.因此，将重点放在可以在发病前确定的可能的治疗和预防目标上， 已知可治疗的临床疾病是解决AD的关键。血管对 认知障碍和痴呆症，包括AD，为预防和治疗提供了重要机会。 此外，有证据表明，血管风险因素，包括高血压和糖尿病，以及大脑 脑血管变化（即白色物质高信号）对认知功能的发展贡献最大 衰退和痴呆，当他们出现在中年（早在临床AD通常出现）。其中一些 正在进行的社区动脉粥样硬化风险（ARIC）研究已经建立了证据， 一项基于社区的birthday队列研究，对来自美国四个社区的个人进行了近30年的研究， 血管危险因素和标记物数据，及其主要辅助研究，ARIC神经认知研究（ARIC- NCS）。ARIC-PET淀粉样蛋白成像研究，在本申请中正在提出更新， ARIC和ARIC-NCS中的宝贵数据。通过关注大脑淀粉样蛋白沉积， 主要假设是负责AD的发展，ARIC-PET研究进一步评估了 中年血管危险因素与AD的关系在这项研究的最初阶段，我们完成了347 大脑淀粉样蛋白PET扫描，使用florbetapir PET，来自三个ARIC站点的参与者。我们发现 老年女性参与者的脑淀粉样蛋白比率携带APOE β 4等位基因（主要遗传因素）， AD的危险因素），并且是黑人。尽管我们的数据并不支持 中年血管危险因素和脑淀粉样蛋白之间的关系，对于有“两个打击”的人：高遗传风险（携带者） APOE β 4等位基因）和中年血管风险升高，我们的数据确实表明更多的脑淀粉样蛋白沉积。 最后，我们的数据表明，在大脑淀粉样蛋白升高的参与者中， 在核磁共振成像上显示脑血管疾病的比例很高。这次更新申请提出了一个重复的大脑MRI 和florbetapir（淀粉样蛋白）PET扫描中所有幸存的非痴呆参与者的ARIC-PET，以评估 血管危险因素和脑亚临床血管变化以及APOE基因型各自如何影响 脑淀粉样蛋白的进展以及临床认知状态的进展，包括转化为轻度 认知障碍和痴呆。此外，我们将评估脑血管变化的进展， 脑淀粉样蛋白和临床认知状态进展的危险因素，我们假设这可能提供了一个 关键环节来解释我们观察到的淀粉样蛋白沉积率的种族差异。ARIC-PET队列 在生物多样性抽样中提供了独特的数据;其更新的数据可以确定重要的预防目标。

Project Summary Identification of successful prevention and treatment strategies for Alzheimer’s Disease (AD) has remained elusive, partially because clinical symptoms of AD have a late presentation in disease development, but also because there are not clear targets directly related to AD neuropathology for which definitive treatment is available. Thus, focusing on possible treatment and prevention targets that can be identified well before onset of clinical disease and which are known to be treatable is critical in addressing AD. The vascular contribution to cognitive impairment and dementia, including AD, offers an important opportunity for prevention and treatment. Further, evidence suggests that vascular risk factors, including hypertension and diabetes, as well as brain cerebrovascular changes (i.e. white matter hyperintensities), contribute most to the development of cognitive decline and dementia when they are present in midlife (well before clinical AD usually presents). Some of this evidence has been established by the ongoing Atherosclerosis Risk in Communities (ARIC) study, a community-based biracial cohort study of individuals from four US communities, with nearly 30 years of vascular risk factors and marker data, and its primary ancillary study, the ARIC Neurocognitive Study (ARIC- NCS). The ARIC-PET Amyloid Imaging Study, the renewal of which is being proposed in this application, built on the valuable data available in ARIC and ARIC-NCS. By focusing on brain amyloid- deposition, which in leading hypotheses is responsible for the development of AD, the ARIC-PET study further evaluated the associations between midlife vascular risk factors and AD. In the initial phase of this study, we completed 347 brain amyloid PET scans, using florbetapir PET, among participants from three ARIC sites. We found higher rates of brain amyloid in participants who were older, female, carried an APOE 4 allele (the primary genetic risk factor for AD), and who were of black race. Although our data did not support a general association between midlife vascular risk factors and brain amyloid, for persons with “two hits”: a high genetic risk (carriers of an APOE 4 allele) and elevated midlife vascular risk, our data do suggest more brain amyloid deposition. Finally, our data suggest that cognition is worse among participants who have both elevated brain amyloid and high amounts of brain cerebrovascular disease, on MRI. This renewal application proposes a repeat brain MRI and florbetapir (amyloid) PET scan among all surviving non-demented participants of ARIC-PET, to evaluate how vascular risk factors and brain subclinical vascular changes and APOE genotype each contribute to the progression of brain amyloid as well as the progression of clinical cognitive status, including conversion to mild cognitive impairment and dementia. Further, we will evaluate progression of brain cerebrovascular changes as a risk factor for progression of brain amyloid and clinical cognitive status, which we hypothesize may provide a critical link to explain some of our observed racial disparities in amyloid deposition rates. The ARIC-PET cohort provides unique data in a biracial sample; data from its renewal could identify important targets for prevention.