The ARIC-PET Amyloid Imaging Study

项目摘要 对阿尔茨海默病(AD)成功的预防和治疗策略的确定仍然存在 难以捉摸，部分原因是阿尔茨海默病的临床症状在疾病发展中表现较晚，但也 因为没有明确的靶点与AD神经病理直接相关，因此对其进行明确的治疗 可用。因此，重点放在可以在发病前很久就确定的可能的治疗和预防目标 临床疾病和已知可治疗的疾病对解决阿尔茨海默病至关重要。血管对血管的贡献 认知障碍和痴呆，包括阿尔茨海默病，为预防和治疗提供了重要的机会。 此外，有证据表明，血管危险因素，包括高血压和糖尿病，以及大脑 脑血管改变(即脑白质高信号)对认知发展的贡献最大 当他们出现在中年时(早在临床AD通常出现之前)，他们就会衰退和痴呆。这其中的一些 正在进行的社区动脉粥样硬化风险(ARIC)研究证实了这一证据 对来自美国四个社区的个人进行了近30年的基于社区的混血队列研究 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，在本申请中建议更新，建立 关于ARIC和ARIC-NCS中可获得的宝贵数据。通过关注大脑淀粉样蛋白-β的沉积，它在 领先的假说负责AD的发展，ARIC-PET研究进一步评估了 中年血管危险因素与阿尔茨海默病的关系。在这项研究的初始阶段，我们完成了347 在来自三个ARIC地点的参与者中，使用florbetapir PET进行脑淀粉样蛋白PET扫描。我们发现更高的 携带载脂蛋白Eϵ4等位基因(主要基因)的老年女性参与者的脑淀粉样蛋白比率 AD的危险因素)，以及谁是黑人种族。尽管我们的数据不支持一般的关联 在中年血管风险因素和脑淀粉样蛋白之间，对于有两次命中的人：高遗传风险(携带者 ApoEϵ4等位基因)和中年血管风险增加，我们的数据确实表明大脑淀粉样蛋白沉积更多。 最后，我们的数据表明，大脑淀粉样蛋白升高和脑内淀粉样蛋白升高的参与者的认知能力较差 核磁共振显示有大量脑血管疾病。这一续订应用程序建议进行重复的脑部核磁共振 和florbetapir(淀粉样蛋白)PET扫描在所有存活的ARIC-PET非痴呆参与者中进行，以评估 血管危险因素、脑亚临床血管改变和载脂蛋白E基因分型是如何导致高血压的 脑淀粉样蛋白的进展以及临床认知状态的进展，包括向轻度转化 认知障碍和痴呆症。此外，我们将评估脑血管变化的进展情况 大脑淀粉样蛋白进展和临床认知状态的危险因素，我们假设这可能提供一个 这是解释我们观察到的淀粉样蛋白沉积率种族差异的关键环节。ARIC-PET队列 提供双重样本中的独特数据；来自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-β 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 ϵ4 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 ϵ4 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.