The Macrovascular and Microvascular Contributions to Alzheimer's Disease: MESA VASCAD

项目摘要 改善血管健康以延迟阿尔茨海默病（AD）的发作被确定为一个关键目标， 阿尔茨海默病和相关痴呆症会议，2015年NIA AD峰会和PAR-15 - 356（以 此应用程序正在响应）。然而，实施血管预防策略存在关键障碍 阐明中年代谢、大血管和微血管因素在AD中的作用， 解决这些障碍。每种类型的因素可能在大脑中表现出不同的病理， 痴呆亚型，使一个新的和足够全面的临床试验是昂贵和耗时的 事业。为了解决这一重要差距，我们建议利用来自 多种族动脉粥样硬化研究（MESA）研究，增加了详细的认知测试， 多模式脑神经成像-MESA VASCAD研究。维克森林场地的MESA参与者（46% 非裔美国人，54%非西班牙裔高加索人）已经经历了广泛的代谢和血管 在2010 - 2012年，进行了表型分析、重复视网膜成像和简短的认知评估。MESA VASCAD 研究将增加临床和认知评估（统一数据集和补充认知测试）; 神经成像（MRI，淀粉样蛋白PET）;和视网膜图像的再分析。我们建议招收540名MESA 参与者在2年后进行评估，并在3年后进行重复评估，以更全面地描述目标明确、可修改 AD的血管危险因素。通过我们的具体目标，我们将（1）测试假设，基线 中年大血管和微血管生物标志物可预测标准AD神经影像学结局 (e.g.海马体积和淀粉样蛋白沉积评估PET）和更多的新的脑血管疾病 生物标志物（例如微梗塞、腔隙性梗塞、神经突密度和脑微出血）;（2）确定是否 15年内代谢和血管生物标志物的变化可预测认知和AD生物标志物轨迹; 以及（3）使用高维机器学习方法，确定共同的、差异的和交互的 在种族和APOE基因型组中的代谢和血管危险因素谱。这一建议的辅助 由MESA指导委员会批准的研究由一名新研究者领导，该研究者拥有经验丰富的多学科专家， 合作者的纪律团队。MESA研究是询问这一问题的理想队列。 建议：它有高度详细的纵向风险因素数据，收集了15年以上的不同队列， 我们可以利用脑血管生物标志物、AD生物标志物和认知重新评估， - 从而为血管和AD风险因素创建全面的脑表型数据集。这些新 数据将使我们能够检查血管生物标志物对痴呆生物标志物的时机和影响， 在诊断为临床前和临床AD相关疾病之前的认知轨迹， 在信息，这将有助于指导新的治疗或预防战略的发展， AD相关的痴呆症。

Project Summary Improving vascular health for delaying the onset of Alzheimer’s disease (AD) is identified as a critical goal by the Alzheimer’s Disease and Related Dementias Conference, the 2015 NIA AD Summit and PAR-15-356 (to which this application is responding). Yet, critical barriers exist to implementing vascular prevention strategies for AD, and elucidating the role of midlife metabolic, macro- and micro- vascular factors in AD is essential to addressing these barriers. Each type of factor may manifest different pathologies in the brain that contribute to dementia sub-types, making a new and sufficiently comprehensive clinical trial a costly and time-consuming undertaking. To address this essential gap, we propose to leverage the rich longitudinal cohort data from the Multi-Ethnic Study of Atherosclerosis (MESA) study with the addition of detailed cognitive testing and multimodal brain neuroimaging – the MESA VASCAD study. MESA participants at the Wake Forest site (46% African-American, 54% non-Hispanic Caucasian) have already undergone extensive metabolic and vascular phenotyping, repeated retinal imaging and a brief cognitive assessment in 2010-2012. The MESA VASCAD study will add clinical and cognitive assessments (Uniform Data Set and supplemental cognitive tests); neuroimaging (MRI, amyloid PET); and reanalysis of retinal images. We propose to enroll 540 MESA participants in 2 years and repeat assessments 3 years later to more fully characterize targeted, modifiable vascular risk factors for AD. Through our Specific Aims, we will (1) test the hypothesis that baseline macrovascular and microvascular biomarkers in middle-age predict both standard AD neuroimaging outcomes (e.g. hippocampal volume and amyloid deposition assessed with PET) and more novel cerebrovascular biomarkers (e.g. microinfarcts, lacunar infarcts, neurite density and cerebral microbleeds); (2) determine if changes in metabolic and vascular biomarkers over 15 years predict cognitive and AD biomarker trajectory; and (3) using high-dimensional machine learning approaches, determine common, differential and interactive metabolic and vascular risk factor profiles among racial and APOE genotype groups. This proposed ancillary study, approved by the MESA Steering Committee, is led by a New Investigator with an experienced, multi- disciplinary team of collaborators. The MESA study is an ideal cohort for interrogating the questions in this proposal: it has highly detailed longitudinal risk factor data collected over 15+ years in a diverse cohort, which we can leverage and augment with cerebrovascular biomarkers, AD biomarkers, and cognitive reassessments - thereby creating a comprehensive brain phenotype dataset for vascular and AD risk factors. These new data will enable us to examine the timing and impact of vascular biomarkers on dementia biomarkers and cognitive trajectories before a diagnosis of pre-clinical and clinical AD-related disorders, meeting a critical gap in information that will help guide the development of novel therapeutic or prevention strategies for various forms of AD-related dementias.