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

项目摘要 改善血管健康以延缓阿尔茨海默病(AD)的发病被认为是一个关键目标 阿尔茨海默病和相关痴呆症会议、2015年NIA AD峰会和PAR-15-356(至 该应用程序正在响应的)。然而，实施血管预防战略存在关键障碍。 对于AD来说，阐明中年代谢、宏观和微观血管因素在AD中的作用是必不可少的 解决这些障碍。每种类型的因子在大脑中可能表现出不同的病理机制，这些因素有助于 痴呆症亚型，使得新的和足够全面的临床试验既昂贵又耗时 承诺。为了解决这一根本差距，我们建议利用来自 动脉粥样硬化的多种族研究(MESA)研究增加了详细的认知测试和 多模式脑神经成像--MESA VASCAD研究。维克森林遗址的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 2010-2012年的表型、重复视网膜成像和简短的认知评估。梅萨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(核磁共振、淀粉样蛋白PET)；以及视网膜图像的重新分析。我们建议招收540名梅萨学生 参与者在2年内重复评估，并在3年后重复评估，以更全面地描述目标明确、可修改的特征 AD的血管危险因素。通过我们的具体目标，我们将(1)检验基线的假设 中年大血管和微血管生物标记物均可预测AD的标准神经影像结果 (例如，用PET评估海马体积和淀粉样蛋白沉积)和更多新的脑血管 生物标志物(例如微梗塞、腔隙梗塞、轴突密度和脑微出血)；(2)确定 代谢和血管生物标记物15年来的变化预测认知和AD生物标记物的轨迹； (3)使用高维机器学习方法，确定共性、差异性和互动性 种族和载脂蛋白E基因组间的代谢和血管危险因素分布。这项拟议的附属 这项研究由MESA指导委员会批准，由一名新的调查员领导，具有经验丰富的多名 合作者组成的纪律团队。MESA研究是询问这一问题的理想队列 建议：它拥有在不同的队列中收集的超过15年的高度详细的纵向风险因素数据， 我们可以利用和增强脑血管生物标记物、AD生物标记物和认知重新评估 -从而为血管和AD风险因素创建一个全面的脑表型数据集。这些新的 数据将使我们能够检查血管生物标记物对痴呆症生物标记物和 在诊断临床前和临床AD相关疾病之前的认知轨迹，遇到关键差距 信息将有助于指导各种疾病的新治疗或预防策略的发展 阿尔茨海默病相关痴呆的各种形式。

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.