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

大血管和微血管对阿尔茨海默病的影响：MESA VASCAD

• 批准号: 9335219
• 负责人: Timothy M. Hughes
• 金额: $ 75.9万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335219
• 关键词: Address; African American; Age; Age of Onset; Age-Years; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid deposition; Ancillary Study; Architecture; Biological Markers; Blood Vessels; Brain; Calcium; Caliber; Cardiovascular Diseases; Cardiovascular system; Caucasians; Cerebrovascular Disorders; Clinical; Clinical Trials; Clinical assessments; Cognition; Cognitive; Complex; Coronary; Data; Data Set; Dementia; Development; Diagnosis; Disease; Enrollment; Genetic Markers; Genotype; Goals; Health; Hippocampus (Brain); Image; Individual; Lacunar Infarctions; Longitudinal cohort; Machine Learning; Magnetic Resonance Imaging; Measures; Metabolic; Metabolic Diseases; Microvascular Dysfunction; Modality; Multi-Ethnic Study of Atherosclerosis; Neurites; Not Hispanic or Latino; Observational Study; Outcome; Participant; Pathology; Pathway interactions; Phenotype; Positron-Emission Tomography; Prevention; Prevention strategy; Preventive Intervention; Research Personnel; Resources; Retinal; Risk Factors; Role; Route; Scanning; Site; Standardization; Structure; Testing; Therapeutic Intervention; Time; United States National Institutes of Health; Vascular Diseases; adjudicate; age related; arterial stiffness; brain health; cerebral microbleeds; cerebrovascular; cognitive testing; cohort; cost; cost effective; density; digital; disorder prevention; epigenetic marker; experience; falls; forest; high dimensionality; improved; macrovascular disease; meetings; middle age; modifiable risk; multidisciplinary; multimodality; neuroimaging; novel; novel therapeutics; phenotypic data; pre-clinical; resilience; response; screening; symposium; vascular contributions; vascular factor; vascular risk factor

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.

项目摘要 改善血管健康以延迟阿尔茨海默氏病（AD）的发作，被确定为关键目标 阿尔茨海默氏病和相关痴呆症会议，2015年NIA AD Summit和Par-15-356（致 然而，存在实施血管预防策略的关键障碍 对于AD，并阐明中年代谢，宏观和微血管因素在AD中的作用至关重要 解决这些障碍。每种类型的因素可能表现出大脑中不同的病理 痴呆症子类型，使一项新的且充分全面的临床试验成为一项昂贵且耗时的 承诺。为了解决这一基本差距，我们建议从 动脉粥样硬化（MESA）研究的多种族研究，并添加了详细的认知测试和 多模式脑神经影像学 - Mesa Vascad研究。 Wake Forest网站的MESA参与者（46％ 非裔美国人，54％非西班牙裔高加索人）已经发生了广泛的代谢和血管 表型，再次重复成像，并在2010-2012进行了简短的认知评估。梅萨·瓦斯卡（Mesa Vascad） 研究将增加临床和认知评估（统一的数据集和补充认知测试）； 神经影像学（MRI，淀粉样宠物）；以及残留图像的重新分析。我们建议注册540 Mesa 参与者在2年内和3年后重复评估，以更充分地定义针对性，可修改 AD的血管风险因素。通过我们的具体目标，我们将（1）检验基线的假设 中年龄的大血管和微血管生物标志物预测这两个标准AD神经影像学结果 （例如，用PET评估的海马体积和淀粉样蛋白沉积物）和更新颖的脑血管 生物标志物（例如微吸收，lacunar Infacts，神经密度和脑微粒）； （2）确定是否 15年来，代谢和血管生物标志物的变化预测了认知和AD生物标志物轨迹； （3）使用高维机学习方法，确定常见，差异和互动性 种族和APOE基因型组之间的代谢和血管危险因素谱。这提出了辅助 由MESA指导委员会批准的研究由具有经验，多种经验的新调查员领导 合作者的纪律团队。梅萨研究是询问问题的理想人群 提案：它具有高度详细的纵向风险因素数据，该数据在15多年以上的潜水员队列中，该数据收集了15年以上，该研究 我们可以使用脑血管生物标志物，AD生物标志物和认知重新评估来利用和增强 - 从而为血管和AD风险因素创建一个全面的大脑表型数据集。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 诊断前临床和临床广告相关疾病的诊断之前的认知轨迹，达到临界差距 在有助于指导各种新型疗法或预防策略的信息中 与广告相关的痴呆症形式。