Assessing the role of cerebrovascular brain injury and dysfunction in Alzheimer’s disease pathogenesis in the BEACoN Cohort

在 BEACoN 队列中评估脑血管损伤和功能障碍在阿尔茨海默病发病机制中的作用

• 批准号: 10604863
• 负责人: Michael A Yassa
• 金额: $ 256.18万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604863
• 关键词: Address; Adopted; Adverse event; Affect; African American population; Age; Age Years; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Award; Awareness; Biological Markers; Black Populations; Black race; Blood Pressure; Blood Vessels; Brain; Brain Injuries; Brain imaging; Cardiovascular Diseases; Cerebrovascular Circulation; Cerebrovascular Disorders; Chronic; Classification; Clinical; Clinical Research; Clinical Trials; Cognitive; Complement; Data; Dementia; Deterioration; Development; Diffusion Magnetic Resonance Imaging; Discrimination; Education; Elderly; Enrollment; Ethnic Population; Etiology; Exclusion; Female; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gases; Goals; Health; Hemorrhage; Hippocampus; Hispanic; Hispanic Populations; Image; Imaging Techniques; Impaired cognition; Income; Individual; Infrastructure; Injury; Intervention; Intervention Trial; Latino; Latino Population; Life Style; Longitudinal Studies; Machine Learning; Magnetic Resonance Imaging; Maps; Medial; Mediating; Memory; Memory Loss; Minority Groups; Minority Recruitment; Modeling; Multimodal Imaging; Natural History; Neighborhoods; Neurobiology; Neuronal Dysfunction; Neuropsychological Tests; Obesity; Observational Study; Occupations; Outcome Measure; Paper; Participant; Pathogenesis; Patients; Pattern; Performance; Physical activity; Population; Population Heterogeneity; Positron-Emission Tomography; Predisposition; Prevalence; Public Health; Publications; Recording of previous events; Resolution; Rest; Risk; Risk Factors; Role; Sampling; Severities; Sleep; Social support; Statistical Models; Stroke; Structure; Sum; Temporal Lobe; Testing; Thick; Vascular Dementia; Vascular Diseases; White Matter Hyperintensity; Work; aging population; asymptomatic Alzheimer' s disease; brain dysfunction; caucasian American; cerebrovascular; clinical outcome assessment; cognitive testing; cohort; community partnership; digital; ethnic disparity; ethnic diversity; fitness; follow up assessment; health care availability; health disparity; high dimensionality; high risk; innovation; insight; modifiable risk; multimodality; neural; non-demented; novel; novel marker; pre-clinical; precision medicine; primary outcome; racial disparity; racial diversity; racial population; recruit; risk prediction; secondary outcome; social health determinants; social stress; sound; structural determinants; tau Proteins; tau aggregation

PROJECT SUMMARY A critical gap in understanding the etiology of sporadic Alzheimer's disease (AD) is identifying the upstream factors that lead to the development of both Alzheimer’s pathology and related neural dysfunction. Vascular disease is found in approximately 80% of patients with concomitant AD pathology and thus may be an important contributor to the development of AD, however relationships between vascular health and the emergence of AD pathophysiology has not yet been comprehensively investigated in cognitively normal samples. While large vascular adverse events such as stroke are known to confer risk for developing vascular dementia, growing evidence suggests that subtle vascular damage accrued through a lifetime of injury could predispose neural structure and function to become more susceptible to AD-related pathophysiology. Critically, chronic and subtle forms of vascular disease are more commonly found in Black and Hispanic populations with reduced access to healthcare and could help explain the increased prevalence of AD in these populations. The goal of this renewal project is to establish the role of cerebrovascular injury and dysfunction (CVID) in the pathophysiology of preclinical AD and develop individualized imaging-based cerebrovascular profiles that predict memory decline across racially and ethnically diverse populations. We will conduct follow-up assessments in 100 nondemented older adults (over 60 years of age) in our current award (BEACoN Cohort: R01AG053555), which includes amyloid-PET (florbetapir), serial high-resolution MRI and tau-PET (MK-6240), our innovative digital cognitive biomarkers which assess pattern separation, and a full UDS-3 neuropsychological testing battery. We will complement this with targeted new recruitment (n = 100) to increase the representation of Hispanic/Latino and Black participants in our cohort. We have built an infrastructure to radically transform recruitment and retention in our study including innovative partnerships with clinical research organizations with a demonstrable track record in minority recruitment. Given focus on subtle vascular damage, we will exclude based on history of stroke or severe cardiovascular disease. Our aims are (1) Assess the novel biomarker framework in which CVID predicts tau accumulation, which predicts structural and functional deterioration of the medial temporal lobes (MTL), subsequently predicting decline in hippocampal pattern separation. (2) Construct individualized brain imaging based CVID profiles that differentially predict decline in hippocampal memory across racially and ethnically diverse populations. (3) Aim 3: Associate CVID profiles with modifiable lifestyle risk factors and structural and social determinants of health that are differentially distributed across racial and ethnic groups. In summary, we will develop a novel mechanistic framework for how CVID contributes to AD pathophysiology and memory/cognitive decline that directly addresses racial and ethnic disparities in AD risk. Cerebrovascular profiles, and their associated modifiable risk factors that confer the greatest risk of AD, will be identified as targets for future intervention.

项目摘要 在了解散发性阿尔茨海默病（AD）的病因学方面的一个关键差距是确定其上游基因。 导致阿尔茨海默病病理学和相关神经功能障碍发展的因素。血管 在大约80%的伴有AD病理的患者中发现了这种疾病，因此可能是一种 然而，血管健康与AD发展之间的关系 AD病理生理学的出现尚未在认知正常的人中进行全面研究。 样品虽然已知大血管不良事件（如中风）会导致血管病变的风险， 越来越多的证据表明，通过一生的伤害， 使神经结构和功能更容易受到AD相关病理生理学的影响。重要的是， 慢性和微妙形式的血管疾病更常见于黑人和西班牙裔人群， 减少了获得医疗保健的机会，并可能有助于解释这些人群中AD患病率的增加。 该更新项目的目标是确定脑血管损伤和功能障碍（CVID）在脑血管疾病中的作用。 临床前AD的病理生理学，并开发基于成像的个性化脑血管特征， 预测不同种族和民族人群的记忆力下降。我们会跟进 在我们目前的奖项中，对100名非痴呆老年人（60岁以上）进行评估（BEACoN队列： R 01 AG 053555），包括淀粉样蛋白-PET（florbetapir）、系列高分辨率MRI和tau-PET（MK-6240）， 我们的创新数字认知生物标志物，评估模式分离，以及完整的UDS-3 神经心理学成套测验我们将通过有针对性的新招募（n = 100）来补充这一点， 增加西班牙裔/拉丁裔和黑人参与者在我们队列中的代表性。我们已经建立了一个 基础设施，从根本上改变招聘和保留在我们的研究，包括创新的伙伴关系， 临床研究组织在少数民族招聘方面有明显的记录。专注于微妙的 血管损伤，我们将根据中风或严重心血管疾病史排除。我们的目标是 (1)评估新型生物标志物框架，其中CVID预测tau累积，从而预测结构性 和内侧颞叶（MTL）的功能恶化，随后预测下降， 海马模式分离(2)构建基于CVID特征的个性化脑成像， 差异预测不同种族和民族人群海马记忆的下降。(3)目的 3：将CVID特征与可改变的生活方式风险因素以及健康的结构和社会决定因素相关联 在不同种族和民族群体中的分布差异。总之，我们将开发一个新的 CVID如何促进AD病理生理学和记忆/认知衰退的机制框架， 直接解决了AD风险中的种族和民族差异。脑血管概况及其相关 可改变的风险因素，赋予AD的最大风险，将被确定为未来干预的目标。