Cognitive Impairment and Dementia, Vascular Brain Injury, and Atrial Myopathy: Implications for Prevention of Alzheimer's Disease-Related Dementias

认知障碍和痴呆、血管性脑损伤和心房肌病：对预防阿尔茨海默病相关痴呆的影响

• 批准号: 10814076
• 负责人: Lin Yee Chen
• 金额: $ 439.02万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10814076
• 关键词: Adult; Affect; Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Atherosclerosis Risk in Communities; Atrial Fibrillation; Biological Markers; Black race; Brain Infarction; Cerebrovascular Trauma; Clinical; Clinical Trials; Cognitive; Communities; Data; Dementia; Disease; Echocardiography; Elderly; Electrocardiogram; Ensure; Epidemiologic Methods; Etiology; Evaluation; Funding; Future; Glial Fibrillary Acidic Protein; Heart; Heart Atrium; Hemorrhage; Hypertension; Image; Imaging technology; Impaired cognition; Incidence; Intervention; Ischemia; Jackson Heart Study; Left; Left Atrial Function; Left Ventricular Mass; Life Style; Light; Measurement; Measures; Molecular; Molecular Target; Monitor; Multi-Ethnic Study of Atherosclerosis; Myopathy; Neurocognitive; Organ; Outcome; Participant; Pathology; Persons; Plasma; Population; Prevention; Prevention strategy; Proteins; Proteomics; Public Health Practice; Reproducibility; Research; Risk Factors; Structure; Time; United States National Institutes of Health; Visit; White Matter Disease; abeta deposition; analytical method; apolipoprotein E-4; cardiovascular disorder risk; clinical practice; cognitive function; cohort; dementia risk; follow-up; heart rhythm; high risk; metabolomics; mild cognitive impairment; modifiable risk; neurofilament; neuroimaging; neuroimaging marker; neuropathology; neurovascular unit; novel; prevent; prognostic; symposium; tau-1; vascular cognitive impairment and dementia; vascular risk factor; wearable device

Alzheimer’s Disease (AD) and AD-Related Dementias (ADRD) are projected to affect 115 million people worldwide by 2050. Vascular contributions to cognitive impairment and dementia (VCID)—a primary type of ADRD—is a major research focus for the NIH, which has called for the need to discover novel non-invasive, non-CNS organ-related (e.g., heart) markers to detect presence and progression of VCID (ADRD summit 2022). The oldest-old (>85 years) are the fastest growing segment of the population in most of the world and have the highest rates of dementia. Yet, the risk factors for AD/ADRD in the oldest-old are poorly understood and are different from the young-old (65-74 years) and middle-old (75-84 years). For example, in the oldest- old, hypertension is protective and about half of all dementia cases is related to non-AD pathologies such as microbleeds and small vessel ischemic disease. Atrial myopathy (defined by altered left atrial [LA] function or structure) is an underrecognized but important contributor to VCID, and is associated with lower cognitive function, greater vascular brain injury, and incident dementia. Atrial myopathy is also associated with greater global cortical β-amyloid (AD pathology). However, the extent to which atrial myopathy is associated with dementia risk in the oldest-old is unknown. Furthermore, prior research has evaluated atrial myopathy as a static entity and the etiology and prognostic relevance of atrial myopathy progression are not known. These are crucial barriers to targeting this potentially modifiable risk factor for AD/ADRD prevention. Thus, the overarching objectives of this project are to determine the prognostic importance of atrial myopathy for incident dementia in the oldest-old; relate atrial myopathy progression or trajectories of atrial myopathy in the young-old and middle-old to incident dementia and change in neuroimaging and plasma biomarkers of AD/ADRD; and define the clinical/lifestyle risk factors and proteomic and metabolomic signatures of adverse atrial myopathy trajectories. We will leverage the extensively well-characterized Atherosclerosis Risk in Communities (ARIC) cohort (including the longest followed cohort of Black adults) with existing MCI/dementia ascertainment and neuroimaging data, and will perform serial measurement of LA function, measure circulating AD/ADRD biomarkers, and conduct ambulatory heart rhythm monitoring to rigorously detect atrial fibrillation (AF) so that we can account for the contribution of AF to associations. To ensure rigor and reproducibility, we will replicate findings in 2 independent community-based cohorts: Multiethnic Study of Atherosclerosis and the Jackson Heart Study. This project will have significant impact. Our findings will (a) broaden VCID to encompass atrial myopathy as an insult to the neurovascular unit, thus identifying a new avenue for AD/ADRD treatment or prevention; (b) clarify the pathology underlying the neurocognitive impact of atrial myopathy, hence facilitating research to discover novel AD/ADRD prevention strategies; (c) identify specific lifestyle or molecular targets for atrial myopathy progression, thus informing future clinical trials aimed at preventing AD/ADRD.

阿尔茨海默氏病（AD）和与广告相关的痴呆症（ADRD）预计将影响1.15亿人 到2050年，全球。对认知障碍和痴呆（VCID）的血管贡献 - 主要类型 ADRD是NIH的主要研究重点，该研究呼吁需要发现新颖的非侵入性， 非CNS器官相关（例如心脏）标记以检测VCID的存在和进展（Adrd Summit 2022）。最古老的（> 85年）是世界上大多数人口增长最快的人群， 痴呆症的发生率最高。然而，在最大的老年人中，广告/adrd的危险因素知之甚少 与年龄（65-74岁）和中年（75-84岁）不同。例如，在最古老的 旧的，高血压受到保护，所有痴呆症病例中约有一半与非AD病理有关 微血管和小血管缺血性疾病。心房肌病（由更改的左心房[la]功能定义或 结构）是vCID的未经认可但重要的贡献，并且与较低的认知有关 功能，更大的血管脑损伤和入射痴呆。心房肌病也与更大有关 全球皮质β-淀粉样蛋白（AD病理学）。但是，心房肌病与 最大的老年痴呆症风险是未知的。此外，先前的研究已将心房肌病评估为 静态实体以及心房肌病进展的病因和预后相关性尚不清楚。这些 是针对此潜在可修改的AD/ADRD预防危险因素的关键障碍。那， 该项目的总体目标是确定房屋肌病对事件的预后重要性 最大的痴呆症；与年龄较大的房屋肌病的进展或心房肌病的轨迹相关联 和中间到入射痴呆症以及AD/ADRD的神经影像和血浆生物标志物的变化；和 定义临床/生活方式危险因素以及不良心脏肌病的蛋白质组学和代谢组学特征 轨迹。我们将利用社区（ARIC）的广泛特征性的动脉粥样硬化风险 队列（包括最长的黑人队列）与现有的MCI/痴呆症确定和 神经影像学数据，并将对LA功能进行串行测量，测量循环AD/ADRD 生物标志物并进行卧床心律监测以严格检测房颤（AF），以便 我们可以考虑AF对关联的贡献。为了确保严格和可重复性，我们将复制 2个独立社区的同伙中的发现：动脉粥样硬化的多民族研究和杰克逊 心脏学习。该项目将产生重大影响。我们的发现将（a）扩大VCID以包含房屋 肌病是神经血管单元的伤害，从而确定了新的AD/ADRD治疗途径 预防; （b）构成心房肌病的神经认知影响的基础病理 研究发现新颖的AD/ADRD预防策略； （c）确定特定的生活方式或分子目标 心房肌病的进展，从而为未来的临床试验提供了旨在预防AD/ADRD的临床试验。