Effects of the renin angiotensin system on MRI volumetric measures and cognitive function in the Alzheimer's disease process: the LookAHEAD study

肾素血管紧张素系统对阿尔茨海默病过程中 MRI 体积测量和认知功能的影响：LookAHEAD 研究

• 批准号: 10645040
• 负责人: Sevil Yasar
• 金额: $ 49.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645040
• 关键词: ACE2; ANGPT1 gene; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Ancillary Study; Angiotensin II; Antiinflammatory Effect; Antioxidants; Attention; Biological Markers; Biological Process; Blood; Blood Pressure; Blood Proteins; Blood Vessels; Blood specimen; Brain; Brain imaging; Cerebrovascular Circulation; Clinical Trials; Cognition; Cognitive; Confounding Factors (Epidemiology); Data; Development; Diabetes Mellitus; Disease; Dyslipidemias; Elderly; Enzymes; Future; Health; High Prevalence; Hippocampus; Hypertension; Image; Impaired cognition; Intervention; Learning; Magnetic Resonance Imaging; Measures; Mediating; Medication Systems; Memory; Metabolism; Middle frontal gyrus structure; Modification; Movement; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome Measure; Parietal; Parietal Lobe; Participant; Pathogenesis; Pathologic; Pathologic Processes; Pathway interactions; Peptides; Peptidyl-Dipeptidase A; Persons; Phase; Play; Population; Populations at Risk; Process; Proteins; Protocols documentation; Public Health; Recording of previous events; Renin-Angiotensin System; Research; Role; Sampling; Sampling Studies; Short-Term Memory; Standardization; Symptoms; System; Temporal Lobe; Thick; Time; Vascular Endothelium; White Matter Hyperintensity; blood pressure control; blood pressure regulation; brain magnetic resonance imaging; cardiovascular risk factor; cognitive function; cost effective; effective intervention; executive function; frontal lobe; gray matter; imaging biomarker; improved; ischemic lesion; lifestyle intervention; novel; processing speed; randomized, clinical trials; study population; tau Proteins; treatment trial; vascular endothelial dysfunction; vascular risk factor

ABSTRACT Given the aging of the population, Alzheimer's disease (AD) is a major public health issue. Because of the lack of effective interventions to date, there is a need to identify new treatments. Emerging evidence has shown that AD involves multiple pathological mechanisms, with combinations of various forms of vascular and AD pathology. The renin angiotensin system (RAS) plays a key role in blood pressure (BP) regulation and there is growing evidence about its likely involvement in the pathogenesis of AD, potentially through BP control and associated improvement of cerebral blood flow (CBF) and vascular endothelial function, but also through other mechanisms, including antioxidant, and anti-inflammatory effects, in addition to modulation of amyloid and tau metabolism. There are very few studies, including our studies, evaluating the role of RAS in cognitively normal at-risk population to evaluate associations between RAS peptides, structural brain changes and cognitive function, and none following participants over long period of time. In this study we propose to extend our previous research in cognitively normal participants who are obese with T2DM, thus at increased risk for AD , from Look AHEAD (Action for Health in Diabetes) study by measuring RAS peptides to elucidate the underlying mechanism by which the RAS may be involved in structural brain changes affecting cognitive function over an 9-14-year period. The Look AHEAD study was a randomized clinical trial of a lifestyle intervention that is now in an observational phase. Look AHEAD is ideal for the proposed study because of the high prevalence of vascular risk factors (diabetes mellitus, obesity, hypertension, dyslipidemia) as well as 1) stored blood samples and 2) ancillary studies with detailed measures of cognitive function and structural MRI imaging available. Our aims are to examine 1) change of blood RAS peptide and enzyme levels (ACE-1, ACE- 2, ANGII, ANGIII and ANG1-7) over time (collected at years 1 and 4); 2) associations between blood RAS enzyme and peptide levels and brain MRI structural measures related to AD signature regions and vascular measures (collected once through years 9-11); and 3) associations between blood RAS enzymes and peptide levels and global and domain specific cognitive measures (collected longitudinally through years 8-14). In this proposal we aim to elucidate the role of RAS during aging to understand its contribution in the development of AD using cross-disciplinary approach. The results of this study will help understand the relationship between RAS and brain biomarkers and guide future research to examine whether changes in these peptides could serve as predictors of cognitive decline and/or cognitive impairment.

摘要 鉴于人口老龄化，阿尔茨海默病（AD）是一个主要的公共卫生问题。因为缺乏 由于迄今为止没有有效的干预措施，因此需要确定新的治疗方法。新出现的证据表明， AD涉及多种病理机制，具有各种形式的血管和AD病理的组合。 肾素血管紧张素系统（RAS）在血压（BP）调节中起关键作用， 越来越多的证据表明其可能参与AD的发病机制，可能通过BP控制， 相关的脑血流量（CBF）和血管内皮功能的改善，但也通过其他 机制，包括抗氧化剂和抗炎作用，以及调节淀粉样蛋白和tau蛋白 新陈代谢.包括我们的研究在内，很少有研究评估RAS在认知正常人中的作用。 风险人群，以评估RAS肽、脑结构变化和认知功能之间的关联 功能，并且没有在很长一段时间内跟踪参与者。在这项研究中，我们建议扩大我们的 先前在认知正常参与者中的研究 肥胖的2型糖尿病患者， 的AD ，从展望未来（糖尿病健康行动）研究通过测量RAS肽来阐明 RAS可能参与脑结构变化的潜在机制， 9-14年的认知功能。Look AHEAD研究是一项随机临床试验， 生活方式干预目前处于观察阶段。展望未来是拟议研究的理想选择，因为 高患病率的血管危险因素（糖尿病、肥胖、高血压、血脂异常）以及 1)储存的血液样本和2）辅助研究，详细测量认知功能和结构MRI 提供成像。我们的目的是检测1）血液RAS肽和酶水平（ACE-1，ACE-2）的变化， 2）血管紧张素II、血管紧张素III和血管紧张素1 -7）随时间的变化（在第1年和第4年收集）; 2）血液RAS之间的相关性 酶和肽水平， 与AD特征区域和血管相关的脑MRI结构测量 措施 （9-11年收集一次）;和3）血液RAS酶和肽之间的关联 水平和全球和特定领域的认知措施（收集纵向通过年8-14）。 在这项提案中，我们的目标是阐明RAS在衰老过程中的作用，以了解其在发展中的作用。 使用跨学科的方法。这项研究的结果将有助于了解 RAS和脑生物标志物，并指导未来的研究，以检查这些肽的变化是否可以 作为认知衰退和/或认知损害的预测因子。