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.

抽象的 鉴于人口老龄化，阿尔茨海默病（AD）是一个重大的公共卫生问题。因为缺乏 迄今为止，由于缺乏有效的干预措施，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，包括各种形式的血管和 AD 病理学的组合。 肾素血管紧张素系统 (RAS) 在血压 (BP) 调节中发挥着关键作用， 越来越多的证据表明它可能通过血压控制和 AD 的发病机制参与其中 脑血流量（CBF）和血管内皮功能的相关改善，而且还通过其他 除了调节淀粉样蛋白和 tau 蛋白外，还包括抗氧化和抗炎作用等机制 代谢。包括我们的研究在内，很少有研究评估 RAS 在认知正常中的作用 高危人群评估 RAS 肽、大脑结构变化和认知之间的关联 功能，并且没有人长期跟踪参与者。在这项研究中，我们建议扩展我们的 先前对认知正常参与者的研究 肥胖且患有 T2DM 的人，因此风险增加 用于AD ，来自 Look AHEAD（糖尿病健康行动）研究通过测量 RAS 肽来阐明 RAS 可能参与影响大脑结构变化的潜在机制 9-14 年期间的认知功能。 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。 Look AHEAD 非常适合拟议的研究，因为 血管危险因素（糖尿病、肥胖、高血压、血脂异常）的高患病率以及 1) 储存的血液样本和 2) 详细测量认知功能和结构 MRI 的辅助研究 可用成像。我们的目标是检查 1) 血液 RAS 肽和酶水平（ACE-1、ACE- 2、ANGII、ANGIII 和 ANG1-7) 随着时间的推移（在第 1 年和第 4 年收集）； 2) 血液RAS之间的关联 酶和肽水平以及 与 AD 特征区域和血管相关的脑部 MRI 结构测量 措施 （9-11 年级收集一次）； 3) 血液 RAS 酶和肽之间的关联 水平以及全局和特定领域的认知测量（在 8-14 岁期间纵向收集）。 在本提案中，我们旨在阐明 RAS 在衰老过程中的作用，以了解其在发育中的贡献 AD 使用跨学科方法。这项研究的结果将有助于理解两者之间的关系 RAS 和大脑生物标志物，并指导未来的研究，以检验这些肽的变化是否可以发挥作用 作为认知能力下降和/或认知障碍的预测因子。