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