Given the aging of the population, dementia is a rapidly increasing public health issue. Because of the lack of effective interventions to date, there is a need to identify new treatments. The renin angiotensin system (RAS) plays a key role in blood pressure regulation and there is emerging evidence about its possible involvement AD pathology. Effects by the RAS are associated with elevated angiotensin II (ANGII) levels resulting in an over activation of angiotensin receptor type-1 (AT1R), which is associated with accumulation of amyloid-? and tau, in addition to elevated blood pressure. ANGII level increase is the result of increased conversion from angiotensin I mediated by the angiotensin converting enzyme (ACE). Epidemiological studies suggest that antihypertensive medications acting via the RAS, including ACE inhibitors and AT1R blockers, protect against cognitive decline and re-purposing these drugs may have therapeutic potential in AD. There are currently very few studies available evaluating associations between blood ACE or ANG II levels and cognitive aging or imaging. We, in this proposed study, will leverage on available data to evaluate associations between ACE and ANGII blood levels, blood pressure and MRI brain volumetric measures of regions vulnerable to AD. We have completed collection of blood and measuring ACE and ANGII levels at baseline, and evaluated associations with cognitive function in non-demented, community dwelling older population (N=56) of the Brain Health Study (BHS), a sub-study of the Baltimore Experience Corps Trial (BECT). We found in our cross-sectional analysis significant positive associations between ANGII and verbal memory, in our longitudinal analysis a significant negative association between ACE and working memory, and these were not mediated by blood pressure. At the time of blood collection we also obtained brain MRI on participants (N= 46) that have not been processed. We now seek support to obtain MRI volumetric measures of the hippocampus, entorhinal cortex, and other regions implicated in AD in order to evaluate these new markers and targets as potentially important predictors in the development of AD.
Our aims are to examine cross-sectional associations between: 1) Blood ACE and ANGII levels and available MRI data by obtaining brain volumes implicated in AD. 2) Blood ACE and ANGII levels and blood pressure (BP) measurements, including systolic (SBP) and diastolic blood pressure (DBP). 3) Systolic (SBP) and diastolic blood pressure (DBP), and MRI brain volumes. The results of this study will help elucidate the relationship between RAS and brain biomarkers, and guide future research to examine whether ACE and ANGII level changes could serve as predictors of cognitive decline and/or cognitive impairment. At the same time, these brain biomarkers can inform potential mechanisms of action that may lead to the development of a potential new pharmacological target.

Public Health Relevance

Dementia is a rapidly increasing clinical and public health issue, primarily as a result of aging of the population. Identifying new and potentially effective pharmacological approaches to aid early detection and for possible development of a potential new pharmacological target is critical. In this proposal, we will evaluate associations between blood levels of angiotensin II (ANGII) and angiotensin converting enzyme (ACE), blood pressure and brain MRI volumes, to help elucidate the effect of renin-angiotensin system in the role of cognitive function and furthermore help identify a potential new pharmacological target.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
1R03AG058043-01
Application #
9434313
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Mackiewicz, Miroslaw
Project Start
2018-01-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205