Hypertension is associated with cognitive impairment even in the absence of dementia. These vascular-related mild cognitive impairments are undetected and are commonly characterized by executive dysfunction. To date, no specific treatment is available for executive mild cognitive impairment which is associated with poor outcomes in hypertension. The PI has recently completed, with support from a K23 award, a preparatory pilot study (n=47) to test the feasibility, safety and effect size of candesartan, an angiotensin receptor blocker, compared to hydrochlorothiazide and lisinopril, in individuals with hypertension and mild cognitive impairment characterized by executive dysfunction. Our preliminary analysis which was recently accepted for publication in the Archives of Internal Medicine, suggests that, independent of blood pressure, candesartan is superior to other antihypertensives in preserving executive function. Candesartan was also associated with an increase in cerebral blood flow velocity that only reached significance in those with low flow velocity at baseline (n=23). We hypothesized based on these data to further test the effect of angiotensin receptor blockers on cognitive function by conducting a 1-year double blind randomized active-control trial of candesartan vs. lisinopril in 160 individuals with hypertension and evidence of mild cognitive impairment in the executive domain.
The specific aims of this proposal are to investigate the effects of candesartan on executive function decline and on change in cerebral perfusion, cerebrovascular reserve and microvascular brain injury. We also aim at Identifying potential underlying mechanisms related to vascular structure and function by which candesartan may affect the cognitive and cerebrovascular outcomes. Participants will be recruited from the greater Los Angeles Area and evaluated at the University of Southern California. Cognitive tests that assess executive function and other cognitive domains will be administered at baseline and 12 months after treatment. Neuroimaging which includes perfusion (continuous arterial spin labeling) and micro-structure (diffusion tensor imaging), carotid ultrasound (carotid intima-media thickness), and endothelial and vascular inflammatory markers will be performed at baseline and after 12 months of treatment. This trial will shed more light onto the potential therapeutic effects of angiotensin receptor blockers on executive dysfunction and related vascular brain injury. This project will also improve our understanding of the possible mechanisms of action of this class of antihypertensives.

Public Health Relevance

Hypertension is associated with a pattern of cognitive decline characterized by executive dysfunction. Although great advances have been made in treating hypertension, cognitive decline is on the rise. This study investigates the effect and mechanism of action of an angiotensin receptor blocker compared to an angiotensin converting enzyme inhibitor (an antihypertensive medication) on executive function and related cognitive domains. The effects of this medication will also be assessed based on cerebral circulatory function and structure.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG042127-04
Application #
8704358
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Ryan, Laurie M
Project Start
2013-08-15
Project End
2017-04-30
Budget Start
2014-08-15
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$598,586
Indirect Cost
$201,207
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Hajjar, Ihab; Rodgers, Kathleen (2013) Do angiotensin receptor blockers prevent Alzheimer's disease? Curr Opin Cardiol 28:417-25