Chronic diseases, which increase in prevalence with age, impair intellectual functioning. We and others have found that patients with essential hypertension have impaired performance on neuropsychological tests relative to age-matched controls. At the initiation of our project, the mechanism by which hypertension impaired intellectual function was unknown. We hypothesized that the morphological changes (vascular remodeling) associated with hypertension might interfere with regional cerebral blood flow (rCBF) responses induced by information processing. We have now shown with Positron Emission Tomography (PET) that hypertension impairs rCBF, altering both flow volume and the patterning of flow within the brain. The differences in flow volume are specific to hypertensives performing poorly on a test of working memory. Overall, hypertensive performing mnemonic tasks show a left lateralized increase in rCBF in prefrontal, and perhaps, posterior parietal areas that exceeds that of normotensives. As a result of this difference, hypertensives process the mnemonic task bilaterally; while normotensives tend to show a dominant right hemisphere processing. During the current project, we have also tested a second hypothesis that other vascular pathology might contribute to the cognitive impairment of hypertensives, either atherosclerotic changes assessed indirectly from thickening of the carotid artery wall and/or white matter lesions in the brain detected by magnetic resonance imaging (MRI). Initial data analyses, however, fail to provide strong support for this second hypothesis. We now propose to test our vascular hypothesis of the source of cognitive impairments associated with hypertension. We suggest that reversing both the heightened blood pressure and vascular remodeling of hypertension will also normalize both rCBF and cognitive performance. Pharmacological advances in the treatment of hypertension have now shown that angiotension converting enyzme (ACE) inhibitors and beta-blockers differ in their influence on the vasculature. Both medications reduce blood pressure, but ACE inhibitors also reduce medial wall thickness and restore the sensitivity of the vascular endothelium to nitric oxide. This permits us to test our vascular model. We hypothesize that an ACE inhibitor, lisinopril, will normalize rCBF and cognitive function relative to the actions of a beta-blocker, atenolol. We further suggest that this effect will be mediated by lisinopril's action on the vasculature as assessed peripherally via a brachial artery flow mediated vasodilation probe and centrally via testing for cerebrovascular reserve with the administration of acetazolamide (Diainox). Based on the literature, a one-year treatment period will be required to adequately test our hypothesis. Should we be successful, our project will have advanced considerably toward our ultimate goal of identifying mechanisms for how diseases of aging influence intellectual functioning. Successful completion will clarify a) how one major disease of aging reduces intellectual functioning and b) permit a rational choice of clinical regimen to treat this disease while minimizing neuropsychological side effects.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-RPHB-3 (01))
Program Officer
Jobe, Jared B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Jennings, J Richard; Heim, Alicia F; Kuan, Dora Chieh-Hsin et al. (2013) Use of total cerebral blood flow as an imaging biomarker of known cardiovascular risks. Stroke 44:2480-5
Heim, Alicia F; Coyne, Melissa J; Kamboh, M Ilyas et al. (2013) The catechol-o-methyltransferase Val158 Met polymorphism modulates organization of regional cerebral blood flow response to working memory in adults. Int J Psychophysiol 90:149-56
Jennings, J R; Mendelson, D N; Muldoon, M F et al. (2012) Regional grey matter shrinks in hypertensive individuals despite successful lowering of blood pressure. J Hum Hypertens 26:295-305
Jennings, J Richard; Mendelson, David N; Redfern, Mark S et al. (2011) Detecting age differences in resistance to perceptual and motor interference. Exp Aging Res 37:179-97
Richard Jennings, J; Christie, Israel C; Muldoon, Matthew F et al. (2010) Brain function, cognition, and the blood pressure response to pharmacological treatment. Psychosom Med 72:702-11
Jennings, J Richard; Zanstra, Ydwine (2009) Is the brain the essential in hypertension? Neuroimage 47:914-21
Jennings, J Richard; Muldoon, Matthew F; Whyte, Ellen M et al. (2008) Brain imaging findings predict blood pressure response to pharmacological treatment. Hypertension 52:1113-9
Jennings, J Richard; Muldoon, Matthew F; Price, Julie et al. (2008) Cerebrovascular support for cognitive processing in hypertensive patients is altered by blood pressure treatment. Hypertension 52:65-71
Christie, Israel C; Price, Julie; Edwards, Louisa et al. (2008) Alcohol consumption and cerebral blood flow among older adults. Alcohol 42:269-75
Jennings, J Richard; van der Veen, Frederik M; Meltzer, Carolyn C (2006) Verbal and spatial working memory in older individuals: A positron emission tomography study. Brain Res 1092:177-89

Showing the most recent 10 out of 19 publications