The central question addressed by this proposal is whether hypertension accelerates the cognitive and neurobiological changes that occur in late middle age. To address this question we propose to assess the separate and combined effects of hypertension and late middle age on cognition and brain integrity in a non-human primate model. With the benefit of experience from two well established non-humanprimate models, one on normal aging and the other on hypertensive cerebrovascular disease, we believe we are now ready to pursue the long-standing clinical issue of the effect of elevated blood pressure and aging on cognition and brain integrity. A total of 40 rhesus monkeys, 20 of late middle age, and 20 young adults, will be used in this study. All 40 animals will first undergo MR imaging, a battery of behavioral testing, and telemetric blood pressure monitor implants to establish baseline brain white and grey matter volume, cognitive function, and blood pressure, respectively. Upon completion of testing, monkeys will be distributed into four groups in a 2 x 2 design to assess the separate and combined effects of late middle age and hypertension. Each of the ten late middle aged and ten young adult hypertensive monkeys, together with each of the ten late middle aged and ten young adult normotensive monkeys will be evaluated for a period of 18 months. During this period they will be behaviorally retested at two time intervals and receive a second MRI at the end of the study. Blood pressure will be measured in the awake unrestrained state using telemetric probes. Upon the conclusion of behavioral testing, the brains will be processed for the presence and extent of neuropathological change with emphasis on the pattern and extent of white matter involvement using immunocytochemistry to assess the presence and extent of LN-3 positive microglial cells.
The specific aims of this proposal are as follows: 1) To determine the extent to which hypertension exacerbates the effects of late middle age on cognition and brain integrity. 2) To determine if the behavioral and brain degenerative effects of hypertension on aging are additive or act in a synergistic manner and, 3) to assess the individual effects of late middle age and hypertension on cognition and brain integrity.
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