Hypertension, a common condition among the elderly and even middle aged adults, has long been associated with cognitive dysfunction, particularly in the domain of memory. However, the neurobiological basis for this impairments is not well understood. This project will determine the cognitive effects on monkeys at known risk for cerebrovascular disease from hypertension alone, or in combination with an atherogenic diet. We plan to assess the cognitive function of monkeys using behavioral tasks which were developed for, or adapted from neuropsychological batteries used i the evaluation of geriatric populations and, in particular, patients with cerebrovascular disease. The performance of monkeys will be followed in cohorts at six months intervals for either 12 or 48 months. In this matter, a profile of change in cognitive function, including memory, executive function (cognitive flexibility, attention, visuospatial function and psychometric speed) will be determined. We expect to see measurable cognitive impairment, primarily in memory function, occurring as a consequence of hypertension alone, or in combination with atherogenic diet, but not from atherogenic diet alone. This change should be observable by 12 months following induction of hypertension with or without maintenance on atherogenic diet. We expect the long term consequences (48 months) of hypertension to produce a progressive decline in memory function as well as produce impairments in other cognitive domains including executive system function, visuopatial abilities and attention, producing, in effect, a cerebrovascular dementia. We expect that monkeys with hypertension combined with atherogenic diet will also develop a dementia state, but, owing to possible differences in focal neuropathology, the pattern of deficits may be more variable than that found with hypertension alone. The 48 month behavioral assessment of a subset of monkeys in this project will allow us to determine whether early cognitive changes identified at 12 months will progress toward a """"""""dementia"""""""" state, as defined by criteria parallel to those for dementia in humans. Furthermore, the changes in cognition charted in this project will be correlated with anatomical, imaging and neuropathological data collected from the same animals to determine the extent of the relationship between these variables. This approach may also permit the identification of a relevant behavioral or neurobiological marker of cognitive impairment and cerebrovascular dementia. Further, a composite index of cognitive decline will be correlated with an overall index of changes on MRI and PET in the same animals. In this manner, we will be able to determine if metabolic hypofunction identified on PET precedes or occurs concomitantly with cognitive impairment. A composite index of behavioral findings as well as changes in individuals domains will be correlated with the presence of blood brain barrier compromise the and extent and pattern of retinopathy. Finally, the relationship between cognitive decline, systolic blood pressure and serum cholesterol level will be measured.
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