This is a multidisciplinary program to assess the separate and combined effects of hypertension and atherogenic diet for periods of 12 to 48 months on the central nervous system of the cynomolgus monkey. This monkey was chosen because hypertension experimentally induced by coarctation of the aorta and determine how these two variables contribute to the development of cerebrovascular disease and the effects of that disease on the brain and behavior. Our overall hypothesis is that hypertension alone, or in combination with a hypercholesterolemic diet, leads to a breakdown of the blood brain barrier with consequent disruption of synaptic function resulting in impaired cognitive function after as little as 12 months of disease. A further hypothesis is that the pathology will progress from scattered microinfarction at 12 months to extensive infarction throughout the brain by 48 months. To test this hypothesis all animals will be behaviorally tested on tasks sensitive to memory impairments in both monkeys and humans. Periodic clinical measures will be taken including physical exams, fundus photography and fluorescein angiography of the retina, clinical blood chemistry as well as MRI and PET scans of the brain. At the end of testing, the effects of disease on the cerebral vasculature, the brain and the eyes will be examined. One project will assess the integrity of the blood brain barrier and determine whether complement proteins are extravasated and whether these might induce cytotoxic damage in the brain. Parallel immunocytochemical studies will localize the presence of such extravasated plasma proteins and reactive astrocytes in the brain. In another project on hemisphere of the brain will be serially sectioned and the distribution of cerebrovascular changes including microinfarction, stroke and white matter changes will be determined. A related study will analyze the temporal lobe limbic system, the areas most likely to account for the early onset of the observed memory deficits. Analyses of the hippocampus, amygdala and entorhinal cortex will include volumetric measures and ligand binding assessment of the major chemical neuroanatomical systems (GABA, glutamateaspartate and acetylcholine). The final study will examine the clinical progression of changes in the eye to determine whether the reflect concomitant changes in the brain. Neuroanatomical studies will examine how specific populations of retinal neurons and glia are affected. Finally an overall statistical analysis of these measures will be performed using structural equation modeling to test the hypothesized relationships among hypertension, atherogenic diet, breakdown of the blood brain barrier and consequent changes in behavior, the brain and the retina.
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