The rhesus monkey is a model of normal human aging that enables cognitive testing to be followed by optimal preservation of brain tissue for multidisciplinary studies. The proposed studies will test the hypothesis that age-related cognitive decline results from a cascade of mild degenerative changes beginning in early middle age with inflammation and damage in white matter that leads to functional changes in axons and progresses to functional and structural changes in neurons. We will study three cohorts of monkeys to test various aspects of this hypothesis. The first cohort of 36 monkeys will be used in a cross-sectional study and consist of subjects covering the adult life span from 5 to 30 years old. After behavioral testing, MRI scans will be followed by in vivo neurophysiology and a new two stage perfusion fixation to provide fresh and fixed tissue to identify brain changes underlying cognitive decline. A second cohort of 6 middle aged monkeys will be treated like cohort 1 except they will be perfusion fixed with mixed aldehydes for electron microscopy to supplement existing samples and allow identification of the ultrastructural changes that are the first changes to appear in middle age in association with cognitive decline. A third cohort of 12 early middle aged monkeys (ages 13-15) will be followed longitudinally for 4+ years with repeated behavioral testing, MRI scans of the brain, and samples of blood and CSF. As the prevalence of cognitive impairment is low at 13-15 but high by 20, behavioral data will identify the cognitive profile and rate of decline of individual monkeys. Longitudinal MRIs will reveal concurrent changes in the in vivo brain structure, and CSF and blood samples will allow biomarkers to be followed. For cohorts 1 and 3, perfusion fixation will be preceded by in vivo neurophysiological assessment of compound action potentials. Then the two stage perfusion will follow to allow immediate collection of unfixed samples from one hemisphere before the remainder of the brain is fixed. Fresh tissue will be used for in vitro neurophysiology of synaptic currents and action potentials, for single cell PCR, and for biochemical and molecular studies of underlying mechanisms. Fixed tissue will be used for anatomical studies, including stereological studies of neuron numbers and immunocytochemical studies of inflammation and other degenerative processes.
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