This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. These ongoing studies 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. Three cohorts of monkeys are being studied to test various aspects of this hypothesis. After behavioral testing of the first cohort, MRI scans are followed by in vivo neurophysiology and perfusion fixation to provide fresh and fixed tissue to identify brain changes underlying cognitive decline. A second cohort of 6 middle aged monkeys is being treated like cohort 1 except their samples will be perfusion fixed with mixed aldehydes for electron microscopy to supplement existing samples and allow identification of the ultrastructural changes. A third cohort of 12 early middle aged monkeys (ages 13-15) is being followed longitudinally for with repeated behavioral testing, MRI scans of the brain, and analysis of blood and CSF. 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 is preceded by in vivo neurophysiological assessment of compound action potentials. Two stage perfusion follows to allow immediate collection of unfixed samples from one hemisphere before the remainder of the brain is fixed. Fixed tissue is used for anatomical studies, including stereological studies of neuron numbers and immunocytochemical studies of inflammation and other degenerative processes. Structures of key proteins are being determined by FTMS and LC-MS/MS.