The goal of this project is to describe the structural changes in the aging brain that are associated with cognitive impairment. The most prominent changes in the aging brain include abnormalities in myelin and neuroglial cells, while the changes in neurons are more subtle. The proposed studies build on significant findings suggesting that age-related cognitive impairment may represent a failure of axonal conduction in pathways and brain regions that are critical for memory and executive function. There are five aims: 1) The structure of myelinated nerve fibers in the brain of middle aged monkeys (13 - 19 years of age) will be studied to determine which degenerative changes occur first, and whether these changes precede the onset of cognitive impairment. 2) The ultrastructure of the fiber pathways in the prefrontal cortex will be examined across the lifespan since this is the cortical region implicated in age-related cognitive impairment. The dorsal longitudinal fasciculus will be a particular focus because it appears to be damaged with age as measured by neuroimaging studies. 3) The neurodegenerative changes in the aging neocortex will be assessed, including prefrontal area 8a, where neuron loss has been reported. The mechanism by which damaged neuronal elements are eliminated will also be investigated using antibodies to ubiquitin, and synapse number will be studied in layers 2/3 and layer 5 of prefrontal area 46 and visual area 17 to determine whether changes in symmetric and asymmetric synapses can explain the age-related changes in neuronal excitability described by Project 3. 4) The neuroglial cell population will be examined quantitatively in areas 46 and 17 in relation to age and cognitive status. 5) The ultrastructure of the blood brain barrier will be examined to determine whether degenerative changes might allow molecules into the brain which damage neurons and their axons during the aging process. The studies in this project will provide critical information about the structure of the aging brain and will highlight those changes that may be responsible for cognitive decline.