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