During the last grant period we examined several areas of the cerebral cortex of young (4 to 6 years of age) and old (over 25 years of age) rhesus monkeys and came to the conclusion that there is no significant loss of cortical neurons with age. However there are other significant changes both in the cortex and in the underlying white matter. The most obvious of these is a breakdown in the integrity of myelin. This is not demyelination in the sense that the axons are left bare, but a breakdown in the integrity of the sheats that might best be termed ~dysmyelination~. There is some evidence of axonal degeneration, but this is not pronounced in the cortex. Furthermore, in our study of the frontal cortex we found that there is a correlation between the extent of myelin breakdown and the performance of old monkeys on the delayed nonmatching to sample tasks. In addition, MCI scans of the cerebral hemispheres of our monkeys, show a loss of white matter, but not of gray matter, with age. And when the extent of loss of white matter is plotted against the behavioral performance of the monkeys, there is a significant correlation with the performance of the monkeys on the acquisition component of the delayed nonmatching to sample task. These results have lead us to believe that a breakdown in the integrity of myelin might underlie the cognitive deficits, since this would reduce the conduction rates along some axons and disrupt the timing of synaptic activity in neuronal circuits. Obviously, an in depth study of the effect of aging on myelin is important. We propose to continue MCI scans to obtain better data on the correlation between white matter loss and behavioral performance. In addition, we will use a new tritium quenching technique to determine whether myelin loss is more prevalent in some cortical areas that in others, and will correlate the results with the recorded behavior of the monkeys. Finally, we propose to examine the effect of aging on myelin sheaths by electron microscopy, to determine how sheaths break down, what size fibers are most affected, and whether the breakdown of the myelin occurs equally throughout the CNS, or whether it is more prominent in some fiber pathways than in others. For this purpose, we have chosen to examine the visual pathway, since this system offers a hierarchical system of fiber connections, as well as intracortical and extracortical connections, whose origins and terminations are well known.
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