UC San Diego

Magnetic resonance imaging (MRI) techniques provide a noninvasive, quantitative means to assess spatial and temporal patterns of change that occur in the brain, both as a function of healthy aging and as a function of neurodegenerative disease. In particular, structural MRI can be used to quantify cortical thickness and subcortical volumes across the brain at sub-millimeter accuracy. By tracking these measurements in an individual across time using longitudinal analysis, it is possible to assess the rate and spatial distribution of gross anatomical change, which is believed to correlate with neuronal loss and shrinkage. Further, diffusion tensor imaging (DTI) allows assessment of the brain at the level of local microstructure and is believed to be sensitive to changes in white matter integrity. These quantitative neuroimaging techniques have been applied to three distinct studies in this dissertation. In Chapter One, it is shown that neurodegeneration can be quantified in healthy elderly subjects across a time period as short as six months, and this quantification might help identify those at risk for subsequent cognitive decline. In Chapter Two, these imaging techniques are used as quantitative phenotypes in a genetic analysis to show that polymorphisms in the cholesteryl ester transfer protein (CETP) gene associate with and therefore may contribute to the genetic variability of brain structure, atrophy rate and Alzheimer's disease susceptibility. Chapter Three of this dissertation applies these techniques to the study of Lewy body dementia, in which it is found that structural change in the Lewy body dementias appears intermediate between that of Alzheimer's disease and healthy aging, whereas DTI data reveals relatively equivalent severities between Alzheimer's disease and dementia with Lewy bodies. These results suggest that Lewy body dementia may be characterized more prominently by microstructural change rather than neuronal loss