Using Magnetic Resonance Imaging (MRI), we have detected abnormal deep white matter lesions (DWMLs) in 20-30% of subjects over age 60. The DWMLs are difficult or impossible to detect with x-ray computed tomography (CT), and their clinical significance is unknown. Our pilot studies indicate that DWMLs are associated with increasing age, dementia, and cardiovascular disease. Our goal is to establish the clinical significance of DWMLs. We will employ a longitudinal design utilizing MRI, Xenon CT, and Positron Emission Tomography (PET) brain imaging modalities, and cognitive assessment to examine the interrelationships among DWMLs, regional Cerebral Blood Flow (rCBF) and Metabolic Rate (rCMR) as measured by 18F-2FDG uptake, and cognitive function. We will determine the optimal method for quantification of rCBF by comparing Xenon CT with 122I tracer PET methodologies on the first 25 subjects. We will use the better method for the remainder of the project. We will study 60 demented and 60 non-demented subjects 60-70 years of age. Half of each group will have both hypertension and cerebrovascular disease, the rest will be without cardiovascular risk factors. All subjects will be studied initially and again 2.5 years later. Examining autopsy material, we will determine the neuropathologic basis of MRI detected DWMLs. We will determine the degree to which early stages in the development of DWMLs are predictive of future course. Do DWMLs become more extensive over time? Are DWMLs associated with cardiovascular disease? Are DWMLs associated with dementia? Are DWMLs ischemic in origin, asociated with progressive reductions in rCBF and rCMR? Is there decreased rCBF and rCMR in the cerebral cortex subserved by the areas of abnormal white matter? Are the rCBF and rCMR changes associated with severe DWMLs in dementia different from those associated with senile dementia of Alzheimer's type (SDAT)? In non-demented subjects, is the presence of DWMLs associated with increased risk for developing cognitive impairments over time? What is the neuropathologic basis of the abnormalities we identify with MRI and PET?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Diagnostic Radiology Study Section (RNM)
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University of California San Francisco
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