The goal of this revised R01 application is to investigate the relationships among late-life depression (LLD), cognitive impairment and progressive neurodegeneration. The guiding hypothesis is that LLD patients have evolving cognitive impairments as a consequence of distinct underlying neuropathological changes, which frequently are expressed as Mild Cognitive Impairment (MCI). These neuropathological and cognitive changes are risk modifiers, lowering brain reserve capacity, and in turn, increasing risk of developing Alzheimer's Disease (AD). In order to pursue this goal we will enroll LLD, MCI, and normal control subjects to enrich our existing cohort (gathered through Dr. Butters'existing K01 Award (MH01684), """"""""The Course of Cognitive Functioning in Late-Life depression"""""""" to include a total of 150 elderly, non-demented, non-depressed subjects, 60 nondepressed MCI subjects and 270 LLD subjects. Using the joint infrastructure of the University of Pittsburgh's Intervention Research Center for Late-Life Mood Disorders (MH52247) and the Alzheimer's Disease Research Center (AG05133) we will complete a detailed neurobehaviora! evaluation, including clinical, neuropsychological, neuroimaging and biological markers, using these data to evaluate the factors associated with the development of MCI or dementia. Subjects will be studied annually for at least three years, allowing us to use longitudinal data to evaluate a series of linked hypotheses that postulate the pathways by which elderly, depressed patients develop cognitive impairment, and which may lead some to develop dementia.
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