The broad, long-term goal of this research is to develop antemortem markers that are sensitive to the detection of the earliest neuronal changes in Alzheimer's disease (AD). Such markers may be useful to characterize subjects at risk, to differentiate normal age-related memory changes from prodromal dementia, and to monitor the effects of therapy as adjuncts to neuropsychological and clinical assessments. The short term goals of this proposal are to further elucidate the specific neural substrates and potential compensatory mechanisms underlying the memory deficits in early AD. AD is a progressive neurodegenerative dementia associated with disruption of neuronal function. Accumulating evidence suggests that histological changes in specific temporal and frontal lobe structures may begin years prior to the development of clinical symptoms. Further, the diagnosis of probable AD is often preceded by a prodromal phase in which specific memory deficits may precede other cognitive or functional impairments. In longitudinal studies, approximately 10-15 percent of such """"""""prodromal AD"""""""" patients progress to diagnosable probable AD annually. Functional magnetic resonance imaging (fMRI) offers great promise to study neuronal activation patterns in specific brain regions during the performance of memory tasks in early AD. Clinically, such studies may offer diagnostic or prognostic potential by revealing subtle neural deficits not obvious on resting scans or clinical assessments alone. We have validated a novel event- related working memory fMRI paradigm that can study activation during component processes of memory as well as how such patterns are affected by increasing memory load. We propose to use this paradigm to study three carefully characterized groups of elderly subjects: mild AD, prodromal AD, and matched controls. Our primary aim is to study the neural correlates of memory impairment in memory specific brain regions of the frontal and medial temporal lobes in early or questionable AD. We will also examine whether there is recruitment of """"""""new"""""""" brain regions in patients with prodromal AD compared to normals as well as the differential effects of increasing memory load on the """"""""reserve"""""""" capacity to activate these same brain regions. As a secondary aim, we will test the sensitivity of fMRI activation patterns to separate mild AD cases from controls as well as the prognostic utility of a baseline fMRI, as an adjunct to genetic and neuropsychological tests, in predicting cognitive decline over a 3-5 year follow-up period in prodromal AD.
