Relational memory - the encoding and retrieval of the relations or associations among informational elements - is particularly sensitive to the effects of advancing age. Furthermore, deficits in relational memory are some of the earliest impairments observed in individuals with Alzheimer's Disease (AD). To date, the cognitive processes and neural mechanisms underlying relational memory deficits in aging and AD are poorly understood. Elucidating the neural bases of relational memory deficits should prove useful in understanding differences between normal and pathological aging at very early stages of AD, in subjects with mild cognitive impairment (MCI). Functional neuroimaging studies of healthy young adults suggest that relational memory is mediated by the prefrontal cortex (RFC) and the medial temporal lobe (MIL). Whereas the PFC is thought to mediate strategic processes necessary to encode and retrieve relational information, the MIL is considered to play a critical role in binding or linking together the various cognitive, affective, and perceptual components of a event into an integrated memory trace. Recent data suggest that age-related deficits in relational memory are likely due to declines in RFC-mediated strategic, controlled processing, whereas AD-related impairments in relational memory reflect disruption of MIL binding mechanisms. The central aim of this application is to elucidate the core cognitive processes and fundamental neural mechanisms that give rise to relational memory impairments in aging and early AD. We will utilize anatomically constrained fMRI to assess PFC and MIL activations during memory performance in three groups: young adults, healthy older adults, and subjects who meet criteria for amnestic MCI. The proposed experiments incorporate cognitive paradigms that directly manipulate the contribution of strategic and binding processes to relational memory and then examine the effect on functional neural architecture. As part of the proposed K01 application, the candidate seeks training in: 1) advanced functional MRI techniques, 2) clinical research design, and 3) integration of functional and structural MRI data. The proposed research plan will foster the candidate's development into an independent scientist, using cognitive and neuroimaging methods to study the nature of memory deficits in normal and pathological aging.
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