Memory in Aging, Mild Cognitive impairment and AD

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The proposed studies, by a newly independent investigator, aim to further our understanding of the physiological bases of the memory impairments found with aging and in patients with memory disorders. We will use Event-Related Potentials (ERPs) and Functional-Magnetic Resonance Imaging (FMRI) to investigate verbal memory processes in aging, Mild Cognitive Impairment (MCI), and Alzheimer's disease (AD). The specific brain potentials of interest are the N400, a negativity which peaks near 400 msec post-stimulus, and the late positive component (LPC) which follows. The N400 amplitude is sensitive to the ease/difficulty with which the eliciting word is integrated with its semantic context. The LPC has been closely linked to memory processes. We have adapted our ERP word repetition paradigm, which utilizes repeating auditory context/visual target word pairs during a semantic categorization task, for use with FMRI. This paradigm provides electrophysiological measures of both implicit and explicit verbal memory processes, and may shed light on the neuroanatomical substrates of these processes. We have shown that amnesic patients have an abnormal reduced ERP repetition effect to "congruous" category-exemplar words (the "LPC repetition effect"). The degree of this reduction correlates well with severity of declarative memory impairment. We have recently found that patients with MCI also have a reduced LPC word repetition effect. Further, a severely reduced LPC repetition effect amplitude appears to increase the likelihood of subsequent conversion to AD. Our main specific aims are: 1) To quantify the decline in the ERP word repetition effects that occurs in normal aging. A reduced ERP word repetition effect may be a sensitive sign of memory impairment and pathological brain aging. 2) To test the sensitivity of our ERP and FMRI paradigms to mild AD and to "pre-clinical" AD. 3) To improve our understanding of which neural substrates generate the N400 and LPC in normal elderly and in patients with very early AD. Research design: Case-control and longitudinal studies and ERPs in conjunction with FMRI studies and selected behavioral measures. Methods: ERP and FMRI data will be obtained from normal, MCI, and AD subjects during semantic categorization. Repetition and congruity (degree of fit with a category) will be varied systematically to modulate the N400 and LPC. Comparisons of N400 and LPC characteristics will be made (between-and within- group) and related to memory and other cognitive abilities. Event-related FMRI BOLD response patterns will be used to constrain source dipole models for the neural generations of the N400 and LPC.