This is an application for a Mentored Research Scientist Development Award. In Alzheimer's disease (AD), degeneration due to amyloid plaques and neurofibrillary tangles occurs early in the entorhinal-hippocampal-subicular complex as well as in the olfactory bulb and tract. AD patients consistently show deficits in olfactory identification compared to age-matched controls, as do patients with mild cognitive impairment (MCI), who are thought to be in the preclinical stages of the illness. While progress is being made in understanding the neuroanatomical and neurophysiological basis of olfaction, there has been a lack of clinical studies examining the neural correlates of AD-related olfactory deficits. The primary goal of the current research project will be to examine the degree to which odorant-induced brain activation in olfactory-related brain regions can be used as a reliable index that differentiates mild AD patients, MCI patients, and healthy age-matched elders. To implement this goal, the proposed project will conduct an olfactory fMRI study. The focus will be on cross-sectional analyses of the fMRI response to odorants in olfactory-related brain regions. Ultimately, the clinical goal is to use differential odorant-induced activation profiles in MCI patients as an early diagnostic marker of AD. Such markers are critical for the development of effective treatments that can slow disease progression early in its course. The proposal provides for a staged training schedule designed to build on the candidate's background in neuropsychology and develop expertise in olfaction and neuroimaging, within a clinical research context. The career development activities and research plan capitalize on the resources of Columbia University to aid in achieving the candidate's long-term goal of becoming an independent investigator, focusing on early detection of psychiatric and neurological disease, limbic system functions, and brain imaging. In the training plan, he will receive expert mentorship in key areas, including psychophysics and neuroscience of olfaction, technical and theoretical aspect of fMRI, research design and quantitative methods, clinical assessment and diagnosis, and in the ethical treatment of patients and research conduct. This will be complemented by a comprehensive didactic program.
