Hippocampal Structure and Function in Cognitive Impairment

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DESCRIPTION (provided by applicant): In this application for a Paul B. Beeson Patient-Oriented Research Career Development Award in Aging, the candidate seeks 5 years of salary and research support to obtain training and to pursue a research project related to neuroimaging and preclinical Alzheimer's disease (AD). The long term goal is to become an independent investigator and to establish a laboratory dedicated to the study of AD and other neurodegenerative diseases. The specific hope is to use advanced neuroimaging technologies to create novel, sensitive biomarkers for early AD diagnosis and disease monitoring. Despite substantial progress in his training so far, gaps remain in his knowledge and skills. Short term goals, aimed at filling these gaps, include: (1) to expand upon previous training in 7-Tesla (7T) magnetic resonance imaging (MRI); (2) to develop new skills in designing, performing, and interpreting fMRI experiments; (3) to achieve new skills in clinical epidemiology and statistics; and (4) to solidify skills in clinical research design. With his mentorship team, he has developed a comprehensive training program, which includes the research project outlined below, coursework, and regular meetings with his mentors. His overall goal in this proposal is to develop the skills and preliminary data needed to submit a successful RO1 application during Years 4-5 of the award. The proposed research seeks to fill a critical need for biomarkers that can detect the earliest, preclinical signs of AD, during a period of amnestic Mild Cognitive Impairment (aMCI). Such biomarkers may facilitate the eventual delivery of novel disease-modifying therapeutics to the minimally affected patients who stand the most to benefit. Neuroimaging holds great promise, but conventional technologies are insensitive to early disease. Post-mortem studies reveal that specific subfields of the hippocampus, including the CA1 apical neuropil, develop pathology around the time that patients begin to experience early memory impairment. Therefore, to be maximally sensitive to early disease, neuroimaging biomarkers should be able to assay the integrity of focal hippocampal subfield areas. Here, the candidate proposes to apply two complementary, highresolution, advanced imaging technologies to the problem: (1) 7T MRI, which can reveal hippocampal microstructure at ~200 ¿m resolution; and (2) high-resolution 3T fMRI coupled with an event-related face-name pairing task, to study patterns of hippocampal subfield activation that correlate with remembering or forgetting. He will assemble cohorts of 30 patients with aMCI and 30 age-matched normal controls, and in Aim 1 will use the neuroimaging tools to discover the structural and functional correlates of memory impairment. He will follow subjects annually (average span 40 months), and in Aim 2 will identify the baseline structural and functional imaging metrics that are most predictive of subsequent cognitive decline. In addition to contributing to preclinical AD biomarker development, this work promises to reveal basic details of the structural and functional underpinnings of hippocampal-dependent memory loss in aMCI and AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is epidemic. In addition to the need for new treatments that can stop or slow the disease, there is a parallel need for biomarkers capable of identifying the illness in its earliest possible stages, in order to facilitate the evenual delivery of new treatments to patients with the most to lose. The proposed work focuses on two advanced neuroimaging technologies that may help to fill this critical gap.