Project 2 is a direct extension of Project 1 utilizing the same controlled manipulations of glucose and insulin in the same normal young and older adults and patients with T2DM. The proposed experiments in Project 2 will employ fMRI BOLD imaging in the resting state (quiet wakefulness) to probe the effect of changes in glucose and insulin availability on the ongoing functional organization within and among brain systems and during the performance of a task designed to explore the acute mnemonic effects of hyperinsulinemia. To accomplish these aims we utilize fMRI BOLD imaging in two ways. First, we will evaluate the patterns of spatial coherence in the resting-state (quiet wakefulness) fMRI BOLD signal which have been shown to delineate relationships both within and among the major brain systems and their subcortical connections and to exhibit changes in patients with Alzheimer's disease particularly in relation to the brain's DMN. Second, we will evaluate regional, task-induced changes in the fMRI BOLD signal based on the observation that increasing insulin levels can improve cognitive performance, particularly in the memory domain. We propose to use a task, face-name recall, which can be implemented in the scanner, is commonly used in AD researchand exhibits stable test-retest reliability in older adults. Experiments in Project 2 also dovetail with and are greatly enriched by the studies in Project 3 which uses optical intrinsic signal (OIS) imaging a technique based on the same underlying physiology. fMRI and OIS are posited to depend on changes in glycolysis linked to blood flow and largely independent of oxygen consumption. We consider the changes they detect to be largely a glycolytically-driven, synaptic signal resulting in changes in hemoglobin oxygenation detectable by MRI and OIS imaging.
Project 2 will provide fMRI measures of the brain's functional status, both during task performance and in the resting state, to be correlated with PET metabolic measures in humans and corresponding functional measures (lactate and fcOIS) in mice.
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