Compelling evidence demonstrates that the brain's capacity to utilize glucose and respond to insulin is impaired in Alzheimer's disease (AD). A striking finding from human studies is the unique susceptibility of particular brain regions, particularly the "default mode network" (DMN) of the brain, to A? deposition in AD and cortical volume loss in diabetes. Although the cause of this regional disparity is unknown, understanding characteristics common to these regions could elucidate mechanisms of selective vulnerability in AD and perhaps lead to new treatment strategies. The DMN is a set of widespread but interconnected brain regions, with increased glucose uptake in excess of that used for oxidative phosphorylation despite sufficient oxygen to completely metabolize glucose to carbon dioxide and water, which we refer to as glycolysis. It has been hypothesized that the DMN's high rate of glycolysis augments an activity-dependent or metabolism-dependent cascade that is conducive to the formation of brain pathology in diseases such as AD, thus leading to the observed preferential vulnerability of this network. It is unclear whether increased glucose/insulin levels can increase glycolysis within the DMN above a certain threshold that could make brain tissue more vulnerable to A? deposition, damage or dysfunction. Data suggest that brain insulin dysregulation may be a critical aspect of AD risk. These relationships are of particular interest given the increased risk of AD in patients suffering from diabetes. Project 1 tests whether hyperglycemia and/or hyperinsulinemia affect glycolysis (as measured through PET imaging) in the DMN and whether the precuneus region is preferentially affected in the brains of controls and of those at higher risk for developing AD (older adults and in patients with Type 2 Diabetes (T2DM) with defective insulin signaling). Results will address fundamental questions about normal human brain metabolism as well as provide systems-level neurobiological data implicating alterations in glucose and insulin in DMN vulnerability.

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This work will determine if hyperglycemia and hyperinsulinemia, at levels commonly experienced by humans with diabetes, affect glycolysis in the DMN, a fundamental brain metabolic process, which may have profound clinical implications. Characterizing the pattern of these effects on glycolysis could provide support for a plausible neurobiological mechanism linking Alzheimer disease (AD) and diabetes.

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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Washington University
Saint Louis
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Lim, Miranda M; Gerstner, Jason R; Holtzman, David M (2014) The sleep-wake cycle and Alzheimer's disease: what do we know? Neurodegener Dis Manag 4:351-62
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