HDO Imaging is a Quantitative Marker of Cerebral Glucose Oxidation

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Project Summary Deuterium magnetic resonance imaging, DMI, has demonstrated ability to identify changes in brain metabolism associated with cancer. However, downstream products of glucose metabolism, glutamate/glutamine (glx) and lactate, have intrinsically low signal to noise ratios that make detection challenging. This work posits that imaging of HDO following metabolism of [2H7]glucose will produce a more sensitive means of detecting glycolysis and glucose oxidation in the Krebs cycle. Towards this end we will establish optimal dosing levels of substrate as well as the impact of insulin sensitivity on cerebral metabolism of the glucose substrate. The high signal to noise of the HDO peak allows simple gradient echo methods to be used for detection, facilitating higher spatial resolution in the images. After injection of [2H7]glucose in vivo, a ~15 minute window exists where HDO appearance matches the generation of deuterated glx almost exactly, indicating the HDO can serve as a surrogate of oxidative flux in the brain. To take full advantage of this window, we will develop compressed sensing methods for accelerating acquisition of the 2H images. HDO is freely diffusible, and at long times we believe excess HDO appearance in the brain is related to vascular HDO generated by peripheral metabolism. We will use diffusion weighted imaging to test the hypothesis that suppression of the vascular HDO signal will render the remaining HDO component a faithful reporter of cerebral glucose metabolism. We will compare our new methods to 8F-deoxyglucose - positron emission tomography (FDG-PET) to determine if the two techniques provide complementary information about metabolism in animal models of brain cancer. The overall goal in this proposal is to establish HDO imaging as a robust marker of cerebral glucose metabolism. Relevance Metabolic imaging of the brain is of general interest across all of neuroscience, from basic biochemistry, to cognition science, to the study of pathophysiologies, and in the clinical diagnoses of multiple brain related diseases. The primary method currently used for metabolic brain imaging is FDG-PET, which cannot be used for longitudinal studies or in the pediatric population due to guidelines for total radiation exposure. Development of a magnetic resonance based method, which is safe for repeated use, would significantly enhance our ability to study brain function across all of neuroscience. The basic research described in this proposal will improve the robustness of a new method for detecting brain metabolism based on the detection of HDO following metabolism of a perdeuterated glucose tracer. Glucose is the primary substrate used for energy production in the brain, and is therefore the most appropriate substrate for development in this context.