Novel methodology for studing oxidative metabolism

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): Oxygen consumption provides vital information about neuronal activity. Neurological disorders such as Alzheimer's disease, Parkinson's disease, and schizophrenia are associated with hampered enzymatic activity that catalyzes the reaction of oxidative metabolism. Oxygen consumption also has the potential for detecting regions of viable tissue following cerebral ischemia. Quantitative mapping of cerebral oxygen consumption contributes to the better understanding of the patho-physiology of several neurological disorders. A current method for such measurements is positron emission tomography (PET), which provides a low-resolution image and involves radioactive isotopes. Current 17O magnetic resonance imaging (MRI) based methods, have limitations such as low sensitivity and requirement of invasive procedure and requirement of ultra-high magnetic fields. These limitations, coupled with the high cost of 17O2 gas, limit the applicability of direct 17O MRI methods to small animal studies. Consequently, there are no non-invasive methods for measuring oxygen consumption in humans in vivo combining safety with high spatial and temporal resolution. This proposal deals with the development of an integrated approach that combines an efficient 17O2 gas delivery system with improved, noninvasive, MRI strategies for computing cerebral metabolic rate of oxygen consumption (CMRO2). Specifically, an efficient 17O2 gas delivery system, that reduces the 17O2 gas requirement by an order of magnitude will be designed and optimized for use on large animals and in humans. Efficacy of this system will be tested on a swine model. MRI methods will be designed to measure arterial input function of metabolically produced water (mpH217O) and cerebral blood flow. Finally, the above-mentioned system and MRI techniques will be integrated into an improved MRI strategy for measuring mpH217O to compute CMRO2 in the brain in vivo. Once the aims are accomplished, a noninvasive tool will become available to measure CMRO2 with high spatial resolution, which can be immediately extended to in vivo human studies. This approach will have substantial impact on the both scientific and clinical studies of neurological disorders and in the development and evaluation of novel therapies.