Ketone flux and oxidation following human TBI: Implications for cerebral metabolism

University Of California Los Angeles, Los Angeles CA

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Abstract

? DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a serious health problem in both civilian and military populations. The CDC estimates the occurrence of TBI to be 1.7 million cases per yr, of which 275,000 are classified as severe, and 300,000 are sports-related. Traumatic brain injury remains difficult to treat despite advances in diagnostic brain imaging, psychological profiling and emergency medical attention. To date, no specific therapy or medication has proved effective in reversing the devastating consequence of TBI. Our unique insight into TBI is that the traumatized brain experiences metabolic distress, causing unmet energy demands which impairs plasticity and increases the chances of long term neural degeneration. We have recently shown that metabolic dysfunction following TBI is characterized by massive body catabolism, depressed and alternative, non-energy producing, cerebral glucose utilization, depressed oxygen consumption, abnormal microdialysate lactate to pyruvate ratio (L/P), and greater atrophy when metabolism is depressed. However, using dual (D2-glucose and [3-13C]-L-lactate) tracer technologies, we have observed undiminished cerebral fractional extraction of lactate from arterial blood (Glenn, submitted). That the body and brain are catabolic following cerebral injury represents a major clinical problem. To better describe the overriding metabolic crises to the brain following brain we propose to study the flux and oxidation of another family of monocarboxylates, the ketone bodies. We hypothesize that great cerebral ketone flux will occur in TBI subjects compared to healthy controls. Additionally, the overall rates of oxidation will not be decreased by the injured brain. By infusing isotopically labeled ketone bodies (13C) we will be able to evaluate both cerebral flux and oxidation. This proposal is the culmination of over 10 years of successful collaboration between the laboratories of Dr. George Brooks at UC Berkeley and Thomas Glenn and Mayumi Prins at the UCLA Brain Injury Research Center. Through the unique use of stable isotope tracer studies we have reliably shown that the body and brain are in states of energy demand. The results from this research will provide health care professionals with personalized and actionable data and materials with which to improve short and long-term patient outcomes.