In keeping with the mission of the NIH to support basic, translational, and clinical research on the normal and diseased nervous system including traumatic brain injury (NINDS) and development of new biomedical imaging and bioengineering techniques and devices to fundamentally improve the detection, treatment, and prevention of disease (NIBIB), the overarching goal of this proposal is to develop novel imaging methods for the assessment of perturbations in brain energy metabolism after traumatic brain injury (TBI). TBI is the leading cause of death and disability in people under age 45, affecting an estimated 1.4 million people in the United States each year. TBI contributes to ~30% of all injury deaths, and the estimated TBI-related healthcare expenses exceed 70 billion dollars annually. Survivors of TBI often face life-long disability, cognitive and memory impairments, and are at increased risk for mood disorders as well as neurological and neurodegenerative diseases. Primary head trauma sets off a cascade of pathological changes that lead to secondary insults including mitochondrial dysfunction and dysregulated energy metabolism. While the precise pathophysiological mechanisms are still not yet completely understood, it is increasingly recognized that the early perturbation of energy metabolism, which manifests specifically as a relative increase of anaerobic over oxidative metabolism, might have important implications in patient management and ultimately neurological outcome. Therefore, a quantitatively and spatially precise assessment of brain energy metabolism is indispensable. However, currently used diagnostic tools such as measurement of cerebral blood flow and arteriovenous metabolite concentration differences, microdialysis, and positron emission tomography are limited in either spatial information or metabolic specificity. The recent development of hyperpolarized 13C magnetic resonance spectroscopy (MRS) enables for the first time the real-time non-invasive measurement of critical dynamic metabolic processes in vivo. Given pyruvate's central role in energy metabolism as it links glycolysis to the Krebs cycle, we propose to use metabolic imaging of hyperpolarized [1-13C]pyruvate for noninvasive assessment of brain energy metabolism after TBI. Specifically, we will develop optimized MR acquisition techniques combined with kinetic modeling tools for the improved measurement of apparent rate constants for the conversion of pyruvate to lactate (kPL) and to bicarbonate (kPB) as surrogate markers for glycolytic and oxidative metabolism, respectively (Aim 1). Secondly, we will apply these techniques in a controlled cortical impact rat model of TBI to test the hypotheses that the MR biomarkers will differentiate severity of injury and that the acute and/or sub-acute measurements will be predictive of outcome (Aim 2). Not only will these noninvasive tools/biomarkers be useful in the development of new therapies in preclinical studies, there is a clear translational path of this technology toward the application in patients with TBI given that hyperpolarized 13C MRS is being actively investigated in patients with numerous diseases.
In traumatic brain injury (TBI), which is the leading cause of death and disability in people under age 45 and affecting an estimated 1.4 million people in the United States each year, the primary head trauma sets off a cascade of pathological changes that lead to secondary insults including mitochondrial dysfunction and deregulated energy metabolism. As these are potential targets for therapeutic interventions, diagnostic tools for the noninvasive and spatially resolved assessment of brain energy metabolism would be beneficial for both improved diagnosis in clinical practice and more effective drug development in both preclinical and clinical research. In this preclinical study we will address this unmet need by developing non-invasive imaging biomarkers for the assessment of brain energy metabolism after TBI that can easily be translated into clinical use.