Metabolic imaging of energy metabolism in traumatic brain injury using hyperpolarized 13C pyruvate

 描述(由申请人提供)：NIH的使命是支持“对正常和疾病神经系统的基础、翻译和临床研究”，包括创伤性脑损伤(NINDS)和开发“新的生物医学成像和生物工程技术和设备，以从根本上改进疾病的检测、治疗和预防”(NIBIB)，本提案的总体目标是开发新的成像方法，用于评估创伤性脑损伤(TBI)后大脑能量代谢的扰动。脑外伤是45岁以下人群死亡和残疾的主要原因，影响 据估计，美国每年有140万人。创伤性脑损伤占所有伤害死亡的30%，估计每年与脑损伤相关的医疗费用超过700亿美元。脑外伤的幸存者通常面临终身残疾、认知和记忆障碍，并面临更高的情绪障碍以及神经和神经退行性疾病的风险。原发性头部创伤会引发一连串的病理变化，导致二次损伤，包括线粒体功能障碍和能量代谢失调。虽然确切的病理生理机制尚不完全清楚，但人们越来越认识到，能量代谢的早期扰动，具体表现为无氧代谢相对于氧化代谢的相对增加，可能在患者管理和最终神经预后方面具有重要意义。因此，对大脑能量代谢进行定量和空间上的精确评估是必不可少的。然而，目前使用的诊断工具，如测量脑血流和动静脉代谢物浓度差、微透析和正电子发射断层扫描，无论是在空间信息上还是在代谢特异性上都是有限的。超极化~(13)C磁共振波谱(MRS)的最新发展首次实现了对体内关键动态代谢过程的实时无创测量。鉴于丙酮酸在能量代谢中的核心作用，因为它将糖酵解与Krebs循环联系起来，我们建议使用超极化[1-13C]丙酮酸的代谢成像来无创性评估脑损伤后的脑能量代谢。具体地说，我们将开发优化的磁共振采集技术，并结合动力学建模工具，改进丙酮酸转化为乳酸(KPL)和转化为碳酸氢盐(KPB)的表观速率常数的测量，分别作为糖酵解和氧化代谢的替代标记(目标1)。其次，我们将在受控皮质撞击大鼠脑外伤模型中应用这些技术，以检验MR生物标记物将区分损伤严重程度以及急性和/或亚急性测量将预测结果的假设(目标2)。这些非侵入性工具/生物标志物不仅将在临床前研究中用于新疗法的开发，而且这项技术在脑外伤患者中的应用有一条明确的转换路径，因为超极化13C MRS正在许多疾病的患者中进行积极的研究。

 DESCRIPTION (provided by applicant): 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.