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

 描述(申请人提供)：创伤性脑损伤(TBI)是平民和军人群体中的一个严重的健康问题。疾控中心估计，每年发生的脑损伤病例为170万例，其中275,000例为严重病例，300,000例与运动有关。尽管在诊断脑成像、心理特征和紧急医疗护理方面取得了进展，但创伤性脑损伤仍然很难治疗。到目前为止，还没有特定的治疗方法或药物被证明能有效逆转脑外伤的破坏性后果。我们对脑外伤的独特见解是，受创伤的大脑经历新陈代谢困难，导致未得到满足的能量需求，从而削弱可塑性并增加长期神经退化的机会。我们最近发现，颅脑损伤后代谢功能障碍的特点是机体大量分解代谢、抑郁和交替、无能量产生、脑葡萄糖利用、氧耗降低、微透析液乳酸/丙酮酸比值异常(L/P)，以及代谢受抑时更严重的萎缩。然而，使用双重(D2-葡萄糖和[3-13C]-L-乳酸)示踪技术，我们观察到从动脉血中提取乳酸的脑部分没有减少(Glenn，提交)。脑损伤后身体和大脑的分解代谢是一个主要的临床问题。为了更好地描述 超越脑后大脑的代谢危机，我们建议研究另一类单羧酸盐的通量和氧化，酮体。我们假设，与健康对照组相比，脑外伤受试者会出现较大的脑酮流量。此外，受损的大脑不会降低总的氧化速率。通过注入同位素标记的酮体(13C)，我们将能够评估脑流量和氧化。这项提议是加州大学伯克利分校的George Brooks博士和加州大学洛杉矶分校脑损伤研究中心的Thomas Glenn和Mayumi Prins实验室10多年来成功合作的结果。通过稳定同位素示踪研究的独特使用，我们已经可靠地表明身体和大脑处于能量需求状态。这项研究的结果将为卫生保健专业人员提供个性化和可操作的数据和材料，以改善患者的短期和长期结果。

 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.