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

使用超极化 13C 丙酮酸盐对创伤性脑损伤中的能量代谢进行代谢成像

• 批准号: 9092692
• 负责人: Dirk Mayer
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9092692
• 关键词: Acute; Address; Affect; Age; Animals; Basic Science; Bicarbonates; Biological Assay; Biological Markers; Biomedical Engineering; Brain; Cause of Death; Cell Death; Cell Respiration; Cerebrovascular Circulation; Cessation of life; Citric Acid Cycle; Clinical; Clinical Research; Control Groups; Craniocerebral Trauma; Decarboxylation; Detection; Development; Devices; Diagnosis; Diagnostic; Disease; Energy Metabolism; Equilibrium; Evaluation; Face; Glucose; Glycolysis; Goals; Healthcare; Histopathology; Image; Impaired cognition; In Vitro; Incidence; Injury; Kinetics; Lead; Life; Link; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Memory impairment; Metabolic; Metabolic Pathway; Metabolism; Methods; Microdialysis; Mission; Modeling; Monitor; Mood Disorders; National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Disorders and Stroke; Nervous system structure; Neurodegenerative Disorders; Neurological outcome; Noise; Nuclear; Oxidative Phosphorylation; Patients; Phosphorylation; Physiologic pulse; Play; Positron-Emission Tomography; Preventive measure; Procedures; Process; Pyruvate; Pyruvate Metabolism Pathway; Rattus; Relaxation; Risk; Role; Scheme; Secondary to; Severities; Signal Transduction; Specificity; Surrogate Markers; Survivors; TBI Patients; Techniques; Technology; Testing; Therapeutic Intervention; Time; Translating; Translational Research; Traumatic Brain Injury; United States; United States National Institutes of Health; bioimaging; brain metabolism; clinical practice; controlled cortical impact; disability; disorder prevention; drug development; enzyme activity; imaging biomarker; imaging modality; improved; in vivo; injured; mitochondrial dysfunction; nervous system disorder; new technology; non-invasive imaging; novel; novel diagnostics; novel therapeutics; outcome prediction; pre-clinical research; preclinical study; public health relevance; pyruvate dehydrogenase; research study; response; sham surgery; spectroscopic imaging; targeted treatment; tool; treatment choice; uptake

 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.

 描述（申请人提供）：为了与NIH的使命保持一致，以支持“对正常和患病神经系统的基础、转化和临床研究”，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，从根本上改善疾病的检测、治疗和预防”（NIBIB），该建议的首要目标是开发新的成像方法，用于评估创伤性脑损伤（TBI）后脑能量代谢的扰动。TBI是45岁以下人群死亡和残疾的主要原因， 据估计，美国每年有140万人。TBI占所有伤害死亡的约30%，估计每年与TBI相关的医疗费用超过700亿美元。TBI的幸存者往往面临终身残疾，认知和记忆障碍，并且情绪障碍以及神经和神经退行性疾病的风险增加。 原发性头部创伤引发一系列病理变化，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未完全理解，但人们越来越认识到，能量代谢的早期扰动，特别是表现为无氧代谢相对于氧化代谢的相对增加，可能对患者管理和最终的神经结局具有重要意义。因此，定量和空间上精确地评估大脑能量代谢是必不可少的。然而，目前使用的诊断工具，如脑血流量和动静脉代谢物浓度差异的测量，微透析，正电子发射断层扫描是有限的空间信息或代谢特异性。 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，因为它将糖酵解与克雷布斯循环联系起来，我们建议使用超极化[1- 13 C]丙酮酸的代谢成像来无创评估TBI后的脑能量代谢。具体而言，我们将开发优化的MR采集技术结合动力学建模工具，用于改进丙酮酸转化为乳酸（kPL）和碳酸氢盐（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志物（目标1）。其次，我们将在TBI的受控皮质撞击大鼠模型中应用这些技术，以测试MR生物标志物将区分损伤的严重程度以及急性和/或亚急性测量将预测结果的假设（目的2）。 这些非侵入性工具/生物标志物不仅可用于临床前研究中新疗法的开发，而且鉴于超极化13 C MRS正在许多疾病患者中积极研究，因此该技术在TBI患者中的应用有明确的转化路径。