In vivo measures of mitochondrial function in epilepsy

癫痫线粒体功能的体内测量

• 批准号: 6616366
• 负责人: Hoby P Hetherington
• 金额: $ 22.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6616366
• 关键词: Krebs' cycle; bioenergetics; bioimaging /biomedical imaging; brain metabolism; clinical research; glucose metabolism; high energy compound; human subject; mitochondria; neurochemistry; nuclear magnetic resonance spectroscopy; partial seizure; positron emission tomography; temporal lobe /cortex disorder

Epilepsy is one of the most common neurological disorders, affecting one to two million Americans. For approximately 10% of these individuals, the debilitating effects of the disease can not be controlled by medication. Although surgical intervention is highly effective, accurate lateralization and localization of seizure foci based on metabolic measurements have been developed. These techniques include measures of CMRglucose by FDG PET, high-energy phosphates (PCr and ATP) by 31 NMR and measurements of neuronal dysfunction with 1H NMR measurements of N-acetyl aspartate. Although these methodologies have been quite successful (sensitivity and specificity of 70-95%) in the lateralization of mesial temporal lobe epilepsy, the biological mechanisms underlying these observations remains controversial. The findings of decreased high- energy phosphates along with decreased CMRglucose suggest that energy production is impaired. Furthermore, the finding that NAA reductions are 1) reversible and 2) not solely due to neuronal loss; in conjunction with 3) results in mitochondrial preparations linking NAA synthesis rates, ATP production and inhibition of mitochondrial enzymes suggest that the metabolic defect may be due to impaired mitochondrial function. Therefore, the goal of this project is to investigate the role of impaired mitochondrial function. Therefore, the goal of this project is to investigate the role of impaired mitochondrial function as a primary cause for the observed metabolic alterations in temporal lobe epilepsy. To achieve this goal we will combine in vivo measurements of high energy phosphates, NAA, glutamate and TC cycle rate (NMR) and CMRglucose (PET) from patients with temporal lobe epilepsy with detailed measurements of anapleurosis, neurotransmitter cycling (Project 2), mitochondrial function (Project 3) from the resected tissue and the corresponding functional changes in ion homeostasis (Project 4).

癫痫是最常见的神经系统疾病之一，影响一到两百万美国人。对于其中大约 10% 的人来说，药物无法控制这种疾病造成的衰弱影响。尽管手术干预非常有效，但基于代谢测量的癫痫病灶的精确偏侧化和定位已经开发出来。这些技术包括通过 FDG PET 测量 CMR 葡萄糖、通过 31 NMR 测量高能磷酸盐（PCr 和 ATP）以及通过 1 H NMR 测量 N-乙酰天冬氨酸测量神经元功能障碍。尽管这些方法在内侧颞叶癫痫的偏侧化方面非常成功（敏感性和特异性为 70-95%），但这些观察结果背后的生物学机制仍然存在争议。高能磷酸盐减少以及 CMR 葡萄糖减少的结果表明能量产生受到损害。此外，发现 NAA 减少是 1) 可逆的，2) 不仅仅是由于神经元损失；与 3) 线粒体制剂的结果相结合，将 NAA 合成率、ATP 产生和线粒体酶的抑制联系起来，表明代谢缺陷可能是由于线粒体功能受损所致。因此，该项目的目标是研究线粒体功能受损的作用。因此，该项目的目标是研究线粒体功能受损作为颞叶癫痫中观察到的代谢改变的主要原因。为了实现这一目标，我们将结合颞叶癫痫患者的高能磷酸盐、NAA、谷氨酸和 TC 循环率 (NMR) 和 CMR 葡萄糖 (PET) 的体内测量，以及回覆膜、神经递质循环（项目 2）、线粒体的详细测量。功能（项目 3）以及离子稳态的相应功能变化（项目 4）。