CEREBRAL MITOCHONDRIAL METABOLISM IN NEURODEGENERATION

神经退行性变中的大脑线粒体代谢

• 批准号: 6540477
• 负责人: WILLIAM J POWERS
• 金额: $ 34.65万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540477
• 关键词: Huntington's disease; Parkinson's disease; adult human (21+); brain metabolism; caudate nucleus; cerebral degeneration; diagnosis design /evaluation; electron transport; glucose metabolism; human subject; magnetic resonance imaging; mitochondria; nervous system disorder diagnosis; neuropsychological tests; patient oriented research; platelets; positron emission tomography; putamen; substantia nigra

DESCRIPTION (Adapted from the abstract provided by the applicant): Several lines of evidence suggest that Huntington's disease (HD) and Parkinson's disease (PD) have defects in mitochondrial function that impair oxidative phosphorylation and play a key role in the mechanism of neuronal death. To date, however, there have been no direct measurements of cerebral oxygen to glucose metabolic ratios to demonstrate an in vivo defect in cerebral mitochondrial metabolism in these diseases. We will use positron emission tomography (PET) to measure in vivo regional cerebral oxygen metabolism (CMR02) and cerebral glucose metabolism (CMRglc) to test two primary hypotheses: 1) Patients with HD have a generalized defect in cerebral mitochondrial metabolism. To test this hypothesis, we will measure whole brain CMR02/CMRgIc in 15 gene-positive pre-symptomatic patients with HD, 15 gene-positive patients with HD and definite motor signs and 30 age/gender-matched normal controls. 2) Patients with PD have a generalized defect in cerebral mitochondrial metabolism. To test this hypothesis, we will measure whole brain CMR02/CMRgIc in 15 never-medicated, early PD patients and 15 age/gender-matched normal controls. In the same subjects, we also will test two secondary hypotheses: 3) Regions vulnerable to pathologic insult have larger magnitude or selective defects in cerebral mitochodrial metabolism - caudate and putamen in HD and substantia nigra and putamen in PD. 4) In PD and HD, the degree of dysfunction in platelet electron transport complex function measured in vitro correlates with the degree of abnormal cerebral mitochondrial metabolism measured in vivo. At this time it is not clear how the abnormalities in electron transport chain activity measured in vitro in these two diseases correspond to cerebral mitochondrial metabolism in vivo. Direct in vivo regional PET measurements of CMR02 and CMRglc will allow us to demonstrate the extent and magnitude of mitochondrial dysfunction in vivo. Establishing the existence of cerebral mitochondrial dysfunction early in the course of these diseases will not only provide insights into the pathogenesis, but it will provide a measurable biological abnormality that can be monitored to determine the effect of treatments aimed at slowing or halting the progression of neuronal loss. The opportunity to determine the relation between platelet mitochondrial function and cerebral mitochondrial metabolism in patients with PD and HD is uniquely important. If such a relationship can be established in untreated patients in this study, then we would pursue further studies to determine the effects on cerebral mitochondrial metabolism of agents that alter platelet mitochondrial function. If such studies yield consistent results, they will establish the basis for the utilization of platelet rnitochondrial function assays to monitor cerebral mitochondrial metabolism.

描述（根据申请人提供的摘要改编）：几个 证据表明，亨廷顿氏病（HD）和帕金森氏病 疾病（PD）的线粒体功能缺陷可损害氧化 磷酸化并在神经元死亡机理中起关键作用。到 但是，日期尚无直接测量的脑氧 葡萄糖代谢比以证明脑体内缺陷 这些疾病中的线粒体代谢。我们将使用正电子排放 层析成像（PET）测量体内脑氧代谢（CMR02） 和脑葡萄糖代谢（CMRGLC）测试两个主要假设：1） HD患者在脑线粒体中具有普遍的缺陷 代谢。为了检验这一假设，我们将测量整个大脑CMR02/CMRGIC 在15个基因阳性症状前HD患者中，15例基因阳性患者 具有高清和确定的电动机标志和30年龄/性别匹配的正常对照。 2） PD患者在脑线粒体中具有普遍的缺陷 代谢。为了检验这一假设，我们将测量整个大脑CMR02/CMRGIC 在15例从未服用的早期PD患者和15岁/性别匹配的正常状态中 控件。在同一主题中，我们还将检验两个次要假设：3） 容易受到病理侮辱的地区具有更大的幅度或选择性 脑线粒体代谢缺陷 - 高清尾状和壳核 pd中的黑质尼格拉和ph。 4）在PD和HD中，功能障碍程度 在血小板电子传输复合函数中的体外相关性 在体内测量的脑线粒体代谢的程度。 目前尚不清楚电子传输链中的异常 在这两种疾病中在体外测量的活性对应于脑 线粒体代谢在体内。直接体内区域宠物测量 CMR02和CMRGLC将使我们能够证明 体内线粒体功能障碍。建立大脑的存在 在这些疾病的早期，线粒体功能障碍不仅会 提供有关发病机理的见解，但它将提供可测量的 可以监测的生物异常以确定 旨在减慢或停止神经元丧失进展的治疗方法。这 确定血小板线粒体功能之间关系的机会 PD和HD患者的脑线粒体代谢是独特的 重要的。如果可以在未处理的患者中建立这种关系 这项研究，然后我们将进行进一步的研究，以确定对 改变血小板线粒体的药物的脑线粒体代谢 功能。如果这些研究产生一致的结果，他们将确定 利用血小板rnitochrial功能测定的基础 大脑线粒体代谢。