CEREBRAL MITOCHONDRIAL METABOLISM IN NEURODEGENERATION

描述(改编自申请人提供的摘要)：几个 一系列证据表明，亨廷顿病(HD)和帕金森氏症 疾病(PD)具有损害氧化的线粒体功能缺陷 磷酸化并在神经元死亡机制中发挥关键作用。至 然而，到目前为止，还没有直接测量到脑氧含量 用葡萄糖代谢率来显示大脑的体内缺陷 这些疾病中的线粒体代谢。我们将使用正电子发射 体层摄影术(PET)测量活体局部脑氧代谢(CMR02) 和大脑葡萄糖代谢(CMRglc)来检验两个主要假设：1) HD患者大脑线粒体存在全身性缺陷 新陈代谢。为了验证这一假设，我们将测量整个大脑的CMR02/CMRgIc 在15例基因阳性的HD症状前患者中，15例基因阳性患者 有明确运动体征的HD患者和30名年龄/性别匹配的正常对照。2) 帕金森病患者大脑线粒体存在全身性缺陷 新陈代谢。为了验证这一假设，我们将测量整个大脑的CMR02/CMRgIc 15名从未服用药物的早期帕金森病患者和15名年龄/性别匹配的正常人 控制。在同一主题中，我们还将检验两个次要假设：3) 易受病理性侮辱的区域具有更大的规模或选择性 HD和HD患者的脑线粒体代谢缺陷--尾状核和壳核 帕金森病黑质和壳核。4)PD和HD患者的功能障碍程度 体外测定的血小板电子传递复合体功能与 用活体测量脑线粒体代谢异常的程度。 目前还不清楚电子传递链的异常是如何 在体外测量的这两种疾病的活动对应于大脑 体内线粒体代谢。直接活体区域PET测量 CMR02和CMRglc将使我们能够展示 体内线粒体功能障碍。确立脑的存在 线粒体功能障碍在这些疾病的病程早期不仅会 提供了对发病机制的洞察，但它将提供一个可测量的 可以监测的生物异常，以确定 旨在减缓或阻止神经元丢失进展的治疗。这个 确定血小板线粒体功能之间关系的时机 PD和HD患者的脑线粒体代谢是独特的 很重要。如果这样的关系可以在未接受治疗的患者中建立 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，他们将建立 利用血小板线粒体功能测定进行监测的依据 大脑线粒体代谢。

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.