Selegiline, Oxidative Stress and MRS in HIV Dementia

描述：(申请人提供)认知无罪是一种常见的 可导致痴呆的HIV-I感染并发症。免疫标志物 中枢神经系统(CNS)的激活已被证明是最好的 与认知障碍的程度相关。有趣的是，大多数产品 免疫激活通过诱导氧化应激诱导细胞毒性。在……里面 在这方面，我们的初步数据表明，氧化应激水平， 脑脊液(CSF)诱导的神经元线粒体改变 膜电位和脑脊液中蛋白质羰基的水平，与 HIV相关认知损害的严重程度。线粒体膜 潜在的异常可以被具有抗氧化特性的药物逆转 包括司来吉兰(L-异丙肾上腺素)。值得注意的是，两个初步的 研究表明司来吉兰可能改善相关的认知障碍 感染了艾滋病毒。基于这些观察，艾滋病临床试验小组 (ACTG)已经批准了一项使用司来吉兰(A5090)的大型多中心试验。我们 假设氧化应激是发病的重要机制 与HIV相关的认知障碍有关，并将与 脑损伤的磁共振波谱(MRS)测量和 包括脑脊液艾滋病毒在内的HIV相关认知损害的既定预测因素 RNA(病毒载量)和B2微球蛋白水平。我们还假设 抗氧化化合物，如司来吉兰，将改善认知能力 HIV感染者脑损伤的代谢标记物和 这种反应将与氧化应激的水平相关。我们建议 进一步研究氧化应激在HIV相关认知中的作用 通过解决以下具体目标来实现损害：1)比较 HIV感染者与非HIV感染者脑脊液中的氧化应激反应 认知障碍与11W阴性对照；2)评估两者之间的关系 氧化应激水平与脑脊液HIV病毒载量和B_2微球蛋白的关系 水平；3)评估氧化应激水平与体内 用磁共振波谱测量HIV感染者的活体脑代谢 无认知损害；4)评价司来吉兰对脑脊液的影响 氧化应激标志物与活体脑代谢的关系 与11W相关的认知损害相关，并将 氧化应激与MRS和认知表现。拟议的研究将 利用ACTG支持A5090研究和现有MRS的优势 将允许我们执行多中心MRS的财团基础设施 学习。

DESCRIPTION: (provided by applicant) Cognitive impainnent is a common complication of HIV- I infection that can lead to dementia. Markers of immune activation in the central nervous system (CNS) have been shown to best correlate with the degree of cognitive impairment. Interestingly, most products of immune activation induce cytotoxicity via induction of oxidative stress. In this regard, our preliminary data indicate that levels of oxidative stress, measured by cerebrospinal fluid (CSF) induced changes in neuronal mitochondrial membrane potential and CSF levels of protein carbonyl, correlate with the severity of HIV-associated cognitive impairment. The mitochondrial membrane potential abnormalities can be reversed by drugs with antioxidant properties including selegiline (L-deprenyl). It is noteworthy that two preliminary studies suggest that selegiline may improve cognitive impairment associated with HIV infection. Based on these observations, the AIDS Clinical Trials Group (ACTG) has approved a large multicenter trial with selegiline (A5090). We hypothesize that oxidative stress is an important mechanism in the pathogenesis of HIV-associated cognitive impairment and will correlate with markers of cerebral injury as measured by magnetic resonance spectroscopy (MRS) and with established predictors of HIV-associated cognitive impairment including CSF HIV RNA (viral load) and B2 microglobulin levels. We also hypothesize that antioxidant compounds such as selegiline will improve the cognitive performance and metabolic markers of cerebral injury in HIV infected individuals and that this response will correlate with the levels of oxidative stress. We propose to further investigate the role of oxidative stress in HIV-associated cognitive impairment by addressing the following specific aims: 1) to compare markers of oxidative stress in the CSF among HIV infected subjects with and without cognitive impairment and 11W negative controls; 2) to assess the relationship between levels of oxidative stress and CSF HIV viral load and B2-microglobulin levels; 3) to assess the relationship between levels of oxidative stress and in vivo brain metabolism, as measured by MRS in HIV infected subjects with and without cognitive impairment; 4) to assess the effect of selegiline on CSF markers of oxidative stress and on in vivo brain metabolism (MRS) in subjects with 11W-associated cognitive impairment and to correlate changes in markers of oxidative stress with MRS and cognitive performance. The proposed study will take advantage of the ACTG supporting A5090 study and of the existing MRS consortium infrastructure that will allow us to perform multicenter MRS studies.