PROTON MRS STUDIES OF CEREBRAL INJURY IN HIV INFECTION

最近采用的高效抗逆转录病毒疗法极大地改变了艾滋病流行的自然历史。尽管如此，在这种情况下，神经损伤的范围和程度，它与神经认知功能和对抗逆转录病毒治疗变化的反应性的关系仍然是重要的和未解决的问题。这项申请是为了更新对HIV MRS联盟的支持，提出了一项为期五年的横断面和纵向研究，以检查HAART治疗下HIV感染大脑区域损伤的模式和动态。在当前资助周期的前两年，MRS联盟确定了皮质下区域代谢异常与认知功能之间的显著关系。具体而言，较低水平的NAA在额叶白质区分ADC和NA受试者；与对照组相比，神经无症状（NA）组的Cho和MI显著增加，神经心理表现与皮质下区域，特别是基底神经节的代谢物水平显著相关。因此，磁共振成像提供了一种有价值的、无创的体内方法来研究和监测大脑微环境的变化。最近的数据支持认知障碍及其对治疗的反应与脑脊液的病毒学和免疫活性密切相关的假设。然而，人们对这些事件与HAART治疗中不同脑损伤模式之间的关系知之甚少。MRS联盟将承担以下具体目标：1)检查80名ADC和80名NA受试者的大脑微环境对脑脊液和外周室中不同水平HIV RNA和趋化因子的反应与抗逆转录病毒治疗和神经认知表现的变化之间的关系；2)确定NA晚期患者中枢神经系统损伤与神经认知功能障碍发生的关系的程度和意义；3)利用纵向统计模型评估ADC和NA受试者脑损伤模式的演变以及宿主和病毒因素的影响。基底神经节、额叶白质和皮层的MRS研究将与认知功能测量、HIV RNA和免疫激活标记物的测定相结合，包括100名接受抗逆转录病毒治疗的HIV RNA大于2000拷贝/ml的受试者和60名接受稳定治疗且血浆HIV RNA检测不到的受试者的CSF和外周室中的趋化因子。纵向和横断面分析将结合各种单变量，多变量和回归模型，这将使我们能够1)比较和关联代谢和神经认知反应的强度和持续时间与CSF和外周室中HIV RNA水平和免疫激活的关系，2)评估这些宿主和病毒因素对脑损伤和认知表现的相对贡献和相互作用。

The recent introduction of highly active antiretroviral therapy (HAART) has dramatically altered the natural history of the AIDS epidemic. Nonetheless, the spectrum and extent of neurological injury in this setting, its relationship to neurocognitive function and responsiveness to changes in antiretroviral therapy remain important and unresolved issues. This application to renew support for the HIV MRS consortium proposes a five year cross sectional and longitudinal study to examine the pattern and dynamics of regional injury in the HIV infected brain in the setting of HAART. During the first two years of the current grant cycle, the MRS consortium identified significant relation- ships between metabolic abnormalities in the subcortical regions and cognitive function. Specifically, lower levels of NAA in the frontal white matter distinguished ADC from NA subjects; significant increases in Cho and MI were found in the neuroasymptomatic (NA) group compared to controls and neuropsychological performance was significantly correlated with metabolite levels in the subcortical regions, particularly the basal ganglia. MRS thus provides a valuable, noninvasive in vivo method to study and monitor changes in the cerebral microenvironment. Recent data support the hypothesis that cognitive impairment and its response to treatment correlates strongly with virological and immunologic activity in the CSF. Yet little is known about the relationships of these events to varying patterns of brain injury in the setting of HAART. The MRS consortium will undertake the following specific aims: 1) Examine the response of the cerebral microenvironment to varying levels of HIV RNA and chemokines in the CSF and peripheral compartments of 80 ADC and 80 NA subjects in relationship to changes in antiretroviral therapies and neurocognitive performance; 2) Determine the extent and significance of CNS injury in NA subjects with advanced disease in relationship to the development of neurocognitive impairment; and 3) Assess the evolution of brain injury patterns in ADC and NA subjects and the impact of host and viral factors using longitudinal statistical models. MRS studies of the basal ganglia, frontal white matter and cortex will be combined with measurements of cognitive function and assays of HIV RNA and markers of immune activation, including chemokines in the CSF and peripheral compartments of 100 subjects with HIV RNA greater than 2000 copies/ml undergoing changes in antiretroviral therapy and 60 subjects on stable therapy with undetectable plasma HIV RNA. Longitudinal and cross sectional analysis will be done incorporating various univariate, multivariate, and regression models that will allow us 1) to compare and correlate the magnitude and duration of the metabolic and neurocognitive response in relation to levels of HIV RNA and immune activation in the CSF and peripheral compartments and 2) to assess the relative contributions and interactions of these host and viral factors to brain injury and cognitive performance.