In vivo proton MRS studies:cerebral injury in HIV infection

描述(申请人提供)：高效抗逆转录病毒疗法(HAART)导致艾滋病毒感染者的存活率显著上升。目前尚不清楚这种治疗在多大程度上对脑室有好处，特别是在晚期，甚至是稳定的疾病中。最近的研究表明，在HAART和稳定期疾病的背景下，脑损伤和神经认知障碍可以持续或展开。因此，神经损伤的频率、范围和程度、其与认知功能的关系以及对抗逆转录病毒治疗的反应仍然是重要但尚未解决的问题。HIV MRS联盟已经发现了HIV相关认知障碍(艾滋病痴呆复合体，ADC)不同阶段特有的区域和细胞异常，以及脑损伤的体内模型，表明基底节和神经元事件可能对ADC的发展至关重要。它还在基线上确定了可能增加神经认知障碍(NCI)或其进一步下降风险的潜在宿主(如年龄、血浆MCP-1、CSFIP-10、CSFIP-10、CSF Fractalkine)和病毒因子(CSF HIV RNA)。这是一项为期五年的多中心纵向研究，研究对象为310名HIV阳性受试者的脑损伤(MRS测量)和NCI，这些受试者有HAART晚期免疫抑制史(最低免疫抑制水平为100/毫升)。这项研究将通过在前瞻性设计中实施MRS来填补文献中的一个重要空白，以便确定NCI的风险受试者。我们将在250名神经无症状(NA)和60名ADC受试者中检测MRS对局部损伤的模式和动力学。大多数受试者将从三个具有良好特征的现有预期队列中招募，包括两项ACTG研究(N=210)和来自UCLA NNAB和UCSD CNTN的脑库研究(N=100)。受试者将根据进入时的CD4计数进行分层，即200或200个细胞/毫升。脑库受试者将进一步分为病毒抑制组和非抑制组。主要目标是：1)通过MRS确定有脑损伤风险的NA患者，并检测基线水平上可能增加随后神经损伤和NCI风险的宿主(例如年龄、趋化因子)和病毒因素(HIV RNA)；2)确定基底节和神经因素的出现是否预测NCI的发生或进展；3)研究神经功能、反映病毒学和免疫学活性变化的生物标志物与治疗变化之间的动态关系。多变量纵向模型和变量选择将被用来研究作为相互关联因素的动态系统的HIV感染的神经学效应。在HAART上检测NA受试者的脑损伤并面临ADC的风险将对整体健康结果和早期治疗干预具有关键影响。

DESCRIPTION (provided by applicant): Highly active antiretroviral therapy (HAART) has resulted in a marked rise in survival rates among HIV-infected persons. To what extent the brain compartment benefits from such treatment, particularly in the setting of advanced, even stable, disease, remains unclear. Recent studies suggest that cerebral injury and neurocognitive impairment can persist or unfold in the setting of HAART and stable disease. The frequency, spectrum and extent of neurological injury, its relationship to cognitive functioning and responsiveness to antiretroviral therapies thus remain important yet unresolved issues. The HIV MRS consortium has identified regional and cellular abnormalities specific to different stages of HIV-associated cognitive impairment (AIDS dementia complex, ADC) as well as an in vivo model of brain injury that suggests basal ganglia and neuronal events may be critical to the development of ADC. It has also identified potential host (e.g. age, plasma MCP-1, CSFIP-10, CSF fractalkine) and viral factors (CSF HIV RNA) at baseline that may increase the risk for neurocognitive impairment (NCI) or its further decline. This is a five-year multicenter longitudinal study of cerebral injury (as measured by MRS) and NCI in 310 HIV-positive subjects with a history of advanced immunosuppression (nadir CD4<100/mL) on HAART. The study will fill an important gap in the literature by implementing MRS in a prospective design in order to identify subjects at risk for NCI. We will examine the pattern and dynamics of regional injury by MRS among 250 neurologically asymptomatic (NA) and 60 ADC subjects. The majority of subjects will be enrolled from three well characterized existing prospective cohorts, including two ACTG studies (N= 210) and from the brain bank studies UCLA NNAB and UCSD CNTN (N= 100). Subjects will be stratified by CD4 count at entry, <200 or >200 cells/ml. The brain bank subjects will be further divided into virologically suppressed and nonsuppressed groups. The primary aims are: 1) to identify NA subjects at risk for brain injury as measured by MRS and examine host (e.g. age, chemokines) and viral factors (HIV RNA) at baseline that may increase the risk for subsequent neurological injury and NCI; 2) to determine whether the emergence of basal ganglia and neuronal factors predict the onset of NCI or its progression; 3) to examine dynamic relationships between neurologic function, biomarkers that reflect changing virologic and immunologic activity and changes in treatment. Multivariate longitudinal models and variable selection will be used to study the neurological effects of HIV infection as a dynamic system of interrelated factors. Detection of brain injury among NA subjects on HAART and at risk for ADC will have critical ramifications for overall health outcome and early therapeutic intervention.