In vivo proton MRS studies:cerebral injury in HIV infection

描述（由申请人提供）：高效抗逆转录病毒疗法（HAART）已导致艾滋病毒感染者的存活率显着上升。在何种程度上，脑区室受益于这种治疗，特别是在设置先进的，甚至稳定的疾病，仍然不清楚。最近的研究表明，脑损伤和神经认知功能障碍可以持续存在或在HAART和稳定疾病的设置展开。因此，神经系统损伤的频率、范围和程度、其与认知功能的关系以及对抗逆转录病毒疗法的反应性仍然是重要但尚未解决的问题。HIV MRS联盟已经确定了特定于不同阶段的HIV相关认知障碍（AIDS痴呆综合征，ADC）的区域和细胞异常，以及脑损伤的体内模型，表明基底神经节和神经元事件可能对ADC的发展至关重要。它还确定了基线时可能增加神经认知障碍（NCI）风险或进一步降低风险的潜在宿主（例如年龄、血浆MCP-1、CSFIP-10、CSF fractalkine）和病毒因子（CSF HIV RNA）。这是一项为期5年的多中心纵向研究，在310名有HAART晚期免疫抑制史（最低CD 4 <100/mL）的HIV阳性受试者中进行脑损伤（通过MRS测量）和NCI。该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，以识别存在NCI风险的受试者。我们将通过MRS检查250例神经系统无症状（NA）和60例ADC受试者的区域损伤模式和动力学。大多数受试者将从3个充分表征的现有前瞻性队列中入组，包括2项ACTG研究（N= 210）和脑库研究UCLA NNAB和UCSD CNTN（N= 100）。受试者将按入组时的CD 4计数（200<200 or >个细胞/ml）分层。脑库受试者将进一步分为病毒学抑制组和非抑制组。主要目标是：1）鉴定如通过MRS测量的处于脑损伤风险的NA受试者，并检查宿主（例如年龄、趋化因子）和病毒因子（HIV RNA）在基线时可能增加后续神经损伤和NCI的风险; 2）确定基底神经节和神经元因子的出现是否预测NCI的发作或其进展; 3）检查神经功能、反映变化的病毒学和免疫学活性的生物标志物与治疗变化之间的动态关系。将使用多变量纵向模型和变量选择来研究HIV感染作为相互关联因素的动态系统的神经效应。在接受HAART和ADC风险的NA受试者中检测脑损伤将对整体健康结局和早期治疗干预产生重要影响。

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.