CNS METABOLIC CORRELATES OF HIV DEMENTIA BY MRS IMAGING

人类免疫缺陷病毒1型（HIV）在感染过程的早期进入中枢神经系统（CNS）。尽管如此，约15%的HIV阳性个体出现由HIV- d引起的痴呆，这是一种相对较晚的疾病表现，通常发生在严重免疫功能低下状态和高病毒载量的背景下。一旦艾滋病毒越过血脑屏障（BBB），就有可能在大脑内不受控制地复制，即使外周病毒水平已经通过高活性抗逆转录病毒疗法（HAART）降低到无法检测的水平。大约50%的患者使用HAART治疗失败，新的艾滋病毒痴呆病例仍在发展。目前尚不清楚痴呆症在多大程度上是由于疾病晚期大脑的重新播种引起的，也不清楚皮层下或新皮层结构在多大程度上导致了痴呆症。是否存在可以无创测量的标志物，反映中枢神经系统病毒载量的变化和随之而来的脑损伤？是否有一种标记物可以很容易地评估，以反映对HAART的耐药性？区域性脑损伤的时间进程能否在大脑中无创地绘制出来？磁共振波谱（MRS）是一种测量脑代谢物，反映中枢神经系统功能的无创工具，具有易于重复性。我们打算在人类中使用MRS和MRS成像（MRSI）来解决这些问题，提出脑代谢物浓度可能作为CNS HIV活性的替代标记。通过测量适当的脑脊液和外周标志物，同时评估中枢神经系统免疫激活、血脑屏障完整性和病毒载量，将进一步增强对体内病毒中枢神经系统活性的了解，以及这种活性在HAART治疗期间继续导致痴呆的能力。拟议研究的主要目标是确定a)通过MRS和MRSI测量的HIV相关中枢神经系统活动水平如何与神经系统状态相关；b)脑代谢物水平是否反映了在中枢神经系统中控制HIV治疗的充分性。

The human immunodeficiency virus type 1 (HIV) gains access to the central nervous system (CNS) early in the course of infection. Nevertheless, dementia due to HIV (HIV-D), seen in about 15 percent of HIV+ individuals, is a relatively late manifestation of the illness occurring usually in the context of a severely immunocompromised state and a high viral load. Once HIV has transgressed the blood-brain barrier (BBB), the potential exists for unchecked replication within the brain, even after peripheral viral levels have been reduced to undetectable levels by highly active antiretroviral therapy (HAART). Therapeutic failures with HAART occur in about 50 percent of patients and new cases of HIV dementia are still developing. It is unclear as to what extent dementia arises due to reseeding of the brain late in the disease or to what extent subcortical or neocortical structures contribute to dementia. Are there markers that could be measured noninvasively that reflect changes in CNS viral load and the attendant brain injury? Is there a marker that could be assessed easily that reflects a developing resistance to HAART? Can the temporal course of regional brain injury be mapped in the brain, noninvasively? Magnetic resonance spectroscopy (MRS) is a noninvasive tool with easy reproducibility that measures brain metabolites, reflecting CNS function. We intend to address these questions in humans using MRS and MRS imaging (MRSI), proposing that brain metabolite concentrations may serve as surrogate markers of CNS HIV activity. Concurrent assessment of CNS immune activation, BBB integrity and viral load through measurement of appropriate CSF and peripheral markers would further enhance understanding of viral CNS activity in vivo, and the ability for that activity to continue to engender dementia even during HAART. The broad objectives of the proposed research are to determine a) how the level of HIV- related CNS activity, as measured by MRS and MRSI, can be correlated to neurological status and b) whether brain metabolite levels reflect the adequacy of therapy at keeping HIV in check in the CNS.