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）。然而，艾滋病病毒（HIV-D）引起的痴呆症，在大约15%的艾滋病病毒阳性个体中可见，是通常在严重免疫功能低下状态和高病毒载量的情况下发生的疾病的相对晚期表现。 一旦HIV越过血脑屏障（BBB），即使在通过高效抗逆转录病毒疗法（HAART）将外周病毒水平降低至无法检测的水平后，也存在脑内不受抑制复制的可能性。 HAART治疗失败发生在大约50%的患者中，艾滋病毒痴呆症的新病例仍在发展中。目前还不清楚痴呆症在多大程度上是由于疾病后期大脑的再播种引起的，或者皮层下或新皮层结构在多大程度上导致痴呆症。 是否有可以无创测量的标志物，反映CNS病毒载量的变化和伴随的脑损伤？ 是否有一个标志物，可以很容易地评估，反映了发展中国家的耐药性HAART？ 区域性脑损伤的时间进程可以在脑中非侵入性地绘制吗？ 磁共振波谱（MRS）是一种非侵入性的工具，具有易于重复性，可测量大脑代谢物，反映CNS功能。 我们打算解决这些问题，在人类使用MRS和MRS成像（MRSI），提出脑代谢物浓度可能作为中枢神经系统HIV活性的替代标志物。通过测量适当的CSF和外周标志物同时评估CNS免疫活化、BBB完整性和病毒载量将进一步增强对体内病毒CNS活性的理解，以及即使在HAART期间该活性继续引起痴呆的能力。 拟议研究的广泛目标是确定a）通过MRS和MRSI测量的HIV相关CNS活性水平如何与神经系统状态相关，以及B）脑代谢物水平是否反映了治疗在CNS中保持HIV检查的充分性。

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.