CNS METABOLIC CORRELATES OF HIV DEMENTIA BY MRS IMAGING

通过 MRS 成像研究 HIV 痴呆的中枢神经系统代谢相关性

• 批准号: 6187592
• 负责人: MARTIN G POMPER
• 金额: $ 43.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-28 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6187592
• 关键词: AIDS dementia complex; HIV infections; antiAIDS agent; bioimaging /biomedical imaging; biomarker; blood brain barrier; brain metabolism; cell adhesion molecules; cerebrospinal fluid; choline; clinical research; drug resistance; human immunodeficiency virus 1; human subject; human therapy evaluation; longitudinal human study; monocyte chemoattractant protein 1; neuropathology; nuclear magnetic resonance spectroscopy; postmortem; virus load; virus replication

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.

1 型人类免疫缺陷病毒 (HIV) 在感染过程的早期就进入中枢神经系统 (CNS)。然而，艾滋病毒引起的痴呆症 (HIV-D) 见于约 15% 的艾滋病毒阳性者，是一种相对较晚的疾病表现，通常发生在严重的免疫功能低下状态和高病毒载量的情况下。 一旦 HIV 突破血脑屏障 (BBB)，即使通过高效抗逆转录病毒治疗 (HAART) 将外周病毒水平降低至无法检测到的水平，HIV 病毒仍有可能在大脑内不受控制地复制。 大约 50% 的患者会出现 HAART 治疗失败的情况，并且新的 HIV 痴呆病例仍在出现。目前尚不清楚痴呆症在多大程度上是由于疾病后期大脑的重新播种而引起的，也不清楚皮质下或新皮质结构在多大程度上导致了痴呆。 是否有可以无创测量的标记物来反映中枢神经系统病毒载量的变化和随之而来的脑损伤？ 是否有一个易于评估的标志物可以反映对 HAART 耐药性的形成？ 能否以无创方式在大脑中绘制区域性脑损伤的时间过程？ 磁共振波谱 (MRS) 是一种无创工具，具有易于重复性，可测量大脑代谢物，反映中枢神经系统功能。 我们打算使用 MRS 和 MRS 成像 (MRSI) 来解决人类的这些问题，提出大脑代谢物浓度可以作为中枢神经系统 HIV 活动的替代标志物。通过测量适当的脑脊液和外周标志物来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，以及即使在HAART期间该活性也能继续引起痴呆的能力。 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，以及 b) 大脑代谢水平是否反映了维持 HIV 治疗的充分性检查中枢神经系统。