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: 6392768
• 负责人: MARTIN G POMPER
• 金额: $ 38.47万
• 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 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6392768
• 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.

在感染过程中，人类免疫缺陷病毒1型（HIV）在早期获得了中枢神经系统（CNS）的通道。然而，在大约15％的艾滋病毒+个体中，由于HIV（HIV-D）引起的痴呆症是通常在严重免疫功能低下的状态和高病毒负荷的情况下发生的疾病的相对晚期表现。 一旦HIV侵犯了血脑屏障（BBB），即使高度活跃的抗逆转录病毒疗法（HAART）将外周病毒水平（HAART）降低至无法检测到的水平，即使外周病毒水平已降低至无法检测到的水平，也存在潜在的大脑内复制的潜力。 HAART的治疗失败发生在约50％的患者中，而新的HIV痴呆症患者仍在发展。目前尚不清楚由于疾病后期在大脑的恢复或皮质下或新皮质结构在多大程度上导致痴呆症导致痴呆症导致痴呆症。 是否有可以无创测量的标记，以反映中枢神经系统病毒负荷和随之而来的脑损伤的变化？ 是否可以轻松地评估标记，以反映对HAART的发展抵抗力？ 区域脑损伤的时间病程是否可以无创地映射在大脑中？ 磁共振光谱（MRS）是一种无创的工具，具有易于可重复性，可测量脑代谢物，反映CNS功能。 我们打算使用MRS和MRS Imaging（MRSI）在人类中解决这些问题，并提出脑代谢产物浓度可以作为CNS HIV活性的替代标志物。通过测量适当的CSF和外围标记，对CNS免疫激活，BBB完整性和病毒载荷的同时评估将进一步增强对体内病毒CNS活性的理解，即使在HAART期间，该活动的能力甚至在HAART期间也会继续引起痴呆症。 拟议研究的广泛目标是确定a）MRS和MRSI衡量的HIV相关CNS活性水平如何与神经系统状况相关以及b）b）b）脑代谢水平是否反映了治疗在CNS检查中保持HIV方面的适当性。