CNS METABOLIC CORRELATES OF HIV DEMENTIA BY MRS IMAGING

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。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，艾滋病毒引起的痴呆症(艾滋病毒-D)出现在约15%的艾滋病毒+患者中，是这种疾病相对较晚的表现，通常发生在免疫功能严重受损和病毒载量较高的情况下。一旦艾滋病毒越过血脑屏障(BBB)，即使在外周病毒水平通过高效抗逆转录病毒疗法(HAART)降至无法检测的水平后，仍有可能在大脑内无节制地复制。大约50%的患者使用HAART治疗失败，新的艾滋病毒痴呆症病例仍在发展中。目前尚不清楚痴呆在多大程度上是由于疾病后期大脑重新播种引起的，也不清楚皮质下或新皮质结构在多大程度上导致痴呆。是否有可以非侵入性测量的标记物来反映中枢神经系统病毒载量和随之而来的脑损伤的变化？有没有一种可以容易评估的标记物来反映对HAART正在形成的抵抗力？局部脑损伤的时间进程能在大脑中无创地绘制出来吗？磁共振波谱(MRS)是一种非侵入性的工具，具有易重复性，可以测量大脑代谢物，反映中枢神经系统的功能。我们打算在人类中使用MRS和MRS成像(MRSI)来解决这些问题，提出大脑代谢物浓度可以作为CNS HIV活性的替代标记物。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的免疫激活、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动的了解，以及这种活动即使在HAART期间也会继续导致痴呆的能力。拟议研究的广泛目标是确定a)MRS和MRSI测量的艾滋病毒相关中枢神经系统活动水平如何与神经状况相关，以及b)大脑代谢物水平是否反映了在中枢神经系统控制艾滋病毒的治疗是否充分。本R01特别涉及本资源申请中提议的项目2。由于HIV痴呆症患者长时间在MR扫描仪中感到不适，快速MRSI技术的开发对这一项目至关重要。此外，肯尼迪·克里格研究所F.M.柯比功能脑成像中心舒适的环境，特别是磁铁的短孔和宽孔，将确保患者在本研究中尽可能地依从性。技术开发的第二个领域(项目2)是开发短回声时间磁共振成像技术，以便对肌醇进行定量测绘。以前使用单体素技术表明，肌醇是检测HIV感染早期中枢神经系统异常最重要的代谢物之一。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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% 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% 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. This R01 relates specifically to project 2 proposed in this resource application. Since patients with HIV dementia are uncomfortable in the MR scanner for long periods of time, the development of fast MRSI techniques are of critical importance to this project. Also, the comfortable environment of the Kennedy Krieger Institute F.M. Kirby Center for Functional Brain Imaging, in particular the short and wide bore of the magnets, will ensure maximum possible patient compliance in this study. A second area of technical development (project 2) is the development of short echo time MRSI techniques, so that quantitative mapping of myo-inositol will be possible. It has previously been shown using single voxel techniques that myo-inositol is one of the most important metabolites for the detection of early CNS abnormalities in HIV infection.