CNS METABOLIC CORRELATES OF HIV DEMENTIA BY MRS IMAGING

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。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，约15%的HIV阳性个体出现由HIV- d引起的痴呆，这是该疾病的一种相对较晚的表现，通常发生在严重免疫功能低下状态和高病毒载量的情况下。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。约50%的患者使用HAART治疗失败，艾滋病毒痴呆的新病例仍在发展。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。此R01与此资源应用程序中提出的项目2特别相关。由于HIV痴呆患者长时间在MR扫描仪中不舒服，因此快速mri技术的发展对该项目至关重要。此外，肯尼迪克里格研究所F.M.柯比功能性脑成像中心的舒适环境，特别是磁铁的短孔和宽孔，将确保本研究中患者的最大依从性。技术发展的第二个领域（项目2）是短回声时间核磁共振成像技术的发展，从而使肌醇的定量制图成为可能。先前已使用单体素技术证明肌醇是检测HIV感染早期中枢神经系统异常的最重要代谢物之一。

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.