Novel Methods to Access Brain Function in HIV-1

自从出现有效的抗逆转录病毒疗法以来，发达国家中 HIV-1 感染者的机会性感染和肿瘤的发生率已大幅下降。相比之下，痴呆症的发病率下降幅度较小。造成这种差异的原因尚不清楚，但可能是由于某些抗逆转录病毒药物无法渗透中枢神经系统（CNS）。我们的初步临床研究和其他小组的研究数据表明，治疗和预防 HIV-1 相关认知障碍需要在整个病程中控制外周和中枢 HIV-1 感染。该 R21 应用程序的主要目标是生成功能磁共振成像 (fMRI) 和功能磁共振波谱 (fMRS) 的初步数据。这些数据将用于支持一项试验，该试验利用功能性神经影像学评估中枢神经系统抗逆转录病毒治疗的疗效。本申请是为了回应 NIMH PA-99-134“MH 干预研究的探索性/发展资助”而编写的。正如计划公告 (PA) 中所建议的，我们将试点测试一种干预措施（fMRI 和 fMRS），以识别高危人群（患有晚期 HIV-1 相关疾病的受试者）的疾病早期迹象（HIV-1 感染导致的脑功能障碍）。我们将解决 PA 中概述的干预措施发展的第二阶段和第三阶段。在第二阶段，我们将开发 fMRI 和 fMRS 作为 HIV-1 未感染者和 HIV-1 感染者大脑功能的诊断测试。在第三阶段，我们将对这些功能性神经影像学指标的变化进行初步研究，以应对有效的抗逆转录病毒治疗。具体来说，该项目的目标是： 1) 优化 fMRI 和 fMRS 方法，包括校正脑灌注，并估计这些未感染 HIV-1 的受试者脑激活测量值随时间的变化； 2) 通过 fMRI 和 fMRS 测量，估计 HIV-1 未感染者和 HIV-1 感染者之间大脑激活的差异； 3) 进行一项试点研究，通过功能磁共振成像（fMRI）和功能磁共振成像（fMRS）以及神经心理学测试表现来估计 HIV-1 感染者对有效抗逆转录病毒治疗的反应，从而估计大脑激活变化的程度。本申请中提出的研究可能最终导致更好的方法来评估中枢神经系统隔室中的治疗效果，从而提高我们预防和治疗HIV-1相关痴呆的能力。

Since the availability of potent antiretroviral therapy, the incidence of opportunistic infections and neoplasms in HIV-1-infected individuals in the developed world has dramatically declined. In contrast, the incidence of dementia has declined less. The reason for this difference is not known, but it may be due to the inability of some antiretroviral agents to penetrate the central nervous system (CNS). Data from our preliminary clinical studies and from studies of other groups suggest that treatment and prevention of HIV-1-associated cognitive impairment will require control of both peripheral and central HIV-1 infection throughout the course of disease. The primary goal of this R21 application is to generate preliminary data on functional magnetic resonance imaging (fMRI) and functional magnetic resonance spectroscopy (fMRS). These data will be used to support a trial that assesses the efficacy of antiretroviral therapy in the CNS using functional neuroimaging. This application is written in response to NIMH PA-99-134, "Exploratory/Developmental Grants for MH Intervention Research". As suggested in the Program Announcement (PA), we will pilot test an intervention (fMRI and fMRS) that identifies early signs of a disorder (brain dysfunction due to HIV-1 infection) in a high-risk group (subjects with advanced HIV-1-associated disease). We will address stage 2 and stage 3 of intervention development as outlined in the PA. In stage 2, we will develop fMRI and fMRS as diagnostic tests of brain function in HIV-1-uninfected and HIV-1-infected subjects. In stage 3, we will perform a pilot study of changes in these functional neuroimaging measures in response to potent antiretroviral therapy. Specifically, the aims of this project are: 1) Optimize the fMRI and fMRS method, including correction for brain perfusion, and estimate variability of these measures of brain activation over time in HIV-1-uninfected subjects; 2) Estimate differences in brain activation as measured by fMRI and fMRS between HIV-1-uninfected and HIV-1-infected individuals; 3) Perform a pilot study to estimate the magnitude of changes in brain activation as measured by fMRI and fMRS and by neuropsychological test performance in response to potent antiretroviral therapy in HIV-1- infected individuals. The studies proposed in this application may ultimately lead to better means of assessing the efficacy of therapy in the CNS compartment and thus to an improvement in our ability to prevent and treat HIV-1 -associated dementia.