Novel Methods to Access Brain Function in HIV-1

自从提供了有效的抗逆转录病毒疗法以来，发达国家艾滋病毒-1感染者的机会性感染和肿瘤发生率急剧下降。相比之下，痴呆症的发病率下降较少。造成这种差异的原因尚不清楚，但可能是由于一些抗逆转录病毒药物无法穿透中枢神经系统（CNS）。我们的初步临床研究和其他组的研究数据表明，HIV-1相关认知障碍的治疗和预防需要在整个疾病过程中控制外周和中枢HIV-1感染。本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使用功能性神经影像学评估抗逆转录病毒治疗在中枢神经系统疗效的试验。本申请是根据NIMH PA-99-134“MH干预研究的探索性/发展性资助”而写的。正如项目公告（PA）所建议的那样，我们将在高风险人群（患有晚期HIV-1相关疾病的受试者）中试点测试一种干预措施（fMRI和fMRS），以识别疾病的早期迹象（由HIV-1感染引起的脑功能障碍）。我们将讨论《行动纲领》中概述的干预措施发展的第2和第3阶段。在第二阶段，我们将发展fMRI和fMRS作为hiv -1未感染和hiv -1感染受试者脑功能的诊断测试。在第三阶段，我们将进行一项实验性研究，研究这些功能神经影像学指标对强效抗逆转录病毒治疗的反应。具体来说，该项目的目标是：1)优化fMRI和fMRS方法，包括脑灌注校正，并估计这些测量大脑激活的方法在hiv -1未感染受试者中随时间的变化；2)通过功能磁共振成像（fMRI）和功能磁共振成像（fMRS）估计hiv -1未感染者和hiv -1感染者之间脑激活的差异；3)开展一项试点研究，以估计在对HIV-1感染者进行有效抗逆转录病毒治疗后，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测量的大脑激活变化的幅度。本应用程序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室治疗的疗效，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.