Novel Methods to Access Brain Function in HIV-1

研究 HIV-1 大脑功能的新方法

• 批准号: 6639253
• 负责人: Christina M Marra
• 金额: $ 18.95万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6639253
• 关键词: AIDS dementia complex; AIDS therapy; HIV infections; antiAIDS agent; antiviral agents; brain disorder diagnosis; chemoprevention; drug screening /evaluation; enzyme linked immunosorbent assay; functional magnetic resonance imaging; human immunodeficiency virus 1; human subject; human therapy evaluation; medical complication; neuroimaging; neuropsychological tests; nuclear magnetic resonance spectroscopy; patient oriented research; western blottings

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.

自从有了有效的抗逆转录病毒疗法以来，发达国家HIV-1感染者的机会性感染和肿瘤发病率已大幅下降。相比之下，痴呆症的发病率下降较少，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穿透中枢神经系统（CNS）。我们的初步临床研究和其他研究组的数据表明，治疗和预防HIV-1相关的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性磁共振成像（fMRI）和功能性磁共振波谱（fMRS）的初步数据。这些数据将用于支持一项试验，该试验使用功能性神经影像学评估抗逆转录病毒治疗在CNS中的疗效。本申请书是根据NIMH PA-99-134“MH干预研究的探索/发展赠款”编写的。正如计划公告（PA）中所建议的那样，我们将在高危人群（晚期HIV-1相关疾病受试者）中进行一项干预（fMRI和fMRS）的试点测试，以识别疾病（HIV-1感染引起的脑功能障碍）的早期迹象。我们将处理巴勒斯坦权力机构所概述的干预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未感染和HIV-1感染受试者脑功能的诊断测试。在第3阶段，我们将进行一项试验性研究，研究这些功能性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，本项目的目标是：1）优化fMRI和fMRS方法，包括校正脑灌注，并估计这些测量的脑激活随时间的变化在HIV-1未感染的受试者中：2）估计HIV-1未感染和HIV-1感染个体之间的fMRI和fMRS测量的脑激活的差异; 3）进行一项初步研究，以估计HIV-1感染者在接受强效抗逆转录病毒治疗后，通过fMRI和fMRS以及神经心理学测试表现测量的脑激活变化幅度。本申请中提出的研究可能最终导致更好的方法来评估CNS隔室治疗的疗效，从而提高我们预防和治疗HIV-1相关痴呆的能力。