A Novel FMRI Biomarker of Asymptomatic HIV-Associated Neurocognitive Disorders

 描述（由申请人提供）： 尽管广泛使用联合抗逆转录病毒疗法（cART），但大约一半的HIV感染者受到HIV相关神经认知障碍（HAND）的影响。即使是最轻微的HAND，即无症状神经认知障碍（ANI），也会增加抗逆转录病毒治疗不依从性，病毒学失败，失业和死亡的风险。识别神经靶点进行干预行为和药物治疗的压力越来越大，特别是在有进展为症状性HAND风险的人群中。早期干预（在潜在的附加神经损伤之前）可能更有效，并且有更好的机会保持和改善认知功能。尽管有这一重大的公共卫生需求，但找到一种可以准确评估当前神经认知疾病阶段并可靠预测未来HAND进展的生物标志物仍然是一个重大挑战。在这里，我们假设，在没有症状的手，微妙的神经元功能障碍，由于突触树突损伤，目前尚未进行临床评估，是存在的，可以检测和定量使用新的功能磁共振成像（fMRI）技术，我们最近开发和验证。在这项为期5年的横向和纵向研究中，我们的目标是进一步验证和改善这些fMRI生物标志物（基于两种新技术），样本量更大，横向和纵向（主要目标）。我们将在五年内研究总共160个主题。这些将包括100名接受cART治疗的神经认知正常/ANI HIV阳性、病毒抑制的成年人和60名匹配的HIV阴性对照。HIV阳性者将接受24个月的随访。根据最近的一项研究（Grant等人，Neurology，2014），我们预计约20名HIV+参与者将在2年内从神经认知正常或ANI转变为症状性HAND。这种纵向数据将为我们提供一个机会，用新的功能磁共振成像技术跟踪过渡的轨迹，并确定进展为症状性手（次要目标）的潜在风险标志物。该项目有三个具体目标：目标1：测试HIV通过降低关键脑区的神经特异性来损害神经认知功能的假设，并确定最易受HIV疾病影响的脑区（即，神经特异性降低最大的那些）。目标二：为了检验HAND导致大脑加速/过早老化的假设，通过使用相对于HIV未感染对照的fMRI激活的多变量模式分析（MVPA）计算HIV感染大脑的功能年龄，并在全脑水平上将HIV的加速老化量化为单个诊断数字，Hage（Hage =功能年龄减去实际年龄）可能与HAND进展和未来风险相关，具有很强的潜力作为临床环境中HAND的生物标志物。目标3：评估HIV感染导致执行功能降低的神经基础，这是一种最常见和关键的缺陷，是与HAND相关的广泛神经认知障碍的基础。该拟议项目的成功有望为临床医生和研究人员提供一套经验证的工具/生物标志物，以定量评估早期病理变化并预测未来的HAND进展，具有指导和评估可能减缓或预防症状性HAND进展的干预措施的强大潜力。

 DESCRIPTION (provided by applicant): Despite the widespread use of combination antiretroviral therapy (cART), approximately half of individuals with HIV-infection are affected by HIV-associated neurocognitive disorders (HAND). Individuals with even the mildest form of HAND, asymptomatic neurocognitive impairment (ANI), are at increased risk of antiretroviral non-adherence, virologic failure, unemployment and mortality. There has been increasing pressure to identify neural targets for interventional behavioral and medical therapies, especially among persons at risk of progression to symptomatic HAND. Early interventions (prior to potentially additive neural damage) are likely to be more effective and have a better chance to preserve and improve cognitive function. Despite this significant public health need, finding a biomarker that can accurately assess current neurocognitive disease stage and reliably predict future HAND progression remains a major challenge. Here we hypothesize that, in HIV+ individuals without symptomatic HAND, subtle neuronal dysfunction due to synaptodendritic injury, not currently assessed clinically, is present and can be detected and quantitated using the novel functional magnetic resonance imaging (fMRI) techniques we recently developed and validated. In this 5-year cross- sectional and longitudinal study, we aim to further validate and improve these fMRI biomarkers (based on two novel techniques) with a larger sample size, both cross-sectionally and longitudinally (primary goal). We will study a total of 160 subjects over five years. These will include 100 neurocognitively normal/ANI HIV-positive, virally suppressed adults on cART, and 60 matched HIV negative controls. HIV+ individuals will have a 24- month follow-up visit. Based on a recent study (Grant et al., Neurology, 2014), we expect about 20 HIV+ participants will transition from neurocognitively normal or ANI to symptomatic HAND over the 2-year period. This longitudinal data will provide us an opportunity to follow the trajectories of transition with novel fMRI techniques and to identify potential markers of risk for progression to symptomatic HAND (secondary goal). This project has three specific aims: Aim 1: To test the hypothesis that HIV impairs neurocognitive function by decreasing neural specificity in key brain regions and to identify brain regions that are most vulnerable to HIV- disease (i.e., those with the greatest reductions in neural specificity). Aim 2: To test the hypothesis that HAND leads to accelerated/premature aging of the brain, by calculating a functional age of the HIV-infected brain with multivariate pattern analysis (MVPA) of fMRI activations relative to HIV-uninfected controls, and to quantify accelerated aging in HIV at the whole-brain level as a single diagnostic number, Hage (Hage = functional age minus chronological age) that can be linked to HAND progression and future risk, with a strong potential to serve as a biomarker of HAND in clinical settings. Aim 3: To evaluate the neural bases of reduced executive function due to HIV infection, one of the most common and key deficits that underlies a broad range of neurocognitive impairments associated with HAND. The success of this proposed project is expected to provide clinicians and researchers with a validated set of tools/biomarkers to quantitatively assess early pathological changes and to predict future HAND progression, with a strong potential to guide and evaluate interventions that might slow down or prevent progression to symptomatic HAND.