A Novel FMRI Biomarker of Asymptomatic HIV-Associated Neurocognitive Disorders

 描述(由申请人提供)： 尽管联合抗逆转录病毒疗法(CART)被广泛使用，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。即使是最轻微的手部无症状神经认知障碍(ANI)的患者，也会面临更高的抗逆转录病毒不依从性、病毒学失败、失业和死亡的风险。为介入性行为和医学治疗确定神经靶点的压力越来越大，特别是在有发展为有症状手的风险的人中。早期干预(在潜在的附加神经损伤之前)可能更有效，有更好的机会保存和改善认知功能。尽管有这种重大的公共卫生需求，但寻找一种能够准确评估当前神经认知疾病阶段并可靠地预测未来手部进展的生物标记物仍然是一个重大挑战。在这里，我们假设，在没有手部症状的HIV患者中，存在由突触树突损伤引起的细微神经元功能障碍，目前尚未进行临床评估，并可以使用我们最近开发和验证的新功能磁共振成像(FMRI)技术进行检测和定量。在这项为期5年的横断面和纵向研究中，我们的目标是用更大的横断面和纵向样本量(主要目标)进一步验证和改进这些功能磁共振生物标记物(基于两种新技术)。我们会在五年内研究共160个课题。这些研究将包括100名神经认知正常/ANI HIV阳性的成年人，接受CART治疗的病毒抑制的成年人，以及60名匹配的HIV阴性对照。艾滋病患者将接受为期24个月的随访。根据最近的一项研究(Grant等人，Neuroology，2014)，我们预计大约20名艾滋病毒参与者将在两年内从神经认知正常或ANI过渡到有症状的手。这些纵向数据将为我们提供一个机会，用新的fMRI技术跟踪过渡的轨迹，并确定进展为有症状手的潜在风险标记物(次要目标)。该项目有三个具体目标：目标1：检验艾滋病毒通过降低关键脑区的神经特异性而损害神经认知功能的假设，并确定最容易受到艾滋病毒疾病影响的大脑区域(即神经特异性下降最严重的区域)。目的2：通过使用多变量模式分析(MVPA)来计算HIV感染者脑的功能年龄(相对于未感染HIV的对照组)，并在全脑水平上将HIV的加速老化量化为单一的诊断数HAGE(HAGE=功能年龄减去时间年龄)，以检验手部导致大脑加速/过早老化的假设，HAGE(HAGE=功能年龄减去未来风险)具有在临床环境中作为手部生物标志物的强大潜力。目的3：评估HIV感染导致执行功能降低的神经基础，这是与手相关的广泛神经认知障碍的最常见和关键缺陷之一。这一拟议项目的成功有望为临床医生和研究人员提供一套有效的工具/生物标记物来定量评估早期病变和预测未来手的进展，并具有指导和评估干预措施的强大潜力，这些干预措施可能会减缓或防止出现症状的手的进展。

 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.