Neural mechanisms of HIV-associated CNS dysfunction despite viral suppression

项目摘要/摘要 尽管有有效的抗逆转录病毒疗法，但艾滋病毒感染者(HIV+)仍存在认知缺陷 个人。例如，在妇女机构间艾滋病毒研究(WIHS)中，艾滋病毒+病毒抑制(HIV+VS) 女性在语言学习和记忆以及工作记忆方面表现出神经认知障碍(NCI)， 注意力和执行功能。这些认知操作领域与陈述性记忆和 NIMH研究领域标准(RDoC)的认知控制子域，这是一个尚未 促进对造成艾滋病毒非传染性感染模式的机制的了解。有一种强烈的 科学假设艾滋病毒相关的脑损伤源于免疫过程，尤其是 神经炎症，由单核/巨噬细胞系的细胞介导。为了支持这一观点， 我们的团队和其他人证明了HIV中的NCI与小胶质细胞激活和单核细胞激活有关。 在这项提案中，我们的多学科团队将通过开展一项 纵向神经影像研究，不仅使用RDoC框架，还评估神经炎症。 在我们横断面神经成像研究的基础上，我们将首先使用基于任务的功能磁共振 人类免疫缺陷病毒感染者和非感染者的功能磁共振成像(FMRI)和静息状态功能磁共振成像(FMRI)识别神经 导致陈述性记忆和认知控制缺陷的回路。第二，我们将使用正电子 放射断层扫描(PET)评估慢性神经炎中HIV相关改变与NCI的关系。 第三，我们将对与认知变化相关的多模式成像数据进行计算整合 随时间推移的性能。为了实现我们的目标，我们建议在表型良好的情况下进行单点纵向研究。 来自WIHS和多中心艾滋病队列研究的HIV+VS(N=100)和HIV控制组(N=50)的特征 (Mac)。参与者将完成神经成像评估(静息状态和基于任务的功能磁共振成像、结构性 磁共振扩散加权成像)，为期三年，此后每六个月进行一次认知评估 同样的时间。纵向设计允许评估关键发现随时间的重现性，以及 这些神经成像测量对认知表现变化的敏感性。检查与艾滋病毒相关的 慢性神经炎的改变，一部分人(总共42人；24名HIV+VS)也将完成PET 使用[11C]DPA-713(DPA)进行评估。在5年的潜力之后，与NIH的研究优先事项保持一致 资金，这一R01对实地的影响将使我们了解与以下有关的机制 并提供新的、更灵敏的神经成像生物标志物来指导新的 针对HIV+患者的认知疗法。

PROJECT SUMMARY/ABSTRACT Despite the availability of effective antiretroviral therapies, cognitive deficits persist in HIV-infected (HIV+) individuals. For example, in the Women's Interagency HIV Study (WIHS), HIV+ virally suppressed (HIV+VS) women showed neurocognitive impairment (NCI) in verbal learning and memory as well as working memory, attention and executive function. These domains of cognitive performance relate to the declarative memory and cognitive control subdomains of the NIMH Research Domain Criteria (RDoC), a framework that has not yet been leveraged to advance understanding of the mechanisms contributing to patterns of NCI in HIV. There is a strong scientific premise that HIV-associated brain injury stems from immunological processes, particularly neuroinflammation, mediated by cells of the monocyte/macrophage lineage. In support of this view, studies by our team and others demonstrate that NCI in HIV is associated with microglial activation and monocyte activation. In this proposal, our multidisciplinary team will provide innovation to this line of inquiry by conducting a longitudinal neuroimaging study that not only uses the RDoC framework but also assesses neuroinflammation. Building on our cross-sectional neuroimaging studies, we will first use task-based functional magnetic resonance imaging (fMRI) and resting state fMRI in HIV+VS individuals and HIV-uninfected individuals to identify the neural circuitry contributing to deficits in declarative memory and cognitive control. Second, we will use positron emission tomography (PET) to assess HIV-related alterations in chronic neuroinflammation in relation to NCI. Third, we will computationally integrate the multimodal imaging data in relation to changes in cognitive performance over time. To achieve our goal, we propose a single-site, longitudinal study in phenotypically well- characterized HIV+VS (N=100) and HIV- controls (N=50) from the WIHS and Multicenter AIDS Cohort Study (MACS). Participants will complete neuroimaging assessments (resting state and task-based fMRI, structural MRI, diffusion-weighted MRI) annually for three years and cognitive assessments every six months over that same time. The longitudinal design allows an assessment of the reproducibility of key findings over time and the sensitivity of these neuroimaging measures to changes in cognitive performance. To examine HIV-related alterations in chronic neuroinflammation, a subset of individuals (total n =42; 24 HIV+VS) will also complete PET assessments using [11C]DPA-713 (DPA). In keeping with NIH research priorities, after 5 years of potential funding, the impact of this R01 on the field will be to inform our understanding of the mechanisms linked to neurological comorbidity and to provide novel, more sensitive neuroimaging biomarkers to guide testing of new cognitive therapies for HIV+ individuals.