Neural mechanisms of HIV-associated CNS dysfunction despite viral suppression

项目总结/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+）的认知缺陷仍然存在。 个体例如，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。认知表现的这些领域涉及陈述性记忆， NIMH研究领域标准（RDoC）的认知控制子领域，这是一个尚未被 利用这些信息来促进对艾滋病毒NCI模式的机制的理解。有很强 科学假设，艾滋病毒相关的脑损伤源于免疫过程，特别是 神经炎症，由单核细胞/巨噬细胞谱系的细胞介导。为了支持这一观点， 我们的研究小组和其他研究人员证明，HIV中的NCI与小胶质细胞活化和单核细胞活化有关。 在这项提案中，我们的多学科团队将通过开展一项 纵向神经影像学研究，不仅使用RDoC框架，而且还评估神经炎症。 基于我们的横断面神经影像学研究，我们将首先使用基于任务的功能磁共振 在HIV+VS个体和HIV未感染个体中进行功能磁共振成像（fMRI）和静息状态fMRI，以确定神经元 导致陈述性记忆和认知控制缺陷的回路。其次，我们将使用正电子 放射断层扫描（PET），以评估与NCI相关的慢性神经炎症中的HIV相关改变。 第三，我们将计算整合与认知变化相关的多模态成像数据， 性能随着时间的推移。为了实现我们的目标，我们提出了一个单一的网站，纵向研究表型良好- 来自WIHS和多中心AIDS队列研究的特征性HIV+VS（N=100）和HIV-对照（N=50） （MACS）.参与者将完成神经影像学评估（静息状态和基于任务的fMRI，结构 MRI，弥散加权MRI）每年一次，持续三年，在此期间每六个月进行一次认知评估 同时还研究与讨论纵向设计允许评估关键发现随时间推移的再现性， 这些神经成像测量对认知表现变化的敏感性。检查与艾滋病毒有关的 在慢性神经炎症的改变中，一个个体子集（总n =42; 24 HIV+VS）也将完成PET 使用[11 C]DPA-713（DPA）进行评估。为了与NIH的研究重点保持一致，经过5年的潜力， 资金，本R 01对实地的影响将使我们了解与以下方面有关的机制： 并提供新的，更敏感的神经影像学生物标志物，以指导新的 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.