SIGNATURES OF CANNABIS ABUSE IN NEUROHIV (SCAN): AN INTEGRATED MOLECULAR AND IMAGING APPROACH

项目摘要/摘要 在西方世界，感染艾滋病毒的成年人的预期寿命接近于普通人群，但处于 极大地增加了患认知缺陷的风险。这种损伤是最常见的神经系统损伤 艾滋病毒疾病的并发症，流行率估计在所有艾滋病毒感染者中从35%到70%不等， 针对这种合并症的研究已被艾滋病研究办公室确定为首要任务 (非-OD-15-137)。物质使用障碍(Sud)在艾滋病毒感染人群中也更为普遍，但 他们对这一群体中认知障碍发生率增加的相对贡献仍然知之甚少。 在这一领域取得进展的一个关键障碍是历史上缺乏能够 准确评估艾滋病毒感染的神经系统并发症，这几乎排除了量化 SUD合并症的相加影响。这一障碍是请求应用程序的RFA-DA-18-023的核心 促进生物标记物和签名鉴定，可以推进临床评估的程度 功能储备的恶化或损害，以及宿主防御机制对艾滋病毒的韧性- 艾滋病毒与肥胖症的感染和共病。具体地说，RFA要求提出识别生物标记物的建议 来自血液、血浆、非侵入性神经成像方式和/或其他来源，重点是 可以量化的生物标记物，评估其预测疾病进展的能力。 目前的项目直接针对这一RFA中确定的科学空白，即艾滋病毒生物标志物的识别 发病机制和药物滥用共病，使用包括最新技术在内的多管齐下的方法 神经生理、结构和光谱非侵入性成像、认知评估和细胞和 大麻使用障碍(CUD)背景下的血液/血浆分子分析。具体地说，签名 大麻滥用在神经艾滋病毒(SCAN)协会将使用先进的脑磁图(MEG) 成像以量化神经动力学，为认知处理、3-特斯拉磁共振和多模式分离服务 方法绘制脑结构图、血流动力学和内部网络的功能磁共振成像(FMRI)和7-特斯拉 光谱成像，以量化整个大脑的局部GABA水平。这些数据将与 全面的分子筛查，包括35个血浆生物标志物，涵盖免疫、炎症、 凝血、血管内皮细胞和神经系统：10色流式细胞仪板勾画出CD4和CD8 T细胞、B细胞、NK细胞、单核细胞亚群和激活标记、已知的临床标记和线粒体 用海马氏分析仪方法检测免疫细胞的功能。提高严格性，与人口统计相匹配 将登记一组有和没有CUD的未感染对照，这将使艾滋病毒和 CUD有待量化。总而言之，为了真正达到RFA的目标，我们将使用广泛的神经成像， 分子和细胞功能分析，以揭示艾滋病毒和CUD的生物标记物签名，将使 识别早期功能障碍、进展和预后，使未来的预防和治疗试验成为可能。

Project Summary/Abstract HIV-infected adults in the western world have a life expectancy near that of the general population, but are at a significantly elevated risk of developing cognitive deficits. Such impairments are the most common neurological complication of HIV disease, with prevalence estimates ranging from 35-70% of all HIV-infected individuals, and research targeting such comorbidities has been identified as a top priority by the Office of AIDS Research (NOT-OD-15-137). Substance use disorders (SUD) are also more prevalent in the HIV-infected population, yet their relative contribution to the increased rate of cognitive impairment in this group remains poorly understood. A key barrier to progress in this area has been the historic lack of diagnostic tests and biomarkers that can precisely assess the neurological complications of HIV-infection, which has all but precluded quantification of the additive impact of SUD comorbidity. This barrier is central to RFA-DA-18-023, which requests applications that “foster biomarker and signature identification that could advance the clinical assessment of the degree of deterioration or damage, of functional reserve, and of resilience of host defense mechanisms, towards HIV- infection and comorbidity of HIV with SUDs.” Specifically, the RFA requests proposals that identify biomarkers derived from blood, plasma, noninvasive neuroimaging modalities, and/or other sources, with an emphasis on biomarkers that can be quantitated, with levels assessed for their ability to predict disease progression. The current project directly targets the scientific gaps identified in this RFA, Identification of Biomarkers of HIV Pathogenesis and Substance Abuse Comorbidity, using a multipronged approach that includes state-of-the-art neurophysiological, structural, and spectroscopic noninvasive imaging, cognitive assessment, and cellular and molecular analyses of blood/plasma in the context of cannabis use disorder (CUD). Specifically, the Signatures of Cannabis Abuse in NeuroHIV (SCAN) Consortium will utilize advanced magnetoencephalographic (MEG) imaging to quantify the neural dynamics serving cognitive processing, 3-Tesla MRI and multimodal parcellation methods to map brain architecture, functional MRI (fMRI) for hemodynamics and intrinsic networks, and 7-Tesla spectroscopic imaging to quantify local GABA levels across the brain. These data will be integrated with a comprehensive molecular screen that includes 35 plasma biomarkers covering the immune, inflammatory, coagulation, endothelial, and neurological systems, a 10-color flow cytometry panel delineating CD4 and CD8 T cells, B cells, NK cells, monocyte subsets, and activation markers, known clinical markers, and mitochondrial function in immune cells using the Seahorse Analyzer method. To enhance rigor, demographically-matched groups of uninfected controls with and without CUD will be enrolled, which will enable the interaction of HIV and CUD to be quantified. In sum, to truly meet the goals of this RFA, we will use a broad range of neuroimaging, molecular, and cellular functional assays to uncover biomarker signatures of HIV and CUD that will enable identification of early dysfunction, progression, and prognosis, enabling future preventative and treatment trials.