Identification of Biomarkers of CNS injury and resilience related to HIV-1 and Methamphetamine

项目总结 甲基苯丙胺(冰毒)被普遍滥用，是艾滋病毒的一个危险因素。冰毒也会增加患上 艾滋病毒期间的不良后果，包括艾滋病毒相关的神经认知障碍(手)。多项研究 已经证明了冰毒和艾滋病毒对大脑结构和功能的神经毒性作用，以及 神经行为和功能表现。中枢神经系统损伤和恢复力的生物标志物 将是了解冰毒和艾滋病毒相关发病机制的有价值的工具，并可以提供 对药物开发的有价值的见解。冰毒和艾滋病毒在中枢神经系统外的影响(例如，血管和 代谢性疾病)也是需要考虑的重要问题，也是该领域的一个关键空白。该领域的另一个关键差距 是将研究成果转化为临床，包括可能用于检测冰毒和 HIV相关的中枢神经系统损伤和不同疾病阶段的功能损害。人们对此知之甚少 宿主防御机制弹性的生物标志物。因此，为了响应RFA-DA-18-023，本项目 建议筛选一套全面的临床和研究生物标志物，以反映病理和 Resilience，目标是识别和验证可能改善临床评估的生物签名 以及与冰毒和艾滋病毒相关的脑部和外周并发症的诊断。为了实现这一目标，我们 提议利用NIDA对UCSD资助的NIDA资助的转化型甲基苯丙胺艾滋病的先前投资 研究中心(TMARC)，执行标准化的神经行为、神经成像和神经医学 对不同冰毒使用和艾滋病毒感染的参与者进行评估。我们将召回并全面 重新评估其中的200名参与者。神经成像方法将包括测量脑血流量，中枢神经系统 代谢物水平，以及一种新的神经成像测量方法来评估血脑屏障(BBB)的完整性。我们 将在血液、脑脊液(CSF)和粪便样本中测量全面的生物标志物小组， 保存上一次基线访问的标本，以及新访问的样本，然后分析数据 使用传统的统计方法以及植根于机器学习和因果关系的新技术 推理建模。这种方法将提供独特的纵向数据，以便识别 预测中枢神经系统损伤和恢复能力变化的生物特征。我们将验证观察到的生物签名 在一个由100名参与者组成的独立队列中，这些参与者之前曾在加州大学圣地亚哥分校的艾滋病毒研究所接受过评估 神经行为研究计划，并拥有全面的数据和存储的样本(例如，脑脊液) 可用。为了更好地响应RFA的临床翻译目标，我们还将比较衡量 在常规临床评估期间获得的数据的生物标记物，目的是识别临床 冰毒和艾滋病毒相关中枢神经系统损伤的生物特征。彻底了解冰毒和艾滋病毒的影响 关于系统性和中枢神经系统的进程将解决这一领域的主要差距。这一洞察力也应该让 为诊断和有效的疾病和治疗监测提供信息的分析方法的发展。

PROJECT SUMMARY Methamphetamine (METH) is commonly abused and is a risk factor for HIV. METH also increases risk for adverse outcomes during HIV, including HIV-associated neurocognitive disorder (HAND). Multiple studies have demonstrated the neurotoxic effects of METH and HIV on brain structure and function, as well as neurobehavioral and functional performance. Biomarkers of central nervous system (CNS) injury and resilience would be valuable tools for understanding the METH- and HIV-associated pathogenesis and could provide valuable insights for drug development. The effects of METH and HIV outside the CNS (e.g., vascular and metabolic disease) are also important to consider and are a key gap in the field. Another key gap in the field is the translation of research findings to the clinic, including biomarkers that may be used to detect METH- and HIV-associated CNS injury and functional impairment across disease stages. Even less is known about biomarkers of resilience of the host defense mechanisms. Thus, in response to RFA-DA-18-023, this project proposes to screen a comprehensive panel of clinical and research biomarkers reflective of pathology and resilience with the goal of identifying and validating biosignatures that may improve the clinical assessment and diagnosis of brain and peripheral complications associated with METH and HIV. To accomplish this, we propose to leverage NIDA’s prior investment in UCSD’s NIDA-funded Translational Methamphetamine AIDS Research Center (TMARC), which performed standardized neurobehavioral, neuroimaging, and neuromedical assessments of participants who differed by METH use and HIV infection. We will recall and comprehensively re-assess 200 of these participants. Neuroimaging methods will include measures of cerebral blood flow, CNS metabolite levels, and a novel neuroimaging measure to estimate integrity of the blood-brain barrier (BBB). We will measure a comprehensive biomarker panel in blood, cerebrospinal fluid (CSF), and stool samples, in specimens from their prior baseline visit, which are stored, and from their new visit and then analyze the data using traditional statistical approaches as well as novel techniques rooted in machine-learning and causal inference modeling. This approach will provide unique longitudinal data that will allow for the identification of biosignatures that predict changes in CNS injury and resilience. We will validate the observed biosignatures in an independent cohort of 100 participants who have been previously assessed at UCSD’s HIV Neurobehavioral Research Program and who have comprehensive data and stored specimens (e.g., CSF) available. To better respond to the clinical translation objective of the RFA, we will also compare measured biomarkers to data that are obtained during routine clinic assessments with the goal of identifying a clinical biosignature of METH- and HIV-related CNS injury. A thorough understanding of the impact of METH and HIV on systemic and CNS processes will address key gaps in the field. This insight should also inform the development of assays to inform diagnosis and effective disease and treatment monitoring.