Comparative Study of Molecular Signatures in HIV-Related Neuropathogenesis and Alzheimer's Disease

摘要 问题.联合抗逆转录病毒疗法（cART）的使用使艾滋病毒感染者（PLWH）能够 活得更久更健康然而，超过一半的艾滋病毒感染者仍然有不同程度的艾滋病毒相关性。 神经认知障碍（HAND），尽管使用cART抑制病毒。艾滋病毒感染持续时间较长， 衰老可能对认知功能和神经退化具有联合的负面影响。正如PLWH 随着年龄的增长，将HAND与影响全身神经系统的神经退行性疾病区分开来非常重要。 老年人，如阿尔茨海默病（AD）。HAND和AD可能具有共同的神经病理学特征 机制，尚未系统研究，在PLWH在抑制性cART。 总体目标。为了表征HAND在病毒抑制期间的分子特征， cART，并描述与AD相关的分子特征的共性和差异。 队列和样本。我们将使用具有广泛纵向特征的互补和良好特征的队列， 现有的临床、神经认知和实验室数据来自两个主要的研究项目： 研究计划（HNRP）和Shiley-Marcos阿尔茨海默病研究中心（ADRC）。 A. HNRP：我们将回顾性纳入来自以下参与者的CSF和血液样本：（i）正常 在基线时认知，并在随后的时间点发生HAND（HAND组，n=100），和（ii）年龄- 匹配的参与者在基线时具有正常认知，并且在任何一项研究中都没有发展出HAND。 随后的时间点（无手组，n=100）。对于HAND组，我们还将在 第一次被诊断为HAND的时间点。对于参与者的子集（n=20），我们将包括存储的后- 尸检脑组织进行探索性评估 B。ADRC：我们将回顾性纳入以下受试者的CSF和血液样本：（i）轻度 基线时的神经认知障碍（MCI）和随后时间点的AD（AD组， n=50）和（ii）在所有观察时间点具有正常认知的年龄匹配的参与者（对照 组，n=50）。还将提供一部分受试者（n=20）的脑组织用于探索性评价。 Approach.我们提出了一个高度创新的方法，通过生成和分析高维数据 重点关注设计用于响应母RFA-AG-18-023的研究目标。具体来说，我们将 生成代谢组学和脂质组学（目标1），转录组学（目标2），我们将整合这些数据， 相关AD相关遗传变异、临床变量和经典AD生物标志物的测量（目的3）， 开发HAND和AD的分子相互作用网络和预测模型。我们的研究有可能 通过确定可以针对改善老年人护理的途径， 艾滋病人群和AD人群。作为该项目的一部分收集的数据也将为以下方面奠定基础： 未来的研究可以解决有关衰老，艾滋病毒和神经变性的各种开放问题。

Abstract Problem. The use of combination antiretroviral therapy (cART) has allowed people living with HIV (PLWH) to live longer and healthier. Nevertheless, more than half of PLWH still have varying degrees of HIV Associated Neurocognitive Disorder (HAND) despite viral suppression with cART. Longer duration of HIV infection and aging may have conjoining negative effects on cognitive function and neurodegeneration. As the PLWH are growing older, it is important to differentiate HAND from neurodegenerative diseases affecting the general aging population, such as Alzheimer's Disease (AD). Both HAND and AD might share neuropathological mechanisms, which have not been systematically studied, in PLWH during suppressive cART. Overarching Goal. To characterize the molecular signatures underlying HAND during viral suppression on cART, and describe the commonalities and differences with those molecular signatures associated with AD. Cohorts and Samples. We will use complementary and well-characterized cohorts with extensive longitudinal available clinical, neurocognitive and laboratory data from two major research programs: HIV Neurobehavioral Research Program (HNRP) and Shiley-Marcos Alzheimer's Disease Research Center (ADRC). A. HNRP: We will retrospectively include CSF and blood samples from participants who (i) had normal cognition at baseline and had incident HAND at a subsequent time-points (HAND group, n=100) and, (ii) age- matched participants who had normal cognition at baseline and did not develop HAND in any of the subsequent time-points (no-HAND group, n=100). For the HAND group, we will also evaluate samples at the time-point when HAND was first diagnosed. For subset of participants (n=20), we will include stored post- mortem brain tissue for exploratory evaluation. B. ADRC: We will retrospectively include CSF and blood samples from participants who: (i) had Mild Neurocognitive Impairment (MCI) at baseline and developed AD in the subsequent time-point (AD group, n=50) and, (ii) age-matched participants who had normal cognition during all observational time-points (control group, n=50). Brain tissue will also be available for a subset of participants (n=20) for exploratory evaluation. Approach. We propose a highly innovative approach by generating and analyzing high dimensional data focused on study objectives designed to be responsive to the parent RFA-AG-18-023. Specifically, we will generate metabolomics and lipidomics (aim 1), transcriptomics (aim 2), and we will integrate these data with relevant AD-associated genetic variants, clinical variables and measures of classical AD biomarkers (aim 3) to develop molecular interaction networks and predictive models of HAND and AD. Our study has the potential to yield highly translatable results by identifying pathways that can be targeted to improve care for both ageing HIV population and AD population. The data collected as part of this project will also lay the groundwork for future studies that can tackle a wide variety of open questions concerning aging, HIV and neurodegeneration.