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

摘要 有问题。联合抗逆转录病毒疗法(CART)的使用使艾滋病毒携带者(PLWH)能够 活得更长、更健康。尽管如此，超过一半的PLWH仍然有不同程度的HIV相关 神经认知障碍(手)，尽管病毒抑制与CART。艾滋病毒感染持续时间更长，以及 衰老可能会对认知功能和神经退化产生共同的负面影响。就像PLWH一样 随着年龄的增长，区分手部和影响全身的神经退行性疾病是很重要的 老龄化人口，如阿尔茨海默病(AD)。手部和阿尔茨海默病可能具有共同的神经病理 抑制车运动中PLWH的作用机制尚未有系统的研究。 首要目标。在病毒抑制过程中表征潜在的分子特征 CART，并描述与AD相关的分子签名的共性和差异。 队列和样本。我们将使用具有广泛纵向的互补和特征良好的队列 可获得两个主要研究项目的临床、神经认知和实验室数据：艾滋病毒神经行为 研究计划(HNRP)和Shiley-Marcos阿尔茨海默病研究中心(ADRC)。 答：HNRP：我们将追溯纳入(I)正常的参与者的脑脊液和血液样本 在基线时的认知和在随后的时间点有事件的手(手组，n=100)和，(Ii)年龄- 配对的参与者在基线时认知正常，并且在任何 后续时间点(无手组，n=100)。对于HAND组，我们还将在 首次诊断为HAND的时间点。对于参与者子集(n=20)，我们将包括存储的帖子- 用于探索性评估的尸检脑组织。 B.ADRC：我们将追溯包括以下参与者的脑脊液和血液样本：(I)轻度 基线时的神经认知功能障碍(MCI)和随后的时间点发展为AD(AD组， N=50)和，(Ii)年龄匹配的参与者，他们在所有观察时间点都有正常的认知(对照组 组，n=50)。脑组织也将可供部分参与者(n=20)进行探索性评估。 接近。我们提出了一种高度创新的方法，通过生成和分析高维数据 侧重于研究目标，旨在响应父母的RFA-AG-18-023。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)，我们将把这些数据与 与阿尔茨海默病相关的遗传变异、临床变量和经典阿尔茨海默病生物标志物的测量(目标3)至 建立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 通过确定可针对性地改善对两种老龄化的护理，产生高度可翻译的结果 HIV人群和AD人群。作为该项目的一部分收集的数据也将为 未来的研究可以解决关于衰老、艾滋病毒和神经退化的各种悬而未决的问题。

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.