Vascular contributions to HIV-associated Neurocognitive Disorders (HAND)

项目总结/摘要： 随着艾滋病毒感染者（PWH）年龄的增长，慢性合并症，如脑血管疾病和认知能力下降， 变得更加普遍。脑血管疾病和痴呆症的发病率在以下人群中存在差异： PWH。可能的影响因素包括血管风险因素的不成比例的患病率，例如 高血压、糖尿病、血脂异常和吸烟。此外，威尔斯亲王医院的社会经济背景 (that包括但不限于同性恋恐惧症，结构性种族主义和社会耻辱）可能转化为压力源 这可能会导致更差的血管健康。在这个建议中，我们试图填补知识空白， 血管危险因素和社会经济压力因素可能影响PWH患者的脑血管疾病和认知能力。 我们认为，可溶性血液内皮细胞活化的生物标志物，如血管细胞粘附分子-1， 血管细胞粘附分子-1（VCAM-1）、细胞间粘附分子-1（ICAM-1）和肿瘤坏死因子α（TNFα）的表达， 更重要的是，它们可能是治疗靶点。在目标1中，我们 假设不受控制的血管危险因素和社会经济压力因素与艾滋病毒相互作用，从而与 与年龄、性别和种族匹配相比，内皮活化的血液生物标志物水平升高 未感染的对照组。在目标2中，我们提出，艾滋病毒相关脑血管疾病与 未感染的对照由内皮活化的血液生物标志物水平的增加介导。在目标3中，我们 假设PWH患者与对照组相比，在基于MRI神经变性和认知方面的差异 未感染的对照组是由内皮活化和MRI的血液生物标志物水平升高介导的。 脑血管疾病。为了证实内皮激活剂在其他炎症反应中的中心作用， 分子，我们将进行验证性分析，使用五种模型，包括LASSO没有相互作用 项、Lasso与交互作用项、RF、XGBoost和模型平均值。为了实现这些目标，我们 将产生严格的科学证据，支持艾滋病毒相关脑血管疾病的独特生理病理学， 疾病和神经变性。此外，通过建立内皮激活作为一个关键途径， 调解艾滋病毒相关的脑血管疾病和神经变性的差异，我们将提供 初步支持，以测试这些炎症通路的修饰（例如TNFα阻断）是否可以 证明对PWH或本研究中确定的某些亚组有益。

PROJECT SUMMARY/ABSTRACT: As people with HIV (PWH) age, chronic comorbidities such as cerebrovascular disease and poorer cognition become more prevalent. There exist a disparity in the rates of cerebrovascular disease and dementia among PWH. Possible contributing factors include disproportionate prevalence of vascular risk factors such as hypertension, diabetes, dyslipidemia and smoking in PWH. Additionally, the socioeconomic context of PWH (that includes but is not limited to homophobia, structural racism and societal stigma) may translate in stressors that may contribute to poorer vascular health. In this proposal, we attempt to fill in the knowledge gap of how vascular risk factors and socioeconomic stressors may affect cerebrovascular disease and cognition in PWH. We propose that soluble blood biomarkers of endothelial activation such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and tumor necrosis factor alpha (TNFα), are key mediators of these relationships, and more importantly, they could be therapeutic targets. In aim 1, we hypothesize that uncontrolled vascular risk factors and socioeconomic stressors interact with HIV to relate to increased levels of blood biomarkers of endothelial activation compared to age-, sex-, and ethnicity-matched uninfected controls. In aim 2, we propose that disparities in HIV-related cerebrovascular disease compared to uninfected controls are mediated by increased levels of blood biomarkers of endothelial activation. In aim 3, we hypothesize that disparities in MRI-based neurodegeneration and cognition in PWH compared to matched uninfected controls are mediated by increased levels of blood biomarkers of endothelial activation and MRI- based cerebrovascular disease. To confirm the central role of endothelial activators over other inflammatory molecules, we will carry out confirmatory analyses using five models that include LASSO without interaction terms, Lasso with interaction terms, RF, XGBoost and Model Average. With the execution of these aims, we will produce rigorous scientific evidence supporting the unique physiopathology of HIV-related cerebrovascular disease and neurodegeneracion. Furthermore, by establishing endothelial activation as a key pathway in mediating HIV-related disparities in cerebrovascular disease and neurodegeneration, we will provide preliminary support to test whether modification of these inflammatory pathways (e.g. TNFα blockade) may prove beneficial in PWH or in certain subgroups to be identified in this study.