Role of Myeloid Cells in Cerebrovascular Permeability and Reactivity in Older HIV Infected Individuals

感染艾滋病毒的人，特别是年长的人，患脑血管疾病的风险更高。 (CBVD)。虽然最近的大多数研究都集中在大血管疾病，但脑小血管疾病 疾病(CSVD)尽管其已知的作用和对认知的长期影响，但受到的关注要少得多 表现，可能与艾滋病毒相关的免疫失调有更直接的联系。CSVD通过以下方式诊断 神经成像。典型的表现包括皮质下小梗塞、腔隙、白质高信号、增大。 血管周围间隙、脑微出血和脑萎缩。定量磁共振技术间接评估 通过测量血管反应性、脑血流量、 脑白质微结构和组织敏感性。重要的是，这些定量成像方式可以 即使是细微的大脑异常，也可以通过标准的临床成像技术进行测量。 CSVD与髓系细胞分泌的标志物有关。这与艾滋病毒尤其相关。 被感染的人。我们和其他人已经证明，在HIV/SIV感染过程中，血小板的异常激活 导致血小板-单核细胞复合体(PMC)增加，从而推动单核细胞成熟 CD14/CD16-与促炎性CD14(低)/CD16表型有关 CD14/CD16单核细胞与前AS改变、血脑屏障通透性和衰老有关。因此，私营军事公司 可作为CSVD的标志物和治疗靶点。基于这些观察，我们假设 PMC通过影响血管通透性和反应性，在介导CSVD中发挥关键作用，特别是在 年长的艾滋病毒感染者。 在一个具有良好特征的脑血管病风险因素队列中，包括老年艾滋病毒人群(年龄≥，50岁) 和年龄匹配的非感染者，我们建议解决以下与CSVD相关的具体目标 在一项为期3年的纵向研究中。在目标1中，我们将评估血管反应性的变化(通过 MRI)和脑白质微结构完整性(通过DTI测量)与PMC水平相关。在……里面 次目标1我们将确定组织敏感度增加和血管减少的区域 反应性与脑血流量(CBF)下降有关。在目标2中，我们将确定 血管反应性和白质微结构完整性的变化与可溶性产物相关 促炎症单核细胞(血浆sCD163、新喋呤和HMGB1水平)、血小板活化(血小板 因子4[PF-4]和血管内皮细胞功能障碍的血浆标志物(细胞间黏附分子1[sICAM-1] 1]、血管细胞黏附分子-1[sVCAM-1]、护骨素和脂蛋白相关 磷脂酶A2[Lp-PLA2]质量)。在次级目标2中，我们将确定脑铁沉积的变化 与PMCs、PF-4、血浆单核细胞和内皮可溶性产物水平相关。 在目标3中，我们将在认知表现的背景下模拟从先前目标产生的数据。

HIV infected individuals, especially those older, are at increased risk of developing cerebrovascular disease (CBVD). While most of the recent investigations have focused on large vessel disease, cerebral small vessel disease (CSVD) has received much less attention despite its known role and long-term effect on cognitive performance and potentially more direct link to HIV-associated immune dysregulation. CSVD is diagnosed via neuroimaging. Typical findings include small subcortical infarcts, lacunes, white matter hyperintensity, enlarged perivascular spaces, cerebral microbleeds and brain atrophy. Quantitative MR techniques assess indirectly the altered microcirculation and blood brain barrier (BBB) by measuring vascular reactivity, cerebral blood flow, white matter microstructure and tissue susceptibility. Importantly, these quantitative imaging modalities can measure even subtle brain abnormalities that escape the evaluation by standard clinical imaging techniques. CSVD has been associated with markers secreted by myeloid cells. This is particularly relevant to HIV infected individuals. We and others have shown that the aberrant platelet activation during HIV/SIV infection causes an increase in platelet-monocyte complexes (PMCs) that drives monocyte maturation from CD14+/CD16- to the pro-inflammatory CD14(low)/CD16+ phenotype and that the reduced numbers of CD14+/CD16- monocytes are associated with pro-AS changes, BBB permeability and aging. Thus, PMCs could serve as markers and a therapeutic target of CSVD. Based on these observations, we hypothesize that PMCs, by affecting vascular permeability and reactivity, play a crucial role in mediating CSVD, especially in older HIV infected individuals. In a well characterize cohort for CBVD risk factors that includes an older-enriched HIV population (age≥50) and age matched uninfected individuals, we propose to address the following Specific Aims pertinent to CSVD in a 3-year longitudinal study. In Aim 1 we will assess whether changes in vascular reactivity (measured via rs-fMRI) and white matter microstructural integrity (measured via DTI) are associated with levels of PMCs. In Sub-Aim 1 we will determine whether areas with increased tissue susceptibility and decreased vascular reactivity are associated with decreased cerebral blood flow (CBF). In Aim 2 we will determine whether changes vascular reactivity and white matter microstructural integrity are associated with soluble products of pro-inflammatory monocytes (plasma levels of sCD163, neopterin, and HMGB1), platelet activation (platelet factor 4 [PF-4]) and with plasma markers of endothelial dysfunction (intercellular adhesion molecule 1 [sICAM- 1], vascular cellular adhesion molecule-1 [sVCAM-1], osteoprotegerin and lipoprotein-associated phospholipase A2 [Lp-PLA2] mass). In Sub-Aim 2 we will determine whether changes in brain iron deposition are associated with levels of PMCs, PF-4, plasma monocyte and endothelial soluble products. In Aim 3 we will model data generated from the previous aims in the context of cognitive performance.