Department of Neurology, University of Rochester, Rochester, NY, United States.
Department of Microbiology and Immunology, University of Rochester, Rochester, NY, United States.
Front Cell Infect Microbiol. 2024 Oct 23;14:1405431. doi: 10.3389/fcimb.2024.1405431. eCollection 2024.
Despite antiretroviral treatment (cART), aging people living with HIV (PWH) are more susceptible to neurocognitive impairment (NCI) probably due to synergistic/additive contribution of traditional cerebrovascular risk factors. Specifically, transmigration of inflammatory CD16+ monocytes through the altered blood brain barrier (BBB) may exacerbate cerebral small vessel disease (CSVD), a known cause of vascular cognitive impairment.
PWH on cART (n=108) and age, sex, and Reynold's cardiovascular risk score-matched uninfected individuals (PWoH, n=111) were enrolled. This is a longitudinal observational study but only cross-sectional data from entry visit are reported. Neuropsychological testing and brain magnetic resonance imaging (MRI) were performed. CSVD was diagnosed by Fazekas score ≥1. Flow cytometric analyses of fresh whole blood were conducted to evaluate circulating levels of monocyte subsets (classical, intermediate, and non-classical) and markers of monocyte activation (CCR2, CD40, PSGL-1, TNFR2 and tissue factor). ELISAs were used to measure sCD14, ICAM, and Osteoprotegerin. Two-way analysis of variance (ANOVA), and linear regression models were performed to study the effects of HIV status, CSVD status, and their interaction to outcome variables such as cognitive score. Two-sample t-tests and correlation analyses were performed between and within PWoH with CSVD and PWH with CSVD participants.
PWH with CSVD (n=81) had significantly lower total cognitive scores, higher levels of NCMs and soluble CD14 and intracellular adhesion molecule 1 (ICAM-1) as compared to PWoH with CSVD group (n=68). sCD14 and ICAM1 were positively correlated with each other indicating that monocyte and endothelial activation are associated with each other. Cognition was negatively correlated with NCMs, especially in the PWH with CSVD group. Among other blood biomarkers measured, osteoprotegerin levels showed mild negative correlation with cognitive performance in individuals with CSVD irrespective of HIV status.
Elevated levels of NCMs may contribute to neuroinflammation, CSVD and subsequent cognitive impairment. This finding is of particular relevance in aging PWH as both HIV and aging are associated with increased levels of NCMs. NCMs may serve as a potential biomarker to address these comorbidities. Further longitudinal studies are needed to evaluate whether changes in NCM levels are associated with changes in CSVD burden and cognitive impairment.
尽管进行了抗逆转录病毒治疗（cART），但感染艾滋病毒的老年人（PWH）更容易受到神经认知障碍（NCI）的影响，这可能是由于传统的脑血管危险因素的协同/附加作用。具体来说，炎症性 CD16+单核细胞通过改变的血脑屏障（BBB）的迁移可能会加剧脑小血管疾病（CSVD），这是血管性认知障碍的已知原因。
纳入了正在接受 cART 的 PWH（n=108）和年龄、性别和 Reynold 心血管风险评分匹配的未感染个体（PWoH，n=111）。这是一项纵向观察性研究，但仅报告了入组时的横断面数据。进行了神经心理学测试和脑磁共振成像（MRI）。通过 Fazekas 评分≥1 诊断 CSVD。通过流式细胞术分析新鲜全血，评估单核细胞亚群（经典、中间和非经典）和单核细胞激活标志物（CCR2、CD40、PSGL-1、TNFR2 和组织因子）的循环水平。使用 ELISA 测量 sCD14、ICAM 和骨保护素。采用双向方差分析（ANOVA）和线性回归模型研究 HIV 状态、CSVD 状态及其相互作用对认知评分等结果变量的影响。对 PWoH 中伴有 CSVD 和 PWH 中伴有 CSVD 的参与者进行了两样本 t 检验和相关性分析。
与 PWoH 伴有 CSVD 组（n=68）相比，PWH 伴有 CSVD 组（n=81）的总认知评分显著较低，NCMs 水平以及可溶性 CD14 和细胞间黏附分子 1（ICAM-1）水平较高。sCD14 和 ICAM1 之间呈正相关，表明单核细胞和内皮细胞的激活相互关联。认知能力与 NCMs 呈负相关，尤其是在 PWH 伴有 CSVD 组。在所测量的其他血液生物标志物中，骨保护素水平与 CSVD 个体的认知表现呈轻度负相关，无论 HIV 状态如何。
NCMs 水平升高可能导致神经炎症、CSVD 和随后的认知障碍。这一发现对于衰老的 PWH 尤为重要，因为 HIV 和衰老都会导致 NCMs 水平升高。NCMs 可能是解决这些合并症的潜在生物标志物。需要进一步的纵向研究来评估 NCM 水平的变化是否与 CSVD 负担和认知障碍的变化相关。
