Marques de Menezes Erika G, Bowler Scott A, Shikuma Cecilia M, Ndhlovu Lishomwa C, Norris Philip J
Vitalant Research Institute, San Francisco, CA, United States.
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, United States.
Front Neurol. 2024 Apr 23;15:1383227. doi: 10.3389/fneur.2024.1383227. eCollection 2024.
Although effective antiretroviral therapy (ART) has improved the life expectancy of people with HIV (PWH), the prevalence of milder forms of HIV-associated neurocognitive disorders (HAND) persist, and it is associated with systemic and neuro-inflammatory processes that could impact other organ systems. However, the complex signaling mechanisms between the bone-kidney systems and the brain in HAND remain unknown. Extracellular vesicles (EVs) play a potential role in inter-organ communication and are involved in regulating cell activity in distant tissues. In this study, we examined whether levels of EVs from bone-and kidney-related cells associate with cognitive dysfunction and explored the relationship between kidney-bone EV axis in PWH experiencing cognitive deficits.
EV subtypes were characterized in plasma from 61 PWH with either cognitive impairment (CI, = 53) or normal cognition (NC, = 8) based on the American Academy of Neurology criteria for HIV-associated dementia (HAD, = 11), minor cognitive motor disorder (MCMD, = 25) or asymptomatic neurocognitive impairment (ANI, = 17) by spectral flow cytometry. EVs were profiled with markers reflecting bone and kidney cell origin. A support vector machine learning-based model was employed for analyses of EV phenotypes to predict the cognitive dysfunction.
Plasma-EVs expressing osteocalcin, sclerostin, and nephrin were significantly higher in the cognitive impairment group compared to the normal cognition group. EVs bearing kidney cell markers correlated significantly with bone-derived EVs. A machine learning-based model, comprised of osteocalcin+, nephrin+, and CD24+ EVs predicted cognitive impairment in PWH on ART.
Our study reveals that neurocognitive impairment in PWH is associated with increased levels of plasma EVs enriched with the bone markers osteocalcin and sclerostin and the kidney marker nephrin, suggesting that these EV subtypes may be novel candidate biomarkers for disease-spanning neurocognitive dysfunction. Moreover, the relationship between bone-derived EVs with kidney-derived EVs may suggest their role in mediating inter-organ crosstalk in the pathogenesis of HIV-associated cognitive impairment.
尽管有效的抗逆转录病毒疗法（ART）提高了人类免疫缺陷病毒感染者（PWH）的预期寿命，但轻度形式的HIV相关神经认知障碍（HAND）仍然普遍存在，并且它与可能影响其他器官系统的全身和神经炎症过程有关。然而，HAND中骨-肾系统与大脑之间复杂的信号传导机制仍然未知。细胞外囊泡（EVs）在器官间通讯中发挥潜在作用，并参与调节远处组织中的细胞活性。在本研究中，我们检查了来自骨和肾相关细胞的EVs水平是否与认知功能障碍相关，并探讨了认知功能缺损的PWH中肾-骨EV轴之间的关系。
根据美国神经病学学会关于HIV相关痴呆（HAD，n = 11）、轻度认知运动障碍（MCMD，n = 25）或无症状神经认知障碍（ANI，n = 17）的标准，通过光谱流式细胞术对61例有认知障碍（CI，n = 53）或正常认知（NC，n = 8）的PWH血浆中的EV亚型进行表征。用反映骨和肾细胞起源的标志物对EVs进行分析。采用基于支持向量机学习的模型对EV表型进行分析，以预测认知功能障碍。
与正常认知组相比，认知障碍组中表达骨钙素、硬化蛋白和肾足蛋白的血浆EVs显著更高。携带肾细胞标志物的EVs与骨源性EVs显著相关。一个由骨钙素阳性、肾足蛋白阳性和CD24阳性EVs组成的基于机器学习的模型预测了接受ART治疗的PWH的认知障碍。
我们的研究表明，PWH中的神经认知障碍与富含骨标志物骨钙素和硬化蛋白以及肾标志物肾足蛋白的血浆EVs水平升高有关，这表明这些EV亚型可能是跨疾病神经认知功能障碍的新型候选生物标志物。此外，骨源性EVs与肾源性EVs之间的关系可能表明它们在HIV相关认知障碍发病机制中介导器官间串扰的作用。
