Quantitative Susceptibility Mapping of Brain Iron in People with HIV: Mechanistic Links to Neuropsychiatric Disorders

项目总结 情绪障碍造成的公共健康负担，如抑郁、焦虑和冷漠，在有 尽管病毒得到了控制，但艾滋病毒(PWH)仍然居高不下。神经精神障碍或症状(NPS)，困扰30- 60%的PWH，由于联合抗逆转录病毒治疗延长了寿命，患病率有所上升 时代。此外，情绪障碍和认知障碍经常在PWH中并存，通常是治疗- 抗药性，并对整个临床护理构成重大挑战，因为坚持 治疗、生活质量和功能状态。然而，病毒性肺炎NPS的致病机制 抑制的(VS)PWH和新的治疗靶点仍然难以捉摸。 已知未感染艾滋病毒的人的情绪障碍涉及铁代谢的改变，我们的初步研究 研究表明，铁失衡与PWH患者的认知障碍和抑郁有关。铁是人体所必需的 神经递质平衡、少突胶质细胞合成和维持髓鞘及能量代谢 大脑。铁的调节会被HIV感染、神经炎症和血脑屏障(BBB)泄漏所扰乱。 然而，尚不清楚艾滋病毒相关的铁运输变化是否会影响大脑铁的积累，这是 与许多认知障碍有关。定量磁化率图磁共振成像 (QSM/MRI)是一种强大的、最先进的神经成像技术，可以通过以下方式弥补这一研究空白 提供了量化局部脑铁沉积(或负荷)的方法。具体来说，我们将1)确定 VS-PWH与HIV阴性患者局部脑铁负荷的变化及其作用 奖赏和认知过程的改变，以及2)决定脑铁、少突胶质细胞的贡献 铁传递蛋白，改变髓鞘和多巴胺/5-羟色胺的稳态，扰乱奖赏和认知 VS-PWH与HIV阴性个体的过程。该项目将使用现有的QSM数据和 美国国立卫生研究院资助的一项正在进行的研究的参与者在RDoC认知系统中的行为指标，我们对此进行了研究 将在奖励处理和铁输送、髓鞘维持和生物标记物方面增加行为措施 与额纹状体功能相关的单胺类物质。我们将测试大脑铁负荷较高的中心假说 额纹状体区域将显著促进奖赏和认知过程的变化，这 严重依赖于PWH的前额叶区域(认知控制、工作记忆、注意力)。调查结果来自 本研究将为未来VS-PWH和心境障碍的深入机制研究提供基础 建议潜在的治疗靶点。

PROJECT SUMMARY The public health burden of mood disorders, such as depression, anxiety, and apathy, among people with HIV (PWH) remains high, despite control of the virus. Neuropsychiatric disorders or symptoms (NPS), afflict 30- 60% of PWH and have risen in prevalence, owing to increased longevity in the combination antiretroviral therapy era. Furthermore, mood disorders and cognitive impairment frequently co-occur in PWH, are often treatment- resistant, and present substantial challenges to clinical care overall, due to adverse impacts on adherence to treatment, quality of life, and functional status. However, the causative mechanisms underlying NPS in virally suppressed (VS) PWH, and new therapeutic targets, remain elusive. Mood disorders in people without HIV are known to involve altered iron metabolism, and our preliminary studies implicate iron imbalances in cognitive impairment and depression in PWH. Iron is essential for neurotransmitter balance, synthesis and maintenance of myelin by oligodendrocytes, and energy metabolism in the brain. Iron regulation is disrupted by HIV infection, neuro-inflammation, and a leaky blood-brain barrier (BBB). It is unknown, however, whether HIV-related changes in iron transport influence brain iron accumulation, which is linked to many cognitive disorders. Quantitative Susceptibility Mapping magnetic resonance imaging (QSM/MRI) is a powerful, state-of-the-art neuroimaging technique which can address this research gap by providing the means to quantify regional brain iron deposition (or load). Specifically, we will 1) Determine alterations in regional brain iron load in VS-PWH versus HIV-negative individuals, and the contribution of these alterations to reward and cognitive processes, and 2) Determine the contributions of brain iron, oligodendrocyte iron-delivery proteins, and altered myelin and dopamine/serotonin homeostasis to disrupted reward and cognitive processes in VS-PWH versus HIV-negative individuals. The project will employ existing QSM data and behavioral metrics in RDoC cognitive systems from participants in an ongoing NIH-funded study, to which we will add behavioral measures in reward processing and biomarkers of iron delivery, myelin maintenance and mono-amines relevant to frontostriatal function. We will test the central hypotheses that higher brain iron load in frontostriatal regions will significantly contribute to changes in reward as well as cognitive processes, which are strongly reliant on prefrontal regions (cognitive control, working memory, attention) in PWH. Findings from this study will provide the basis for future in-depth mechanistic investigations of mood disorders in VS-PWH and suggest potential therapeutic targets.