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

HIV 感染者脑铁的定量敏感性图谱：与神经精神疾病的机制联系

• 批准号: 10628697
• 负责人: ASHA R KALLIANPUR
• 金额: $ 26.69万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628697
• 关键词: Accounting; Address; Adherence; Affective; Age; Anabolism; Anti-Retroviral Agents; Anxiety; Area; Attention; Basal Ganglia; Behavioral; Biological Availability; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Mapping; Brain imaging; Brain region; Cerebrospinal Fluid; Cerebrovascular Circulation; Chronic; Clinical Management; Cognition Disorders; Corpus striatum structure; Data; Deposition; Depressive disorder; Disease; Dopamine; Energy Metabolism; Equilibrium; Etiology; Foundations; Funding; Future; Genetic study; HIV; HIV Infections; HIV Seronegativity; Hippocampus; Homeostasis; Imaging Techniques; Impaired cognition; Individual; Inflammation; Investigation; Iron; Link; Longevity; Magnetic Resonance Imaging; Maintenance; Maps; Measures; Mental Depression; Mental disorders; Mitochondria; Modeling; Molecular Epidemiology; Mood Disorders; Moods; Motivation; Myelin; NIH Office of AIDS Research; Nerve Degeneration; Neurologic; Neurotransmitters; Oligodendroglia; Parents; Participant; Pathogenicity; Pathway interactions; Persons; Pharmaceutical Preparations; Predisposition; Prefrontal Cortex; Prevalence; Process; Proteins; Public Health; Quality of life; Regulation; Research; Research Domain Criteria; Research Personnel; Resistance; Rewards; Risk; Semaphorins; Serotonin; Serum; Short-Term Memory; Symptoms; Techniques; Testing; Thalamic structure; United States National Institutes of Health; Viral; Virus; antiretroviral therapy; behavior measurement; blood-brain barrier disruption; blood-brain barrier permeabilization; clinical care; cognitive control; cognitive function; cognitive process; cognitive system; depressive symptoms; experience; functional status; iron metabolism; monoamine; mortality; neuroAIDS; neuroimaging; neuroinflammation; neuropsychiatric disorder; neuropsychiatric symptom; neuropsychiatry; new therapeutic target; novel; reward processing; sex; therapeutic target; treatment adherence

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.

项目摘要 情绪障碍的公共卫生负担，例如抑郁，焦虑和冷漠，患有 尽管控制了病毒，但HIV（PWH）仍然很高。神经精神疾病或症状（NP），折磨30-- 60％的PWH，并且由于组合抗逆转录病毒疗法的寿命增加而患病率增加 时代。此外，情绪障碍和认知障碍经常在PWH中共同发生，通常是治疗的 由于对依从性的不利影响 治疗，生活质量和功能状况。但是，病毒中NP的基础机制 被抑制（VS）PWH和新的治疗靶标仍然难以捉摸。 众所周知，没有艾滋病毒的人的情绪障碍涉及改变铁的代谢，而我们的初步 研究暗示了PWH中认知障碍和抑郁症的铁不平衡。铁是必不可少的 神经递质的平衡，少突胶质细胞对髓磷脂的合成和维持，以及能量代谢 大脑。铁调节受HIV感染，神经炎症和漏水的血脑屏障（BBB）破坏。 然而，未知铁相关的铁转运的变化是否影响脑铁的积累，这是 与许多认知障碍有关。定量敏感性映射磁共振成像 （QSM/MRI）是一种强大的，最先进的神经影像学技术，可以通过 提供量化区域脑铁沉积（或负载）的手段。具体来说，我们将确定 VS-PWH与HIV阴性个体的区域脑铁负荷的改变，这些贡献的贡献 奖励和认知过程的改变，以及2）确定脑铁的贡献 铁输送蛋白，改变髓鞘和多巴胺/5-羟色胺稳态以破坏奖励和认知 VS-PWH与HIV阴性个体中的过程。该项目将采用现有的QSM数据，并且 参与者的RDOC认知系统的行为指标正在进行的NIH资助研究中 将在奖励加工和铁输送，髓鞘维护和生物标志物中添加行为措施 与额叶功能相关的单胺。我们将测试较高脑铁负荷的中心假设 在额叶区域，区域将大大促进奖励的变化以及认知过程，这些过程 PWH中强烈依赖前额叶区域（认知控制，工作记忆，注意）。来自 这项研究将为VS-PWH和 建议潜在的治疗靶标。