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 在患有抑郁症、焦虑症和冷漠症的人群中， 艾滋病毒（PWH）尽管得到控制，但仍然很高。神经精神障碍或症状（NPD），折磨30- 60%的PWH，由于抗逆转录病毒联合治疗延长了寿命， 时代此外，情绪障碍和认知障碍经常在PWH中同时发生，通常需要治疗- 由于对依从性的不利影响， 治疗、生活质量和功能状态。然而，致病机制的基础上， 抑制的（VS）PWH和新的治疗靶点仍然难以捉摸。 没有艾滋病毒的人的情绪障碍已知涉及铁代谢的改变，我们的初步研究表明， 研究表明，铁失衡与PWH的认知障碍和抑郁症有关。铁对于 神经递质平衡，少突胶质细胞髓鞘的合成和维持，以及 大脑铁调节被HIV感染、神经炎症和血脑屏障（BBB）渗漏破坏。 然而，目前尚不清楚HIV相关的铁转运变化是否会影响脑铁积累， 与许多认知障碍有关磁共振定量磁敏感性成像 (QSM/MRI）是一种强大的、最先进的神经成像技术，可以通过以下方式解决这一研究空白： 提供了量化局部脑铁沉积（或负荷）的手段。具体而言，我们将1）确定 VS-PWH与HIV阴性个体局部脑铁负荷的变化，以及这些变化的贡献。 改变奖励和认知过程，2）确定脑铁，少突胶质细胞 铁传递蛋白，髓鞘和多巴胺/血清素稳态改变，破坏奖励和认知 VS-PWH与HIV阴性个体的过程。该项目将使用现有的QSM数据， 在一项正在进行的NIH资助的研究中，我们从参与者那里获得了RDoC认知系统的行为指标， 将增加奖励过程中的行为测量和铁输送的生物标志物，髓鞘维持和 与额纹状体功能相关的单胺。我们将测试核心假设，即较高的大脑铁负荷 在额纹状体区域的变化将显着有助于奖励以及认知过程的变化， 在PWH中强烈依赖于前额叶区域（认知控制，工作记忆，注意力）。的结果 这项研究将为未来对VS-PWH中情绪障碍的深入机制研究提供基础， 提示了潜在的治疗靶点。