Elucidating the Role of Frontostriatal Neural Circuits in HIV-Associated Neurocognitive Disorders

阐明额纹状体神经回路在 HIV 相关神经认知障碍中的作用

• 批准号: 10319253
• 负责人: Shiva Hassanzadeh-Behbahani
• 金额: $ 3.43万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319253
• 关键词: Address; Adherence; Aging; Atlases; Atrophic; Brain; Clinical; Cognitive; Committee Members; Computer software; Data; Data Analyses; Development; Diagnostic Procedure; Diffusion Magnetic Resonance Imaging; Educational process of instructing; Ensure; Fellowship; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Goals; Grant; HIV; HIV-associated neurocognitive disorder; Health; High Prevalence; Hospitals; Human; Immunosuppression; Impaired cognition; Injury; Knowledge; Lead; Longevity; Magnetic Resonance Imaging; Manuscripts; Measures; Mediating; Mental Depression; Mentors; Mentorship; Methods; Modality; Nature; Neurocognitive; Neurocognitive Deficit; Neurosciences; Patients; Peripheral; Phase; Play; Positioning Attribute; Prefrontal Cortex; Quality of life; Recording of previous events; Research; Research Personnel; Research Project Grants; Risk; Role; Severity of illness; Structure; Students; Symptoms; Techniques; Testing; Thinness; TimeLine; Training; Unemployment; Universities; Viral; Work; Writing; aging population; antiretroviral therapy; career; clinical application; cognitive control; cohort; comorbidity; executive function; frontal lobe; improved; innovation; insight; interest; mild cognitive impairment; mortality; multimodality; neural circuit; neurobehavioral; neuroimaging; neuromechanism; pre-doctoral; programs; skills; success; symposium; targeted treatment; therapeutic target; tractography; white matter

PROJECT SUMMARY/ABSTRACT While combination antiretroviral therapy (cART) has significantly extended the lifespan of people with HIV (PWH), nearly half of all PWH are estimated to have HIV-associated neurocognitive disorders (HAND). Even mild forms of HAND, which are more prevalent in the cART era, significantly reduce quality of life for PWH and can result in unemployment, lack of adherence to antiretroviral therapy, and increased mortality. With a rapidly aging population, there is increased demand for improved understanding of the neural mechanisms of HAND – especially prior to the onset of clinical symptoms – as older PWH are at an increased risk of developing HAND. While dysfunction within the frontostriatal circuits has been implicated in HAND, the profile of disruption within these circuits remains elusive. The goal of this work is to determine whether functional and structural frontostriatal abnormalities present in older, virally suppressed PWH with minimal cognitive impairment. Utilizing structural and functional MRI techniques, this proposal will address the following specific aims. My dissertation research thus far (Aim 1) indicates that older, virally suppressed PWH with minimal cognitive impairment have reduced frontostriatal functional connectivity compared to controls. In addition, increased HIV disease severity and decreased neurocognitive function were associated with cortical thinning in PWH, especially in the prefrontal cortex. In the next phase of my dissertation (F99, Aim 2), I will test the hypotheses that frontostriatal white matter connections are compromised in older PWH compared to controls and that the relationship between HIV disease severity and executive function is mediated by frontostriatal white matter integrity. Results from these studies will provide critical insights into the neural mechanisms of HAND, inform the development of early diagnostic methods, and help identify potential therapeutic targets. Upon completion of my dissertation, I plan to complete a postdoctoral fellowship (K00, Aim 3) studying how comorbid conditions (e.g. depression) in people with HIV contribute to HAND development and progression.

项目总结/摘要 虽然联合抗逆转录病毒疗法（cART）显着延长了艾滋病毒感染者的寿命， (PWH)据估计，近一半的PWH患有HIV相关的神经认知障碍（HAND）。甚至 轻度HAND在cART时代更为普遍，显著降低了PWH的生活质量， 可能导致失业、不坚持抗逆转录病毒治疗和死亡率增加。的快速 随着人口老龄化，人们越来越需要更好地了解手的神经机制， 特别是在临床症状出现之前-因为老年PWH发生HAND的风险增加。 虽然额纹状体回路内的功能障碍与HAND有关，但HAND内的破坏情况与HAND的发病有关。 这些电路仍然难以捉摸。这项工作的目标是确定是否功能和结构 额纹状体异常存在于老年人，病毒抑制PWH与最小的认知障碍。 利用结构和功能MRI技术，本提案将解决以下具体目标。我 迄今为止的论文研究（目标1）表明，老年人，病毒抑制PWH与最小的认知 与对照组相比，损伤降低了额纹状体功能连接。此外，艾滋病毒增加 疾病严重程度和神经认知功能下降与PWH中的皮质变薄相关， 尤其是在前额叶皮层在我论文的下一阶段（F99，目标2），我将检验这些假设 与对照组相比，老年PWH的额纹状体白色连接受损， HIV疾病严重程度与执行功能之间的关系是由额纹状体白色物质介导的 完整这些研究的结果将为HAND的神经机制提供重要的见解， 早期诊断方法的发展，并帮助确定潜在的治疗靶点。完成后 我的论文，我计划完成博士后奖学金（K 00，目标3）研究如何共病条件 (e.g.抑郁症）在艾滋病毒感染者中有助于HAND的发展和进展。