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

项目摘要/摘要 虽然联合抗逆转录病毒疗法(CART)显著延长了艾滋病毒携带者的生命 (PWH)，据估计，近一半的PWH患者患有艾滋病毒相关的神经认知障碍(手)。连 在购物车时代更为普遍的轻度手部畸形，显著降低了PWH和 可能导致失业、缺乏对抗逆转录病毒治疗的坚持，并增加死亡率。以迅速的速度 随着人口老龄化，人们越来越需要更好地了解手-手的神经机制。 特别是在出现临床症状之前--因为年龄较大的PWH发生手部疾病的风险增加。 虽然额纹状体环路内的功能障碍已被牵连到手部，但 这些电路仍然难以捉摸。这项工作的目标是确定功能性和结构性 额纹状体异常出现在病毒抑制的老年PWH中，并伴有轻微的认知损害。 利用结构和功能磁共振技术，这项提案将解决以下具体目标。我的 到目前为止的论文研究(目标1)表明，较老的、病毒抑制的PWH只有最小的认知能力 与对照组相比，损伤降低了额纹状体功能的连通性。此外，艾滋病毒的增加 PWH患者的疾病严重程度和神经认知功能下降与皮质变薄有关， 尤其是在前额叶皮质。在我的论文的下一阶段(F99，目标2)，我将检验这些假设 与对照组相比，老年PWH患者额叶-纹状体白质连接受损，而且 额纹状体白质介导HIV疾病严重程度与执行功能的关系 正直。这些研究的结果将对手、信息的神经机制提供关键的见解 开发早期诊断方法，并帮助确定潜在的治疗靶点。完工后 在我的论文中，我计划完成博士后奖学金(K00，目标3)，研究如何在 艾滋病毒携带者的精神疾病(如抑郁症)有助于手部的发育和进展。

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.