PET IMAGING OF SYNAPTIC DENSITY COMBINED WITH NEUROIMMUNOLOGIC MEASURES TO REVEAL MECHANISMS OF HIV NEUROPATHOGENESIS DURING ART

摘要/摘要 在过去的二十年里，有效的抗逆转录病毒疗法(ART)的广泛应用已经有所改善。 精神分裂症患者的临床表现和神经系统疾病的病理改变 艾滋病毒(PLWH)。然而，在这种治疗的背景下，成功地延长了数百万 关于持续性神经疾病的病因，出现了新的紧迫问题 以及认知障碍，经常表现在ART的PLWH中。人脑是一种 复杂和难以接近的器官，到目前为止，无视对 动态平衡和疾病的背景。因此，艾滋病毒的标志性神经病理发现 相关的神经认知障碍(手)，突触树突触损伤，到目前为止 在人类尸检大脑和动物模型中评估艾滋病毒的可能性。我们的 耶鲁大学的研究小组最近开发并验证了一种新的正电子发射断层扫描(PET) 突触前囊泡膜蛋白突触的配体放射性示踪剂[11C]UCB-J 囊泡糖蛋白2A(SV2A)，用于成像人脑中的突触密度。的前提是 这一应用是基于我们正在进行的试点研究，该研究证明了Brain SV2APET 成功识别出突触密度降低的区域--包括在海马区-- 额纹状体神经回路与中枢神经系统功能障碍相关--在ART上的PLWH。在 目前的建议，我们寻求在更大的24个月内纵向测量突触密度 接受抗逆转录病毒治疗的PLWH组与匹配的预期登记的HIV阴性组相比。我们 将把这种突触密度的突触密度成像方法与PET成像结合起来 神经免疫状态(使用针对18-kDa转位蛋白的放射性配体[11C]PBR28，或 TSPO，对小胶质细胞敏感)，以探索神经免疫失调在 ART介导突触密度降低。最后，我们的目标是纵向整合这些 在并行处理模型中使用神经认知和实验室评估进行测量 使我们能够剖析HAND的机制和临床结果。我们的应用程序基于 稳健和令人信服的初步数据，证明了SV2APET成像在 在ART上识别PLWH中突触密度降低的区域。我们提议的项目将 为潜在的可逆脑改变提供强大的临床-翻译支持 突触密度及其与小胶质细胞水平、临床和生物学指标的关系 PLWH。该计划将为确定治疗靶点奠定基础，并提供 旨在改善中枢神经系统艾滋病毒相关损伤的介入研究的生物标记物。

Summary/Abstract Widespread use of effective antiretroviral therapy (ART) in the past two decades has improved the clinical manifestations and altered the pathology of neurologic disease in people living with HIV (PLWH). However, in the context of this treatment that has successfully prolonged millions of lives, new pressing questions have emerged regarding the etiology of persistent neurological and cognitive impairment that frequently manifests in PLWH on ART. The human brain is a complex and inaccessible organ that, to date, defies comprehensive understanding in the context of homeostasis and disease. Thus, the hallmark neuropathologic finding of HIV associated neurocognitive disorder (HAND), synaptodendritic injury, has thus far only been possible to evaluate in post-mortem human autopsy brains and animal models of HIV. Our group at Yale recently developed and validated a novel positron-emission tomography (PET) radiotracer, [11C]UCB-J, a ligand for the presynaptic vesicular membrane protein synaptic vesicular glycoprotein 2A (SV2A), to image synaptic density in the human brain. The premise of this application is based on our ongoing pilot study which demonstrates that brain SV2A PET successfully identifies regions of reduced synaptic density -- including in a hippocampal- frontostriatal neural circuit that correlates with CNS dysfunction -- in PLWH on ART. In the current proposal, we seek to measure synaptic density longitudinally over 24 months in a larger group of PLWH on ART relative to a matched prospectively enrolled HIV-negative group. We will combine this breakthrough imaging methodology of synaptic density with PET imaging of neuroimmune status (using radioligand [11C]PBR28 targeting the 18-kDa translocator protein, or TSPO, sensitive to microglia) to explore the premise that neuroimmune dysregulation during ART mediates reduced synaptic density. Finally, we aim to longitudinally integrate these measures with neurocognitive and laboratory assessments in parallel processing models that allow us to dissect mechanisms and clinical outcomes of HAND. Our application is based on robust and compelling preliminary data that demonstrates the utility of SV2A PET imaging in identifying regions of reduced synaptic density in PLWH on ART. Our proposed project will generate powerful clinical-translational support for potentially reversible brain alterations in synaptic density, and their relation to microglia levels and clinical and biological measures in PLWH. This program will set the stage for identification of therapeutic targets and provide a biomarker for interventional studies aimed to improve HIV-related injury in the CNS.