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

摘要/摘要 在过去二十年中，有效的抗逆转录病毒疗法（ART）的广泛使用有所改善 临床表现和改变的病理神经系统疾病的人生活在 艾滋病毒（艾滋病毒携带者）。然而，在这种成功延长数百万人生命的治疗方法的背景下， 关于持续性神经系统疾病的病因学， 和认知障碍，经常表现在PLWH对艺术。人类的大脑是一个 复杂和难以接近的器官，迄今为止，在世界范围内无法全面理解， 稳态和疾病的背景。因此，艾滋病毒的标志性神经病理学发现 相关的神经认知障碍（HAND），突触树突损伤，迄今为止只 可以在人类尸检大脑和HIV动物模型中进行评估。我们 耶鲁大学的一个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） 放射性示踪剂，[11 C]UCB-J，突触前囊泡膜蛋白突触的配体 囊泡糖蛋白2A（SV 2A），以成像人脑中的突触密度。的前提 这项应用是基于我们正在进行的试点研究，该研究表明，大脑SV 2A PET 成功地识别出突触密度降低的区域--包括海马体-- 与CNS功能障碍相关的额纹状体神经回路--在PLWH的ART中。 目前的建议，我们试图测量突触密度纵向超过24个月，在一个更大的 与匹配的前瞻性入组的HIV阴性组相比，PLWH组接受ART治疗。我们 将联合收割机结合突触密度的突破性成像方法和PET成像， 神经免疫状态（使用靶向18-kDa转运蛋白的放射性配体[11 C] PBR 28，或 TSPO，对小胶质细胞敏感），以探讨在 ART介导突触密度降低。最后，我们的目标是纵向整合这些 在平行处理模型中， 使我们能够剖析HAND的机制和临床结果。我们的应用程序是基于 有力且令人信服的初步数据证明了SV 2A PET成像在 识别ART上PLWH中突触密度降低的区域。我们提出的项目将 为潜在的可逆性脑改变提供强有力的临床翻译支持， 突触密度，以及它们与小胶质细胞水平和临床及生物学指标的关系， PLWH。该计划将为确定治疗靶点奠定基础，并提供一个 用于干预性研究的生物标志物，旨在改善CNS中的HIV相关损伤。

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.