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

突触密度 PET 成像结合神经免疫学措施揭示艺术期间 HIV 神经发病机制

• 批准号: 10263367
• 负责人: SERENA S SPUDICH
• 金额: $ 110.4万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10263367
• 关键词: Address; Age; Animal Model; Autopsy; Binding; Biological; Biological Markers; Blood; Brain; Cerebrospinal Fluid; Chronic; Clinical; Complex; Data; Disease; Enrollment; Ethnic Origin; Etiology; Functional disorder; Future; Gender; Glycoproteins; Goals; HIV; HIV Seronegativity; HIV encephalitis; HIV-associated neurocognitive disorder; Hippocampus (Brain); Homeostasis; Human; Image; Impaired cognition; Impairment; Inflammation; Injury; Intervention; Intervention Studies; Investigation; Laboratories; Learning; Ligands; Measures; Mediating; Membrane Proteins; Memory; Methodology; Microglia; Modeling; Molecular; Monitor; Neuraxis; Neurocognitive; Neuroimmune; Neurologic; Neuronal Injury; Neuropathogenesis; Organ; Outcome; Participant; Pathology; Pilot Projects; Population; Positron-Emission Tomography; Presynaptic Terminals; Proteins; Recording of previous events; Research Priority; Role; Sampling; Scanning; Structural defect; Synapses; Synaptophysin; Therapeutic Studies; Tracer; Vesicle; Viral; antiretroviral therapy; base; brain dysfunction; brain tissue; cerebral atrophy; density; imaging agent; imaging biomarker; immunoreactivity; improved; mild neurocognitive impairment; multimodality; nervous system disorder; neural circuit; neuroinflammation; neurological pathology; neuron loss; novel; novel therapeutic intervention; parallel processing; presynaptic; presynaptic neurons; programs; prospective; radioligand; radiotracer; substance use; therapeutic target; treatment effect; virology; white matter

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.

摘要/摘要 在过去的二十年中，广泛使用有效的抗逆转录病毒疗法（ART）有所改善 临床表现并改变了患有神经系统疾病的病理 艾滋病毒（PLWH）。但是，在这种治疗的背景下，已成功延长了数百万美元 关于生活，关于持续神经系统的病因已经出现了新的紧迫问题 和认知障碍经常在艺术中表现出来。人脑是 迄今为止，复杂且无法接近的器官违反 体内平衡和疾病的背景。因此，艾滋病毒的标志性神经病理发现 迄今为止 可以在验尸后的尸检大脑和艾滋病毒模型中评估。我们的 耶鲁大学的小组最近开发并验证了一项新型的正电子发射断层扫描（PET） radiotracer，[11C] UCB-J，一种突触前囊泡膜蛋白突触的配体 囊泡糖蛋白2a（SV2A），以图像人脑中的突触密度。前提 该应用基于我们正在进行的试点研究，该研究表明脑SV2A PET 成功识别突触密度降低的区域 - 包括在海马 与中枢神经系统功能障碍相关的额叶神经回路 - 在ART上使用PLWH。在 当前的建议，我们试图在24个月内纵向测量突触密度 相对于匹配的前瞻性招募的HIV阴性组，ART的PLWH组。我们 将结合这种突触密度的突破性成像方法与PET成像 神经免疫性状态（使用靶向18-kDa转运蛋白的辐射[11C] PBR28或 TSPO，对小胶质细胞敏感）探讨了神经免疫失调的前提 ART介导了突触密度降低。最后，我们旨在纵向整合这些 在平行处理模型中使用神经认知和实验室评估的措施 允许我们剖析手的机制和临床结果。我们的申请基于 强大而引人注目的初步数据，证明了SV2A PET成像的实用性 识别ART PLWH中突触密度降低的区域。我们提议的项目将 产生强大的临床翻译支持，以实现可能可逆的大脑改变 突触密度及其与小胶质细胞水平以及临床和生物学措施的关系 plwh。该计划将为识别治疗目标奠定阶段，并提供 介入研究的生物标志物旨在改善中枢神经系统中与HIV相关的损伤。