In vivo imaging of synaptic density in virally suppressed HIV-1 infection using 11CUCB-J PET

使用 11CUCB-J PET 对病毒抑制的 HIV-1 感染中的突触密度进行体内成像

• 批准号: 9622028
• 负责人: SERENA S SPUDICH
• 金额: $ 25.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9622028
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Age; Animal Model; Animals; Autopsy; Biological; Biological Markers; Blood; Brain; Cerebrospinal Fluid; Cessation of life; Clinical; Comorbidity; Corpus striatum structure; Ethnic Origin; Evaluation; Functional disorder; Future; Gender; Glycoproteins; HIV; HIV encephalitis; HIV-1; HIV-associated neurocognitive disorder; Hippocampus (Brain); Human; Image; Imaging technology; Impaired cognition; Impairment; In Vitro; Individual; Infection; Inflammation; Injury; Intervention; Intervention Studies; Investigation; Laboratories; Ligands; Measures; Membrane Proteins; Methodology; Modality; Modeling; Monitor; Myelogenous; Neopterin; Neuraxis; Neurocognitive Deficit; Neurologic; Neurons; Outcome; Participant; Pathologic; Pathology; Patients; Pilot Projects; Positron-Emission Tomography; Presynaptic Terminals; Recording of previous events; Sampling; Seminal; Specimen; Structural defect; Structure; Synapses; Synaptophysin; Therapeutic; Time; Tissue Sample; Viral; Viral Proteins; antiretroviral therapy; brain dysfunction; brain tissue; cerebral atrophy; cohort; density; frontal lobe; immune activation; immunoreactivity; improved; in vivo imaging; neuron loss; novel; novel therapeutic intervention; novel therapeutics; opioid exposure; opioid use; pre-clinical; preclinical study; presynaptic; radiotracer; research study; therapeutic target; treatment effect; virology; white matter

The most pressing neurologic priorities relevant to the 37 million people living with HIV (PLWH) worldwide are to identify causes of central nervous system (CNS) dysfunction during virally suppressive combination antiretroviral therapy (cART) and interventions to correct them. Gaps in our understanding of the biological basis of HIV associated neurocognitive disorder (HAND) during cART impede progress in ameliorating neurocognitive impairment in long-term surviving PLWH. More than 20 years ago, reduced synaptic density was recognized as the primary pathology in autopsy specimens from HIV infected donors with mild forms of cognitive impairment at the time of death. Reduction in density of synaptophysin-immunoreactive terminals was identified in early stage impairment, in the absence of classical findings of HIV encephalitis. These compelling findings set the groundwork for subsequent important preclinical in vitro and animal studies revealing further understanding of reduced synaptic density in HIV, including regional vulnerability, contributory mechanisms, and potential interventions. However, confirmation of these findings and further investigation has not been possible to date in living, virologically suppressed humans due to lack of access to brain tissue samples. Additionally, unlike frank neuronal loss, synaptodendritic injury may be reversible. Thus, the ability to detect decreases in synaptic density in living humans and to identify potential mechanisms that correlate to its presence would guide therapeutic approaches and provide a critical biomarker for monitoring effects of novel therapeutics to reduce brain dysfunction in HIV. This application capitalizes on recent unprecedented expansion of imaging technologies to apply the understanding gained by pre-clinical studies to investigation of synaptic density in living humans. We have recently developed a novel radiotracer, 11C—UCB—J, for imaging synaptic density in the human brain using positron- emission tomography (PET). In the proposed research studies, we will apply this breakthrough methodology to explore whether observations of decreased synaptic density in postmortem human samples and animal models will be found living PLWH with suppressed HIV replication. Further exploratory studies will investigate associations between synaptic density and laboratory and clinical measures implicated by preclinical studies, including levels of systemic and CNS immune activation and history of opioid use. Our pilot study validating this modality as a means to detect aberrant synaptic density in cART-treated HIV will have a major impact, setting the stage for future studies of the relationship of synaptic density to clinical outcomes of HAND, and providing a therapeutic target and a biomarker for treatment studies aimed to improve HIV-related injury in the CNS.

与全世界3700万人（PLWH）患者有关的最紧迫的神经系统优先事项是 在几乎抑制性组合抗逆转录病毒中确定中枢神经系统（CNS）功能障碍的原因 治疗（购物车）和干预措施以纠正它们。我们对艾滋病毒生物学基础的理解差距 卡车期间相关的神经认知障碍（手）阻碍了神经认知的进展 长期幸存的PLWH的损害。 20多年前，降低的突触密度被认为是尸检标本中的主要病理 从艾滋病毒感染的供体中，死亡时具有轻度认知障碍的供体。降低密度 在没有经典的情况下，在早期障碍中鉴定出突触素 - 免疫反应性末端 HIV脑炎的发现。这些引人入胜的发现为随后的重要临床前奠定了基础 体外和动物研究揭示了对HIV中突触密度降低的进一步了解，包括区域 脆弱性，贡献机制和潜在干预措施。但是，确认这些发现以及 由于缺乏访问权限，还无法进一步调查人类的生活，在病毒学上受到抑制 到脑组织样品。此外，与坦率的神经元丧失不同，突触don损伤可能是可逆的。那， 检测到生物中突触密度下降的能力以及确定潜在机制的能力 与其存在相关的将指导治疗方法，并为监测提供关键的生物标志物 新型疗法减少HIV中脑功能障碍的影响。 该应用程序利用了最新的成像技术的前所未有的扩展 通过临床前研究获得的理解，以研究活着的人类突触密度。我们最近有 开发了一种新型的放射性示踪剂，11C -UCB-J，用于使用正电子 - 排放断层扫描（PET）。在拟议的研究中，我们将将这种突破方法应用于 探索是否观察到死后人类样品和动物模型中突触密度降低 将发现抑制艾滋病毒复制的生活PLWH。进一步的探索性研究将研究关联 在临床前研究实施的合成密度与实验室和临床测量之间，包括 全身和中枢神经系统免疫激活和阿片类药物使用史。我们的试点研究将这种方式验证为一种手段 为了检测货物处理的艾滋病毒中异常突触密度将产生重大影响，为将来奠定了基础 研究突触密度与手的临床结果的关系，并提供治疗靶标和 治疗研究的生物标志物旨在改善CNS中与HIV相关的损伤。