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.

与全球3700万艾滋病毒感染者（PLWH）相关的最紧迫的神经病学优先事项是： 确定病毒抑制性联合抗逆转录病毒治疗期间中枢神经系统（CNS）功能障碍的原因 治疗（cART）和干预措施，以纠正他们。我们对艾滋病毒生物学基础的理解存在差距 cART期间相关的神经认知障碍（HAND）阻碍了改善神经认知障碍的进展， 长期存活的PLWH的损害。 20多年前，突触密度降低被认为是尸检标本的主要病理 来自于在死亡时有轻度认知障碍的HIV感染者。密度降低 突触素免疫反应终末在早期损伤中被鉴定，在缺乏经典的突触素免疫反应终末的情况下， HIV脑炎的发现。这些令人信服的发现为随后的重要临床前研究奠定了基础。 体外和动物研究揭示了对HIV中突触密度降低的进一步理解，包括区域性突触密度降低。 脆弱性、促成机制和潜在干预措施。然而，这些发现的证实和 由于缺乏途径，迄今为止还不可能在活的、病毒学抑制的人类中进行进一步的研究。 脑组织样本此外，与坦率的神经元损失不同，突触树突损伤可能是可逆的。因此，在本发明中， 能够检测活体人类突触密度的降低，并识别 与其存在相关将指导治疗方法，并提供用于监测的关键生物标志物 新疗法对减少艾滋病毒脑功能障碍的影响。 该应用利用成像技术最近前所未有的扩展来应用 通过临床前研究获得的理解，以研究活体人类中的突触密度。我们最近 开发了一种新的放射性示踪剂，11 C-UCB-J，用于使用正电子成像人脑中的突触密度， 发射断层扫描（PET）。在建议的研究中，我们会采用这一突破性的方法， 探索在死后人类样本和动物模型中观察到的突触密度降低是否 将发现艾滋病毒复制受到抑制的艾滋病毒携带者。进一步的探索性研究将调查 突触密度与临床前研究所涉及的实验室和临床测量之间的关系，包括 全身和CNS免疫激活以及阿片类药物使用史。我们的试点研究验证了这种模式作为一种手段， 检测cART治疗的HIV中异常的突触密度将产生重大影响，为未来的研究奠定基础。 研究突触密度与HAND临床结局的关系，并提供治疗靶点， 用于治疗研究的生物标志物，旨在改善CNS中的HIV相关损伤。