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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

基本信息

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
项目类别：
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

项目摘要

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3700万艾滋病毒感染者（PLWH）相关的最紧迫的神经学优先事项是