SIGNATURES OF CANNABIS ABUSE IN NEUROHIV (SCAN): AN INTEGRATED MOLECULAR AND IMAGING APPROACH

神经艾滋病毒中大麻滥用的特征（扫描）：一种综合的分子和成像方法

• 批准号: 10430165
• 负责人: JAMES T. BECKER
• 金额: $ 77.56万
• 依托单位: FATHER FLANAGAN'S BOYS' HOME
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430165
• 关键词: AIDS dementia; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adult; Affect; Architecture; Area; Attention; B-Lymphocytes; Behavioral; Biological Assay; Biological Markers; Blood; Brain; Brain Mapping; CD8-Positive T-Lymphocytes; Cannabis Abuse; Cells; Chemicals; Chronic; Clinical Markers; Clinical assessments; Coagulation Process; Cognition Disorders; Cognitive; Cognitive deficits; Collection; Color; Complication; Data; Databases; Deterioration; Diagnostic tests; Disease; Disease Progression; Early identification; Economics; Endothelium; Enrollment; Exhibits; Flow Cytometry; Fostering; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Future; General Population; Genus Hippocampus; Goals; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Host Defense Mechanism; Immune; Immunologic Markers; Impaired cognition; Impairment; Individual; Infection; Inflammation; Inflammatory; Life Expectancy; Magnetic Resonance Imaging; Magnetoencephalography; Maps; Matched Group; Medical center; Methods; Mitochondria; Modality; Molecular; Molecular Analysis; Monitor; National NeuroAids Tissue Consortium; Natural Killer Cells; Nature; Nebraska; Neurocognitive; Neurologic; Neuropsychological Tests; Neuropsychology; Neurosecretory Systems; Participant; Pathogenesis; Performance; Persons; Plasma; Population; Prevalence; Preventive treatment; Prognosis; Quality of life; Request for Applications; Request for Proposals; Research; Resources; Risk; Source; Substance Use Disorder; Substance abuse problem; Sum; System; Targeted Research; Terminal Disease; The Multicenter AIDS Cohort Study; Unemployment; Universities; Visual Perception; Visual attention; Western World; antiretroviral therapy; biomarker identification; biomarker signature; cognitive function; cognitive performance; cognitive testing; comorbidity; comparative; diagnostic biomarker; gamma-Aminobutyric Acid; hemodynamics; imaging approach; imaging modality; immune activation; indexing; innovation; marijuana use disorder; medication compliance; molecular imaging; molecular marker; monocyte; multimodality; neural circuit; neuroAIDS; neuroimaging; neurophysiology; non-invasive imaging; predictive marker; prevent; prognosis biomarker; quantitative imaging; relating to nervous system; resilience; spectroscopic imaging; treatment trial

Project Summary/Abstract HIV-infected adults in the western world have a life expectancy near that of the general population, but are at a significantly elevated risk of developing cognitive deficits. Such impairments are the most common neurological complication of HIV disease, with prevalence estimates ranging from 35-70% of all HIV-infected individuals, and research targeting such comorbidities has been identified as a top priority by the Office of AIDS Research (NOT-OD-15-137). Substance use disorders (SUD) are also more prevalent in the HIV-infected population, yet their relative contribution to the increased rate of cognitive impairment in this group remains poorly understood. A key barrier to progress in this area has been the historic lack of diagnostic tests and biomarkers that can precisely assess the neurological complications of HIV-infection, which has all but precluded quantification of the additive impact of SUD comorbidity. This barrier is central to RFA-DA-18-023, which requests applications that “foster biomarker and signature identification that could advance the clinical assessment of the degree of deterioration or damage, of functional reserve, and of resilience of host defense mechanisms, towards HIV- infection and comorbidity of HIV with SUDs.” Specifically, the RFA requests proposals that identify biomarkers derived from blood, plasma, noninvasive neuroimaging modalities, and/or other sources, with an emphasis on biomarkers that can be quantitated, with levels assessed for their ability to predict disease progression. The current project directly targets the scientific gaps identified in this RFA, Identification of Biomarkers of HIV Pathogenesis and Substance Abuse Comorbidity, using a multipronged approach that includes state-of-the-art neurophysiological, structural, and spectroscopic noninvasive imaging, cognitive assessment, and cellular and molecular analyses of blood/plasma in the context of cannabis use disorder (CUD). Specifically, the Signatures of Cannabis Abuse in NeuroHIV (SCAN) Consortium will utilize advanced magnetoencephalographic (MEG) imaging to quantify the neural dynamics serving cognitive processing, 3-Tesla MRI and multimodal parcellation methods to map brain architecture, functional MRI (fMRI) for hemodynamics and intrinsic networks, and 7-Tesla spectroscopic imaging to quantify local GABA levels across the brain. These data will be integrated with a comprehensive molecular screen that includes 35 plasma biomarkers covering the immune, inflammatory, coagulation, endothelial, and neurological systems, a 10-color flow cytometry panel delineating CD4 and CD8 T cells, B cells, NK cells, monocyte subsets, and activation markers, known clinical markers, and mitochondrial function in immune cells using the Seahorse Analyzer method. To enhance rigor, demographically-matched groups of uninfected controls with and without CUD will be enrolled, which will enable the interaction of HIV and CUD to be quantified. In sum, to truly meet the goals of this RFA, we will use a broad range of neuroimaging, molecular, and cellular functional assays to uncover biomarker signatures of HIV and CUD that will enable identification of early dysfunction, progression, and prognosis, enabling future preventative and treatment trials.

项目总结/文摘