Marijuana, the mostly widely used illicit drug in the United States, is disproportionately prevalent in persons with HIV. Despite the promise of cannabinoids as a therapeutic agent for HIV disease, chronic marijuana use is also associated with potential neurobiological harms. Neurological complications of HIV disease remain a persistent clinical problem even in the
age of combination antiretroviral therapy. The CHI project uses an in vivo model to investigate the underlying pathophysiological mechanisms of HIV-associated brain dysfunction. Specifically, the project aims to: (1) investigate the independent and additive effects of HIV disease and chronic marijuana use on inflammatory processes linked to brain injury; (2) model the longitudinal relationship of chronic marijuana use to HIV-induced inflammation and its relationship to brain injury; and (3) determine the relationship of cannabinoid metabolites to inflammatory and neuronal markers. A prospective cohort stratified by HIV and marijuana status will complete cutting-edge neuroimaging, immune and cytokine profiling, and neuropsychological testing three times over 2 years. Capitalizing on ultrahigh-resolution magnetic resonance imaging (MRI) capabilities at Duke, we will use multimodal, multi-parametric sequences to investigate neuroinflammatory and neurodegenerative processes. The central hypothesis is that marijuana use disrupts the central nervous system through both anti-inflammatory and neurotoxic pathways. By considering both beneficial and adverse effects of marijuana available in the United States market, our proposal has strong translational potential to guide clinical recommendations for medical and recreational marijuana in persons with HIV.
Funding: R01-DA0452827 (Meade PI)
Alterations in brain structure and function are consistently linked to HIV-associated neurocognitive disorders (HAND), but the mechanisms through which HIV causes alterations in neural networks and associated cognitive function are not well characterized. Marijuana use, which is disproportionately prevalent among persons with HIV, may increase the risk of HAND. This prospective cohort study applies connectomic analyses to achieve the following aims: (1) examine the independent and interactive effects of HIV and marijuana on structural and functional organization of the brain; (2) investigate the longitudinal relationship between network-level disruptions in brain organization and cognitive impairment; and (3) use machine deep learning algorithms to develop individualized prediction models for HAND diagnosis and severity based on multimodal graph features. Using a longitudinal design, 200 adults stratified by HIV and marijuana status (4 groups) will have multimodal MRIs and cognitive testing at baseline and 1 year later. The central hypothesis is that marijuana use will exacerbate structural and functional disruptions in brain organization that underlie the expression and progression of HAND. This innovative project has strong potential to identify appropriate neural biomarkers that may aid in the diagnosis and monitoring of HAND in persons with chronic substance use disorders and serve as targets for novel clinical interventions. Our classification models are expected to provide a generalizable framework applicable to individual patients for tailoring of treatment approaches.
Funding: R01-DA047149 (Meade PI)
Drug abuse, a highly prevalent comorbidity in HIV+ persons, increases the risk of HIV-associated neurocognitive impairments (NCI) that are linked underlying structural and functional changes in the brain. This project applies innovative fusion approaches that exploit the richness of multimodal data to discover covariations across multiple neuroimaging modalities and cognitive measures simultaneously. Capitalizing on existing data from three completed projects on the neurobehavioral effects of HIV and drug abuse, the amalgamated dataset consists of 207 unique cases with in-depth substance use histories, multimodal brain images, comprehensive neurocognitive batteries, and a wide range of other phenotypic data. Using complementary multimodal analyses, we aim to: (1) identify neural biomarkers of HIV neurological disease and associated NCI; and (2) test cocaine as a moderator of HIV-specific co-alterations in brain structure and function and associated NCI. In addition, the project will develop new, advanced methods to improve MRI data quality for cross-study harmonization and to optimize the prediction of NCI based on multimodal indices. Our overarching goal is to identify appropriate neural biomarkers of neuroHIV that may facilitate diagnosis and treatment monitoring in active drug users and serve as targets for clinical interventions to mitigate the burden caused by HIV-associated NCI.
Funding: R01-DA045565 (Meade PI)
Nearly half of HIV-infected Americans experience neurocognitive impairment (NCI) that impacts daily functioning and increases morbidity and mortality. Marijuana and cocaine, two of the mostly commonly abused drugs among HIV-infected persons, additionally cause alterations in neural and cognitive functioning, and have significant immunomodulatory effects. This study uses a systems biology approach to investigate the role of neuroinflammation in the link between drug abuse and HIV-associated NCI. The study assesses adults with HIV infection who use cocaine only, marijuana only, cocaine and marijuana, or neither drug, comprising 4 distinct groups. The assessment includes comprehensive neuropsychological testing, multi-modal brain imaging, and blood and cerebrospinal fluid sampling. The specific aims of the study are to: (1) identify the independent and joint effects of cocaine and marijuana use on MRI measures of cerebral volume, white matter integrity, and functional connectivity, and on behavioral measures of neurocognition; (2) quantify differences in peripheral and central nervous system immune function between marijuana and cocaine users; and (3) employ a systems biology approach to integrate immunology, neuroimaging, and behavioral data into a multi-level predictive model.
Funding: R01-DA043241 (Meade/Murdoch MPI)
This project uses novel approaches to advance our understanding of how HIV infection and drug addiction impact decision-making processes relevant to real-world HIV risk behaviors. The study aims to: use respondent driven sampling to engage stimulant users, both HIV-positive and HIV-negative, from the community; conduct laboratory-based assessments of neurobehavioral functioning every 3 months for 1 year to capture changes in drug use, decision making, and HIV risk behavior in 200 stimulant users; and use mobile health (mHealth) technology to assess cognitive functioning and risk behaviors in real-time in natural settings in a sub-set of participants.
Funding: DP2-DA040226 (Meade PI)