Christine Fennema-Notestine, PhD - US grants

DESCRIPTION (provided by applicant): Despite significant advances in the era of highly active anti-retroviral therapy, central nervous system (CNS) effects of human immunodeficiency virus (HIV) have remained prevalent. In this light, we continue to search for sensitive, non-invasive biomarkers to guide treatment, monitor therapeutic intervention, and identify individuals at risk for CNS decline. Previous work has supported the value of neuroimaging for identifying biomarkers in HIV, particularly in the white matter and caudate nucleus. Recent clinical neuroimaging efforts within the multi-site CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) program have employed multiple modalities including structural and diffusion tensor MR imaging to assess the brain's response to HIV infection. CHARTER has employed multi-channel MRI (T1, T2, PD) to produce tissue segmentations with manual delineation of global regions, resulting in successful identification of neuroimaging correlates of HIV, such as abnormalities in the white matter (AbWM). Manual delineation of individual structures (e.g., caudate), however, is prohibitive on large-scale studies. Recent methodological advancements offer promise for automating regional delineation, however, these methods have not yet been validated in HIV. The reliance of these methods solely on T1 sequences can result in the misclassification of AbWM as gray matter, leading to decreased sensitivity and errors in structural volume estimates. Such classification errors may result in systematic bias, due to the correlation of AbWM with disease severity. Utilizing data from CHARTER, we propose to critically assess the performance of two relatively automated subcortical labeling methods in HIV and to examine a statistical pre-processing procedure that may enhance performance of these methods. In particular, we will examine the degree to which HIV-related AbWM affects method performance relative to a morphometric "gold standard." The gold standard regions of interest (e.g., caudate) will be defined upon existing CHARTER morphometry, thus increasing the reliability of the manual delineations. We also will investigate the value of statistically enhancing the input T1 volumes, with information from PD, T2, and diffusion tensor imaging (DTI) volumes, through the use of alternating conditional expectations (ACE), which will use the supplemental volumes to enhance tissue contrast in the T1 volumes. Further validation efforts will examine the relationship between resultant structural volumes and neurobehavioral and medical biomarkers. The systematic assessment and enhancement of structural neuroimaging methodology will allow us to better characterize the underlying neuropathogenesis of HIV, to potentially validate these tools for use in HIV, to provide guidance to end-users, and to offer insight to developers for future work. Importantly, this work will provide regional morphometric data to the CHARTER as a Resource initiative for the exploration of additional, more specific hypothesis testing, such as the value of caudate volume as a biomarker of HIV-related cognitive decline, risk for decline, or effectiveness of therapeutic intervention. PUBLIC HEALTH RELEVANCE: Despite significant advances in the era of highly active anti-retroviral therapy, central nervous system (CNS) effects of human immunodeficiency virus (HIV) have remained prevalent, and the impact of neurological impairment and neurocognitive dysfunction on individuals daily lives, work performance, and care needs can be significant. The on-going multi-site CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) program provides a unique multidisciplinary setting for the characterization of such effects, within which we propose a systematic assessment and enhancement of structural neuroimaging methods, not previously validated in HIV. This work will provide regional morphometric data to the CHARTER as a Resource initiative for the exploration of additional, more specific neuroimaging correlates of HIV to guide treatment, monitor therapeutic intervention, and identify individuals at risk for CNS decline.

? DESCRIPTION (provided by applicant): The purpose of the proposed research is to develop a multimodal approach to elucidate the combined effects of HIV infection and cannabis use on the brain in youth. An increasing proportion of new human immunodeficiency virus (HIV) infections occur in adolescents and young adults, or youth, living with HIV (YLWH; 25-30% in 2010). YLWH are in the midst of completing CNS development and will live with HIV infection and associated treatment for a long time. Evidence from adults suggests continuing CNS effects of HIV infection despite antiretroviral therapy; however, we know little about the impact of HIV infection and its treatments on the CNS in YLWH. Recent findings suggest significant cognitive impairments in behaviorally- infected YLWH, although the causal factors are unknown and likely multifactorial. Current theories of HIV- associated neuropathogenesis focus on the role of systemic and neural inflammation, although existing findings come largely from studies of adults with complex comorbidities and treatment histories. A better understanding of CNS changes in behaviorally-infected YLWH, then, will provide important insight and may have clinical implications regarding CNS pathogenesis. Of importance, this cohort is characterized by a high rate of cannabis use, which may impact the progression of HIV infection and associated cognitive and neurological alterations. Cannabinoids have been linked to greater immune suppression and increased vulnerability to infection; however, they also may alter cytokine and chemokine expression, driving an anti- inflammatory response. The literature suggests a potential increase in susceptibility to more rapid disease progression alongside parallel anti-inflammatory effects. Cannabis use in adolescence has been linked independently to changes in neuroimaging and cognitive functioning. The possibility of complex interplay among the CNS effects of HIV infection and cannabis use requires further investigation for guidance on the development of relevant treatment interventions in youth. The proposed study aims to explore the impact of cannabis use on HIV-associated CNS effects by studying YLWH (age 18-24) and control participants using an interdisciplinary approach that will include multimodal neuroimaging measures, plasma biomarkers of inflammation and immune function, and neurocognitive outcomes. This pilot project will initiate an essential characterization of the CNS effects of behaviorally-acquired HIV infection in YLWH; explore the impact of comorbid cannabis use; initiate the critical assessment of inflammation as a mediator of observed effects; and explore promising combinations of neuroimaging, plasma biomarker, and clinical variables for future studies. The resultant findings will set the stage for multisite, multi-disciplinary investigations by characterizing the neurologic and inflammatory signatures of HIV and comorbid cannabis use in youth and suggesting functionally meaningful biomarkers for identifying individuals at risk for CNS decline, monitoring effectiveness and toxicity associated with ART, and exploring interactions with other common substances of abuse.

Antiretroviral therapy (ART) has lessened but not eliminated the central nervous system (CNS) impact of human immunodeficiency virus (HIV). With effects on cognition and brain integrity now subtler, yet chronic with unknown long-term implications, the potential of comorbid conditions to moderate, obscure or ameliorate HIV effects is increasingly important. Young adults (?youth?) have high rates of both new HIV infection and understudied common comorbidities with significant potential to influence HIV?s CNS presentation: cannabis use and cumulative adversity. Both may alter immune functioning and inflammation as pathways for their influence on HIV?s CNS effects, in addition to their independent impact. Our preliminary data show that worse cognitive and neuroimaging outcomes in youth with HIV (YWH) compared to controls (e.g., worse memory and executive functioning, thinner prefrontal cortex, altered functional activation using magnetoencephalography [MEG]) are attenuated or, in some cases, reversed by light to moderate, but not heavy, cannabis use. We hypothesize that worse cognitive and neuroimaging outcomes in treated YWH, compared to controls, in the context of no cannabis use will be ameliorated by mild to moderate cannabis use, while high cannabis use frequency will be associated with worse outcomes in both groups. Of importance, fully understanding the interplay of HIV and cannabis may require consideration of lifetime experiences of adversity. Strong evidence shows that exposure to adverse circumstances, such as maltreatment, violence, and stress, can alter immune and CNS systems, and such exposure is common among YWH and comparable seronegative risk groups. We will assess the influence of cumulative adversity in mediating effects of cannabis and HIV. The proposed study will determine the interactive effects of HIV, cannabis and cumulative adversity on CNS structure and function in 75 YWH (age 18-24) and 75 comparable controls. We will use innovative neuroimaging approaches (MEG to measure functional activity and advanced diffusion approaches), along with brain structure and metabolism and neurocognitive assessment. We will examine mediation of HIV, cannabis and cumulative adversity interactions by inflammation and immune activation, assessed using plasma biomarkers. Examining the interplay of these influences on CNS function and structure will be facilitated by careful characterization of substance use, assessment of cumulative adversity burden rather than single traumatic events, and advanced statistical techniques. Thus, we will examine interactive HIV and cannabis effects on key brain systems; model underlying mechanisms; and examine an important yet understudied influence, cumulative adversity. The study has potential for high impact by improving detection of HIV?s CNS effects and our understanding of pathogenesis. It would enable better prevention of CNS decline, institution of CNS-targeted treatments and cure strategies, and in general mitigation of the CNS impact of HIV for individuals who are early in infection and still in the midst of neurodevelopment where early detection may have the greatest benefit.