Behaviorally acquired HIV infection during adolescence occurs in the midst of key brain developmental processes such as frontal lobe neuronal pruning and network selection. While incident HIV cases declined by 19% in the U.S. over the last decade, there was an 87% increase in new infections among subsets of 13-24 year-old youth, who now account for 26% of all new HIV infections. Despite this profound shift in the domestic epidemic, we know little about the effects of acquired HIV at these ages on brain development. This application proposes a mentored patient-oriented career development award (K23) for Jennifer McGuire, MD, MSCE, a Child Neurologist and Epidemiologist at the Children's Hospital of Philadelphia and the University of Pennsylvania. Her long-term goal is to use computational neuroimaging metrics to identify biomarkers and evaluate therapeutic targets in HIV and other virally-mediated neuroinflammatory disorders. These markers will be used to test hypotheses regarding specific pathologic mechanisms and potential interventions to limit brain damage. The objective of this proposal is to train Dr. McGuire in the planning, use, and analysis of structural and functional neuroimaging measurements correlated with cognitive assessments as a cross-sectional window into the effects of HIV on the developing brain. The central hypothesis, supported by related pilot data, is that HIV infection during adolescence has a particularly deleterious effect on vulnerable actively maturing neural networks. As such, this study hypothesizes that fronto-striatal pathways subserving executive function will be profoundly negatively impacted functionally and as evidenced by reduced striatal volumes.
Specific aims are therefore to: 1. Define the overall prevalence and subdomain patterns of cognitive impairment in youth with behaviorally acquired HIV compared to controls using validated cognitive tests. 2. Determine the difference in striatal volumes in HIV+ youth (with and without cognitive impairment) and controls using MRI structural morphometry. 3. Quantify fronto-striatal activation signal as a measure of functional circuitry in HIV+ youth (with and without cognitive impairment) and controls using functional MRI (fMRI) activation signal during an executive function task (N-back). The proposed research will be performed in a cross-sectional study of 16-20 year old male and female Philadelphia youth of all racial and ethnic backgrounds with behaviorally acquired HIV (n=40) compared to age/sex/demographic/risk factor-matched uninfected controls (n=30). Cognitive testing, structural MRI, and fMRI will be performed during a single study visit that will include complete medical and medication histories, neurologic examinations, and immune function assessment on all youth. The NINDS mission is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurologic disease. By developing reliable cognitive and imaging metrics of the effects of acquired HIV on the adolescent brain in this K23, in future R01 projects Dr. McGuire will: 1) follow this cohort longitudinally to determine how brain growth and cognition trajectories differ from age-expected growth and development; 2) determine if optimization of cART regimens is neuro-protective in this population; 3) develop testable mechanistic hypotheses based on these data to lead to future studies of adjunctive therapies (pharmacologic and/or cognitive rehabilitation/ enrichment) to maximize neurodevelopment in HIV and later in other neuroinflammatory disorders; and 4) examine if maximizing executive function in HIV+ youth improves medication adherence, retention in care, and safe sex practices, ultimately helping to prevent this growing group from becoming an ongoing reservoir of HIV transmission.
While the total annual incidence of new HIV infections in the United States has decreased in the last ten years, it is currently increasing in subsets of 13-24 year old youth, who now account for about of all new HIV infections in this country. However, we know very little about the effect of acquiring HIV at these ages on normal brain maturation, which typically includes the development of complex reasoning, problem solving, and self-control during adolescence. This application aims to be the first to examine the structural and functional brain differences between 16-20 year old HIV+ youth and uninfected controls: understanding these differences is critical to developing long-term treatment strategies to help this vulnerable population, and to interventions that may prevent this group from becoming an ongoing reservoir of HIV transmission.
| Gofshteyn, Jacqueline S; Shaw, Pamela A; Teachey, David T et al. (2018) Neurotoxicity after CTL019 in a pediatric and young adult cohort. Ann Neurol 84:537-546 |
