White matter microstructure among youth with perinatally acquired HIV is associated with disease severity

ObjectivesWe investigated whether HIV disease severity was associated with alterations in structural brain connectivity, and whether those alterations in turn were associated with cognitive deficits in youth with perinatally acquired HIV (PHIV).DesignPHIV youth (n = 40) from the Pediatric HIV/AIDS Cohort Study (PHACS) (mean age: 16 ± 2 years) were included to evaluate how current and past disease severity measures (recent/nadir CD4%; peak viral load) relate to white matter microstructure within PHIV youth. PHIV youth were compared with 314 controls from the Pediatric Imaging, Neurocognition and Genetics (PING) study.MethodsDiffusion tensor imaging and tractography were utilized to assess white matter microstructure. Mediation analyses were conducted to examine whether microstructure alterations contributed to relationships between higher disease severity and specific cognitive domains in PHIV youth.ResultsWhole brain fractional anisotropy was reduced, but radial and mean diffusivity were increased in PHIV compared with control youth. Within PHIV youth, more severe past HIV disease was associated with reduced fractional anisotropy of the right inferior fronto-occipital (IFO) and left uncinate tracts; elevated mean diffusivity of the F minor; and increased streamlines comprising the left inferior longitudinal fasciculus (ILF). Associations of higher peak viral load with lower working memory performance were partly mediated by reductions in right IFO fractional anisotropy levels.ConclusionOur findings suggest that PHIV youth have a higher risk of alterations in white matter microstructure than typically developing youth, and certain alterations are related to past disease severity. Further, white matter alterations potentially mediate associations between HIV disease and working memory

Default Mode Connectivity in Youth With Perinatally Acquired HIV.

Youth with perinatally acquired human immunodeficiency virus (PHIV+) survive longer with combination antiretroviral therapy, but remain at risk for poor cognitive outcomes. We evaluated whether markers of HIV disease severity relate to default mode resting-state functional connectivity in PHIV+ youth. We conducted resting-state functional neuroimaging and cognitive testing in a subset of 40 PHIV+ youth recruited from a single study site of the Adolescent Master Protocol study conducted by the Pediatric HIV/AIDS Cohort Study (PHACS) network. Current and past HIV disease severity measures (nadir CD4 lymphocyte percentages and peak HIV RNA plasma levels) were obtained from medical charts. We evaluated associations of both HIV disease severity measures and cognitive functioning with between- and within- default mode network (DMN) connectivity using Analysis of Functional NeuroImaging multiple regression analyses, controlling for multiple comparisons. Of the 40 youth, 31 (mean age = 16.5 years) with minimal motion during scans were included. We observed global alterations in DMN within- and between-network connectivity, with significant associations between disease severity and DMN BOLD correlations. Furthermore, patterns of connectivity with the posterior cingulate cortex (PCC) and medial prefrontal cortex (mPFC) that varied as a function of peak HIV RNA were found to predict processing speed ability. Alterations in within- and between-network DMN connectivity in PHIV+ youth may reflect global reorganization of the DMN; this could lead to compensatory alterations in both the within- and between-connectivity of large-scale networks, which may ultimately relate to known cognitive processing difficulties in PHIV+ youth

Default Mode Connectivity in Youth With Perinatally Acquired HIV.

Youth with perinatally acquired human immunodeficiency virus (PHIV+) survive longer with combination antiretroviral therapy, but remain at risk for poor cognitive outcomes. We evaluated whether markers of HIV disease severity relate to default mode resting-state functional connectivity in PHIV+ youth. We conducted resting-state functional neuroimaging and cognitive testing in a subset of 40 PHIV+ youth recruited from a single study site of the Adolescent Master Protocol study conducted by the Pediatric HIV/AIDS Cohort Study (PHACS) network. Current and past HIV disease severity measures (nadir CD4 lymphocyte percentages and peak HIV RNA plasma levels) were obtained from medical charts. We evaluated associations of both HIV disease severity measures and cognitive functioning with between- and within- default mode network (DMN) connectivity using Analysis of Functional NeuroImaging multiple regression analyses, controlling for multiple comparisons. Of the 40 youth, 31 (mean age = 16.5 years) with minimal motion during scans were included. We observed global alterations in DMN within- and between-network connectivity, with significant associations between disease severity and DMN BOLD correlations. Furthermore, patterns of connectivity with the posterior cingulate cortex (PCC) and medial prefrontal cortex (mPFC) that varied as a function of peak HIV RNA were found to predict processing speed ability. Alterations in within- and between-network DMN connectivity in PHIV+ youth may reflect global reorganization of the DMN; this could lead to compensatory alterations in both the within- and between-connectivity of large-scale networks, which may ultimately relate to known cognitive processing difficulties in PHIV+ youth

Lower total and regional grey matter brain volumes in youth with perinatally-acquired HIV infection: Associations with HIV disease severity, substance use, and cognition

Despite improved survival due to combination antiretroviral therapy (cART), youth with perinatally-acquired HIV (PHIV) show cognitive deficits and developmental delay at increased rates. HIV affects the brain during critical periods of development, and the brain may be a persistent reservoir for HIV due to suboptimal blood brain barrier penetration of cART. We conducted structural magnetic resonance imaging (sMRI) and cognitive testing in 40 PHIV youth (mean age=16.7years) recruited from the NIH Pediatric HIV/AIDS Cohort Study (PHACS) who are part of the first generation of PHIV youth surviving into adulthood. Historical and current HIV disease severity and substance use measures were also collected. Total and regional cortical grey matter brain volumes were compared to a group of 334 typically-developing, HIV-unexposed and uninfected youth (frequency-matched for age and sex) from the Pediatric Imaging, Neurocognition, and Genetics (PING) study (mean age=16.1years). PHIV youth had smaller (2.8-5.1%) total and regional grey matter volumes than HIV-unexposed and uninfected youth, with smallest volumes seen among PHIV youth with higher past peak viral load (VL) and recent unsuppressed VL. In PHIV youth, worse cognitive performance correlated with smaller volumes. This pattern of smaller grey matter volumes suggests that PHIV infection may influence brain development and underlie cognitive dysfunction seen in this population. Among PHIV youth, smaller volumes were also linked to substance use (alcohol use: 9.0-13.4%; marijuana use: 10.1-16.0%). In this study, collection of substance use information was limited to the PHIV cohort; future studies should also collect substance use information in controls to further address interactions between HIV and substance use on brain volume

Brain morphometric differences in youth with and without perinatally-acquired HIV: A cross-sectional study.

Youth with perinatally-acquired HIV (PHIV) experience specific and global cognitive deficits at increased rates compared to typically-developing HIV-uninfected youth. In youth with PHIV, HIV infects the brain early in development. Neuroimaging studies have demonstrated altered grey matter morphometry in youth with PHIV compared to typically-developing youth. This study examined cortical thickness, surface area, and gyrification of grey matter in youth (age 11-20 years old) with PHIV (n = 40) from the Pediatric HIV/AIDS Cohort Study (PHACS) compared to typically-developing presumed HIV uninfected and unexposed youth (n = 80) from the Pediatric Imaging, Neurocognition and Genetics Study (PING) using structural magnetic resonance imaging. This study also examined the relationship between grey matter morphometry and age. Youth with PHIV had reduced cortical thickness, surface area, and gyrification compared to typically-developing youth. In addition, an inverse relationship between age and grey matter volume was found in typically-developing youth, but was not observed in youth with PHIV. Longitudinal studies are necessary to understand the neurodevelopmental trajectory of youth with PHIV