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

Abstract

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=16.7 years) 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=16.1 years). 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.

Larger Subcortical Gray Matter Structures and Smaller Corpora Callosa at Age 5 Years in HIV Infected Children on Early ART

“…This is the first study to examine over a narrow age range the impact of HIV on subcortical gray matter and corpus callosum volumes in a cohort of children receiving ART before 18 months of age and VL suppression by 109 weeks in all but three children. In contrast to most previous studies in HIV+ adults and children that reported gray matter atrophy (Tardieu et al, 2000 ; Crain et al, 2010 ; Becker et al, 2011 ; Chang et al, 2011 ; Cohen et al, 2016 ; Musielak and Fine, 2016 ; Lewis-de Los Angeles et al, 2017 ), we found HIV-related subcortical GM volume increases at 5 years in the left GP and bilaterally in the NA and Pu, but CC reductions. Association of increasing age of ART initiation with greater volumes in the Pu suggest that treatment timing plays a role in these observed volume increases.…”

“…Even though most studies in children find cortical and total gray matter atrophy in HIV infection (Cohen et al, 2016 ; Lewis-de Los Angeles et al, 2017 ), regional GM volume increases have been reported (Sarma et al, 2014 ). Although, few studies have examined subcortical volumes specifically, two recent studies reported HIV-related regional subcortical GM increases.…”

“…Since lower total GM and WM volumes have been reported in HIV+ youths (Cohen et al, 2016 ; Lewis-de Los Angeles et al, 2017 ), total intracranial volumes (ICVs) were derived for all children using FreeSurfer (Fischl, 2012 ) and considered a potential confounder. Additional control variables considered included age at scan and birthweight.…”

“…Although neuroimaging can provide insights into the mechanisms underpinning neurobehavioral outcomes in HIV+ children (Hoare et al, 2014 ; Musielak and Fine, 2016 ), such studies are rare, even in developed countries, and have typically included children across wide age ranges who either started ART late (Hoare et al, 2015 ) or some on early ART but small numbers with VL suppression (van Arnhem et al, 2013 ; Sarma et al, 2014 ). Studies in children and youths where most (>85%) have suppressed viral loads, and some received early ART, have demonstrated lower global and local cortical and total gray matter (GM) volumes (Cohen et al, 2016 ; Lewis-de Los Angeles et al, 2017 ), white matter (WM) alterations (Ackermann et al, 2014 , 2016 ; Andronikou et al, 2014 ; Uban et al, 2015 ), and volume reductions (Cohen et al, 2016 ), both subcortical volume increases and decreases and shape deformations (Lewis-de Los Angeles et al, 2016 ; Yadav et al, 2017 ), altered cortical thickness (Yadav et al, 2017 ), and effects of immunocompromise in infancy on basal ganglia metabolism at 5 years (Mbugua et al, 2016 ). These findings suggest that HIV- and/or ART-related damage may be irreversible or ongoing.…”

Machine Learning Methods for Intelligent Abnormal Brain Identification

“…Furthermore, we look forward to make a comparison of the algorithms for detecting other human brain-related diseases, such as sickle cell disease [25], HIV disease [26], etc. Some image preprocessing methods [27][28][29][30][31][32][33][34] may be added to check the performance.…”