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

Sub-Saharan Africa is home to 90% of HIV infected (HIV+) children. Since the advent of antiretroviral therapy (ART), HIV/AIDS has transitioned to a chronic condition where central nervous system (CNS) damage may be ongoing. Although, most guidelines recommend early ART to reduce CNS viral reservoirs, the brain may be more vulnerable to potential neurotoxic effects of ART during the rapid development phase in the first years of life. Here we investigate differences in subcortical volumes between 5-year-old HIV+ children who received early ART (before age 18 months) and uninfected children using manual tracing of Magnetic Resonance Images. Participants included 61 Xhosa children (43 HIV+/18 uninfected, mean age = 5.4 ± 0.3 years, 25 male) from the children with HIV early antiretroviral (CHER) trial; 27 children initiated ART before 12 weeks of age (ART-Before12Wks) and 16 after 12 weeks (ART-After12Wks). Structural images were acquired on a 3T Allegra MRI in Cape Town and manually traced using MultiTracer. Volumetric group differences (HIV+ vs. uninfected; ART-Before12Wks vs. ART-After12Wks) were examined for the caudate, nucleus accumbens (NA), putamen (Pu), globus pallidus (GP), and corpus callosum (CC), as well as associations within infected children of structure volumes with age at ART initiation and CD4/CD8 as a proxy for immune health. HIV+ children had significantly larger NA and Pu volumes bilaterally and left GP volumes than controls, whilst CC was smaller. Bilateral Pu was larger in both treatment groups compared to controls, while left GP and bilateral NA were enlarged only in ART-After12Wks children. CC was smaller in both treatment groups compared to controls, and smaller in ART-After12Wks compared to ART-Before12Wks. Within infected children, delayed ART initiation was associated with larger Pu volumes, effects that remained significant when controlling for sex and duration of treatment interruption (left ß = 0.447, p = 0.005; right ß = 0.325, p = 0.051), and lower CD4/CD8 with larger caudates controlling for sex (left ß = -0.471, p = 0.002; right ß = -0.440, p = 0.003). Volumetric differences were greater in children who initiated ART after 12 weeks. Results suggest damage is ongoing despite early ART and viral load suppression; however, earlier treatment is neuroprotective.

Longitudinal increases of brain metabolite levels in 5-10 year old children.

Longitudinal magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) studies reveal significant changes in brain structure and structural networks that occur together with cognitive and behavioral maturation in childhood. However, the underlying cellular changes accompanying brain maturation are less understood. Examining regional age-related changes in metabolite levels provides insight into the physiology of neurodevelopment. Magnetic resonance spectroscopy (MRS) measures localize brain metabolism. The majority of neuroimaging studies of healthy development are from the developed world. In a longitudinal MRS study of 64 South African children aged 5 to 10 years old (29 female; 29 HIV exposed, uninfected), we examined the age-related trajectories of creatine (Cr+PCr), N-acetyl-aspartate (NAA), the combined NAA+N-acetyl-aspartyl-glutamate (NAAG), choline (GPC+PCh), glutamate (Glu) and the combined Glu+glutamine (Glu+Gln) in voxels within gray and white matter, as well as subcortically in the basal ganglia (BG). In frontal gray matter, we found age-related increases in Cr+PCr, NAA, NAA+NAAG and Glu+Gln levels pointing to synaptic activity likely related to learning. In the BG we observed increased levels of Glu, Glu+Gln and NAA+NAAG with age that point to subcortical synaptic reorganization. In white matter, we found increased levels of Cr+PCr, NAA, NAA+NAAG, Glu and Glu+Gln with age, implicating these metabolites in ongoing myelination. We observed no sex-age or HIV exposure-age interactions, indicating that physiological changes are independent of sex during this time period. The metabolite trajectories presented, therefore, provide a critical benchmark of normal cellular growth for a low socioeconomic pediatric population in the developing world against which pathology and abnormal development may be compared.

Reductions in Corpus Callosum Volume Partially Mediate Effects of Prenatal Alcohol Exposure on IQ.

Disproportionate volume reductions in the basal ganglia, corpus callosum (CC) and hippocampus have been reported in children with prenatal alcohol exposure (PAE). However, few studies have investigated these reductions in high prevalence communities, such as the Western Cape Province of South Africa, and only one study made use of manual tracing, the gold standard of volumetric analysis. The present study examined the effects of PAE on subcortical neuroanatomy using manual tracing and the relation of volumetric reductions in these regions to IQ and performance on the California Verbal Learning Test-Children's Version (CVLT-C), a list learning task sensitive to PAE. High-resolution T1-weighted images were acquired, using a sequence optimized for morphometric neuroanatomical analysis, on a Siemens 3T Allegra MRI scanner from 71 right-handed, 9- to 11-year-old children [9 fetal alcohol syndrome (FAS), 19 partial FAS (PFAS), 24 non-syndromal heavily exposed (HE) and 19 non-exposed controls]. Frequency of maternal drinking was ascertained prospectively during pregnancy using timeline follow-back interviews. PAE was examined in relation to volumes of the CC and left and right caudate nuclei, nucleus accumbens and hippocampi. All structures were manually traced using Multitracer. Higher levels of PAE were associated with reductions in CC volume after adjustment for TIV. Although the effect of PAE on CC was confounded with smoking and lead exposure, additional analyses showed that it was not accounted for by these exposures. Amongst dysmorphic children, smaller CC was associated with poorer IQ and CVLT-C scores and statistically mediated the effect of PAE on IQ. In addition, higher levels of PAE were associated with bilateral volume reductions in caudate nuclei and hippocampi, effects that remained significant after control for TIV, child sex and age, socioeconomic status, maternal smoking during pregnancy, and childhood lead exposure. These data confirm previous findings showing that PAE is associated with decreases in subcortical volumes and is the first study to show that decreases in callosal volume may play a role in fetal alcohol-related impairment in cognitive function seen in childhood.