A Neurometabolic Pattern of Elevated Myo-Inositol in Children Who Are HIV-Exposed and Uninfected: A South African Birth Cohort Study

Abstract

IntroductionExposure to maternal HIV in pregnancy may be a risk factor for impaired child neurodevelopment during the first years of life. Altered neurometabolites have been associated with HIV exposure in older children and may help explain the mechanisms underlying this risk. For the first time, we explored neurometabolic profiles of children who are HIV-exposed and uninfected (CHEU) compared to children who are HIV-unexposed (CHU) at 2-3 years of age.MethodsThe South African Drakenstein Child Health Study enrolled women during pregnancy and is following mother-child pairs through childhood. MRI scans were acquired on a sub-group of children at 2-3 years. We used single voxel magnetic resonance spectroscopy to measure brain metabolite ratios to total creatine in the parietal grey matter, and left and right parietal white matter of 83 children (36 CHEU; 47 CHU). Using factor analysis, we explored brain metabolite patterns in predefined parietal voxels in these groups using logistic regression models. Differences in relative concentrations of individual metabolites (n-acetyl-aspartate, myo-inositol, total choline, and glutamate) to total creatine between CHEU and CHU groups were also examined.ResultsFactor analysis revealed four different metabolite patterns, each one characterized by covarying ratios of a single metabolite in parietal grey and white matter. The cross-regional pattern dominated by myo-inositol, a marker for glial reactivity and inflammation, was associated with HIV exposure status (OR 1.63; 95% CI 1.11–2.50) which held after adjusting for child age, sex, and maternal alcohol use during pregnancy (OR 1.59; 95% CI 1.07 –2.47). Additionally, higher relative concentrations of myo-inositol to total creatine were found in left and right parietal white matter of CHEU compared to CHU (p=0.025 and p=0.001 respectively).DiscussionIncreased ratios of myo-inositol to total creatine in parietal brain regions at age 2-3 years in CHEU are suggestive of early and ongoing neuroinflammatory processes. Altered relative concentrations of neurometabolites were found predominantly in the white matter, which is sensitive to neuroinflammation, and may contribute to developmental risk in this population. Future work on the trajectory of myo-inositol over time in CHEU, alongside markers of neurocognitive development, and the potential for specific neurodevelopmental interventions will be useful.

Lower academic performance among children with perinatal HIV exposure in Botswana

“…While findings are inconsistent, many studies report a higher risk of infectious morbidity and mortality, poorer growth outcomes and developmental delays among children HIV‐exposed uninfected (HEU) compared to children HIV‐unexposed uninfected (HUU) [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. The aetiology of this higher risk among children HEU is multifactorial, encompassing both biological and social determinants of health, including altered immunity early in life [ 14 , 15 , 16 , 17 , 18 ], a proinflammatory state in infancy [ 19 , 20 , 21 ], higher risk of preterm birth [ 22 , 23 ], suboptimal duration of breastfeeding [ 3 , 24 ], poor maternal health [ 25 ] and household food insecurity [ 26 ].…”

1H-MRS neurometabolite profiles and motor development in school-aged children who are HIV-exposed uninfected: a birth cohort study

“…In contrast, in the same cohort, no Glu neurometabolic differences were reported at 7 years of age ( Robertson et al, 2018 ); however, this may be due to larger variability in the data at this age. Furthermore, in our cohort of CHEU at the age of 2 years, elevated Glu/Cr concentrations were reported in the parietal white matter ( Bertran-Cobo et al, 2022 ). One of the key aspects of MRS studies that requires consideration is that of voxel tissue composition.…”

“…At both age points, reduced concentrations of N-acetyl aspartate (NAA) and Glutamate (Glu) were observed, suggesting that perinatal exposure to HIV and/or ART may affect regional neuronal integrity and glutamatergic pathways in the developing brain. Furthermore, a neurometabolic pattern identified through factor analysis was found to be a predictor of HIV exposure status in young 2-year-old ( Bertran-Cobo et al, 2022 ) CHEU enrolled in the Drakenstein Child Health Study (DCHS). The neurometabolic pattern identified was dominated by myo-inositol (Ins) concentrations, a marker of inflammatory processes across parietal gray and white matter.…”

Neurodevelopment among children exposed to HIV and uninfected in sub‐Saharan Africa

“…Other MRI studies have detected significantly altered metabolites in the basal ganglia, including choline (regulator of mood and intelligence) and creatine (regulator of energy production) among older CHEU [ 66 , 67 , 68 ], while diffusion tensor imaging has revealed altered white matter microstructural integrity (essential for visuospatial and memory cognition) among CHEU [ 69 , 70 ]. Finally, a recent magnetic resonance spectroscopy study suggests perinatal HIV exposure to be associated with neurometabolic patterns indicative of neuroinflammation, which may increase the risk of neurodevelopmental delay [ 71 ]. It will be important to pair cutting‐edge neuroimaging research, leveraging scalable low‐field MRI technologies, with contextually appropriate neurodevelopment assessments to determine whether neuroimaging could represent the earliest signal of suboptimal neurodevelopmental outcomes for which interventions could be developed and tested.…”