The longitudinal effects of HIV and ART on the developing brain: a structural MRI study using manual segmentation

Randall, Steven

The longitudinal effects of HIV and ART on the developing brain: a structural MRI study using manual segmentation

Thesis / Dissertation

2024

Abstract

Background: Previous neuroimaging research into the effects of HIV in paediatric populations receiving treatment has reported brain abnormalities across a variety of ages and modalities. There are limited longitudinal studies, which would clarify if the observed changes represented developmental delay or ongoing damage. In addition, most neuroimaging studies do not include links to functional, immunological, or genetic outcomes which aid in understanding the consequence, mechanisms and factors underlying the brain imaging abnormalities. There is a need for longitudinal work and interdisciplinary crosssectional imaging studies to comprehend the consequences of the current literature. To address literature gap, this thesis builds on a cross-sectional study, by the same author, of this group of 106 children who were perinatally infected with HIV (PHIV), and form part of “Children with HIV early antiretroviral”(CHER) trial who have been followed since birth (Violari et al. 2008; Laughton et al. 2012; Cotton et al. 2013). The study showed larger subcortical gray matter and smaller white matter in children with perinatal HIV infection compared to controls, at 5 years of age. This thesis presents a longitudinal follow-up to assess whether these morphometric differences persisted into later childhood, as well as assess possible early contributors that may exacerbate or predict certain highlighted disturbances observed from 5 to 10 years of age. We aim to determine if the volumetric abnormalities observed at age 5 years represent developmental delay or ongoing injury due to HIV infection. In addition, we seek to identify potential early immune markers and the 5-year-old volume changes to better understand contributing factors. Methods: MRI scans were obtained at ages 5, 7, and 9 years, on a 3 T Allegra MRI (Siemens, Erlangen, Germany), and 10 years 3 T Skyra Siemens. Images were manually traced, by the author, for volumes of basal ganglia structures and corpus callosum using MultiTracer. Twenty-seven individuals were rescanned to assess whether incorporation and integration of 10 year old scanner data with scans from previous ages on a different scanner was possible, as a result of decommissioning the 3 T Allegra scanner. Volumetric growth curves were fit for forty children using mixed effects models with subject-specific random effects, with adjustment for possible two-way interactions between age and diagnosis. We investigated linear, quadratic, cubic and logarithmic fits for each volume. A panel of 44 soluble blood biomarkers were obtained at enrolment for a small sample of infants living with HIV. Cytokine concentrations were Z-score transformed and principle component analysis (PCA) performed. Results: Manual segmentation was reproducible across the different 3 T scanners within this pediatric sample allowing for volumetric data to be combined into one model without a scanner confounder. Across volumes, logarithmic models performed best. Age-related decreases were observed across children in the bilateral caudate and globus pallidus, as well as the corpus callosum. HIV-related alterations to growth trajectories were observed in the right nucleus accumbens and bilateral putamen, driven by volume abnormalitiesreported at 5 years. HIV-related corpus callosum reductions previously reported at age 5 did not alter the growth trajectories. PCA analysis identified a component associated negatively with subcortical volumes. Association with the derived component variable suggest that during the period of initial infection, in infancy, an increase of IL-10, IP-10, LBP and IFN-α, and accompanying decrease in IL-17F and CD40L contribute to smaller basal ganglia volumes at 5 years. Conclusions: This thesis expands cross sectional volumetric work which identified basal ganglia and corpus callosum volume abnormalities in 5-year-old PHIV children. Longitudinal analysis found the 5-year-old volumetric changes were likely HIV-related developmental delays, as volumes differences did not persist. The volume increases in the putamen affected the growth trajectories in PHIV and were related to early immunological factors associated with proinflammatory effects, immune activation and immune dysfunction. The volume decreases in the corpus callosum did not affect the age-related trajectory, and no cytokines related to volume abnormalities at 5 years. While cross sectional HIVrelated results in PHIV are concerning, more work is needed to contextualize their consequences on growth and function.

Keywords

Human Biology

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Collections

PhD / Doctoral

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