Higher subcortical and white matter cerebral blood flow in perinatally HIV-infected children

Abstract

This study aimed to evaluate cerebral blood flow (CBF) in pediatric human immunodeficiency virus (HIV)-infection, and its role in HIV-related cerebral injury and cognitive impairment.This cross-sectional observational study compared 28 perinatally HIV-infected children (8–18 years) to 34 healthy controls matched for age, sex, ethnicity, and socio-economic status. All participants underwent 3-Tesla magnetic resonance imaging, using arterial spin labeling to assess CBF in gray matter (GM), white matter (WM), basal ganglia, and thalamus. We used linear regression analysis to evaluate group differences and associations with HIV disease and treatment characteristics, macrostructural (volume loss, WM lesions) or microstructural injury (increased WM diffusivity, neurometabolite alterations), or poorer cognitive performance.HIV-infected children had higher CBF in WM (+10.2%; P = 0.042), caudate nucleus (+4.8%; P = 0.002), putamen (+3.6%; P = 0.017), nucleus accumbens (+3.9%; P = 0.031), and thalamus (+5.5%; P = 0.032). Thalamus CBF was highest in children with a Centers for Disease Control and Prevention stage B (Coef. = 6.45; P = 0.005) or C (Coef. = 8.52; P = 0.001) diagnosis. Lower GM CBF was associated with higher WM lesion volume in HIV-infected children (Coef. = −0.053; P = 0.001). No further associations with HIV-related cognitive impairment or cerebral injury were found.CBF was higher in WM, basal ganglia, and thalamus in combination antiretroviral therapy (cART)-treated perinatally HIV-infected children, but this was not associated with cerebral injury or cognitive impairment. HIV-infected children with lower GM CBF had a higher volume of WM lesions, which could reflect vascular disease as potential contributing factor to white matter injury. Lifelong exposure to HIV and cART in this population warrants longitudinal assessment of CBF and how it relates to (neuro)inflammation, vascular dysfunction, and cerebral injury in pediatric HIV.

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

“…It has been shown that using age-matched pediatric brain templates in pediatric studies lead to considerably different tissue distribution from that obtained with an adult-based template (Yoon et al, 2009 ). This may explain why previous studies of subcortical volumes using FreeSurfer either failed to detect group differences (Lewis-de Los Angeles et al, 2016 ), or detected fewer and less significant differences (Blokhuis et al, 2017 ; Yadav et al, 2017 ) than in our study. Using FreeSurfer automated segmentation in our cohort, within the gray and white matter structures investigated, there were no significant volumetric differences between groups, apart from the left globus pallidus (GP) which was smaller in infected children (L GP: Mean ( SD ): HIV 1,775 ± 192 mm 3 , controls 1,949 ± 255 mm 3 , F = 7.848, p = 0.007), and the CC that tended to be larger (HIV 469 ± 89 mm 3 , controls 431 ± 68 mm 3 , F = 2.871, p = 0.096).…”

“…Although, few studies have examined subcortical volumes specifically, two recent studies reported HIV-related regional subcortical GM increases. Blokhuis et al ( 2017 ) found trend-level Pu increases in HIV+ children, and Yadav and colleagues larger nucleus accumbens and smaller hippocampi (Yadav et al, 2017 ). The authors postulated inflammatory processes and chronic stress as possible explanations for the volume increases.…”

“…Due to their greater distance from the ventricles, the Pu and NA may be less readily penetrated by the HIV-infected mononuclear cells. However, higher cerebral blood flow of these areas have been observed in HIV+ children (Blokhuis et al, 2017 ). Another hypothesis may be that once HIV invades the area and viral infection spreads, removal of metabolic waste and virions may be slower in these structures compared to the caudate.…”

ExploreASL: an image processing pipeline for multi-center ASL perfusion MRI studies

“…We illustrate the ExploreASL image processing results and reproducibility for three populations with similar 2D-EPI PCASL protocols: perinatally-infected HIV children, healthy adults, and elderly with mild cognitive complaints, from the NOVICE (Blokhuis et al 2017), the Sleep (Elvsåshagen et al 2018), and the European Prevention of Alzheimer’s Dementia (EPAD) studies (Ritchie et al 2016), respectively (Supplementary Table 3). All three studies adhered to the Declaration of Helsinki and were approved by the local ethics committees (Academic Medical Center (AMC) in Amsterdam, Norwegian South East Regional Ethics Committee, and VU Medical Center Amsterdam and University of Edinburgh, respectively).…”

“…Currently in its third decade, following the consensus recommendations for the acquisition and quantification of ASL images (Alsop et al 2015), ASL is ready for large multi-center observational studies and clinical trials (Jack et al 2010; Almeida et al 2018; Blokhuis et al 2017). However, despite the consensus in clinical implementation and image acquisition (Alsop et al 2015), ASL image processing (Wang et al 2008; Shin et al 2016; Melbourne et al 2016; Chappell et al 2010; Mato Abad et al 2016; Li et al 2019; Bron et al 2014) remains disparate among research laboratories.…”