Biomarkers and neurodevelopment in perinatally HIV-infected or exposed youth

Abstract

Objective To examine the relationship between markers of vascular dysfunction and neurodevelopmental outcomes in perinatally HIV-infected (PHIV+) and perinatally HIV-exposed but uninfected (PHEU) youth. Design Cross-sectional design within a prospective, 15-site US-based cohort study. Methods Neurodevelopmental outcomes were evaluated in relation to nine selected vascular biomarkers in 342 youth (212 PHIV+, 130 PHEU). Serum levels were assessed for adiponectin, C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), soluble vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin), monocyte chemoattractant protein (sMCP-1), intercellular adhesion molecule-1 (sICAM-1), and P-selectin (sP-selectin). The Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) was administered at entry, yielding a Full-Scale IQ score, and four index scores. Factor analysis was conducted to reduce the biomarkers to fewer factors with related biological roles. Structural equation models (SEMs) were used to measure associations between resulting factors and WISC-IV scores. Results Mean participant age was 11.4 years, 54% were female, 70% black. The nine biomarkers were clustered into three factor groups: F1 (fibrinogen, CRP, and IL-6); F2 (sICAM-1 and sVCAM-1); and F3 (MCP-1, sP-selectin, and sE-selectin). Adiponectin showed little correlation with any factor. SEMs revealed significant negative association of F1 with WISC-IV processing speed score in the total cohort. This effect remained significant after adjusting for HIV status and other potential confounders. A similar association was observed when restricted to PHIV+ participants in both unadjusted and adjusted SEMs. Conclusion Aggregate measures of fibrinogen, CRP, and IL-6 may serve as a latent biomarker associated with relatively decreased processing speed in both PHIV+ and PHEU youth.

Executive Functioning in Children and Adolescents With Perinatal HIV Infection and Perinatal HIV Exposure

“…It is also consistent with a larger literature that shows that processing speed is a cognitive domain at particular risk for those with HIV infection [6,13,[32][33][34][35]. Processing speed has demonstrated associations with markers of both past [29] and ongoing disease processes, such as functional connectivity using functional magnetic resonance imaging [36], brain metabolites [14], and biomarkers of vascular functioning [37], in youth with PHIV. Longitudinal studies regarding cognitive functions such as processing speed or academic skills such as reading that might underlie EF problems in this population might identify targets for prevention and intervention and early indicators of a need for EF intervention.…”

Contributions of Disease Severity, Psychosocial Factors, and Cognition to Behavioral Functioning in US Youth Perinatally Exposed to HIV

“…The WAIS-IV and WISC-IV demonstrate high reliability and validity [26, 27] and are widely used for research and clinical practice with adolescents and children with HIV infection [28–32]. Each measure provides age-normed standard scores in four domains: verbal comprehension, perceptual reasoning, working memory, and processing speed (mean score = 100; SD = 15).…”

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

“…Proton magnetic resonance spectroscopy studies (MRS) have found that in adult HIV patients, elevated neurofilament light chain in the cerebrospinal fluid correlated with MRS abnormalities in the anterior cingulate, frontal white matter, and parietal grey matter (Peluso et al, 2013). In youth with PHIV, the relationship of brain volumes to inflammatory markers has not yet been studied, though studies in youth with PHIV have found that neopterin and sCD14 levels are elevated (Blokhuis et al, 2016; Sainz et al, 2014; Syed et al, 2013) and that aggregate measures of fibrinogen, CRP, and IL-6 are associated with decreased processing speed in youth with PHIV and in uninfected youth with perinatal HIV exposure (Kapetanovic et al, 2014). Future studies should aim to assess effects of PHIV, cART, and substance use with longitudinal neuroimaging and include diverse measures of HIV disease severity and inflammation, which may provide more information on when the brain is most vulnerable to HIV and substance use, as well as when treatment is most effective.…”