Biomarkers and neurodevelopment in perinatally HIV-infected or exposed youth: a structural equation model analysis

Kapetanovic, Suada; Griner, Rayb; Zeldow, Bretb; Nichols, Sharonc; Leister, Erinb; Gelbard, Harris A.d; Miller, Tracie L.e; Hazra, Rohanf; Mendez, Armando J.g; Malee, Kathleenh; Kammerer, Betsyi; Williams, Paige L.b; for the Pediatric HIVAIDS Cohort Study Team

doi: 10.1097/QAD.0000000000000072
Clinical Science

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.

Author Information

aNational Institute of Mental Health, National Institutes of Health, Bethesda, Maryland

bDepartment of Biostatistics, Harvard School of Public Health, Boston, Massachusetts

cDepartment of Neurosciences, University of California San Diego, San Diego, California

dCenter for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York

eUniversity of Miami Miller School of Medicine, Miami, Florida

fEunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

gDivision of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida

hFeinberg School of Medicine, Northwestern University, Chicago, Illinois

iDepartment of Psychiatry, Boston Children's Hospital, Boston, Massachusetts, USA.

Correspondence to Suad Kapetanovic, MD, NIH, NIMH Office of the Clinical Director, Bldg. 10-CRC, Room 6-5340, 10 Center Drive, Bethesda, MD 20892-1276, USA. Tel: +1 301 827 2435; fax: +1 301 402 2588; e-mail:

Received 20 July, 2013

Accepted 10 September, 2013

© 2014 Lippincott Williams & Wilkins, Inc.