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Observational Study
. 2019 Jul:210:81-90.e3.
doi: 10.1016/j.jpeds.2019.03.018. Epub 2019 May 7.

Association of Circulating Proinflammatory and Anti-inflammatory Protein Biomarkers in Extremely Preterm Born Children with Subsequent Brain Magnetic Resonance Imaging Volumes and Cognitive Function at Age 10 Years

Karl C K Kuban  1 , Hernan Jara  2 , T Michael O'Shea  3 , Timothy Heeren  4 , Robert M Joseph  5 , Raina N Fichorova  6 , Khalid Alshamrani  2 , Adam Aakil  2 , Forrest Beaulieu  2 , Mitchell Horn  2 , Laurie M Douglass  7 , Jean A Frazier  8 , Deborah Hirtz  9 , Julie Vanier Rollins  3 , David Cochran  10 , Nigel Paneth  11 ; ELGAN Study Investigators
Collaborators, Affiliations
Observational Study

Association of Circulating Proinflammatory and Anti-inflammatory Protein Biomarkers in Extremely Preterm Born Children with Subsequent Brain Magnetic Resonance Imaging Volumes and Cognitive Function at Age 10 Years

Karl C K Kuban et al. J Pediatr. 2019 Jul.

Abstract

Objectives: To examine elevated neonatal inflammatory and neurotrophic proteins from children born extremely preterm in relation to later childhood brain Magnetic Resonance Imaging volumes and cognition.

Study design: We measured circulating inflammation-related proteins and neurotrophic proteins on postnatal days 1, 7, and 14 in 166 children at 10 years of age (73 males; 93 females). Top quartile levels on ≥2 days for ≥3 inflammation-related proteins and for ≥4 neurotrophic proteins defined exposure. We examined associations among protein levels, brain Magnetic Resonance Imaging volumes, and cognition with multiple linear and logistic regressions.

Results: Analyses were adjusted for gestational age at birth and sex. Children with ≥3 elevated inflammation-related proteins had smaller grey matter, brain stem/cerebellar, and total brain volumes than those without elevated inflammation-related proteins, adjusted for neurotrophic proteins. When adjusted for inflammation-related proteins, children with ≥4 neurotrophic proteins, compared with children with no neurotrophic proteins, had larger grey matter and total brain volumes. Higher grey matter, white matter, and cerebellum and brainstem volumes were significantly correlated with higher IQ. Grey and white matter volumes were correlated with each other (r = -0.18; P = .021), and cerebellum and brainstem was highly correlated with grey matter (r = 0.55; P < .001) and white matter (r = 0.29; P < .001). Adjusting for other brain compartments, cerebellum and brainstem was associated with IQ (P = .016), but the association with white matter was marginally significant (P = .051). Grey matter was not associated with IQ. After adjusting for brain volumes, elevated inflammation-related proteins remained significantly associated with a lower IQ, and elevated neurotrophic proteins remained associated with a higher IQ.

Conclusions: Newborn inflammatory and neurotrophin protein levels are associated with later brain volumes and cognition, but their effects on cognition are not entirely explained by altered brain volumes.

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Figures

Figure.
Figure.
Mean grey matter and mean cerebellum and brain stem volumes depicted in Table III, adjusted for sex.
See this image and copyright information in PMC

References

    1. Kuban KC, Joseph RM, O’Shea TM, Heeren T, Fichorova RN, Douglass L, et al. Circulating inflammatory-associated proteins in the first month of life and cognitive impairment at age 10 years in children born extremely preterm. J Pediatr 2017;180:116–23.e1. - PMC - PubMed
    1. Allred EN, Dammann O, Fichorova RN, Hooper SR, Hunter SJ, Joseph RM, et al. Systemic inflammation during the first postnatal month and the risk of attention deficit hyperactivity disorder characteristics among 10 year-old children born extremely preterm. J Neuroimmune Pharmacol 2017;12:531–43. - PMC - PubMed
    1. Korzeniewski SJ, Allred EN, O’Shea TM, Leviton A, Kuban KCK. Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation. Transl Psychiatry 2018;8:115. - PMC - PubMed
    1. Kuban KCK, O’Shea TM, Alled EN, Paneth N, Hirtz D, Fichorova RN, Leviton A. Systemic inflammation and cerebral palsy risk in extremely preterm infants. J Child Neurol 2014;29:1692–8. - PubMed
    1. Leviton A, Kuban KC, Allred EN, Fichorova RN, O’Shea TM, Paneth N, et al. Early postnatal blood concentrations of inflammation-related proteins and microcephaly two years later in infants born before the 28th post-menstrual week. Early Hum Dev 2011;87:325–30. - PubMed

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