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Executive Dysfunction Early Postnatal Biomarkers among Children Born Extremely Preterm

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Abstract

We evaluated the relationship between blood levels of inflammatory and neurotrophic proteins during the first postnatal month in 692 children born before the 28th week of gestation and executive function limitations among those 10-year olds who had an IQ ≥ 70. The measures of dysfunction were Z-scores ≤ -1 on the Differential Ability Scales–II working memory (WM) assessment) (N = 164), the NEPSY-II (A Developmental NEuroPSYchological Assessment-II) Inhibition-Inhibition assessment) (N = 350), the NEPSY-II Inhibition-Switching assessment) (N = 345), as well as a Z-score ≤ -1 on all three assessments (identified as the executive dysfunction composite (N = 104). Increased risks of the executive dysfunction composite associated with high concentrations of inflammatory proteins (IL-8, TNF-α, and ICAM-1) were modulated by high concentrations of neurotrophic proteins. This pattern of modulation by neurotrophins of increased risk associated with inflammation was also seen for the working memory limitation, but only with high concentrations of IL-8 and TNF-α, and the switching limitation, but only with high concentrations of ICAM-1. We infer that among children born extremely preterm, risks of executive function limitations might be explained by perinatal systemic inflammation in the absence of adequate neurotrophic capability.

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Abbreviations

Ang-1:

Angiopoietin-1

Ang-2:

Angiopoietin-2

BDNF:

Brain-Derived Neurotrophic Factor

bFGF:

basic Fibroblast Growth Factor

CRP:

C-Reactive Protein

DAS-II:

Differential Ability Scales–II

EP:

Extremely preterm

EPO:

Erythropoietin

ICAM-1:

Intercellular Adhesion Molecule-1

IGF-1:

Insulin-like growth factor-1

IGFBP-1:

Insulin-like growth factor binding protein-1

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

IL-6R:

Interleukin-6 Receptor

IL-8:

Interleukin-8

KBIT-2:

Kaufman Brief Intelligence Test– 2

MMP-9:

Matrix Metalloproteinase-9

MPO:

Myeloperoxidase

NEPSY-II:

A Developmental NEuroPSYchological Assessment

NT-4:

Neurotrophin-4

PIGF:

Placenta Growth Factor

RANTES:

Regulated upon Activation, Normal T cell Expressed, and Secreted

SAA:

Serum Amyloid A

TNF-R1:

Tumor Necrosis Factor-α Receptor-1

TNF-R2:

Tumor Necrosis Factor-α Receptor-2

TNF-α:

Tumor Necrosis Factor-α

TSH:

Thyroid-Stimulating Hormone

VCAM-1:

Vascular Cell Adhesion Molecule-1

VEGF:

Vascular endothelial growth factor

VEGF-R1:

Vascular endothelial growth factor Receptor-1

VEGF-R2:

Vascular endothelial growth factor Receptor-2

DAS-II:

Differential Ability Scales–II

WM:

Working memory

NEPSY-II:

A Developmental NEuroPSYchological Assessment-II

EDC:

Executive Dysfunction Composite

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Acknowledgments

The authors express their gratitude to the children and their families who participated in this study. They also gratefully acknowledge the contributions of the ELGAN Study Investigators, listed below.

Boston Children’s Hospital, Boston MA

Janice Ware, Taryn Coster, Brandi Henson, Rachel Wilson, Kirsten McGhee, Patricia Lee, Aimee Asgarian, Anjali Sadhwani

Brigham and Women’s Hospital- Genital Tract Biology, Boston, MA

Hidemi Yamamoto, Stanthia Ryan, Damilola Junaid, Hassan Dawood, Noah Beatty, Ngan Luu, Vanessa Tang, Rosaria Rita Sassi, Jenna-Malia Pasicznyk

Tufts Medical Center, Boston MA

Ellen Perrin, Emily Neger, Kathryn Mattern, Jenifer Walkowiak, Susan Barron

University of Massachusetts Medical School, Worcester MA

Jean Frazier, Lauren Venuti, Beth Powers, Ann Foley, Brian Dessureau, Molly Wood, Jill Damon-Minow

Yale University School of Medicine, New Haven, CT

Richard Ehrenkranz, Jennifer Benjamin, Elaine Romano, Kathy Tsatsanis, Katarzyna Chawarska, Sophy Kim, Susan Dieterich, Karen Bearrs

Wake Forest University Baptist Medical Center, Winston-Salem NC

T. Michael O’Shea, Nancy Peters, Patricia Brown, Emily Ansusinha, Ellen Waldrep, Jackie Friedman, Gail Hounshell, Debbie Allred (deceased)

University Health Systems of Eastern Carolina, Greenville, NC

Stephen C. Engelke, Nancy Darden-Saad, Gary Stainback

North Carolina Children’s Hospital, Chapel Hill, NC

Diane Warner, Janice Wereszczak, Janice Bernhardt, Joni McKeeman, Echo Meyer

Helen DeVos Children’s Hospital, Grand Rapids, MI

Steve Pastyrnak, Wendy Burdo-Hartman, Julie Rathbun, Sarah Nota, Teri Crumb,

Sparrow Hospital, Lansing, MI

Madeleine Lenski, Deborah Weiland, Megan Lloyd

University of Chicago Medical Center, Chicago, IL

Scott Hunter, Michael Msall, Rugile Ramoskaite, Suzanne Wiggins, Krissy Washington, Ryan Martin, Barbara Prendergast, Megan Scott

William Beaumont Hospital, Royal Oak, MI

Judith Klarr, Beth Kring, Jennifer DeRidder, Kelly Vogt

Financial Support

This study was supported by grants from the National Institute of Neurological Disorders and Stroke (5U01NS040069; 2R01NS040069), the National Institute of Child Health and Human Development (5P30HD018655), The National Eye Institute (1-R01-EY021820), and the Office of the NIH Director (1UG3OD023348).

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Authors and Affiliations

  1. Boston Children’s Hospital and Harvard Medical School, Boston, MA, 02115-5724, USA

    Alan Leviton & Elizabeth N. Allred

  2. Boston University School of Medicine, Boston, MA, USA

    Robert M. Joseph

  3. Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

    Raina N. Fichorova

  4. Rainbow Babies & Children’s Hospital and Case Western Reserve University, Cleveland, OH, USA

    H. Gerry Taylor

  5. University of North Carolina School of Medicine, Chapel Hill, NC, USA

    T. Michael O’Shea

  6. Tufts University School of Medicine, Boston, MA, 02111, USA

    Olaf Dammann

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  1. Alan Leviton
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  2. Robert M. Joseph
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  3. Raina N. Fichorova
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  4. Elizabeth N. Allred
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  5. H. Gerry Taylor
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  6. T. Michael O’Shea
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  7. Olaf Dammann
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Correspondence to Alan Leviton.

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Leviton, A., Joseph, R.M., Fichorova, R.N. et al. Executive Dysfunction Early Postnatal Biomarkers among Children Born Extremely Preterm. J Neuroimmune Pharmacol 14, 188–199 (2019). https://doi.org/10.1007/s11481-018-9804-7

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