Journal of Neuroimmune Pharmacology

, Volume 14, Issue 2, pp 188–199 | Cite as

Executive Dysfunction Early Postnatal Biomarkers among Children Born Extremely Preterm

  • Alan LevitonEmail author
  • Robert M. Joseph
  • Raina N. Fichorova
  • Elizabeth N. Allred
  • H. Gerry Taylor
  • T. Michael O’Shea
  • Olaf Dammann


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.


Infant, premature/blood Neurodevelopment Inflammation Neurotrophic factors Executive function 







Brain-Derived Neurotrophic Factor


basic Fibroblast Growth Factor


C-Reactive Protein


Differential Ability Scales–II


Extremely preterm




Intercellular Adhesion Molecule-1


Insulin-like growth factor-1


Insulin-like growth factor binding protein-1






Interleukin-6 Receptor




Kaufman Brief Intelligence Test– 2


Matrix Metalloproteinase-9




A Developmental NEuroPSYchological Assessment




Placenta Growth Factor


Regulated upon Activation, Normal T cell Expressed, and Secreted


Serum Amyloid A


Tumor Necrosis Factor-α Receptor-1


Tumor Necrosis Factor-α Receptor-2


Tumor Necrosis Factor-α


Thyroid-Stimulating Hormone


Vascular Cell Adhesion Molecule-1


Vascular endothelial growth factor


Vascular endothelial growth factor Receptor-1


Vascular endothelial growth factor Receptor-2


Differential Ability Scales–II


Working memory


A Developmental NEuroPSYchological Assessment-II


Executive Dysfunction Composite



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).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

11481_2018_9804_MOESM1_ESM.docx (114 kb)
ESM 1 (DOCX 113 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Boston Children’s Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Boston University School of MedicineBostonUSA
  3. 3.Brigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  4. 4.Rainbow Babies & Children’s Hospital and Case Western Reserve UniversityClevelandUSA
  5. 5.University of North Carolina School of MedicineChapel HillUSA
  6. 6.Tufts University School of MedicineBostonUSA

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