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Among Children Born Extremely Preterm a Higher Level of Circulating Neurotrophins Is Associated with Lower Risk of Cognitive Impairment at School Age - 21/09/18

Doi : 10.1016/j.jpeds.2018.05.021 
Karl C.K. Kuban, MD, SMEpi 1, * , Timothy Heeren, PhD 2, T. Michael O'Shea, MD, MPH 3, Robert M. Joseph, PhD 4, Raina N. Fichorova, MD, PhD 5, Laurie Douglass, MD 1, Hernan Jara, PhD 6, Jean A. Frazier, MD 7, Deborah Hirtz, MD 8, H. Gerry Taylor, PhD 9, Julie Vanier Rollins, MA 3, Nigel Paneth, MD, MPH 10
for the

ELGAN Study Investigators*

  List of additional members of the ELGAN Study is available at www.jpeds.com (Appendix).
Janice Ware, PhD 11, Taryn Coster, BA 11, Brandi Hanson, PsyD 11, Rachel Wilson, PhD 11, Kirsten McGhee, PhD 11, Patricia Lee, PhD 11, Aimee Asgarian, PhD 11, Anjali Sadhwani, PhD 11, Ellen Perrin, MD 12, Emily Neger, MA 12, Kathryn Mattern, BA 12, Jenifer Walkowiak, PhD 12, Susan Barron, PhD 12, Bhavesh Shah, MD 13, Rachana Singh, MD, MS 13, Anne Smith, PhD 13, Deborah Klein, BSN, RN 13, Susan McQuiston, PhD 13, Lauren Venuti, BA 14, Beth Powers, RN 14, Ann Foley, Ed M 14, Brian Dessureau, PhD 14, Molly Wood, PhD 14, Jill Damon-Minow, PsyD 14, Richard Ehrenkranz, MD 15, Jennifer Benjamin, MD 15, Elaine Romano, APRN 15, Kathy Tsatsanis, PhD 15, Katarzyna Chawarska, PhD 15, Sophy Kim, PhD 15, Susan Dieterich, PhD 15, Karen Bearrs, PhD 15, Nancy Peters, RN 16, Patricia Brown, BSN 16, Emily Ansusinha, BA 16, Ellen Waldrep, PhD 16, Jackie Friedman, PhD 16, Gail Hounshell, PhD 16, Debbie Allred, PhD 16, Stephen C. Engelke, MD 17, Nancy Darden-Saad, BS, RN, CCRC 17, Gary Stainback, PhD 17, Diane Warner, MD, MPH 18, Janice Wereszczak, MSN, PNP 18, Janice Bernhardt, MS, RN 18, Joni McKeeman, PhD 18, Echo Meyer, PhD 18, Steve Pastyrnak, PhD 19, Julie Rathbun, BSW, BSN, RN 19, Sarah Nota, BS 19, Teri Crumb, BSN, RN, CCRC 19, Madeleine Lenski, MPH 20, Deborah Weiland, MSN 20, Megan Lloyd, MA, EdS 20, Scott Hunter, PhD 21, Michael Msall, MD 21, Rugile Ramoskaite, BA 21, Suzanne Wiggins, MA 21, Krissy Washington, MA 21, Ryan Martin, MA 21, Barbara Prendergast, BSN, RN 21, Megan Scott, PhD 21, Judith Klarr, MD 22, Beth Kring, RN 22, Jennifer DeRidder, RN 22, Kelly Vogt, PhD 22, Hidemi Yamamoto, BA 23, Stanthia Ryan, MD Candidate 23, Damilola Junaid, BS 23, Hassan Dawood, BS 23, Noah Beatty, BS 23, Ngan Luu, BA Candidate 23, Vanessa Tang, MD 23, Rosaria Rita Sassi, MD 23, Jenna-Malia Pasicznyk, RN 23
11 ELGAN Study Boston Children's Hospital, Boston, MA 
12 Tufts Medical Center, Boston, MA 
13 Baystate Medical Center, Springfield, MA 
14 University of Massachusetts Medical School, Worcester, MA 
15 Yale University School of Medicine, New Haven, CT 
16 Wake Forest University Baptist Medical Center, Winston-Salem, NC 
17 University Health Systems of Eastern Carolina, Greenville, NC 
18 North Carolina Children's Hospital, Chapel Hill, NC 
19 Helen DeVos Children's Hospital, Grand Rapids, MI 
20 Sparrow Hospital, Lansing, MI 
21 University of Chicago Medical Center, Chicago, IL 
22 William Beaumont Hospital, Royal Oak, MI 
23 Brigham and Women's Hospital, Boston, MA 

1 Department of Pediatrics, Division of Pediatric Neurology, Boston Medical Center, Boston, MA 
2 Department of Biostatistics, Boston University School of Public Health, Boston, MA 
3 Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of North Carolina, Chapel Hill, NC 
4 Department of Anatomy and Neuroanatomy, Boston University School of Medicine, Boston, MA 
5 Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 
6 Department of Radiology, Boston University School of Medicine, Boston, MA 
7 Department of Psychiatry, Eunice Kennedy Shriver Center, UMASS Medical School/ University of Massachusetts Memorial Health Care, Worcester, MA 
8 National Institute of Neurological Disorders and Stroke, Bethesda, MD 
9 Department of Pediatrics, Case Western Reserve University, Cleveland, OH 
10 Department of Epidemiology and Biostatistics and Pediatrics & Human Development, Michigan State University, East Lansing, MI 

*Reprint requests: Karl C.K. Kuban, MD, SMEpi, 1 Boston Medical Center Place, Dowling Building, 3-South, Room 3314, Boston Medical Center, Boston, MA 03118.Boston Medical Center1 Boston Medical Center PlaceDowling Building3-SouthRoom 3314BostonMA03118

Abstract

Objectives

To test the hypothesis that higher blood levels of neurotrophic proteins (proteins that support neuronal survival and function) in the first 2 weeks of life are associated with a lower risk of cognitive impairment at 10 years.

Study design

We evaluated 812 10-year-old children with neonatal blood specimens enrolled in the multicenter prospective Extremely Low Gestational Age Newborn Study, assessing 22 blood proteins collected on 3 days over the first 2 weeks of life. Using latent profile analysis, we derived a cognitive function level based on standardized cognitive and executive function tests. We defined high exposure as the top quartile neurotrophic protein blood level on ≥2 days either for ≥4 proteins or for a specific cluster of neurotrophic proteins (defined by latent class analysis). Multinomial logistic regression analyzed associations between high exposures and cognitive impairment.

Results

Controlling for the effects of inflammatory proteins, persistently elevated blood levels of ≥4 neurotrophic proteins were associated with reduced risk of moderate (OR, 0.35; 95% CI, 0.18-0.67) and severe cognitive impairment (OR, 0.22; 95% CI, 0.09-0.53). Children with a cluster of elevated proteins including angiopoietin 1, brain-derived neurotrophic factor, and regulated upon activation, normal T-cell expressed, and secreted had a reduced risk of adverse cognitive outcomes (OR range, 0.31-0.6). The risk for moderate to severe cognitive impairment was least with 0-1 inflammatory and >4 neurotrophic proteins.

Conclusions

Persisting elevations of circulating neurotrophic proteins during the first 2 weeks of life are associated with lowered risk of impaired cognition at 10 years of age, controlling for increases in inflammatory proteins.

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Keyword : extreme prematurity, early life risks and protectors of later cognition, inflammation and neurotrophins

Abbreviations : ANG, BDNF, CRP, EF, ELGAN, IRG, LCA, NRG, RANTES, SAA


Plan


 J.F. received research support from Fulcrum Therapeutics, F. Hoffman-LaRoche, Ltd, Janssen Research and Development, SyneuRex International Corp, and Neuren Pharmaceuticals. The other authors declare no conflicts of interest.
 Supported by the National Institute of Neurological Disorders and Stroke (5U01NS040069-05; 2R01NS040069-09), the Office of the Director of NIH (1UG3OD023348-01), the National Institute of Child Health and Human Development (5P30HD018655-28), and the National Eye Institute (R01EY021820-01A1).


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Vol 201

P. 40 - octobre 2018 Retour au numéro
Article précédent Article précédent
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