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  • Clinical Research Article
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Serum brain injury biomarkers are gestationally and post-natally regulated in non-brain injured neonates

Pediatric Research volume 93, pages 1943–1954 (2023)Cite this article

Abstract

Background

To determine the association of gestational age (GA) and day of life (DOL) with the circulating serum concentration of six brain injury-associated biomarkers in non-brain injured neonates born between 23 and 41 weeks’ GA.

Methods

In a multicenter prospective observational cohort study, serum CNS-insult, inflammatory and trophic proteins concentrations were measured daily in the first 7 DOL.

Results

Overall, 3232 serum samples were analyzed from 745 enrollees, median GA 32.3 weeks. BDNF increased 3.7% and IL-8 increased 8.9% each week of gestation. VEGF, IL-6, and IL-10 showed no relationship with GA. VEGF increased 10.8% and IL-8 18.9%, each DOL. IL-6 decreased by 15.8% each DOL. IL-10 decreased by 81.4% each DOL for DOL 0-3. BDNF did not change with DOL. Only 49.67% of samples had detectable GFAP and 33.15% had detectable NRGN. The odds of having detectable GFAP and NRGN increased by 53% and 11%, respectively, each week after 36 weeks’ GA. The odds of having detectable GFAP and NRGN decreased by 15% and 8%, respectively, each DOL.

Conclusions

BDNF and IL-8 serum concentrations vary with GA. VEGF and interleukin concentrations are dynamic in the first week of life, suggesting circulating levels should be adjusted for GA and DOL for clinically relevant assessment of brain injury.

Impact

  • Normative data of six brain injury-related biomarkers is being proposed.

  • When interpreting serum concentrations of brain injury biomarkers, it is key to adjust for gestational age at birth and day of life during the first week to correctly assess for clinical brain injury in neonates.

  • Variation in levels of some biomarkers may be related to gestational and postnatal age and not necessarily pathology.

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Fig. 1: Sequential exclusion criteria for the neonatal cohort.
Fig. 2: Relationship of biomarker concentration with gestational age.
Fig. 3: Relationship of CNS-necrosis biomarkers with gestational age and day of life (DOL).
Fig. 4: Relationship of biomarker concentration with day of life (DOL).
Fig. 5: Relationship of biomarker concentration with gestational age in mean model.
Fig. 6: Relationship of biomarker concentration with day of life (DOL) in mean model.

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References

  1. Fenichel, G. M. Hypoxic-ischemic encephalopathy in the newborn. Arch. Neurol. 40, 261–266 (1983).

    Article  CAS  PubMed  Google Scholar 

  2. Chin, E. M. et al. Preschool language outcomes following perinatal hypoxic-ischemic encephalopathy in the age of therapeutic hypothermia. Dev. Neurosci. 40, 627–637 (2019).

    Article  Google Scholar 

  3. Kurinczuk, J. J., White-Koning, M. & Badawi, N. Epidemiology of neonatal encephalopathy and hypoxic – ischaemic encephalopathy. Early Hum. Dev. 86, 329–338 (2010).

    Article  PubMed  Google Scholar 

  4. Shankaran, S. et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N. Engl. J. Med. 353, 1574–1584 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Volpe, J. J. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 8, 110–124 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bolisetty, S. et al. Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants. Pediatrics 133, 55–62 (2014).

    Article  PubMed  Google Scholar 

  7. Chevallier, M. et al. Leading causes of preterm delivery as risk factors for intraventricular hemorrhage in very preterm infants: results of the EPIPAGE 2 cohort study. Am. J. Obstet. Gynecol. 216, 518.e1 (2017).

    Article  PubMed  Google Scholar 

  8. Leviton, A. & Paneth, N. White matter damage in preterm newborns—an epidemiologic perspective. Early Hum. Dev. 24, 1–22 (1990).

    Article  CAS  PubMed  Google Scholar 

  9. Sarnat, H. B. & Sarnat, M. S. Encephalopathy fetal distress a clinical and electroencephalographic study. Arch. Neurol. 33, 696–705 (1976).

    Article  CAS  PubMed  Google Scholar 

  10. Edwards, A. D. et al. Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data. BMJ 340, 409 (2010).

    Article  Google Scholar 

  11. Shankaran, S. et al. Effect of depth and duration of cooling on death or disability at age 18 months among neonates with hypoxic-ischemic encephalopathy a randomized clinical trial. JAMA - J. Am. Med Assoc. 318, 57–67 (2017).

    Article  Google Scholar 

  12. American College of Obstetricians and Gynecologists’ Task Force on Neonatal Encephalopathy. Neonatal encephalopathy and neurologic outcome, second edition. Obstet. Gynecol. 123, 896–901 (2014).

    Article  Google Scholar 

  13. Gerner, G. J. et al. Correlation between white matter injury identified by neonatal diffusion tensor imaging and neurodevelopmental outcomes following term neonatal asphyxia and therapeutic hypothermia: an exploratory pilot study. J. Child Neurol. 34, 556–566 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Salas, J., Reddy, N., Carson, K. A., Northington, F. J. & Huisman, T. A. G. M. Ultrasound predicts white matter integrity after hypothermia therapy in neonatal hypoxic-ischemic injury. J. Neuroimaging 29, 743–749 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Blennow, K. A review of fluid biomarkers for Alzheimer’s disease: moving from CSF to blood. Neurol. Ther. 6, 15–24 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Pelinka, L. E. et al. GFAP versus S100B in serum after traumatic brain injury: relationship to brain damage and outcome. J. Neurotrauma 21, 1553–1561 (2004).

    Article  PubMed  Google Scholar 

  17. Missler, U., Wiesmann, M., Wittmann, G., Magerkurth, O. & Hagenström, H. Measurement of glial fibrillary acidic protein in human blood: analytical method and preliminary clinical results. Clin. Chem. 44, 138–141 (1999).

    Article  Google Scholar 

  18. Ennen, C. S. et al. Glial fibrillary acidic protein as a biomarker for neonatal hypoxic-ischemic encephalopathy treated with whole-body cooling. Am. J. Obstet. Gynecol. 205, 251.e1–251.e7 (2011).

    Article  PubMed  Google Scholar 

  19. Blennow, M., Hagberg, H. & Rosengren, L. Glial fibrillary acidic protein in the cerebrospinal fluid: a possible indicator of prognosis in full-term asphyxiated newborn infants? Pediatr. Res 37, 260–264 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Stewart, A. et al. Glial fibrillary acidic protein as a biomarker for periventricular white matter injury. Am. J. Obstet. Gynecol. 209, 27.e1–27.e7 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Chalak, L. F. et al. Biomarkers for severity of neonatal hypoxic-ischemic encephalopathy and outcomes in newborns receiving hypothermia therapy. J. Pediatr. 164, 468–74.e1 (2014).

  22. Massaro, A. N. et al. Serum biomarkers of MRI brain injury in neonatal hypoxic ischemic encephalopathy treated with whole-body hypothermia: a pilot study. Pediatr. Crit. Care Med. 14, 310–317 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Blennow, M., Savman, K., Ilves, P., Thoresen, M. & Rosengren, L. Brain-specific proteins in the cerebrospinal fluid of severely asphyxiated newborn infants. Acta Paediatr. 90, 1171–1175 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Yang, J., Korley, F. K., Dai, M. & Everett, A. D. Serum neurogranin measurement as a biomarker of acute traumatic brain injury. Clin. Biochem 48, 843–848 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Çevik, S. et al. NRGN, S100B and GFAP levels are significantly increased in patients with structural lesions resulting from mild traumatic brain injuries. Clin. Neurol. Neurosurg. 183, 105380 (2019).

    Article  PubMed  Google Scholar 

  26. Represa, A. et al. Neurogranin: immunocytochemical localization of a brain-specific protein kinase C substrate. J. Neurosci. 10, 3782–3792 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Guadaño-Ferraz, A., Viñuela, A., Oeding, G., Bernal, J. & Rausell, E. RC3/neurogranin is expressed in pyramidal neurons of motor and somatosensory cortex in normal and denervated monkeys. J. Comp. Neurol. 493, 554–570 (2005).

    Article  PubMed  Google Scholar 

  28. Dietrick, B. et al. Plasma and cerebrospinal fluid candidate biomarkers of neonatal encephalopathy severity and neurodevelopmental outcomes. J. Pediatr. 226, 71–79.e5 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. Massaro, A. N. et al. Plasma biomarkers of brain injury in neonatal hypoxic-ischemic encephalopathy. J. Pediatr. 194, 67–75 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. Çelik, Y. et al. The effects of selective head cooling versus whole-body cooling on some neural and inflammatory biomarkers: a randomized controlled pilot study. Ital. J. Pediatr. 41, 1–8 (2015).

    Article  Google Scholar 

  31. Chaparro-Huerta, V. et al. Proinflammatory cytokines, enolase and S-100 as early biochemical indicators of hypoxic-ischemic encephalopathy following perinatal asphyxia in newborns. Pediatr. Neonatol. 58, 70–76 (2017).

    Article  PubMed  Google Scholar 

  32. Barde, Y. A., Edgar, D. & Thoenen, H. Purification of a new neurotrophic factor from mammalian brain. EMBO J. 1, 549–553 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Korte, M. et al. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc. Natl Acad. Sci. USA 92, 8856–8860 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Leal, G., Comprido, D. & Duarte, C. B. BDNF-induced local protein synthesis and synaptic plasticity. Neuropharmacology 76, 639–656 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Park, H. & Poo, M. Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci. 14, 7–23 (2012).

    Article  Google Scholar 

  36. Grad, S. et al. Strongly enhanced serum levels of vascular endothelial growth factor (VEGF) after polytrauma and burn. Clin. Chem. Lab Med 36, 379–383 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Lv, H. et al. Neonatal hypoxic ischemic encephalopathy-related biomarkers in serum and cerebrospinal fluid. Clin. Chim. Acta 450, 282–297 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Sweetman, D. U., Onwuneme, C., Watson, W. R., Murphy, J. F. A. & Molloy, E. J. Perinatal asphyxia and erythropoietin and VEGF: serial serum and cerebrospinal fluid responses. Neonatology 111, 253–259 (2017).

    Article  CAS  PubMed  Google Scholar 

  39. Graham, E. M., Everett, A. D., Delpech, J. C. & Northington, F. J. Blood biomarkers for evaluation of perinatal encephalopathy: state of the art. Curr. Opin. Pediatr. 30, 199–203 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Ramaswamy, V. et al. Systematic review of biomarkers of brain injury in term neonatal encephalopathy. Pediatr. Neurol. 40, 215–226 (2009).

    Article  PubMed  Google Scholar 

  41. Broni, E. K. et al. Blood biomarkers for neonatal hypoxic – ischemic encephalopathy in the presence and absence of sentinel events. J. Perinatol. https://doi.org/10.1038/s41372-020-00850-5 (2020).

  42. Novak, C. M., Eke, A. C., Ozen, M., Burd, I. & Graham, E. M. Risk factors for neonatal hypoxic-ischemic encephalopathy in the absence of sentinel events. Am. J. Perinatol. 36, 27–33 (2019).

    Article  PubMed  Google Scholar 

  43. Schleif, W. et al. Tiny bodies, big needs: prospective biobanking of neonatal clinical remnant samples. Biopreserv. Biobank. 19, 106–110 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Shimada, H. et al. A large, cross-sectional observational study of serum BDNF, cognitive function, and mild cognitive impairment in the elderly. Front. Aging Sci. 6, 1–9 (2014).

    Google Scholar 

  45. Martínez-Moreno, A., Rivera-Olvera, A. & Escobar, M. L. BDNF induces in vivo long-lasting enhancement of synaptic transmission and structural reorganization at the hippocampal mossy fibers in a transcription and translation-independent manner. Neurobiol. Learn. Mem. 167, 107125 (2020).

    Article  PubMed  Google Scholar 

  46. Edelmann, E., Leßmann, V. & Brigadski, T. Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity. Neuropharmacology 76, 610–627 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Panja, D. & Bramham, C. R. BDNF mechanisms in late LTP formation: a synthesis and breakdown. Neuropharmacology 76, 664–676 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Tolwani, R. J. et al. BDNF overexpression produces a long-term increase in myelin formation in the peripheral nervous system. J. Neurosci. Res. 77, 662–669 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Karege, F., Schwald, M. & Cisse, M. Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets. Neurosci. Lett. 328, 261–264 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Sartorius, A. et al. Correlations and discrepancies between serum and brain tissue levels of neurotrophins after electroconvulsive treatment in rats. Pharmacopsychiatry 42, 270–276 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Klein, A. B. et al. Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J. Neuropsychopharmacol. 14, 347–353 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Graham, E. M. et al. Association of intraoperative circulating-brain injury biomarker and neurodevelopmental outcomes at 1 year among neonates who have undergone cardiac surgery. J. Thorac. Cardiovasc. Surg. 157, 1996–2002 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Easley, R. B. et al. Impaired cerebral autoregulation and elevation in plasma glial fibrillary acidic protein level during cardiopulmonary bypass surgery for CHD. Cardiol. Young. 28, 55–65 (2018).

    Article  PubMed  Google Scholar 

  54. Guo, J. H. et al. Expression pattern of NeuN and GFAP during human fetal spinal cord development. Child’s Nerv. Syst. 31, 863–872 (2015).

    Article  Google Scholar 

  55. Nazir, F. H. et al. Expression and secretion of synaptic proteins during stem cell differentiation to cortical neurons. Neurochem. Int. 121, 38–49 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Romero, R. et al. Clinical chorioamnionitis at term V: umbilical cord plasma cytokine profile in the context of a systemic maternal inflammatory response. J. Perinat. Med. 44, 53–76 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Goepfert, A. R. et al. Umbilical cord plasma interleukin-6 concentrations in preterm infants and risk of neonatal morbidity. Am. J. Obstet. Gynecol. 191, 1375–1381 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Sood, B. G., Madan, A., Saha, S., Schendel, D. & Thorsen, P. Perinatal systemic inflammatory response syndrome and retinopathy of prematurity. Pediatr. Res. 67, 394–400 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the patients and their families for their participation and contributions to this study and the Everett research group at Johns Hopkins University School of Medicine for their support and contributions and the Johns Hopkins All Children’s Pediatric Biorepository for its support. We also thank the Johns Hopkins University School of Medicine Scholarly Concentration mentor Dr. Meredith Atkinson and the Johns Hopkins University School of Medicine Dean’s Funding for their support and contributions.

Funding

This study was supported by NIH NICHD R01HD086058 [A.E., F.N., J.Y., D.V., S.B., and E.G.], NINDS KO8NS096115 [R.C.-V.], Thomas-Wilson Foundation [R.C.-V.], and JHACH Foundation Institutional Research Grant Program [S.B.].

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Author notes

  1. These authors contributed equally: Sandra Brooks, Barbara D. Friedes.

Authors and Affiliations

  1. Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA

    Sandra Brooks

  2. Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Barbara D. Friedes

  3. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Frances Northington, Jie Zhu, Raul Chavez-Valdez & Allen D. Everett

  4. Departments of Maternal-Fetal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ernest Graham

  5. Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Aylin Tekes

  6. Kennedy-Krieger Institute, Baltimore, MD, USA

    Vera J. Burton & Gwendolyn Gerner

  7. Department of Intermal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Dhananjay Vaidya

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Contributions

Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data: S.B., B.D.F., F.N., E.G., A.T., J.Z.B.S., D.V., and A.D.E. Drafting the article or revising it critically for important intellectual content: S.B., B.D.F., F.N., E.G., A.T., V.J.B., G.G., R.C.-V., D.V., and A.D.E. Final approval of the version to be published: S.B., B.D.F., F.N., E.G., R.C.-V., D.V., and A.D.E.

Corresponding author

Correspondence to Sandra Brooks.

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Competing interests

Under a license agreement between ImmunArray Ltd. and Johns Hopkins University, the University and Dr. Everett are entitled to royalties on an invention described in this study and discussed in this publication. This arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. Sandra Brooks and Barbara Dietrick wrote the first draft of the manuscript, and no honorarium, grant, or other forms of payment was given to anyone to produce the manuscript. The remaining authors declare no competing interests.

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Brooks, S., Friedes, B.D., Northington, F. et al. Serum brain injury biomarkers are gestationally and post-natally regulated in non-brain injured neonates. Pediatr Res 93, 1943–1954 (2023). https://doi.org/10.1038/s41390-021-01906-8

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