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Increased Brain Perfusion Persists over the First Month of Life in Term Asphyxiated Newborns Treated with Hypothermia: Does it Reflect Activated Angiogenesis?

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Abstract

Many asphyxiated newborns still develop brain injury despite hypothermia therapy. The development of brain injury in these newborns has been related partly to brain perfusion abnormalities. The purposes of this study were to assess brain hyperperfusion over the first month of life in term asphyxiated newborns and to search for some histopathological clues indicating whether this hyperperfusion may be related to activated angiogenesis following asphyxia. In this prospective cohort study, regional cerebral blood flow was measured in term asphyxiated newborns treated with hypothermia around day 10 of life and around 1 month of life using magnetic resonance imaging (MRI) and arterial spin labeling. A total of 32 MRI scans were obtained from 24 term newborns. Asphyxiated newborns treated with hypothermia displayed an increased cerebral blood flow in the injured brain areas around day 10 of life and up to 1 month of life. In addition, we looked at the histopathological clues in a human asphyxiated newborn and in a rat model of neonatal encephalopathy. Vascular endothelial growth factor (VEGF) was expressed in the injured brain of an asphyxiated newborn treated with hypothermia in the first days of life and of rat pups 24–48 h after the hypoxic-ischemic event, and the endothelial cell count increased in the injured cortex of the pups 7 and 11 days after hypoxia-ischemia. Our data showed that the hyperperfusion measured by imaging persisted in the injured areas up to 1 month of life and that angiogenesis was activated in the injured brain of asphyxiated newborns.

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Abbreviations

BG:

Basal ganglia

DAPI:

4,6-Diamidino-2-phenylindole

HI:

Hypoxic-ischemic

HIE:

Hypoxic-ischemic encephalopathy

GFAP:

Glial fibrillary acidic protein

GM:

Gray matter

MRI:

Magnetic resonance imaging

VEGF:

Vascular endothelial growth factor

WM:

White matter

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Acknowledgments

The authors thank the families and their newborns for participating in this study. Special thanks also are due to the NICU nurses, NICU respiratory therapists, and MRI technicians who have made this study possible. We thank Lauren Jantzie for her help in teaching the surgical technique and the basics of immunohistochemical studies. We thank Mr. Wayne Ross Egers for his professional English correction of the manuscript. The work of Pia Wintermark is supported by the William Randolph Hearst Fund Award, the Thrasher Research Fund Early Career Award Program, the FRSQ Clinical Research Scholar Career Award Junior 1, the Canadian Institutes of Health Research Open Operating Grant, and the New Investigator Research Grant from the SickKids Foundation and the CIHR Institute of Human Development, Child and Youth Health (IHDCYH).

Conflict of Interest

This manuscript has been contributed to, seen, and approved by all the authors. No conflict of interest exists. All the authors fulfill the authorship credit requirements. The authors have no financial relationships relevant to this article to disclose. The study was not industry-sponsored. The work of Pia Wintermark is supported by the William Randolph Hearst Fund Award, the Thrasher Research Fund Early Career Award Program, the FRSQ Clinical Research Scholar Career Award Junior 1, the Canadian Institutes of Health Research Open Operating Grant, and the New Investigator Research Grant from the SickKids Foundation and the CIHR Institute of Human Development, Child and Youth Health (IHDCYH).

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Authors and Affiliations

  1. Department of Pediatrics, McGill University, Montreal, QC, Canada

    Henna Shaikh, Michael Shevell & Pia Wintermark

  2. Department of Pathology, University of California Davis Medical Center, Sacramento, CA, USA

    Mirna Lechpammer

  3. Department of Pathology, Boston Children’s Hospital, Boston, MA, USA

    Mirna Lechpammer

  4. Department of Neurology, Boston Children’s Hospital, Boston, MA, USA

    Mirna Lechpammer, Frances E. Jensen & Bela Kosaras

  5. Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA

    Frances E. Jensen

  6. Department of Pediatric Radiology, Boston Children’s Hospital, Boston, MA, USA

    Simon K. Warfield

  7. Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA, USA

    Anne H. Hansen & Pia Wintermark

  8. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    Michael Shevell

  9. Division of Newborn Medicine, McGill University/Montreal Children’s Hospital, 2300 rue Tupper, C-920, Montreal, QC, H3H 1P3, Canada

    Pia Wintermark

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  1. Henna Shaikh
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Correspondence to Pia Wintermark.

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Supplemental Figure 1

Term newborns with neonatal encephalopathy. Relative ratios of increased perfusion in the different regions of interest in asphyxiated newborns developing brain injury — (A) at approximately day 10 of life and (B) at approximately 1 month of life. Box and whisker plots (median, minimum, and maximum, in [mL/100 g/min]) representation. The ratios were obtained by comparing each measured value of cerebral blood flow measured in these newborns in the respective region of interest to the mean value in healthy newborns. The different regions of interest where cerebral blood flow was measured consisted of: (1) cortical grey matter (GM); (2) white matter (WM); and (3) basal ganglia (BG). The relative ratios of increased perfusion were similar around day 10 of life and around 1 month of life in grey matter and basal ganglia; the ratio decreased from around day 10 of life to around 1 month of life in white matter. However, the relative ratios of increased perfusion remained higher in white matter at both time-points, compared to grey matter and basal ganglia. (GIF 28 kb)

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Shaikh, H., Lechpammer, M., Jensen, F.E. et al. Increased Brain Perfusion Persists over the First Month of Life in Term Asphyxiated Newborns Treated with Hypothermia: Does it Reflect Activated Angiogenesis?. Transl. Stroke Res. 6, 224–233 (2015). https://doi.org/10.1007/s12975-015-0387-9

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  • DOI: https://doi.org/10.1007/s12975-015-0387-9

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