Advances in prenatal and neonatal care have significantly improved survival of the prematurely born infant, particularly the most immature. However, as these children approach school age, it is recognized that up to 50% face neurobehavioral challenges. The nature of the cerebral injury that underlies all of these neurobehavioral deficits is not yet fully understood, but common patterns of injury are found in the cerebral white matter including hemorrhage and cystic infarction known as periventricular leukomalacia (PVL). It is also increasingly recognized that there is primary or secondary injury in the cortical and deep gray matter and the hippocampus, which may relate to subsequent intellectual impairments. It is critical that we gain insight into how particular neonatal practices, such as respiratory support, may alter the nature and the severity of cerebral injury in these vulnerable infants. In this study we propose to investigate the nature of cerebral injury in a prematurely born primate model (Papio sp) developed as a model of bronchopulmonary dysplasia, utilizing both magnetic resonance imaging (MR) and histopathology. Our hypothesis is that the prematurely born baboon (Papio sp) will display a pattern of cerebral injury, evident on MR imaging and histopathology, similar to that found in the prematurely born human infant. This pattern of injury will vary in relation to the nature of postnatal therapies, particularly randomized ventilatory strategies. For each of the specific aims the methodologies are identical and will utilize both state-of-the-art advanced MR imaging techniques and histopathological studies in all subjects. The advanced MR imaging techniques will include conventional MR imaging, quantitative volumetric 3-dimensional imaging and diffusion tensor imaging with collaborations between three-world class research MR sites (Washington University, Melbourne University and Harvard Medical School). The histopathology will include immuno-histochemistry including structural classification, cellular characteristics - neuronal and glial, and growth factor and biochemical development. Although histopathological techniques will be the cornerstone of defining the nature and severity of the cerebral injury, the MR studies will allow a direct comparison between this model and the human infant in whom identical protocols of advanced MR studies in vivo are being currently undertaken in our program. These studies may provide insight into the relationship of neonatal respiratory care to risk of cerebral injury, and thus direct us to the safest modes of ventilatory support for the immature brain.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074942-04
Application #
7246480
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Blaisdell, Carol J
Project Start
2006-06-01
Project End
2008-12-31
Budget Start
2007-06-01
Budget End
2008-12-31
Support Year
4
Fiscal Year
2007
Total Cost
$460,800
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Griffith, Jennifer L; Shimony, Joshua S; Cousins, Stephanie A et al. (2012) MR imaging correlates of white-matter pathology in a preterm baboon model. Pediatr Res 71:185-91
Rees, Sandra; Loeliger, Michelle; Shields, Amy et al. (2011) The effects of postnatal estrogen therapy on brain development in preterm baboons. Am J Obstet Gynecol 204:177.e8-14
Rees, Sandra; Harding, Richard; Walker, David (2011) The biological basis of injury and neuroprotection in the fetal and neonatal brain. Int J Dev Neurosci 29:551-63
Verney, Catherine; Rees, Sandra; Biran, Valérie et al. (2010) Neuronal damage in the preterm baboon: impact of the mode of ventilatory support. J Neuropathol Exp Neurol 69:473-82
Loeliger, Michelle; Shields, Amy; McCurnin, Donald et al. (2010) Ibuprofen treatment for closure of patent ductus arteriosus is not associated with increased risk of neuropathology. Pediatr Res 68:298-302
Rees, Sandra M; Loeliger, Michelle M; Munro, Kathryn M et al. (2009) Cerebellar development in a baboon model of preterm delivery: impact of specific ventilatory regimes. J Neuropathol Exp Neurol 68:605-15
Loeliger, Michelle; Inder, Terrie E; Dalitz, Penelope A et al. (2009) Developmental and neuropathological consequences of ductal ligation in the preterm baboon. Pediatr Res 65:209-14
Loeliger, Michelle; Inder, Terrie E; Shields, Amy et al. (2009) High-frequency oscillatory ventilation is not associated with increased risk of neuropathology compared with positive pressure ventilation: a preterm primate model. Pediatr Res 66:545-50
Archip, Neculai; Clatz, Olivier; Whalen, Stephen et al. (2008) Compensation of geometric distortion effects on intraoperative magnetic resonance imaging for enhanced visualization in image-guided neurosurgery. Neurosurgery 62:209-15;discussion 215-6
Kroenke, Christopher D; Van Essen, David C; Inder, Terrie E et al. (2007) Microstructural changes of the baboon cerebral cortex during gestational development reflected in magnetic resonance imaging diffusion anisotropy. J Neurosci 27:12506-15

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