MR imaging correlates of white-matter pathology in a preterm baboon model

Griffith, Jennifer L; Shimony, Joshua S.; Cousins, Stephanie A.; Rees, SM; McCurnin, Donald; Inder, Terrie E.

doi:10.1038/pr.2011.33

Cited by 36 publications

(33 citation statements)

References 41 publications

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“…Despite the greater expense and challenges of nonhuman primate or preterm fetal sheep models, they provide access to forms of white matter pathology that more closely approximate that seen in human preterm survivors [10, 77]. Large pre-clinical animal models also provide access to study gyrencephalic white matter, which more closely approximates the human connectome.…”

Section: Chronic Wmi: What Is the Potential For Regeneration And Repair?mentioning

confidence: 99%

White matter injury in the preterm infant: pathology and mechanisms

2017

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The human preterm brain is particularly susceptible to cerebral white matter injury (WMI) that disrupts the normal progression of developmental myelination. Advances in the care of preterm infants have resulted in a sustained reduction in the severity of WMI that has shifted from more severe focal necrotic lesions to milder diffuse WMI. Nevertheless, WMI remains a global health problem and the most common cause of chronic neurological morbidity from cerebral palsy and diverse neurobehavioral disabilities. Diffuse WMI involves maturation dependent vulnerability of the oligodendrocyte (OL) lineage with selective degeneration of late oligodendrocyte progenitors (preOLs) triggered by oxidative stress and other insults. The magnitude and distribution of diffuse WMI is related to both the timing of appearance and regional distribution of susceptible preOLs. Diffuse WMI disrupts the normal progression of OL lineage maturation and myelination through aberrant mechanisms of regeneration and repair. PreOL degeneration is accompanied by early robust proliferation of OL progenitors that regenerates and augments the preOL pool available to generate myelinating OLs. However, newly generated preOLs fail to differentiate and initiate myelination along their normal developmental trajectory despite the presence of numerous intact-appearing axons. Disrupted preOL maturation is accompanied by diffuse gliosis and disturbances in the composition of the extracellular matrix and is mediated in part by inhibitory factors derived from reactive astrocytes. Signaling pathways implicated in disrupted myelination include those mediated by Notch, WNT-beta catenin and hyaluronan. Hence, there exists a potentially broad but still poorly defined developmental window for interventions to promote white matter repair and myelination and potentially reverse the widespread distrubances in cerebral gray matter growth that accompany WMI.

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Section: Chronic Wmi: What Is the Potential For Regeneration And Repair?mentioning

confidence: 99%

White matter injury in the preterm infant: pathology and mechanisms

2017

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“…A baboon model born at approximately 70% gestation and cared for in a neonatal intensive care unit under conditions attempting to mimic those of the human infant (Inder et al, 2005, Griffith et al, 2012) leads to white matter injury and intraventricular hemorrhages in some animals. Notably, this model does not involve any inflicted injury per se, but rather routine neonatal care with ventilatory support.…”

Section: Modeling White Matter Injury In the Laboratory (Pre-clinicalmentioning

confidence: 99%

The challenge of understanding cerebral white matter injury in the premature infant

Elitt

Rosenberg

2014

Neuroscience

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White matter injury in the premature infant leads to motor and more commonly behavioral and cognitive problems that are a tremendous burden to society. While there has been much progress in understanding unique vulnerabilities of developing oligodendrocytes over the past 30 years, there remain no proven therapies for the premature infant beyond supportive care. The lack of translational progress may be partially explained by the challenge of developing relevant animal models when the etiology remains unclear, as is the case in this disorder. There has been an emphasis on hypoxia-ischemia and infection/inflammation as upstream etiologies, but less consideration of other contributory factors. This review highlights the evolution of white matter pathology in the premature infant, discusses the prevailing proposed etiologies, critically analyzes a sampling of common animal models and provides detailed support for our hypothesis that nutritional and hormonal deprivation may be additional factors playing critical and overlooked roles in white matter pathology in the premature infant.

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“…Instrumentation of the preterm nonhuman primate fetus carries a high risk for premature birth. Although controlled preterm delivery of the nonhuman primate fetus is feasible, neuropathological studies in preterm animals require ventilator support in an intensive care setting [31]. During prolonged ventilation, preterm baboons, for example, sustain disturbances in brain growth and development that make the interpretation of neuropathological studies more challenging [32][33][34].…”

Section: Advantages and Disadvantages Of The Fetal Sheep To Model Wmimentioning

confidence: 99%

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

et al. 2012

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Despite advances in neonatal intensive care, survivors of premature birth remain highly susceptible to unique patterns of developmental brain injury that manifest as cerebral palsy and cognitive-learning disabilities. The developing brain is particularly susceptible to cerebral white matter injury related to hypoxia-ischemia. Cerebral white matter development in fetal sheep shares many anatomical and physiological similarities with humans. Thus, the fetal sheep has provided unique experimental access to the complex pathophysiological processes that contribute to injury to the human brain during successive periods in development. Recent refinements have resulted in models that replicate major features of acute and chronic human cerebral injury and have provided access to complex clinically relevant studies of cerebral blood flow and neuroimaging that are not feasible in smaller laboratory animals. Here, we focus on emerging insights and methodologies from studies in fetal sheep that have begun to define cellular and vascular factors that contribute to white matter injury. Recent advances include spatially defined measurements of cerebral blood flow in utero, the definition of cellular maturational factors that define the topography of injury and the application of high-field magnetic resonance imaging to define novel neuroimaging signatures for specific types of chronic white matter injury. Despite the higher costs and technical challenges of instrumented preterm fetal sheep models, they provide powerful access to clinically relevant studies that provide a more integrated analysis of the spectrum of insults that appear to contribute to cerebral injury in human preterm infants.

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MR imaging correlates of white-matter pathology in a preterm baboon model

Cited by 36 publications

References 41 publications

White matter injury in the preterm infant: pathology and mechanisms

White matter injury in the preterm infant: pathology and mechanisms

The challenge of understanding cerebral white matter injury in the premature infant

The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

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