White matter injury in the preterm infant: pathology and mechanisms

Abstract

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.

White matter properties associated with pre‐reading skills in 6‐year‐old children born preterm and at term

“…Preterm birth was defined as gestational age at 32 weeks or earlier (22–32wks; 470–2180g). This criteria for defining prematurity was used to capture children at greatest risk for white matter injury . Term birth was defined as gestational age at 37 weeks or later or birthweight greater than or equal to 2500g (36–42wks; 2720–4370g).…”

Origin and dynamics of oligodendrocytes in the developing brain: Implications for perinatal white matter injury

“…Various pathological mechanisms have been proposed to contribute to impaired OL maturation in diffuse WMI. For instance, inflammatory mediators negatively affect OL development (van Tilborg et al, ), but also changes in regulatory pathways such as the Daam2/Wnt/β‐catenin and Notch pathways may contribute to impeded OL maturation in preterm infants (Back, ; Fancy et al, ; John et al, ; Lee et al, ). Increased activation of JNK signaling in response to perinatal insults has also been implicated in neonatal WMI (Wang, Tu, Huang, & Ho, ; Wang et al, ).…”

Umbilical cord blood stem cell therapy in premature brain injury: Opportunities and challenges

“…However, this has led to increased incidence of perinatal brain injuries, especially in extremely preterm infants with gestational age less than 28 weeks (Serenius et al, ). White matter injury (WMI) and intraventricular hemorrhage (IVH) are the predominant forms of preterm brain injury (Back, ). About half of preterm infants with WMI suffer from long‐term cognitive, behavioral, and/or mental deficits (Volpe, ), and periventricular leukomalacia (PVL), a severe form of WMI, as well as severe IVH (grade ≥3), can cause a series of neurodevelopmental disorders (Bolisetty et al, ).…”