Periventricular leukomalacia (PVL) is a developmental lesion of the cerebral white matter characterized by focal necrosis in the periventricular region. It is typically associated with diffuse white matter injury, characterized by activated microglia and reactive gliosis. Impaired myelination is a consequence of perinatal white matter injury and has been postulated to underlie, at least in part, neurological deficits in premature infants. The greatest period of risk (24-32 weeks) occurs when cerebral white matter is immature, i.e., when oligodendrocyte precursors are proliferating and differentiating, and before myelin sheaths are actively synthesized.
Although the pathogenesis of PVL likely involves multiple factors, e.g., ischemia, infection, cytokines, and oxidative stress, the correlation of the timing of the lesion with the dominance of developing oligodendrocytes in cerebral white matter suggests that intrinsic factors related to developing oligodendrocytes are critical. A key concept of this program project is that PVL results from ischemia/reperfusion that triggers free radical injury in vulnerable developing oligodendrocytes in perinatal white matter, and that, as a result, developing oligodendrocytes die, in part by apoptosis, thus resulting in decreased mature oligodendrocytes and impaired myelination. The overall hypothesis of this study is two-fold: 1) there is a specific vulnerability of developing oligodendrocytes to oxidative stress in the cerebral white matter in the period of greatest risk for PVL which relates, at least in part, to a mismatch between the development of the expression of antioxidant enzymes and the development of pro-oxidant pathways, such as the acquisition of iron necessary for oligodendrocyte differentiation; and 2) oxidative stress plays a major role in the pathogenesis of PVL.
Our specific aims address issues related to the maturation of cerebral white matter in the human fetus and infant, with a focus upon developmental factors that may put the fetal white matter at risk for injury. In addition, we are examining the role of oxidative and nitrative injury in the pathogenesis of oligodendrocyte injury in PVL. This latter research builds upon our previous findings that markers of oxidative and nitrative injury are increased in PVL, including in developing oligodendrocytes, the dominant population of oligodendrocytes in the fetal period, i..e., the period of greatest risk for PVL. We also are studying the cellular basis of associated gray matter injury.
