Joseph J. Volpe, MD
Director, MRRC
Bronson Crothers Professor of Neurology
Harvard Medical School
Neurologist-in-Chief
Children’s Hospital

MRRC Project(s)

P01 NS38475-01
Periventricular Leukomalacia in the Premature Infant - Program Director
(Co-PI, Projects 1 and 3 - see duPlessis and Rosenberg)

Brain injury in the premature infant is a clinical problem of great importance because of the large absolute number of affected infants encountered yearly in the United States. Periventricular leukomalacia (PVL) is the major form of brain injury in the premature infant. Prevention of this injury will require delineation of pathogenesis. Our work is addressed to the issue of pathogenesis and includes clinical and basic research.

The principal cellular target in PVL is the immature oligodendrocyte. The principal pathogenetic insult appears to be cerebral ischemia, a propensity for which is characteristic of the premature infant. An intrinsic vulnerability of the immature oligodendrocytes of the premature infant to even moderate ischemia is clear. Our basic research has been focussed on the cellular and molecular mechanisms underlying this intrinsic vulnerability. To address the basis of an intrinsic vulnerability of oligodendrocytes, we have studied this cell type in a defined system in culture, as described below. However, before undertaking these studies in depth, we set out to determine the specific stage in the oligodendroglial lineage present in the cerebral white matter of the human premature infant, as outlined below.

Our clinical research also is focused on PVL. PVL consists of two neuropathological components, i.e., focal periventricular necrosis with loss of all cellular elements and a more diffuse oligodendroglial-specific cerebral WM injury. The focal necroses are identified readily in vivo by cranial ultrasonography but the more diffuse injury is invisible to conventional imaging techniques. The deleterious effect of the focal necroses in cerebral WM is obvious but the impact of the more diffuse component, with loss of differentiating oligodendrocytes, i.e., myelin precursors, on subsequent development of WM is unknown. A considerable body of evidence indicates that although the pathogenesis of PVL is multifactorial, cerebral ischemia is probably the most important factor. Studies in animal models and clinical work in human infants suggest that a disturbance in cerebrovascular autoregulation can occur in some premature infants and thus lead to a propensity for cerebral ischemia with modest decreases in mean arterial blood pressure (MAP), so common in these labile sick infants. Thus, our clinical research has had three major objectives: (1) delineation of the role of impaired cerebrovascular autoregulation in premature infants in the genesis of (a) alterations in cerebral blood flow (CBF) and (b) the occurrence of PVL; (2) detection of the diffuse oligodendroglial-specific component of PVL in the neonatal period; and (3) identification of the impact of PVL on subsequent development of brain.