Human myelination and perinatal white matter disorders

Abstract

Human myelination progresses caudally to rostrally, beginning in the first trimester in the spinal cord, and continuing into the third decade in the intracortical fibers of the cerebral cortex. The most rapid changes occur between mid-gestation and the end of the second postnatal year. The major pediatric disorder of central white matter, periventricular leukomalacia (PVL), occurs during this critical developmental period, and is the predominant underlying substrate of cerebral palsy and other neurological handicaps in premature infants [ 1 Kinney H.C. Haynes R.L. Folkerth R.D. White matter lesions in the perinatal period. in: Golden J.A. Harding B. Pathology and genetics: acquired and inherited diseases of the developing nervous system. ISN Neuropathology Press, Basel2004: 156-170 Google Scholar , 2 Volpe J.J. Cerebral white matter injury in the premature infant—more common than you think. Pediatrics. 2003; 112: 176-180 Crossref PubMed Scopus (422) Google Scholar , 3 Kinney H.C. Armstrong D.L. Perinatal neuropathology. in: Graham D.I. Lantos P.E. Greenfield's neuropathology. 7th ed. Arnold, London2002: 557-559 Google Scholar ]. This disease affects the immature white matter of the cerebral hemispheres, and peaks at mid-to-late gestation, before cerebral white matter is myelinated. The focus of our laboratory is upon the delineation of the cellular and molecular pathology of PVL [ 4 Haynes R.L. Folkerth R.D. Keefe R.J. Sung I. Swzeda L.I. Rosenberg P.A. et al. Nitrative and oxidative injury to premyelinating oligodendrocytes in periventricular leukomalacia. J. Neuropathol. Exp. Neurol. 2003; 62: 441-450 Crossref PubMed Scopus (391) Google Scholar , 5 Folkerth R.D. Keefe R.J. Haynes R.L. Trachtenberg F.L. Volpe J.J. Kinney C. Interferon-γ expression in periventricular leukomalacia in the human brain. Brain Pathol. 2004; 14: 265-274 Crossref PubMed Scopus (89) Google Scholar ], and upon the regional, cellular, and biochemical sequences of human CNS myelination that are of major relevance to deciphering the pathogenesis of this devastating disorder [ 6 Brody B.A. Kinney H.C. Kloman A.S. Gilles F.H. Sequence of central nervous system myelination in human infancy: I. An autopsy study of myelination. J. Neuropathol. Exp. Neurol. 1987; 46: 283-301 Crossref PubMed Scopus (551) Google Scholar , 7 Kinney H.C. Brody B.A. Kloman A.S. Gilles F.H. Sequence of central nervous system myelination in human infancy: II. Patterns of myelination in autopsied infants. J. Neuropathol. Exp. Neurol. 1988; 47: 217-234 Crossref PubMed Scopus (607) Google Scholar , 8 Kinney H.C. Karthigasan J. Borenshteyn N.I. Flax J.D. Kirschner D.A. Myelination in the developing human brain: biochemical correlates. Neurochem. Res. 1994; 19: 983-996 Crossref PubMed Scopus (100) Google Scholar , 9 Back S.A. Luo N.L. Borenstein N.S. Levine J.M. Volpe J.J. Kinney H.C. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J. Neurosci. 2001; 21: 1302-1312 PubMed Google Scholar , 10 Back S.A. Luo N.L. Borenstein N.S. Volpe J.J. Kinney H.C. Arrested oligodendrocyte lineage progression during human cerebral white matter development: dissociation between the timing of progenitor differentiation and myelinogenesis. J. Neuropathol. Exp. Neurol. 2002; 61: 197-211 PubMed Google Scholar , 11 Folkerth R.D. Haynes R.L. Borenstein N.S. Belliveau R.A. Trachtenberg R. Rosenberg P.A. et al. Developmental lag of superoxide dismutases relative to other antioxidant enzymes in premyelinated human telencephalic white matter. J. Neuropathol. Exp. Neurol. 2004; 63: 999-1009 Google Scholar , 12 Haynes, R.L., Folkerth, R.D., Borenstein, N.S., et al. Axonal development in the cerebral white matter of the human fetus and infant. J Comp Neurol 2004 (In press). Google Scholar , 13 Billiards S. Haynes R.L. Folkerth R.D. Volpe J.J. Kinney H.C. The developmental profile of microglial density in the cerebral white matter of the human fetus and infant. Abstr.-Soc. Neurosci. 2004; : 609.19 Google Scholar ]. The over-riding hypothesis of our research is that premyelinating oligodendrocytes (pre-OLs) are the targeted cell population in PVL due to preferential vulnerability to free radical, glutamate, and cytokine toxicity in the developmentally immature white matter.