RESEARCH ARTICLE: Myelin Abnormalities without Oligodendrocyte Loss in Periventricular Leukomalacia

Abstract

The cellular basis of myelin deficits detected by neuroimaging in long-term survivors of periventricular leukomalacia (PVL) is poorly understood. We tested the hypothesis that oligodendrocyte lineage (OL) cell density is reduced in PVL, thereby contributing to subsequent myelin deficits. Using computer-based methods, we determined OL cell density in sections from 18 PVL and 18 age-adjusted control cases, immunostained with the OL-lineage marker Olig2. Myelination was assessed with myelin basic protein (MBP) immunostaining. We found no significant difference between PVL and control cases in Olig2 cell density in the periventricular or intragyral white matter. We did find, however, a significant increase in Olig2 cell density at the necrotic foci, compared with distant areas. Although no significant difference was found in the degree of MBP immunostaining, we observed qualitative abnormalities of MBP immunostaining in both the diffuse and necrotic components of PVL. Abnormal MBP immunostaining in PVL despite preserved Olig2 cell density may be secondary to arrested OL maturation, damage to OL processes, and/or impaired axonal-OL signaling. OL migration toward the "core" of injury may occur to replenish OL cell number. This study provides new insight into the cellular basis of the myelin deficits observed in survivors of PVL.

In vivo Magnetization Transfer MRI Shows Dysmyelination in an Ischemic Mouse Model of Periventricular Leukomalacia

“…We also found evidence of axonal injury in the corpus callosum in our model, similar to recent reports from autopsy cases of PVL (Billiards et al, 2008). Therefore, an alternative hypothesis can be offered here: The process of final differentiation and myelin synthesis of OPCs is orchestrated by a complex interaction between axons and these cells (Bozzali and Wrabetz, 2004).…”

“…These cells are prominent during the peak period of PVL (i.e., between 24 and 32 weeks gestational age) (Back et al, 2007). There are also data suggesting that surviving OPCs undergo maturational arrest in PWMI lesions: a recent autopsy study of premature infants detected numerous morphologically immature Olig-2-positive cells in PVL lesions, indicative of arrested differentiation (Billiards et al, 2008).…”

Microglia activation in the extremely preterm human brain

“…Of note, we found that a proportion of CD68-immunopositive cells expressed the marker Ki67 in the PVWM of the hemorrhage brains, indicating that proliferation contributes at least to a minor degree to the increased number of microglia. Our findings, however, support previous human studies in which a quick recruitment, migration, and transformation of microglia of hematopoietic origin to CD68-expressing microglia was suggested as being the main mechanism for the enhanced number of microglia (27). It is unclear how quickly CD45-immunopositive microglia There was evidence of increased apoptosis in the PVWM of the hemorrhage group, and with increased severity there was increased cell apoptosis, which was associated with axonal injury in the PVWM.…”

Neuroscience: The most vulnerable brains

“…It looked as if new oligodendrocyte precursors were migrating to the site of the injury to replace cells that had been destroyed by the stroke 4 . But something was stopping the precursors from developing into oligodendrocytes that produce myelin.…”