Patterns and pathways of calcification in the developing brain

Abstract

To determine specific cell types and pathways involved in calcification of the developing brain. We examined the detailed histopathology of samples from 28 autopsied brains aged from 22 weeks' gestation to 14 years. The samples were selected because they showed calcification associated with a range of different diseases. Samples were examined with routine stains as well as stains to show calcification and specific markers for endothelium and macrophages. Our observations indicate that calcification develops via two main pathways: dystrophic and vascular. Dystrophic calcification results from membrane disruption and uncontrolled calcium entry into necrotic (dead) cells in ischaemia and infections. Vascular calcification appears to be initiated in protein globules, sometimes intracellular, but outside the endothelium of small vessels. One case with mutation of the occludin gene, implicating impaired endothelial integrity, showed this pattern, but identical vascular calcification was seen in other conditions, including Sturge-Weber syndrome. Another form of vascular calcification involved the adventitia of arteries; the endothelium was always spared. Calcification in the developing brain that is not associated with tissue necrosis is initiated in cells associated with blood vessels. Calcium incrustation of blood vessels imposes rigidity, reduced vascular compliance, and altered permeability. This would explain associated atrophy, gliosis, and (in the developing brain) malformations of the cortex. Our findings suggest that pericytes initiate non-dystrophic brain calcification, but further studies are needed to explore this possibility.