Manual Biological Calcification: Normal and Pathological Processes in the Early Stages

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This would explain associated atrophy, gliosis, and in the developing brain malformations of the cortex.


Calcification in the developing brain is common in both pathological and radiological practice. A recent large, systematic review has described radiological patterns of intracranial calcification in a number of known diseases, but in at least half of radiologically identified cases aetiology cannot be defined and no common pathogenetic mechanism has been suggested.

Calcification is seen in many conditions including hypoxic ischaemic injury HII , intrauterine infections, and in genetically determined conditions. More subtle micronodular calcification is a common autopsy finding in foetuses and neonates who may have diffuse white matter disease but sometimes have no other obvious pathology.

Some forms of brain calcification specifically involve blood vessels. The pathology is of calcification in cells close to blood vessels, sparing endothelium; associated polymicrogyria and cortical atrophy suggest ischaemia at multiple developmental stages, disrupting either corticogenesis or growth.

The role of the gasotransmitter hydrogen sulfide in pathological calcification

Calcium is essential for normal cell physiology and, under normal circumstances, homeostatic mechanisms tightly regulate intracellular calcium. When calcium or phosphate metabolism is disturbed calcium may be deposited in otherwise normal tissues. This is termed metastatic calcification. In dystrophic calcification, damaged cell membranes e. In this study we undertook a systematic analysis of the brains of foetuses, infants, and children with cerebral calcification in a range of different genetic and acquired conditions. We used immunohistochemistry in order to identify the specific cell types involved in the hope that this will indicate the probable mechanistic pathways.

Calcification appears histologically as basophilic blue in routine haematoxylin and eosin stains irregular and sometimes concentrically ringed concretions.

Biological Calcification | SpringerLink

The von Kossa method is frequently used to identify calcification, but it in fact labels phosphates rather than calcium. Cases were selected because they showed calcification associated with a range of different diseases.

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In all cases, sections were stained with haematoxylin and eosin, von Kossa, and immunohistochemical markers for endothelium CD34 and macrophages CD This group included cases with little or no other pathology. In this series one case had HII, two were cases of sudden death in epilepsy, and one case was a recent trauma. This group included two cases with intrauterine cytomegalovirus and one case with toxoplasmosis, 10 cases with perinatal or older HII, four cases with vein of Galen malformation VoG , and one case with established bilateral haemorrhagic middle cerebral artery territory infarcts and familial schizencephaly.

Calcification in necrotic brain associated with ischaemia was often in the cortex, particularly in the depths of cortical sulci or deep grey nuclei. More randomly scattered foci of necrosis involving all brain areas were seen in cases with an infectious aetiology.

In VoG it was widespread, most commonly involving the deep cortex and its junction with the white matter and the deep grey nuclei Fig. These cases had a history and other pathology of old ischaemic injury or infection Fig. Calcification was seen in the outer coats of the leptomeningeal arteries. The lumen was severely narrowed by intimal fibrosis Fig. Calcium was deposited in the parenchyma in small granules, often in rounded collections, possibly the remnants of blood vessels, and in areas of ischaemic necrosis dystrophic calcification.

Studying mineralization of the brain in foetuses and children allows description of the processes involved in the earliest stages, before dense mineralization and secondary gliosis obscure tissue pathology. We have studied calcification in a range of diseases including single cases with known or presumed genetic mutations that may suggest a mechanism of calcification.

There are technical limitations in the immunocytochemistry of calcified tissue. Small intracellular deposits do not stain well and may be obscured by immunocytochemical reaction products and their numbers underestimated. Calcification within a cell may have originated there or may have originated on an extracellular matrix and been phagocytosed, a property of macrophages, astrocytes and pericytes.

While calcification in the developing brain is well known, the literature is confusing and the classification erratic.

Atherosclerosis (2009)

Calcification has been classified topographically by radiology 1 and pathologically, based on proposed mechanisms such as primary and secondary or metastatic and dystrophic. While our initial classification was into five pathologically recognized patterns of calcification, further analysis indicates that these five patterns do not reflect the underlying pathways of calcification and that just two processes may account for all these patterns in the developing brain: 1 dystrophic, where injury to the cell membranes leads to influx of calcium, cell mineralization, and death; and 2 vascular, where mineralization appears to be initiated in protein droplets adjacent to, or within, the walls of small blood vessels.

The relative numbers of each pattern 18 cases of dystrophic, six vascular, and four micronodular do not reflect the incidence of these patterns of calcification in childhood.

Our cases were specifically selected to illustrate a range of diseases and the effects of age on calcification in the developing brain. They also reflect the frequency with which cases are available for autopsy study; those with calcification in known mutations are uncommon, whereas HII and congenital infections are relatively common.

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Eighteen of our cases had dystrophic calcification; the diagnoses were HII, intrauterine infections, VoG malformation, and haemorrhagic necrosis. Calcification of necrotic tissue, whatever the cause, is frequent in the immature brain and occurs within 8 to 14 days of injury. In the depths of sulci or deep grey nuclei it suggests ischaemia, but when scattered randomly or in a periventricular band an infectious aetiology is likely.

A fine dusting and coarser intracellular granules may represent calcium deposition in the cytoplasm or in mitochondria. When cells die, release of cytoplasmic granules may allow progression to larger extracellular concretions. Sparing of blood vessels is notable. Dystrophic calcification is described in tumours, tuberous sclerosis, and vascular and cortical malformations.

We observed single cell mineralization after ischaemia of grey matter, which conformed to classic descriptions. Occasionally, single calcified cells were seen within areas of acute necrosis, indicating that they are simply a category of dystrophic calcification. These cells may remain because they have withstood necrosis and avoided phagocytosis, or they may have succumbed to calcium ingress in an insult insufficient to cause the death of surrounding cells but resulting in gliosis.

The pathology in our single case with fetal haemorrhagic infarction and familial schizencephaly was of dystrophic calcification. Additionally, Ca and P concentrations from the osteogenic nodule body were also higher than that of cells. Interestingly, osteogenic calcification possessed a higher concentration of Ca and P than dystrophic calcification. AFM scans of live cells, dystrophic nodules, and osteogenic nodules provide a wide distribution of modulus values that we represent by taking the averaged median value for each cell or CN after multiple successful scans. Averaged modulus median values of kPa, kPa, and kPa were noted for cells, dystrophic nodules, and osteogenic nodules, respectively Fig.

No significant differences in modulus were found between the cell and CN groups suggesting that the nodule surfaces are comprised mostly of cellular material.

Cellular changes and adaptive responses

Live AVICs scans revealed largely homogeneous modulus properties, while certain regions of the osteogenic nodule body were similarly homogeneous Figs. However, osteogenic CN heterogeneity was noted as areas of the osteogenic nodule surface also contained significantly stiffer calcified spheres that were discernable via AFM Figs. Dystrophic calcification scans indicated a more variable modulus map corresponding to changes in topography, but the modulus values were not significantly different than that of AVICs and osteogenic nodules Figs.

Biomechanical analysis reveals nodule heterogeneity. Inset graph shows average median modulus and reveals no significant difference between sample groups; however, osteogenic nodules had bimodal distribution, which likely skews downward their overall stiffness. AVIC and osteogenic nodule body scans display consistent homogeneous modulus scans c and i while dystrophic nodules exhibit heterogeneous modulus scans f. Osteogenic nodules contain dramatically stiffer regions resembling spherical calcifications on the surface of the nodule body revealing the heterogeneous make up of osteogenic nodules.

Since the seminal study describing CNs, much research has been conducted to evaluate the molecular processes that mediate the formation and evolution of these nodules [ 16 ]. However, there has been a lack of clarity regarding the intrinsic physicochemical and biophysical properties of the CNs formed in vitro.

Characterization of these properties is necessary to provide the link between in vitro CN formation and in vivo valvular calcification and strengthen the impact of the findings from these in vitro systems. Additionally, the perception of CN formation has changed drastically in recent years from an understanding of one nodule expressing both dystrophic and osteogenic properties to distinct dystrophic and osteogenic nodules with specific properties [ 5 , 13—16 ].

Defining dystrophic and osteogenic nodule properties will help delineate characteristics unique to each nodule type and may provide important correlations between mechanistic information and biophysical properties. In this study, we sought to define the physicochemical and biophysical properties of dystrophic and osteogenic CNs formed via published in vitro systems. Dystrophic and osteogenic CNs generated in this study were assessed to ensure that they generated distinct nodules that corresponded with previous findings [ 13 , 19 ].

Osteogenic nodules formed after six days in calcifying media on compliant PA gels of 24 kPa. The whole nodule body stained positively for Calcein AM with no uptake of PI stain indicating viable cells.

Both nodules also stained positively for Alizarin red, a calcium stain. These results confirm that two unique nodule types consistent with dystrophic and osteogenic calcification were formed.