Systems biology and proteomic analysis of cerebral cavernous malformation.

UNLABELLED: Cerebral cavernous malformations (CCM) are vascular anomalies caused by mutations in genes encoding KRIT1, OSM and PDCD10 proteins causing hemorrhagic stroke. We examine proteomic change of loss of CCM gene expression. Using human umbilical vein endothelial cells, label-free differential protein expression analysis with multidimensional liquid chromatography/tandem mass spectrometry was applied to three CCM protein knockdown cell lines and two control cell lines: ProteomeXchange identifier PXD000362. Principle component and cluster analyses were used to examine the differentially expressed proteins associated with CCM. The results from the five cell lines revealed 290 and 192 differentially expressed proteins (p < 0.005 and p < 0.001, respectively). Most commonly affected proteins were cytoskeleton-associated proteins, in particular myosin-9. Canonical genetic pathway analysis suggests that CCM may be a result of defective cell-cell interaction through dysregulation of cytoskeletal associated proteins. CONCLUSION: The work explores signaling pathways that may elucidate early detection and novel therapy for CCM.

Evaluation of iron content in human cerebral cavernous malformation using quantitative susceptibility mapping.

OBJECTIVES: The aims of this study were to investigate and validate quantitative susceptibility mapping (QSM) for lesional iron quantification in cerebral cavernous malformations (CCMs). MATERIALS AND METHODS: Magnetic resonance imaging studies were performed in phantoms and 16 patients on a 3-T scanner. Susceptibility weighted imaging, QSM, and R2* maps were reconstructed from in vivo data acquired with a 3-dimensional, multi-echo, and T2*-weighted gradient echo sequence. Magnetic susceptibility measurements were correlated to susceptibility weighted imaging and R2* results. In addition, iron concentrations from surgically excised CCM lesion specimens were determined using inductively coupled plasma mass spectrometry and correlated with QSM measurements. RESULTS: The QSM images demonstrated excellent image quality for depicting CCM lesions in both sporadic and familial cases. Susceptibility measurements revealed a positive linear correlation with R2* values (R(2) = 0.99 for total, R(2) = 0.69 for mean; P < 0.01). Quantitative susceptibility mapping values of known iron-rich brain regions matched closely with those of previous studies and in interobserver consistency. A strong correlation was found between QSM and the concentration of iron phantoms (0.925; P < 0.01), as well as between QSM and mass spectroscopy estimation of iron deposition (0.999 for total iron, 0.86 for iron concentration; P < 0.01) in 18 fragments of 4 excised human CCM lesion specimens. CONCLUSIONS: The ability of QSM to evaluate iron deposition in CCM lesions was illustrated via phantom, in vivo, and ex vivo validation studies. Quantitative susceptibility mapping may be a potential biomarker for monitoring CCM disease activity and response to treatments.

Intracranial lesions with high signal intensity on T1-weighted MR images: differential diagnosis.

Various substances, including methemoglobin, melanin, lipid, protein, calcium, iron, copper, and manganese, are responsible for the intrinsically high signal intensity observed in intracranial lesions at T1-weighted magnetic resonance (MR) imaging. Many of these substances have physical properties that lead to other specific imaging features as well. For example, lipid-containing lesions frequently produce chemical shift artifact, and some melanin-containing lesions exhibit a combination of high signal intensity on T1-weighted images and low signal intensity on T2-weighted images. The location and extent of a region of abnormal signal hyperintensity may be helpful for identifying rare diseases such as an ectopic posterior pituitary gland near the floor of the third ventricle, bilateral involvement of the dentate and lentiform nuclei in Cockayne syndrome, and involvement of the anterior temporal lobe and cerebellum in neurocutaneous melanosis. In cases in which diagnostically specific T1-weighted imaging features are lacking, findings obtained with other MR pulse sequences and other modalities can help narrow the differential diagnosis: An elevated glutamine or glutamate level at MR spectroscopy is suggestive of hepatic encephalopathy; a popcorn ball-like appearance at T2-weighted imaging, of cavernous malformations; and hyperattenuation at computed tomography, of mineral deposition disease. In many cases, a comparison of imaging features with clinical measures enables a specific diagnosis.