Magnetic Resonance Imaging of Mouse Cerebral Cavernomas Reveal Differential Lesion Progression and Variable Permeability to Gadolinium

Abstract

Background: Cerebral cavernous malformations, also known as cavernous angiomas, are blood vessel abnormalities comprised of clusters of grossly enlarged and hemorrhage-prone capillaries. The prevalence in the general population, including asymptomatic cases, is estimated to be 0.5%. Some patients develop severe symptoms, including seizures and focal neurological deficits, whereas others remain asymptomatic. The causes of this remarkable presentation heterogeneity within a primarily monogenic disease remain poorly understood. Methods: We established a chronic mouse model of cerebral cavernous malformations, induced by postnatal ablation of Krit1 with Pdgfb - CreERT , and examined lesion progression in these mice with T2-weighted 7T magnetic resonance imaging (MRI). We also established a modified protocol for dynamic contrast-enhanced MRI and produced quantitative maps of gadolinium tracer gadobenate dimeglumine. After terminal imaging, brain slices were stained with antibodies against microglia, astrocytes, and endothelial cells. Results: These mice develop cerebral cavernous malformations lesions gradually over 4 to 5 months of age throughout the brain. Precise volumetric analysis of individual lesions revealed nonmonotonous behavior, with some lesions temporarily growing smaller. However, the cumulative lesional volume invariably increased over time and after about 2 months followed a po wer trend. Using dynamic contrast-enhanced MRI, we produced quantitative maps of gadolinium in the lesions, indicating a high degree of heterogeneity in lesional permeability. MRI properties of the lesions were correlated with cellular markers for endothelial cells, astrocytes, and microglia. Multivariate comparisons of MRI properties of the lesions with cellular markers for endothelial and glial cells revealed that increased cell density surrounding lesions correlates with stability, whereas denser vasculature within and surrounding the lesions may correlate with high permeability. Conclusions: Our results lay a foundation for better understanding individual lesion properties and provide a comprehensive preclinical platform for testing new drug and gene therapies for controlling cerebral cavernous malformations.

Focused Ultrasound Blood-Brain Barrier Opening Arrests the Growth and Formation of Cerebral Cavernous Malformations

“…two FUS BBBO treatments staged three days apart). Mice were treated between 2 and 3 months of age, a period of rapidly escalating lesion burden 32 . Male and female mice across 9 litters were used ( Table S1 ), and MR images were acquired following each sonication and up to one month thereafter ( Figure 6A, C, E ).…”

“…Even susceptibility-weighted images, which have an increased sensitivity to blood products, demonstrated no acute changes in bleeding between the pre- and post-sonication images ( Figure 2D, E ). T2-weighted spin echo sequences, which can accurately represent lesion volume and internal architecture 32 , displayed no acute changes in lesion volume between the pre- and post-sonication images ( Figure 2B, C ). These results also continued for post-sonication images at later timepoints of up to one month, indicating that FUS BBBO is safe for CCMs both acutely and chronically.…”

“…Mice were housed under standard laboratory conditions (22°C and 12h/12h light/dark cycle). The generation of the CCM murine models ( Pdgfb-CreERT2;Krit1 fl/null or Cdh5-CreERT2;Krit1 fl/null ) that were used in these studies has been described previously 32 . Briefly, Pdgfb-CreERT2 or Cdh5-CreERT2 mice were crossed with Krit1 fl/null male or females.…”