Intracerebral gadolinium deposition following blood-brain barrier disturbance in two different mouse models

Abstract

To evaluate the influence of the blood-brain barrier on neuronal gadolinium deposition in a mouse model after multiple intravenous applications of the linear contrast agent gadodiamide. The prospective study held 54 mice divided into three groups: healthy mice (A), mice with iatrogenic induced disturbance of the blood-brain barrier by glioblastoma (B) or cerebral infarction (C). In each group 9 animals received 10 iv-injections of gadodiamide (1.2 mmol/kg) every 48 h followed by plain T1-weighted brain MRI. A final MRI was performed 5 days after the last contrast injection. Remaining mice underwent MRI in the same time intervals without contrast application (control group). Signal intensities of thalamus, pallidum, pons, dentate nucleus, and globus pallidus-to-thalamus and dentate nucleus-to-pons ratios, were determined. Gadodiamide complex and total gadolinium amount were quantified after the last MR examination via LC-MS/MS and ICP-MS. Dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios showed no significant increase over time within all mice groups receiving gadodiamide, as well as compared to the control groups at last MR examination. Comparing healthy mice with group B and C after repetitive contrast administration, a significant SI increase could only be detected for glioblastoma mice in globus pallidus-to-thalamus ratio (p = 0.033), infarction mice showed no significant SI alteration. Tissue analysis revealed significantly higher gadolinium levels in glioblastoma group compared to healthy (p = 0.013) and infarction mice (p = 0.029). Multiple application of the linear contrast agent gadodiamide leads to cerebral gadolinium deposition without imaging correlate in MRI.

Figure 1

Experimental scheme for mouse groups B (glioblastoma) and C (infarction, MCAO) showing the course of blood–brain barrier disturbance over time.

Figure 2

Contrast enhanced T1 weighted MRI of control group and mice after induction of glioblastoma or infarction, respectively. In healthy mice, the contrast agent cannot pass the blood–brain barrier. In case of cerebral tumor or infarction, however, the barrier is disrupted, resulting in enhancement of damaged tissue (red marking).

Figure 3

Mean globus pallidus-to-thalamus and dentate nucleus-to-pons ratios and 95%-interval at baseline (T₀) and last MR examination (T₁₀) among the different groups A healthy mice, B glioblastoma mice and C cerebral infarction mice.