In vivo amyloid plaque detection using contrast-enhanced magnetic resonance microscopy in transgenic mice

Background: Amyloid plaques have previously been identified in mouse models of Alzheimer's disease (AD) using magnetic resonance microscopy. Because of their high iron content, plaques typically appear as hypointense spots on T2-weighted scans. One of the challenges in imaging plaques is to achieve high-enough resolution and contrast to detect these 50-μm large lesions. While most high-field systems can reach high resolution, the lack of contrast between the plaques and the parenchyma often impedes their detection. Methods: Transgenic mice over-expressing mutations of the human genes responsible for familial forms of AD were studied. A total of eight APP/PS1 mice and seven wild-type mice were used for the in vivo study. The mice were injected in the lateral ventricles with a non-specific gadolinium(Gd)-based contrast agent (CA). Within 6 hours after injections, the animals were imaged in a 7 T Siemens system (Syngo MR VB15) using a 3D turbo spin-echo sequence (resolution = 50×50×200 μm, scan time = 2.5 hours). A total of six APP mice were used for the ex vivo study where the extracted brains were fixed and stained with a Gd CA for at least 24 hours, then imaged (3D FLASH gradient-echo sequence, resolution = 65×65×200 μm and scan time = 1 hour, or resolution = 23×23×90 μm and scan time = 12 hours). Results: There was a continuous diffusion of the CA into the parenchyma for up to 40 min after injection, until it reached a plateau and remained in the brain for at least 5 hours. The images showed that prior to injection of CA, no plaques were detectable in the cortex or hippocampus, whereas some were clearly visible after injection of CA. The ex vivo results showed that 50-μm large plaques could be detected after staining with the CA. However, individual plaques were only well-defined at high resolution, enabling quantification of the plaque load which was about 10% in the cortex. Conclusions: This study shows that amyloid plaques can be detected both in vivo and ex vivo using a non-specific Gd-contrast agent. The level of detail achieved should be sufficient for pharmacology studies.