Contrast Enhanced Magnetic Resonance Imaging of Amyloid-β Plaques in a Murine Alzheimer's Disease Model

Abstract

Background: Early detection of amyloid-β (Aβ) aggregates is a critical step to improve the treatment of Alzheimer's disease (AD) because neuronal damage by the Aβ aggregates occurs before clinical symptoms are apparent. We have previously shown that luminescent conjugated oligothiophenes (LCOs), which are highly specific towards protein aggregates of Aβ, can be used to fluorescently label amyloid plaque in living rodents.

Objective: We hypothesize that the LCO can be used to target gadolinium to the amyloid plaque and hence make the plaque detectable by T1-weighted magnetic resonance imaging (MRI).

Methods: A novel LCO-gadolinium construct was synthesized to selectively bind to Aβ plaques and give contrast in conventional T1-weighted MR images after intravenous injection in Tg-APPSwe mice.

Results: We found that mice with high plaque-burden could be identified using the LCO-Gd constructs by conventional MRI.

Conclusion: Our study shows that MR imaging of amyloid plaques is challenging but feasible, and hence contrast-mediated MR imaging could be a valuable tool for early AD detection.

Keywords: Alzheimer’s disease; amyloid-β (Aβ); fluorescence; magnetic resonance imaging; multimodal imaging.

Fig. 1

The synthesis and resulting chemical structure of the product 3, LCO-DOTA-GD.

Fig. 2

Illustration of experimental sequence and acquired data. A) The age of the Tg-APPSwe mice was 18–30 months. They were pre-imaged, injected with LCO-DOTA, re-imaged 1, 3, and 7 days later. B) Images showing the T1-map, T1-weighted imaging, and the confocal microscopy imaging of the same brain section for wild type and Tg-APPSwe mice.

Fig. 3

Sections from the brain of 28 months old TgAPPSwe mice labelled in vivo with LCO-DOTA (green) and stained with an anti-amyloid plaque (4G8) antibody (red). The images show that the two stains label the same objects albeit at different binding sites.

Fig. 4

T1-values from MRI, compared with LCO fluorescence intensity from CLSM. A) average T1-values in different regions of the brain for middle-aged Tg-APPSwe mice, old Tg-APPSwe mice and wild type mice showing a reduction in T1-values for old mice. Error bars indicate S.E.M. B) T1-values versus fluorescence intensity from the somatosensory cortex and representative CLSM images from the animals of different age and plaque-burden. C) average T1-values vs age. D) Average fluorescence intensities vs age. E–H) average T1-values vs fluorescence intensities in the whole brain (E), entorhinal cortex (F), piriform cortex (G), and frontal region (H).