MR imaging for monitoring therapeutic response in live mice

Alzheimer’s disease (AD) not only leads to memory loss and dementia, but patients become “lost” to their family and friends. This makes AD one of the scariest diagnoses. Currently there are no cures for AD. Current treatments offer only minor benefits and remain mostly palliative in nature. Discovery of new AD therapeutics is impeded by the extended nature of AD development along with the need for postmortem histological analysis for efficacy testing in clinical trials. Therefore, non-invasive technologies that can detect and monitor AD pathologies earlier, such as amyloid plaques, in live patients are required for more rapid discovery of effective AD therapeutics. A new study in NeuroReport (Kim et al. 2014) describes a voxel (volume + pixel)-based analysis of magnetic resonance (MR) images for detection of amyloid plaques and monitoring therapeutic response in live mice.

Voxel-based analysis for monitoring of amyloid plaques in live AD mice

Previous work demonstrated that hollow manganese oxide nanoparticles conjugated to Aβ40 peptide antibodies (HMON-abAβ40) effectively bind to amyloid plaques in B6C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax (034829-JAX) mice (also known as APP/PS1 mice), allowing visualization of the plaques by MR imaging. The current report focuses on using a voxel-based analysis of MR images from APP/PS1 mice to not only detect plaques but monitor plaque size changes in response to therapeutic drug treatment.

Normalized MR signal intensities (voxels) from wild type (WT) and APP/PS1 mice did not differ prior to HMON-abAβ40 injection (D-1). At one day (D+1) and three days (D+3) following HMON-abAβ40 injection, the APP/PS1 mice displayed significantly higher normalized signal intensity in the frontal cortex and hippocampus at D+1 and D+3. WT mice never had significantly higher voxels than the APP/PS1 mice at any of the three time points.

APP/PS1 mice treated with DAPT, a widely used AD therapeutic in mice, show decreased amyloid plaque production. Untreated APP/PS1 mice show significantly higher voxels in the frontal cortex and hippocampus than DAPT-treated AD mice at D+1 and D+3 post HMON-abAβ40 injection and there were no significant differences at D-1, prior to HMON-abAβ40 injection. After comparing the difference in signal intensity from WT vs. APP/PS1 mice to APP/PS1-treated vs. APP/PS1-untreated mice, the intensity of voxels in frontal cortex plaques was found to be reduced to near wild type levels in the drug-treated mice. The data represented by voxels was confirmed histologically by thioflavin staining, validating this method for in vivo tracking of plaque development.

The novel voxel-based MR image analysis represents a powerful, new, non-invasive technology for detecting amyloid plaques in live mice and monitoring the in vivo response of mice to new therapeutics. The data reported by Kim et al. has important implications for human AD patients because this imaging technology may enable tracking drug responses in real time, accelerating the drug-discovery process.