Magnetic resonance imaging of amyloid plaques using hollow manganese oxide nanoparticles conjugated with antibody aβ1–40 in a transgenic mouse model

Abstract

In this study, we have shown the feasibility of hollow manganese oxide nanoparticles (HMON) conjugated with an antibody of Aβ1-40 peptide (abAβ40) (HMON-abAβ40) for MRI of amyloid plaques in APP/PS1 transgenic mice. MR brain images in APP/PS1 transgenic mice and their nontransgenic littermates were acquired using a 7.0 T MRI system before, and 24 and 72 h after an injection of HMON-abAβ40. After the injection of HMON-abAβ40, we found hyperenhanced spots in the frontal cortex area on T1-weighted MR images for transgenic mice, which corresponded qualitatively to amyloid plaques detected by thioflavin-S staining. For quantitative analysis, percent MR signal changes in six brain regions (olfactory cortex, frontal cortex, cerebral cortex, thalamus, hippocampus, and cerebellar cortex) were compared between transgenic and wild-type mice. We found significant increases in the percent MR signal changes in the olfactory cortex, frontal cortex, cerebral cortex, and hippocampus, but there were no significant differences in the thalamus and cerebellar cortex for transgenic mice compared with wild-type mice. This unique strategy allowed us to detect brain regions subjected to amyloid plaque deposition in Alzheimer's disease transgenic mouse models and has a potential to be developed for human applications, which has a current utility in preclinical research, particularly in monitoring therapeutic response for drug development in Alzheimer's disease.

A Novel Liposomal Nanoparticle for the Imaging of Amyloid Plaque by Magnetic Resonance Imaging

“…Assuming intravenous injection the agent would have to cross the blood-brain barrier (BBB), seek out the amyloid plaques, and then generate enough target signal compared to the background noise, to enable accurate detection. Previous efforts to develop an amyloid-targeting MRI agent have primarily focused on either proton T2[4–9] (capitalizing on the high T2 relaxivities of Iron oxide nanoparticles), or 19 F imaging [8,10–13], capitalizing on the extremely high signal-to-noise ratios achievable due to the absence of endogenous signal. High T2 relaxivities, however, lead to the suppression of overall signal, making it difficult to reliably quantitate the image (see for example Figure 4b in [8]).…”

“…Relatively few previous efforts to make a T1 agent for this application have been made [4,6,15], and to our knowledge, none have yet been successful in imaging plaques in vivo following intravenous injection. Kim et al demonstrated [10,11,16] a hollow manganese oxide nanoparticle targeted using the amyloid peptide as a targeting ligand. It was delivered by intracranial injection into the cisterna magna and did not have to negotiate the blood-brain barrier.…”

Magnetic resonance imaging for monitoring therapeutic response in a transgenic mouse model of Alzheimer’s disease using voxel-based analysis of amyloid plaques

“…In our previous work, we showed that hollow manganese oxide nanoparticles conjugated to antibodies of the Aβ40 peptide (HMON-abAβ40) accumulated and bound successfully to amyloid plaques, appearing as a hyperenhanced signal on T1-weighted MR images 14. In the continuing work of this report, we propose a voxel-based analysis of HMON-abAβ40-enhanced MR images not only for detecting amyloid plaques but also for monitoring therapeutic response in AD transgenic mice.…”

“…HMON-abAβ40 was used to target amyloid plaques in the APP/PS1 transgenic mouse brain 14. For the administration of MRI contrast agent, the mouse was anesthetized and the head of the mouse was fixed carefully using a bite/ear bar on a stereotaxic frame.…”

“…A spatial normalization was performed to ensure voxels’ correspondence between different mice for voxel-based analysis. We used a time-specific mouse template at D−1, D+1, and D+3, which was computed from the 14 mouse MR images in our previous study 14. The skull-stripped mouse brain images were spatially normalized to the time-specific mouse templates to avoid registration error induced by the time-specific enhancement of the contrast agent.…”