Improving Delivery and Labeling Efficiency of MRI Probes for Alzheimer's Plaques

This project aims to develop safe MRI molecular probes to visualize amyloid ß (Aß) plaques, one of the earliest pathological hallmark of Alzheimer’s disease that can only be confirmed by post-mortem examination of the brain. New and future therapeutic approaches may be most effective in preventing the irreversible neuronal damage when employed early in the progression of the disease. This project seeks to develop tools allowing for early diagnosis.

Our group has undertaken the task to develop safe MRI molecular probes to visualize amyloid ß (Aß) plaques, one of the earliest pathological hallmark of Alzheimer’s disease that can only be confirmed by post-mortem examination of the brain. The early diagnosis of this slow neurodegenerative disease that leads to dementia and death, would be critical when new and future therapeutic approaches may be most effective in preventing the irreversible neuronal damage. Transgenic mice that develop Aß plaques similar to AD patients are now being used to test experimental approaches for amyloid clearance. We were the first to demonstrate that magnetically labeled peptides could be used to detect Aß plaques in the brain of living mice with MRI. The goal of this proposal is to further improve the means of delivery of our MRI probes as well as their magnetic labeling efficiency. We wish to implement a minimally invasive injection approach while maintaining the shortest injection route to the brain by the use of an ultrasound-guided intra-cardiac injection. We also hypothesize that the pre-opening of the blood-brain-barrier prior to the infusion of our construct and the use of paramagnetic agent with stronger contrast effect will increase the plaque population visualized. Furthermore, increasing the relatively short plasma half-life of our constructs (currently few minutes) will increase their recirculation and diffusion throughout the brain thereby improving their delivery across the entire brain. Our aims are to visualize the AD plaques with a higher specificity and sensitivity by refining the characteristics of the label while assessing the safety and effectiveness of the approach in mouse models of AD. In essence, the work proposed will serve as the basis for establishing a safer and more efficient animal protocol that could be utilized routinely to better understand the role of amyloidosis as well as to test current and new anti-amyloid therapies before their examining in humans.

Progress Updates

Our overall goal is to develop magnetic resonance imaging (MRI) approaches that will be used as a research tool to test the efficacy of pre-clinical treatments for Alzheimer’s disease. MRI is a medical imaging technique that measures internal, soft tissue structures in the body, using powerful magnetic forces to align the hydrogen atoms found in the water.

In this funded project, we investigate the use of targeted MRI contrast agents to detect lesions in living mice that model one of the pathological hallmarks of Alzheimer’s disease. At the moment, histology (looking at brain tissue after death) is the only gold standard method for the assessment of therapeutic efficacy in animal models. However, it cannot measure changes from baseline to treatment endpoint as is done in human therapeutic trials. In addition, large numbers of mice are needed to achieve statistical significance due to the intrinsic variation in plaque load in these models. The MRI method we have developed enables the visualization of Alzheimer’s plaques in living mice. However, our approach needs further improvement on a means of delivery of our MRI probes, as well as their labeling efficiency.

We have focused most of our efforts in making our approach safer while testing the potential increase in sensitivity provided by stronger magnetic probes. Part of the new results obtained from testing the stronger probes for plaque visualization in mice were presented at the 2008 International Conference of Magnetic Resonance in Medicine, demonstrating the expected increase in imaging sensitivity. These findings are currently being finalized for publication. We have also successfully implemented an alternative surgical procedure in substitution of our current intra-carotid injection. The new ultrasound image-guided intracardial infusion method has enabled considerable improvement in the survival and morbidity rates of the mice.