Improving Delivery And Labeling Efficiency Of MRI Probes For Alzheimer's Plaques

Project Summary

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.