MRI contrast for molecular and cellular imaging of the brain

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

There continues to be increasing interest in developing molecular imaging approaches that enable traditional radiological imaging techniques to obtain a wide range of information about molecular and cellular processes. A range of information is considered important such as the ability to monitor cell migration, the development of reporters that enable imaging of gene expression, the development of robust strategies to image receptors, and the development of environmentally sensitive agents that can be used to detect the presence of specific enzymes or monitor changes in ion status. The long term goals of this work are to develop strategies that enable MRI contrast that is sensitive to a wide range of molecular and cellular processes. This work builds on over 30 years of work where we have demonstrated the first MRI strategy for detecting gene expression, the first MRI approach for monitoring a surrogate of calcium influx, the first MRI approach for performing neuronal track tracing, and the first MRI approach for monitoring the migration of single cells in vivo. These all represented initial reports by any radiological imaging technique which enabled measurement of these processes and are finding widespread application to imaging pre-clinical disease model. We have made progress in the specific aims. Aim 1: Develop iron oxide based contrast for labeling and imaging the migration of cells. Over the past few years we have demonstrated the unique advantages of micron sized iron oxide particles for MRI of specific cells. Single cells can be detected and indeed, single particles within single cells can be detected. The ability to detect a single particle enables inefficient labeling strategies. In particular, over the past few years we have demonstrated that injection of particles into the ventricles of the rat brain enables particles to be taken up by neural precursors in the sub-ventricular zone and MRI can monitor the migration of cells to the olfactory bulb. Previously, we have measured the changes in migration of groups of new neurons during unilateral nasal occlusion and recovery showing that the was exquisite coupling between bulb anatomy and cell migration both during nasal block and recovery. Over the period year we have demonstrated the gain of using microfabricated iron particles rather than the micron particles we have used in the past. These microfabricated particles are enabling sensitive detection of single cells as they migrate from the sub-ventricular zone into the rodent olfactory bulb opening a range of interesting experiments. A manuscript is being prepared that has followed the trajectories of individual cells along the migratory pathway to the bulb in normal and naris occluded mice. The trajectories are quite complex with some cells migrating continuously to the bulb some stopping and going, and most interestingly some changing directions and some continuously migrating the wrong direction! This is all affected by naris occlusion. Thus, there is a world of complexity underlying migratory patterns in vivo that will open many interesting questions. We have demonstrated unique potential for magnetocaloric materials for MRI contrast agents. We have gotten a magnetic field shifter working that will enable us to change fields up to 1 Tesla in the MRI magnet which is sufficient to switch these materials from low to high magnetic moment and back again. Preliminary measurements have been made proving this approach will enable very specific detection of single micron scale magnetocaloric particles. Over the next period we will determine if we can label cells and detect them specifically with the combination of the Tesla shifter and the magnetocaloric particles. We have begun to use antibody labeled micron particles to sensitively detect vessel inflammation. We have the sensitivity to detect inflammation at the level of single vessels. We have established positive controls to label normal vessels and have shown we can see vessel inflammation due to LPS. In both cases competing with antibody alone competes for the MRI contrast indicating specificity. Over the next year we will optimize the protocol and begin to determine if we can see inflammation in disease models that have small affects such as neurodegeneration models and short-term feeding of high fat diet. There is little data about inflammation of brain vessels. We are attempting to detect early stages of inflammation and use MRI to guide histology to understand the mechanisms involved. We are helping the Reich group that is attempting similar work to detect early vessel inflammation in animal models of inflammation. There is much interest in imaging neuroinflammation, and our hypothesis is that brain inflammation will be reflected in vessel inflammation even at the very early stages. Aim 2: Develop novel MRI contrast for imaging the brain. We have focused this work on developing a new approach to making an MRI reporter strategy similar to GFP for light microscopy. For over 30 years there have been numerous and clever approaches to solving this problem. Unfortunately, none have risen to widespread use in pre-clinical (or clinical) models. We have demonstrated that the transporter ZIP14 can be used to alter MRI contrast very significantly in a way that is consistent with it being a dominant Mn2+ transporter. Expression of ZIP14 in neurons (and astrocytes) leads to readily detectable MRI contrast without the need to add any contrast agent. The sensitivity is sufficient to detect anterograde projections from specific sites of expression. Retrograde viruses lead to strong expression at sites that project to areas of injection. This is very exciting and should enable us to shift from using direct injection of Mn2+ or other chemical MRI neural tracers to follow changes in neural connectivity over time in individual animals. Over the next year we will try and optimize MRI techniques to visualize as well as other strategies to increase sensitivity especially for detecting anterograde projections. We will test the usefulness for imaging other cell types as well.