MRI contrast for molecular and cellular imaging of the brain

National Institute Of Neurological Disorders And Stroke

Investigators

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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 main paradigm for MRI of cell migration is to label cells ex vivo and monitor migration after transplantation into an animal. A project that images the entire brain to study immune brain interactions using MRI to detect small microbleeds and labeled T cells to follow immune cell infiltration after infection of the brain with VSV. This study has shown that VSV causes microbleeds independent of peripheral immune responses; that virus-specific T cells decrease microbleeds; and that early after viral infection, viral-specific T cells are detected at the site of microbleeds as well as remote sites where virus is produced prior to microbleeds. We have been able to image the initial influx of virus specific T cells prior to bleeding which should enable us to image the processes that lead to bleeding going forward. 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 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 past year we have demonstrated the gain of using microfabricated iron particles rather than the micro 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. These particles will be used for immune cell tracking and potentially for labeling brain vascular inflammation. We have demonstrated unique potential for magnetocaloric materials for MRI contrast agents. We have acquired a magnetic field shifter that will enable us to change fields sufficiently to switch these materials from high to low magnetic moment. Preliminary measurements are being made and we hope to prove this approach for robust use of magnetocaloric materials. We have also established collaborations to see if we can get micron scale magnetocaloric materials made to enable cellular imaging. Aim 2: Develop novel MRI contrast for imaging the brain. Over the past couple of years we have focused this work on increasing the sensitivity of measures of neural connectivity using MRI detectable neural tracing agents. We had shown that the classical neural tracer Cholera Toxin B (CTB) can trace with a small amount of MRI contrast attached. Adding more contrast inhibited the tracer. Therefore we increased the amount of contrast we could attach using a peptide designed to carry five Gd chelates and demonstrated increased detectability of the CTB tracer. Typically the field either adds more contrast to large MW proteins or makes nanoparticle contrast agents to get more contrast payload. This peptide strategy opens a door to increasing contrast payload while maintaining small sizes. We will continue to grow the peptide to see at what size we inhibit CTB tracing to continue to increase sensitivity. This work will be important for our goals of antibody targeting to vascular markers if we find the larger iron particles inhibit antibody antigen recognition.