In FY '97, LDRR was transferred from the Office of Director, NIH to the Clinical Center. Magnetic resonance imaging (MRI) scans were performed on three Shaking Springer Spaniel Dogs (SD), a large animal model, that has significant diffuse hypomyelination of axons. Various MR imaging measures including single voxel spectroscopic imaging and magnetization transfer imaging were performed in the SD's of 6 weeks, 1 year, and 2 years of age along with age-matched control animals. Clearly delineated MRI findings were observed on routine imaging techniques including evidence of hydrocephalus as a result of white matter (WM) thinning in all SDs compared with normal controls. Hypomyelination resulted in a diffusely homogeneous hyperintensity to be observed in all white matter in the SD. Single voxel long and short echo time spectroscopy demonstrated essentially no differences in ratios of choline to creatine, n-acetylaspartate (NAA) to choline, or NAA to creatine between the two groups of animals. Magnetization transfer ratios and histograms revealed a significant shift in mean and peak MTR histogram at three different MT pulse offset frequencies to lower values in shaking dogs compared with age-matched controls. These results indicate that there is less of a magnetization transfer effect occurring in the SD compared with normal and is most likely a direct result of fewer myelin wraps around axons. The combination of a decrease in cerebral volume, along with an increase in T2 signal intensity characteristics, normal proton spectroscopy, and lower MTR ratio in the white matter of the SD compared with control animals would suggest that amount of myelin and its architecture are important contributors to the MRI appearance in the WM and that MRI may be useful in monitoring the extent of remyelination following transplantation with oligodendrocytes. Studies are planned to implant the SD with fetal oligodendrocytes for longitudinal MRI studies in an attempt to characterize remyelination of axons. As part of this oligodendrocyte transplantation study, we plan to magnetically label the oligodendrocytes using monoclonal antibodies to the transferring receptor that is conjugated to iron oxide particles to see if we can enhance the sensitivity of MR to the extent of remyelination. The MR research in the SJL EAE model detected early lesions of approximately 100 microns in diameter, and enabled us to observe signal intensity changes associated with the treatment effect in EAE mice. Based on this, several preliminary MR microscopy (MRM) studies were performed to understand the results of the phenotypic expression in genetic alterations in the animal models. MRM in transgenic mice, deficient in a single myosin gene, showed the early development of hydrocephalus prior to skeletal abnormalities. Therefore, MRM could clearly differentiate these animals from the control wild type. The MRM imaging techniques were applied to several other transgenic animal rodent models including a spontaneous prostate cancer model and viral-induced glioblastoma model and allowed for identification and characterization of some of the genetic alterations produced in these animals.
