STUDIES OF A MOUSE MODEL OF ALS-PDC

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Exposure to cycad (Cycas micronesica K.D. Hill) toxins via diet has been shown to induce neurodegeneration in vivo that mimics the progressive neurological disease, ALS-parkinsonism dementia complex (ALS-PDC). In previous studies, specific cortical and subcortical cell loss was measured with conventional stained sections. We have examined the utility of magnetic resonance (MR) microscopy was used to examine neurodegeneration in 3D in the isolated intact brain and spinal cord. Mice were fed washed cycad for 2 months and showed progressive motor deficits resembling human ALS-PDC. Animals were perfused and CNS tissue was imaged at 17.6 Tesla. T2* scans were conducted on both spinal cord and brain samples with an isotropic resolution of 41 mm. Cycad-fed mice showed significantly decreased volumes in lumbar spinal cord gray matter, substantia nigra, striatum, basal nucleus/internal capsule, and olfactory bulb. Cortical measurements revealed that cycad-fed mice also showed decreased cortical thickness. These results show that MR microscopy is sensitive enough to measure degeneration in this early stage model of a progressive neurological disease, and may be applicable in vivo on the same model. Similar analysis may be used in the future as a diagnostic aid in tracking the early progression of neurological disorders in pre-clinical human subjects. Studies are underway to evaluate the utility of DTI to examine the same brain tissue and detect deformities. We have also begun similar examinations on spinal cord samples from the same animals.