Magnetic resonance imaging reveals progressive neurodegeneration in the spastic Han Wistar rat

Includes bibliographical references (leaves 36-39)Acute and chronic neurodegenerative disorders are characterized by excessive activation of glutamate receptors which mediate neuronal death in specific brain regions. The spastic Han-Wistar (sHW) rat suffers from glutamate excitotoxicity resulting in neurodegeneration within the cerebellum (Purkinje cells) and hippocampus (CA3 pyramidal cells). Mutants homozygous for the autosomal trait begin to exhibit motor tremors and hind limb rigidity as early as 25 days of age with progressive symptoms resulting in mortality at around 60 days of age. Non-invasive magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) can be used to identify neurodegeneration in many animal models of disease, and we hypothesized that these imaging modalities could identify altered tissue structures within selected brain regions in the sHW rat. Mutant and normal siblings were imaged at 4.7T using T2-weighted MRI and MRS at 30, 45, and 60 days postnatal. Neurodegeneration in the hippocampus and cerebellum were quantified and whole brain volumes were calculated. MRS assessment of brain metabolites was limited to the right and left hippocampi. At 60 days, animals were sacrificed, and their brains extracted for conventional histology. Quantification of T2-values was sensitive for detecting neurodegeneration in the cerebellum and whole brain of the mutant rat. T2 values showed a significant increase in these regions between the 45 and 60 day time points. In addition, a temporal reduction in whole brain and cerebellar volumes over the 60-day course was seen compared to the normal littermates. However, T2-values and tissue volumes were not significantly altered at any time point (30, 45, 60 days) VI in the hippocampus. Histology revealed signs of CA3 pyramidal cell loss with an apparent collapse of the suprapyramidal blade of the dentate gyrus in the mutant and an increase in Cresyl violet staining in the stratum oriens near the CA3 region in the normal littermate. MRS demonstrated an increase in metabolite levels, specifically the N-acetyl-aspartate and creatine (NAA/Cr) ratio, at 60 days in the mutant. These data suggest that MRI and MRS may be sensitive enough to be used as a diagnostic tool for assessment of pathology in progressive neurodegenerative disorders