Hidden brain atrophy in ultra-high field MR images in a transgenic rat model of Huntington's disease

The predominant neuropathological sign of Huntington's disease (HD) is a profound and progressive neuronal cell loss in the striatum and the neo-cortex. These histopathological changes have been widely investigated in post-mortem brains obtained from animal models of HD. However, imaging studies in rodents have so far led to conflicting results, where the outcomes have not been in line with histopathological findings. Herein, we aimed to further characterize the progression of neurodegeneration in a transgenic rat model of HD at different ages. Volumetric changes were measured in vivo via ultra-high field MR imaging (7T) and subsequent stereological analysis in the striatum, lateral ventricles, and cerebral cortex of tgHD rats were investigated at 9, 12, and 18-months of age. Histological assessment showed significant atrophy in the striatum, enlarged ventricular volumes, and a thinning of the cerebral cortex in tgHD rats at the late phase of the disease when compared to the wild-type (WT) littermates. Whereas only a reduction in striatal cell volume was observed at the early stage of the disease. MR imaging on the other hand, did not show detectable volumetric change in the investigated structures between tgHD and WT rats at different time-points. Our findings demonstrate neuronal shrinkage precedes striatal atrophy in tgHD rats. As in human HD, the manifestation of striatal atrophy appears prior to cortical thinning in tgHD rats. Surprisingly, contemporary in vivo ultra-high field MR imaging failed to detect these volumetric changes. These findings suggest that contemporary MRI protocols are unsuitable for detecting HD related alterations in rodent brain.