Ex vivo 100 μm isotropic diffusion MRI-based tractography of connectivity changes in the end-stage R6/2 mouse model of Huntington’s disease

BACKGROUND: Huntington’s disease is a progressive neurodegenerative disorder. Brain atrophy, as measured by volumetric magnetic resonance imaging (MRI), is a downstream consequence of neurodegeneration, but microstructural changes within brain tissue are expected to precede this volumetric decline. The tissue microstructure can be assayed non-invasively using diffusion MRI, which also allows a tractographic analysis of brain connectivity. METHODS: We here used ex vivo diffusion MRI (11.7 T) to measure microstructural changes in different brain regions of end-stage (14 weeks of age) wild type and R6/2 mice (male and female) modeling Huntington’s disease. To probe the microstructure of different brain regions, reduce partial volume effects and measure connectivity between different regions, a 100 μm isotropic voxel resolution was acquired. RESULTS: Although fractional anisotropy did not reveal any difference between wild-type controls and R6/2 mice, mean, axial, and radial diffusivity were increased in female R6/2 mice and decreased in male R6/2 mice. Whole brain streamlines were only reduced in male R6/2 mice, but streamline density was increased. Region-to-region tractography indicated reductions in connectivity between the cortex, hippocampus, and thalamus with the striatum, as well as within the basal ganglia (striatum—globus pallidus—subthalamic nucleus—substantia nigra—thalamus). CONCLUSIONS: Biological sex and left/right hemisphere affected tractographic results, potentially reflecting different stages of disease progression. This proof-of-principle study indicates that diffusion MRI and tractography potentially provide novel biomarkers that connect volumetric changes across different brain regions. In a translation setting, these measurements constitute a novel tool to assess the therapeutic impact of interventions such as neuroprotective agents in transgenic models, as well as patients with Huntington’s disease.