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 (11.7T) 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.