Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar 
ataxia in Europe, the US and Japan, leading to disability and death through 
motor complications. Although the affected protein ataxin-3 is found 
ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum 
and the brainstem. White matter pathology is generally less severe and thought 
to occur in the brainstem, spinal cord, and cerebellar white matter. Here, we 
investigated both grey and white matter pathology in a group of 12 SCA3 patients 
and matched controls. We used voxel-based morphometry for analysis of tissue 
loss, and tract-based spatial statistics (TBSS) on diffusion magnetic resonance 
imaging to investigate microstructural pathology. We analysed correlations 
between microstructural properties of the brain and ataxia severity, as measured 
by the Scale for the Assessment and Rating of Ataxia (SARA) score. SCA3 patients 
exhibited significant loss of both grey and white matter in the cerebellar 
hemispheres, brainstem including pons and in lateral thalamus. On between-group 
analysis, TBSS detected widespread microstructural white matter pathology in the 
cerebellum, brainstem, and bilaterally in thalamus and the cerebral hemispheres. 
Furthermore, fractional anisotropy in a white matter network comprising frontal, 
thalamic, brainstem and left cerebellar white matter strongly and negatively 
correlated with SARA ataxia scores. Tractography identified the thalamic white 
matter thus implicated as belonging to ventrolateral thalamus. Disruption of 
white matter integrity in patients suffering from SCA3 is more widespread than 
previously thought. Moreover, our data provide evidence that microstructural 
white matter changes in SCA3 are strongly related to the clinical severity of 
ataxia symptoms.