Background The genetic basis of Huntington’s disease (HD) explains much of the heterogeneity in the age of disease onset, but a substantial portion of this variability remains unexplained. In addition to potential environmental and HD-specific genetic modifiers, biological traits already present in the normal population may also influence HD pathogenesis.

In a recent study, we identified a pattern of diffusivity in the white matter (WM) of HD participants that was independent of other HD-specific factors and was also present in healthy controls.

Aims We used Diffusion Tensor Imaging from the TrackOn-HD study to examine further the role of biological variation in widespread WM tracts in premanifest-HD, early HD and control groups.

Methods Tractography was performed for 36 bilateral WM tracts, including connexions between cortical and subcortical regions and sensorimotor-thalamic connexions. Three diffusivity measures (fractional anisotropy, axial diffusivity and radial diffusivity) were assessed using Principal Components Analysis both within and between the three groups.

Results We found that three independent patterns of diffusivity distinguished premanifest from manifest HD gene-carriers. Three analogous patterns of diffusivity were also evident in the control group. Exaggerated scores on two of these three patterns correlated with other known biological measures of HD severity, and did not independently predict disease stage. The third, however, was independent of other known HD biology and did predict disease status.

Conclusions The overlap in patterns of diffusivity between controls and HD gene-carriers suggests that natural biological variation in the presence of HD-specific factors may influence WM vulnerability to the HD mutation.