Timing of selective basal ganglia white matter loss in premanifest Huntington's disease

Abstract

Objectives: To investigate the timeframe prior to symptom onset when cortico-basal ganglia white matter (white matter) loss begins in premanifest Huntington's disease (preHD), and which striatal and thalamic sub-region white matter tracts are most vulnerable.

Methods: We performed fixel-based analysis, which allows resolution of crossing white matter fibres at the voxel level, on diffusion tractography derived white matter tracts of striatal and thalamic sub-regions in two independent cohorts; TrackON-HD, which included 72 preHD (approx. 11 years before disease onset) and 85 controls imaged at three time points over two years; and the HD young adult study (HD-YAS), which included 54 preHD (approx. 25 years before disease onset) and 53 controls, imaged at one time point. Group differences in fibre density and cross section (FDC) were investigated.

Results: We found no significant group differences in cortico-basal ganglia sub-region FDC in preHD gene carriers 25 years before onset. In gene carriers 11 years before onset, there were reductions in striatal (limbic and caudal motor) and thalamic (premotor, motor and sensory) FDC at baseline, with no significant change over 2 years. Caudal motor-striatal, pre-motor-thalamic, and primary motor-thalamic FDC at baseline, showed significant correlations with the Unified Huntington's disease rating scale (UHDRS) total motor score (TMS). Limbic cortico-striatal FDC and apathy were also significantly correlated.

Conclusions: Our findings suggest that limbic and motor white matter tracts to the striatum and thalamus are most susceptible to early degeneration in HD but that approximately 25 years from onset, these tracts appear preserved. These findings may have importance in determining the optimum time to initiate future disease modifying therapies in HD.

Keywords: Diffusion MRI; Fixel-based analysis; Huntington’s disease; Premanifest; Striatum; Thalamus.

Fig. 1

Overview of study methodology and key results. Diffusion data were analysed from two separate studies; HD-YAS, where HD gene carriers were 25 years before predicted disease onset, and TrackON-HD, where HD gene carriers were 11 years before predicted onset. For each study, scans were registered to a common template. Connectivity based atlases of the striatum and thalamus were registered to the group template. Diffusion tractography was performed on the group template to reconstruct each of the cortico-thalamic and cortico-striatal tracts in right and left hemispheres. Measures of FDC were then computed for each tract. In gene carriers 25 years before predicted onset, there were no differences in any cortico-striatal or cortico-thalamic tract. In HD gene carriers 11 years from predicted onset, we found reduced FDC in limbic and caudal motor cortico-striatal tracts and pre-motor, primary motor and sensory cortico-thalamic tracts cross-sectionally. There were no significant longitudinal changes in gene carriers 11 years before predicted onset. GC = Gene Carriers, FDC = Fibre density and cross-section.

Fig. 2

White matter tracts showing significant cross-sectional differences in the TrackON-HD cohort. White matter tracts that showed a significant (FDR < 0.05) group difference are shown on a single sagittal slice of the template tractogram. For cortico-striatal tracts these were limbic (red) and caudal motor (blue). For cortico-thalamic tracts these were premotor (blue), primary motor (orange) and sensory motor (purple). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Supplementary figure 1

Supplementary figure 2