Objective: To identify when white matter connections first begin to degenerate in HD and which connections are most susceptible to early degeneration.

Background: Huntington’s disease (HD) is a progressive neurodegenerative condition characterised by selective vulnerability of the basal ganglia and associated white matter connections many years before symptom onset. Emerging therapies, such as RNAi and CRISPR will require injecting specific basal-ganglia sub-regions, however which sub-regions have the most vulnerable white matter connections and when they first begin to degenerate is unknown.

Method: We included 277 individuals, from 2 separate studies, HD-YAS with HD gene carriers 24 years from disease onset imaged at one time point and TrackOn-HD with HD gene expansion carriers 10 years from disease onset imaged at three time points over 2 years. We used diffusion MRI tractography and fixel based analysis, which resolves crossing fibres at the voxel level, to investigate basal ganglia sub-region white matter loss. Differences in a measure of fibre density and cross section were compared between gene carriers and matched controls for 7 cortico-striatal and 7 cortico-thalamic tracts.

Results: We found no significant differences in basal ganglia white matter loss in gene carriers 24 years from onset suggesting basal ganglia white matter is normal at this time. However in a cohort 10 years from onset, there were widespread changes in cortico-striatal and cortico-thalamic connectivity at baseline with limbic and motor white matter connections showing greatest vulnerability to presymptomatic neurodegeneration.

Conclusion: For the first time our findings provide time and anatomical specificity of basal ganglia white matter loss in HD. This has important implications for the initiation and anatomical targeting of future disease modifying therapies, where treatment at 24 years from predicted clinical onset could potentially prevent degeneration of white matter connections in HD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/defining-time-and-anatomical-specificity-of-basal-ganglia-white-matter-loss-in-premanifest-huntingtons-disease/