Background Huntington’s disease (HD) is a neurodegenerative disorder associated with both micro and macro structural changes in the brain. Better characterization of longitudinal changes in white matter microstructure is necessary to provide potential new biomarkers to track the effectiveness of potential therapeutics.

Aims To investigate 18 month longitudinal changes in white matter microstructure in premanifest (pre-HD) and symptomatic (symp-HD) Huntington’s disease.

Method/techniques Longitudinal analysis of diffusion tensor imaging (DTI) data was conducted for 28 pre-HD, 25 symp-HD, and 27 controls scanned at baseline and after 18 months. We developed an automated unbiased tensor-based registration pipeline to register diffusion tensor data across time and groups. A tract-based spatial statistics (TBSS) method was used to identify longitudinal changes in fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) in pre-HD and symp-HD compared to controls. Between-group-differences in the change over time was identified non-parametric permutation based comparison. Partial correlations were performed between baseline clinical symptoms (UHDRS) and 18-month change in FA values.

Results/outcome Symp-HD, compared to controls, showed an 18-month reduction in FA in corpus callosum and cingulum white matter. Symp-HD, compared to pre-HD, also showed 18 month increased RD in widespread white matter pathways, including corpus callosum, internal capsule, and striatal projection pathways. There was no longitudinal between-group difference in AD. There was a significant correlation between 18-month change in FA and baseline UHDRS across both HD groups.

Conclusions We provide the first direct evidence of progressive disease related decline in white matter microstructure in HD, which offers a potentially new sensitive biomarker for future therapeutics.