Background Structural MRI of the brain could be a powerful tool for discovering early biomarkers in clinically pre-symptomatic carriers of the Huntington's disease gene mutation (preHD).

Aims The aim of this study was to investigate the sensitivity of different methodological approaches to structural data in far-from onset preHD (mean time to motor onset = 21.4 years) and to explore the relationship between the time to motor onset, cognition and brain structure.

Methods High-resolution MRI data at 3 Tesla were obtained from 20 preHD individuals and 20 healthy participants and subsequently analysed using voxel-based morphometry (VBM), cortical surface modelling and subcortical segmentation analysis techniques.

Results VBM analyses did not reveal significant between-group differences. In contrast, cortical surface modelling and subcortical segmentation analyses showed significant regional cortical thinning and striatal changes in preHD compared to controls (p<0.05, corrected for multiple comparisons). Significant correlations were found between striatal structure, time-to-motor-onset and behavioural performance during card sorting, whereas cortical changes were not significantly correlated with time-to-motor-onset or behavioural parameters.

Conclusions These data suggest that a combined methodological approach to structural MRI data could increase sensitivity to very early neurobiological changes in far-from-onset preHD. As demonstrated across different methodological modalities, the association between striatal structure and clinical measures supports the notion that striatal volume might represent a more robust marker of change than cortical alterations.