Brain Structure in Preclinical Huntington's Disease: A Multi-Method Approach

Abstract

Background: Structural magnetic resonance imaging (MRI) of the brain could be a powerful tool for discovering early biomarkers in clinically presymptomatic carriers of the Huntington's disease gene mutation (preHD). So far, structural changes have been found mainly in preHD approaching the estimated motor onset of the disease (i.e. less than 15 years from onset), whereas structural findings in preHD far from the estimated motor onset have been inconclusive. Objectives: The aims of this study were to investigate the sensitivity of different methodological approaches to structural data in far-from-onset preHD (mean estimated time to motor onset = 21.4 years) and to explore the relationship between brain structure, clinical variables and cognition. Methods: High-resolution MRI data at 3 T were obtained from 20 preHD individuals and 20 healthy participants and subsequently analyzed using voxel-based morphometry (VBM), cortical surface modeling and subcortical segmentation analysis techniques. Results: VBM analyses did not reveal significant between-group differences, whereas cortical surface modeling and subcortical segmentation analyses showed significant regional cortical thinning and striatal changes in preHD compared to controls. Significant correlations were found between striatal structure, estimated time to motor onset and executive performance, whereas cortical changes were not significantly correlated with these parameters. Conclusion: These data suggest that a combined methodological approach to structural MRI data could increase the sensitivity for detecting subtle neurobiological changes in early preHD. As consistently shown across different methods, the association between striatal structure and clinical measures supports the notion that changes in striatal volume could represent a more robust marker of disease progression than cortical changes.

Intact sensory-motor network structure and function in far from onset premanifest Huntington’s disease

“…Given that the disease burden score in our cohort was substantially lower than in other cohorts (e.g. refs 14, 15, 16, 17) people with far from onset preHD may develop structural changes when they get nearer to manifesting diagnostic signs of clinically manifest HD. This suggests that, at least with the methods we used, the structural changes ascribed to the pathogenesis of HD may not be evident far from motor onset.…”

“…refs 14, 15, 16, 17). In agreement with many studies, we found no clinically meaningful motor signs, and cognitive task performance was similar to controls.…”

“…This suggests that, at least with the methods we used, the structural changes ascribed to the pathogenesis of HD may not be evident far from motor onset. However, it is possible that more subtle changes may be detectable depending on the methods used without impacting brain function or clinical measures17.…”

Neuroanatomical correlates of cognitive functioning in prodromal Huntington disease

“…2010; Wolf et al. 2013), most studies report no relationship between cortical volume loss or thinning and cognition (Novak et al. 2012; Wolf et al.…”

“…Yet a recent study of 20 prHD individuals found no statistically significant relationships between cortical morphometry and cognitive functioning on tests of alertness, divided attention, verbal and spatial working memory, inhibition, or executive dysfunction (Wisconsin Card Sorting Test, WCST), irrespective of the structural magnetic resonance imaging (sMRI) method employed (i.e., VBM and cortical surface modeling) (Wolf et al. 2013). These discrepant findings may relate to the small sample sizes, which is problematic given the heterogeneity of symptoms and disease progression in prHD.…”