Contrasting gray and white matter changes in preclinical Huntington disease: an MRI study

Abstract

Background: In Huntington disease (HD), substantial striatal atrophy precedes clinical motor symptoms. Accordingly, neuroprotection should prevent major cell loss before such symptoms arise. To evaluate neuroprotection, biomarkers such as MRI measures are needed. This requires first establishing the best imaging approach.

Methods: Using a cross-sectional design, we acquired T1-weighted and diffusion-weighted scans in 39 preclinical (pre-HD) individuals and 25 age-matched controls. T1-weighted scans were analyzed with gross whole-brain segmentation and voxel-based morphometry. Analysis of diffusion-weighted scans used skeleton-based tractography. For all imaging measures, we compared pre-HD and control groups and within the pre-HD group we examined correlations with estimated years to clinical onset.

Results: Pre-HD individuals had lower gross gray matter (GM) and white matter (WM) volume. Voxel-wise analysis demonstrated local GM volume loss, most notably in regions consistent with basal ganglia-thalamocortical pathways. By contrast, pre-HD individuals showed widespread reductions in WM integrity, probably due to a loss of axonal barriers. Both GM and WM imaging measures correlated with estimated years to onset.

Conclusions: Using automated, observer-independent methods, we found that GM loss in pre-HD was regionally specific, while WM deterioration was much more general and probably the result of demyelination rather then axonal degeneration. These findings provide important information about the nature, relative staging, and topographic specificity of brain changes in pre-HD and suggest that combining GM and WM imaging may be the best biomarker approach. The empirically derived group difference images from this study are provided as regions-of-interest masks for improved sensitivity in future longitudinal studies.

Figure 1 Gross whole-brain segmentation Scatterplots are shown for estimated years to onset in the preclinical Huntington's disease group (n = 38) against normalized brain (A), gray matter (B), white matter (C), and cortical gray matter (D) volumes from the SIENAX analysis. R² values are shown in the bottom right corner; solid horizontal lines indicate the mean volume in controls (n = 25), dashed horizontal lines indicate the 95% confidence interval around this mean.

Figure 2 Voxel-based gray matter analysis (A) Regions of significant gray matter (GM) volume reduction in the preclinical Huntington's disease (pre-HD) group (n = 38) relative to controls (n = 25), whole-brain corrected. (B) Regions where local GM volume decreases with decreasing estimated years to onset in the pre-HD group, whole-brain corrected. (C) Anatomic masks based on the Harvard-Oxford probabilistic labels atlas (25% probability threshold) for reference. Clusters and masks are overlaid on axial slices from the Montreal Neurological Institute–152 template, displayed according to neurologic convention (left = left). Z coordinates in Montreal Neurological Institute space of the individual slices, color labels for the various anatomic masks, and a color bar indicating significance level are displayed at the bottom.

Figure 3 Skeleton-based tractography of major white matter (WM) tracts (A) Regions of significantly lower fractional anisotropy (FA) in the preclinical Huntington's disease (pre-HD) group (n = 38) relative controls (n = 24), whole-brain corrected. (B) Regions of significantly higher transverse diffusivity in pre-HD relative to controls, whole-brain corrected. (C) Regions of significantly higher longitudinal diffusivity in pre-HD relative to controls, whole-brain corrected. (D) Regions where FA values decrease with decreasing estimated years to onset in the pre-HD group, whole-brain corrected. (E) Anatomic masks based on the Johns Hopkins University ICBM-DTI-81 WM labels atlas for reference. Clusters and masks are overlaid on coronal slices from the mean FA image, displayed according to neurologic convention (left = left). The mean FA skeleton, in which voxel-wise permutation testing was performed for all the above results, is shown in green. For better visibility, significant clusters (p values <0.05) have been thickened to fill out local tracts in the FA image. Clusters are shown in yellow with red boundaries. Y coordinates in Montreal Neurological Institute space of the individual slices and color labels for the various anatomic masks are displayed at the bottom.