Linking white matter and deep gray matter alterations in premanifest Huntington disease

Abstract

Huntington disease (HD) is a fatal progressive neurodegenerative disorder for which only symptomatic treatment is available. A better understanding of the pathology, and identification of biomarkers will facilitate the development of disease-modifying treatments. HD is potentially a good model of a neurodegenerative disease for development of biomarkers because it is an autosomal-dominant disease with complete penetrance, caused by a single gene mutation, in which the neurodegenerative process can be assessed many years before onset of signs and symptoms of manifest disease. Previous MRI studies have detected abnormalities in gray and white matter starting in premanifest stages. However, the understanding of how these abnormalities are related, both in time and space, is still incomplete. In this study, we combined deep gray matter shape diffeomorphometry and white matter DTI analysis in order to provide a better mapping of pathology in the deep gray matter and subcortical white matter in premanifest HD. We used 296 MRI scans from the PREDICT-HD database. Atrophy in the deep gray matter, thalamus, hippocampus, and nucleus accumbens was analyzed by surface based morphometry, and while white matter abnormalities were analyzed in (i) regions of interest surrounding these structures, using (ii) tractography-based analysis, and using (iii) whole brain atlas-based analysis. We detected atrophy in the deep gray matter, particularly in putamen, from early premanifest stages. The atrophy was greater both in extent and effect size in cases with longer exposure to the effects of the CAG expansion mutation (as assessed by greater CAP-scores), and preceded detectible abnormalities in the white matter. Near the predicted onset of manifest HD, the MD increase was widespread, with highest indices in the deep and posterior white matter. This type of in-vivo macroscopic mapping of HD brain abnormalities can potentially indicate when and where therapeutics could be targeted to delay the onset or slow the disease progression.

Keywords: Atrophy; DTI; Diffeomorphometry; Huntington; MRI; Shape.

Fig. 1

Template generated for the multiple brain structures. The colors represent the segments used for the surface based morphometry. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Schematic representation of the white matter analysis. A) ROIs in the white matter adjacent to the deep gray matter subregions used for shape diffeomorphometry (B, left panel). B) Examples of connections between deep gray matter and cortex; the cortical subregions in right panel are the parcels pre-defined in the template. C) Parcellation of the whole white matter in the atlas-based approach. GP = globus pallidus.

Fig. 3

Results from shape diffeomorphometry in both lateral (left panel) and medial (right panel) views. The top rows show whether there are significant differences between groups, and the bottom rows show the average degree of atrophy, if any. In the second and fourth rows, putamen (in the lateral view) and thalamus (in the medial view) were removed, to enable the visualization of structures lying behind them.

Fig. 4

Differences in MD between controls and each of the premanifest HD groups in the white matter adjacent to the segments of the deep gray matter and thalamus used for the diffeomorphometry analysis. Lateral view is shown. The top rows show whether there are significant differences between groups, and the bottom rows shows the respective MD increase of each groups compared to controls. In the second and fourth rows, putamen was removed, to enable the visualization of globus pallidum and thalamus.

Fig. 5

Atlas-based white matter DTI analysis. The colors code the increase of MD in areas of significant differences between controls and high-CAP group. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Examples of plots of CAP scores (x-axis) vs. degree of atrophy (first plots, y-axis: log (Jacobian)) in putamen, caudate, globus pallidus, and thalamus; or vs. MD (second plots, y-axis: MD e10^− 4, in mm²/s) in the adjacent white matter. For spatial localization, the various sub-segments of each structure are shown in the center. The colors represent the degree of atrophy in high-CAP versus vs. controls, as in Fig. 2. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)