Early changes in the hypothalamic region in prodromal Huntington disease revealed by MRI analysis

Abstract

Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat. Its length can be used to estimate the time of clinical diagnosis, which is defined by overt motor symptoms. Non-motor symptoms begin before motor onset, and involve changes in hypothalamus-regulated functions such as sleep, emotion and metabolism. Therefore we hypothesized that hypothalamic changes occur already prior to the clinical diagnosis. We performed voxel-based morphometry and logistic regression analyses of cross-sectional MR images from 220 HD gene carriers and 75 controls in the Predict-HD study. We show that changes in the hypothalamic region are detectable before clinical diagnosis and that its grey matter contents alone are sufficient to distinguish HD gene carriers from control cases. In conclusion, our study shows, for the first time, that alterations in grey matter contents in the hypothalamic region occur at least a decade before clinical diagnosis in HD using MRI.

Figure 1. Voxel-based morphometric analysis of prHD_far and controls in the Predict-HD study

The figures show the t-values in regions with significantly altered grey matter content in the prHD_far group compared to controls. The color bar indicates the range of t-values. Positive t-values indicate a decrease in grey matter content in prHD_far participants compared to controls, negative t-values indicate an increase in prHD_far participants compared to controls. All images are corrected for multiple comparisons using FDR and thresholded at q<0.01. Images are shown in neurological convention, overlaid on a standard MNI152 T1 template and viewed with the xjView toolbox in MATLAB (http://www.alivelearn.net/xjview8/). The top row shows the sections at MNI coordinates (−8,−4,10) mm. The following image shows the same statistical parametric map on a series of transverse slices (from MNI coordinates z = −40 to z = 35, slice thickness 5 mm).

Figure 2. Voxel-based morphometric analysis of prHD_mid and controls in the Predict-HD study

The figures show the t-values in regions with significantly altered grey matter content in the prHD_mid group compared to controls. The color bar indicates the range of t-values. Positive t-values indicate a decrease in grey matter content in prHD_mid participants compared to controls, negative t-values indicate an increase in prHD_mid participants compared to controls. All images are corrected for multiple comparisons using FDR and thresholded at q<0.01. Images are shown in neurological convention, overlaid on a standard MNI152 T1 template and viewed with the xjView toolbox in MATLAB (http://www.alivelearn.net/xjview8/). The top row shows the sections at MNI coordinates (−8,−4,10) mm. The following image shows the same statistical parametric map on a series of transverse slices (from MNI coordinates z = −40 to z = 35, slice thickness 5 mm).

Figure 3. Voxel-based morphometric analysis of prHD_near and controls in the Predict-HD study

The figures show the t-values in regions with significantly altered grey matter content in the prHD_near group compared to controls. The color bar indicates the range of t-values. Positive t-values indicate a decrease in grey matter content in prHD_near participants compared to controls, negative t-values indicate an increase in prHD_near participants compared to controls. All images are corrected for multiple comparisons using FDR and thresholded at q<0.01. Images are shown in neurological convention, overlaid on a standard MNI152 T1 template and viewed with the xjView toolbox in MATLAB (http://www.alivelearn.net/xjview8/). The top row shows the sections at MNI coordinates (−8,−4, 10) mm. The following image shows the same statistical parametric map on a series of transverse slices (from MNI coordinates z = −40 to z = 35, slice thickness 5 mm).

Figure 4. Representative images of the hypothalamic region

Representative native-space T1-weighted images from participants in the control (A), prHD_far (B), prHD_mid (C) and prHD_near (D) groups at the plane where the six different points on the borders of the hypothalamic region were identified for validation of the normalization process. The locations of the three points in the left hemisphere are shown in (A) and schematically in (F). The images illustrate a widening of the third ventricle in the groups closer to estimated onset of motor symptoms which is confirmed by a volumetric analysis of the third ventricle (E). Data is presented as mean ± SD. C= control, F= prHD_far, M = prHD_mid and N = prHD_near . **= p<0.001 (adjusting for age effect and using Bonferroni correction) compared to all other groups; * = p<0.05 (adjusting for age effect and using Bonferroni correction) compared to the control group; F= fornix; IFN= the infundibular nucleus; OT= optical tract; PVN= the paraventricular nucleus of the hypothalamus; VMH= the ventromedial nucleus of the hypothalamus.

Figure 5. Validation of the spatial alignment of the hypothalamic region

The mean positions in the normalized images of the six different points of reference on the hypothalamic borders in a plane 2.7 mm posterior to the anterior commissure did not differ by more than 1 mm in any coordinate direction between any pair of participant groups, which is illustrated in a medio-lateral and dorsal-ventral plane. Data is represented as mean ± SD.

Figure 6. Region of interests used for classification analyses in prHD

The anatomical localizations of the five equally sized regions of interests (22 mm × 16 mm × 18 mm, 792 voxels) in the hypothalamic region (1), the left caudate (2), the left insula (3), the cerebral cortex (4), and the cerebellum (5) that were used for the classification analyses.

Figure 7. ROC curves for the classification accuracy in prHD and control participants

ROC curves obtained using a L2-regularized logistic regression model when contrasting controls participants to the different prHD groups, as well as when contrasting prHD groups to each other for the whole brain (A), and regions of interests in the hypothalamic region (B), the caudate nucleus (C), the insula (D), the cerebral cortex (E) and the cerebellum (F). Areas under the ROC curves are indicated in each graph. In each binary comparison, the “positive” group is considered the one closest to expected clinical onset (with the control group considered further from onset than any of the prHD groups).