Regional subcortical shape analysis in premanifest Huntington's disease

Abstract

Huntington's disease (HD) involves preferential and progressive degeneration of striatum and other subcortical regions as well as regional cortical atrophy. It is caused by a CAG repeat expansion in the Huntingtin gene, and the longer the expansion the earlier the age of onset. Atrophy begins prior to manifest clinical signs and symptoms, and brain atrophy in premanifest expansion carriers can be studied. We employed a diffeomorphometric pipeline to contrast subcortical structures' morphological properties in a control group with three disease groups representing different phases of premanifest HD (far, intermediate, and near to onset) as defined by the length of the CAG expansion and the participant's age (CAG-Age-Product). A total of 1,428 magnetic resonance image scans from 694 participants from the PREDICT-HD cohort were used. We found significant region-specific atrophies in all subcortical structures studied, with the estimated abnormality onset time varying from structure to structure. Heterogeneous shape abnormalities of caudate nuclei were present in premanifest HD participants estimated furthest from onset and putaminal shape abnormalities were present in participants intermediate to onset. Thalamic, hippocampal, and amygdalar shape abnormalities were present in participants nearest to onset. We assessed whether the estimated progression of subcortical pathology in premanifest HD tracked specific pathways. This is plausible for changes in basal ganglia circuits but probably not for changes in hippocampus and amygdala. The regional shape analyses conducted in this study provide useful insights into the effects of HD pathology in subcortical structures.

Keywords: circuit; premanifest Huntington's disease; shape; subcortical structures; subregion.

Figure 1

Shape analysis results for the caudate. Statistically significant group comparison results between the control group and each of the three premanifest HD groups (L: Low‐CAP, M: Mid‐CAP, H: High‐CAP) for the caudate shape in each hemisphere as well the corresponding subregion definitions. The color bar represents the percentage of atrophy at a specific vertex in the disease group relative to the control group. The bottom panel illustrates the seven subregions of the bilateral caudate. Two views (left: Lateral, right: Medial) are presented for each case [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

Shape analysis results for the putamen. Statistically significant group comparison results between the control group and each of the three premanifest HD groups (L: Low‐CAP, M: Mid‐CAP, H: High‐CAP) for the putamen shape in each hemisphere as well the corresponding subregion definitions. The color bar represents the percentage of atrophy at a specific vertex in the disease group relative to the control group. The bottom panel illustrates the seven subregions of the bilateral putamen. Two views (left: Lateral, right: Medial) are presented for each case [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

Shape analysis results for the globus pallidus. Statistically significant group comparison results between the control group and each of the three premanifest HD groups (L: Low‐CAP, M: Mid‐CAP, H: High‐CAP) for the globus pallidus shape in each hemisphere. The color bar represents the percentage of atrophy at a specific vertex in the disease group relative to the control group. Two views (left: Lateral, right: Medial) are presented for each case [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 4

Shape analysis results for the thalamus. Statistically significant group comparison results between the control group and each of the three premanifest HD groups (L: Low‐CAP, M: Mid‐CAP, H: High‐CAP) for the thalamus shape in each hemisphere as well the corresponding subregion definitions. The color bar represents the percentage of atrophy at a specific vertex in the disease group relative to the control group. The bottom panel illustrates the seven subregions of the bilateral thalamus. Two views (left: Lateral, right: Medial) are presented for each case [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 5

Shape analysis results for the amygdala. Statistically significant group comparison results between the control group and each of the three premanifest HD groups (L: Low‐CAP, M: Mid‐CAP, H: High‐CAP) for the amygdala shape in each hemisphere as well the corresponding subregion definitions. The color bar represents the percentage of atrophy at a specific vertex in the disease group relative to the control group. The rightmost panel illustrates the four subregions of the bilateral amygdala. Two views (left: Dorsal, right: Ventral) are presented for each case [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 6

Shape analysis results for the hippocampus. Statistically significant group comparison results between the control group and each of the three premanifest HD groups (L: Low‐CAP, M: Mid‐CAP, H: High‐CAP) for the hippocampus shape in each hemisphere as well the corresponding subregion definitions. The color bar represents the percentage of atrophy at a specific vertex in the disease group relative to the control group. The rightmost panel illustrates the four subregions of the bilateral hippocampus. Two views (left: Dorsal, right: Ventral) are presented for each case [Color figure can be viewed at http://wileyonlinelibrary.com]