Cerebral cortex and the clinical expression of Huntington's disease: complexity and heterogeneity

Abstract

The clinical phenotype of Huntington's disease (HD) is far more complex and variable than depictions of it as a progressive movement disorder dominated by neostriatal pathology represent. The availability of novel neuro-imaging methods has enabled us to evaluate cerebral cortical changes in HD, which we have found to occur early and to be topographically selective. What is less clear, however, is how these changes influence the clinical expression of the disease. In this study, we used a high-resolution surface based analysis of in vivo MRI data to measure cortical thickness in 33 individuals with HD, spanning the spectrum of disease and 22 age- and sex-matched controls. We found close relationships between specific functional and cognitive measures and topologically specific cortical regions. We also found that distinct motor phenotypes were associated with discrete patterns of cortical thinning. The selective topographical associations of cortical thinning with clinical features of HD suggest that we are not simply correlating global worsening with global cortical degeneration. Our results indicate that cortical involvement contributes to important symptoms, including those that have been ascribed primarily to the striatum, and that topologically selective changes in the cortex might explain much of the clinical heterogeneity found in HD. Additionally, a significant association between regional cortical thinning and total functional capacity, currently the leading primary outcome measure used in neuroprotection trials for HD, establishes cortical MRI morphometry as a potential biomarker of disease progression.

Fig. 1

The topology of cortical thinning in early HD. Surface maps of cortical thinning were generated by using a general linear model at each vertex across the entire cortical mantle, shown in (A). In Stage I and II HD subjects, significant cortical thinning was present over sensori-motor cortex, portions of parietal cortex and occipital cortex, with relative sparing of anterior frontal and temporal regions. Maps are presented on a semi-inflated cortical surface of an average brain. The colour scale at the bottom represents the significance of the thickness change, transitioning from red (P < 0.01) to yellow (P < 0.00005). The magnitude of cortical thinning in HD is shown in (B). The colour scale at the bottom represents the magnitude of the thickness change, transitioning from red (5% loss) to yellow (>15% loss).

Fig. 2

A model of disease progression. HD subjects were grouped according to Stage. The colour scale at the bottom represents the significance of the thickness difference, with red to yellow indicating regions of more significant thinning in HD compared to matched controls, P < 0.05 to P < 0.0000001. The magnitude of the thickness change is displayed as well, transitioning from red (5% loss) to yellow (>20% loss).

Fig. 3

Relationship between cortical thinning and UHDRS cognitive scores. Performance on the Verbal Fluency, Stroop Color Word and Symbol Digit was inversely correlated with thinning in a number of distinct cortical regions. These findings suggest that greater clinical impairment is associated with a greater magnitude of thinning. Importantly, the topological relationship is unique for each cognitive measure, supporting clinical deficits reflect regional, and not global pathology, and also suggest that regional changes in the cortex may underlie clinical heterogeneity. The conjunction/disjunction analysis of the right more clearly shows correlations that overlap and areas that are unique to each.

Fig. 4

Scatter plots detailing the inverse relationship between performance on Verbal Fluency, Stroop and Symbol Digit and cortical thickness in areas of conjunction.

Fig. 5

Scatter plots detailing the relationship between performance on Verbal Fluency, Stroop and Symbol Digit and normalized caudate volume. There was a significant relationship between caudate volume and performance on the Verbal Fluency and Symbol Digit, but not with Stroop Color Word.

Fig. 6

Differential cortical involvement in distinct motor phenotypes in HD. This suggests that cortical involvement superimposes its own distinctive contributions to the phenotype of HD. In the subjects with more prominent bradykinaesia and dystonia, more significant thinning was present over pre-motor and supplementary motor areas, as more clearly shown in the conjunction/disjunction analyses.

Fig. 7

Relationship between thinning and TFC. More severe impairment was associated with more thinning; red to yellow indicating regions of more significant correlations P < 0.01 to P < 0.001. This implicates the cortex as a major contributor to the progressive symptoms of HD.

Fig. 8

Scatter plots detailing the relationship between TFC and specific regions.