A tale of two factors: what determines the rate of progression in Huntington's disease? A longitudinal MRI study

Abstract

Over the past several years, increased attention has been devoted to understanding regionally selective brain changes that occur in Huntington's disease and their relationships to phenotypic variability. Clinical progression is also heterogeneous, and although CAG repeat length influences age of onset, its role, if any, in progression has been less clear. We evaluated progression in Huntington's disease using a novel longitudinal magnetic resonance imaging analysis. Our hypothesis was that the rate of brain atrophy is influenced by the age of onset of Huntington's disease. We scanned 22 patients with Huntington's disease at approximately 1-year intervals; individuals were divided into 1 of 3 groups, determined by the relative age of onset. We found significant differences in the rates of atrophy of cortex, white matter, and subcortical structures; patients who developed symptoms earlier demonstrated the most rapid rates of atrophy compared with those who developed symptoms during middle age or more advanced age. Rates of cortical atrophy were topologically variable, with the most rapid changes occurring in sensorimotor, posterior frontal, and portions of the parietal cortex. There were no significant differences in the rates of atrophy in basal ganglia structures. Although both CAG repeat length and age influenced the rate of change in some regions, there was no significant correlation in many regions. Rates of regional brain atrophy seem to be influenced by the age of onset of Huntington's disease symptoms and are only partially explained by CAG repeat length. These findings suggest that other genetic, epigenetic, and environmental factors play important roles in neurodegeneration in Huntington's disease.

Conflict of interest statement

Financial Disclosures : There are no financial disclosures or conflicts of interest for any author.

Copyright © 2011 Movement Disorder Society.

Figures

Figure 1

Surface –based maps of the rate of cortical thinning. A. Young B. Middle Age C. Old. Younger patients have a much more rapid rate of thinning, especially in sensori-motor and parietal cortical regions. The general distribution of thinning was similar, however, in the young and middle age groups. In older patients, the rate of thinning was much slower than either group. Maps are presented on a semi-inflated cortical surface of an average brain. The color scale at the bottome represents the yearly rate of thinning, transitioning from red (3% or greater) to yellow (8% or greater).

Figure 2

Rate of change of thickness of select parcellations. Results from the cortical parcellations recapitulate the heterogeneity in the rate and topological distribution of progressive cortical thinning in the three groups.

Figure 3

Relationship between cortical thinning and CAG repeat. A. Surface based maps. B. Scatterplots showing the relationship of the caudate and examples of the cortex. Higher CAG repeats were associated with faster rates in distinct cortical regions, but not globally. This suggests that factors, other than the CAG repeat length, may be important in the variable rate of progression.