Altered white matter microstructure in the corpus callosum in Huntington's disease: implications for cortical "disconnection"

Abstract

The corpus callosum (CC) is the major conduit for information transfer between the cerebral hemispheres and plays an integral role in relaying sensory, motor and cognitive information between homologous cortical regions. The majority of fibers that make up the CC arise from large pyramidal neurons in layers III and V, which project contra-laterally. These neurons degenerate in Huntington's disease (HD) in a topographically and temporally selective way. Since any focus of cortical degeneration could be expected to secondarily de-afferent homologous regions of cortex, we hypothesized that regionally selective cortical degeneration would be reflected in regionally selective degeneration of the CC. We used conventional T1-weighted, diffusion tensor imaging (DTI), and a modified corpus callosum segmentation scheme to examine the CC in healthy controls, huntingtin gene-carriers and symptomatic HD subjects. We measured mid-sagittal callosal cross-sectional thickness and several DTI parameters, including fractional anisotropy (FA), which reflects the degree of white matter organization, radial diffusivity, a suggested index of myelin integrity, and axial diffusivity, a suggested index of axonal damage of the CC. We found a topologically selective pattern of alterations in these measures in pre-manifest subjects that were more extensive in early symptomatic HD subjects and that correlated with performance on distinct cognitive measures, suggesting an important role for disrupted inter-hemispheric transfer in the clinical symptoms of HD. Our findings provide evidence for early degeneration of commissural pyramidal neurons in the neocortex, loss of cortico-cortical connectivity, and functional compromise of associative cortical processing.

Figure 1. Corpus Callosum Segmentation

1A. Segmentation of the Corpus Callosum. The CC was identified in the transformed volume using an automated labeling procedure developed at the Martinos Center. 1B. CC Skeleton. A“skeleton” was generated by creating a line connecting the genu and the splenium such that the value of each voxel making up this line was equal to the minimum distance from the voxel to a point on the CC segmentation border. 1C. CC Thickness. The thickness at each of the 200 points along the skeleton was estimated as the distance between the superior and inferior borders with the constraint that the angle between these was greater than 3.0 radians. 1D.Topography of the midsaggital corpus callosum and proposed fiber composition, based on Hofer and Frahm’s classification. CC1 prefrontal, CC2 Premotor and supplementary motor, CC3-CC4 sensori-motor, CC5: parietal, temporal and occipital.

Figure 2. Summary of Diffusion Alterations in HD

Boxplots of thickness, FA, Radial Diffusivity, and Axial Diffusivity measures. Significant reductions in cross-sectional thickness of each of the CC parcellations were present in symptomatic HD (CC1 p < 10-⁶, CC2 p < 0.005, CC3 p < 0.01, CC4 p < 0.005, CC5 p< 0.001, corrected) but not PHD subjects. Significant reductions in FA (CC1 p < 0.95, CC3 p < 0.005, CC3 p < 0.01, CC4 p < 0.05, CC5 p < 0.01, corrected) and increases in radial (“far” group: regions CC2 p< 0.05and CC5 p < 0.001; “near” :CC2, CC3, and CC5, p < 0.005 for all regions; HD: CC1 p < 0.0001, CC2 p < 0.005, CC3 p < 0.001, CC4 p < 10 -6, CC5 p < 0.0005, corrected) and axial diffusivity in HD subjects (CC1 p < 0.005, CC2 p < 0.05, CC3 p < 0.05, CC4 p < 0.001, CC5 p < 0.05, corrected) were present. The point-by-point plots suggest that diffusion changes may precede measureable morphometric changes. The differences in the magnitude of the effects supports a topographically distinct pattern of CC degeneration.

Figure 3. Scatter plots demonstrating the correlation between diffusion parameters and clinical measures

The scatter plots demonstrate a significant relationship between regional FA and radial diffusivity and performance on the Verbal Fluency and Symbol Digit Scores, with significant correlations in CC1, CC2 and CC5, further supporting an important role of the cortex in cognitive dysfunction in HD.