Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis

Abstract

Objective: While the hallmark of amyotrophic lateral sclerosis (ALS) is corticospinal tract in combination with lower motor neuron degeneration, the clinical involvement of both compartments is characteristically variable and the site of onset debated. We sought to establish whether there is a consistent signature of cerebral white matter abnormalities in heterogeneous ALS cases.

Methods: In this observational study, diffusion tensor imaging was applied in a whole-brain analysis of 24 heterogeneous patients with ALS and well-matched healthy controls. Tract-based spatial statistics were used, with optimized voxel-based morphometry of T1 images to determine any associated gray matter involvement.

Results: A consistent reduction in fractional anisotropy was demonstrated in the corpus callosum of the ALS group, extending rostrally and bilaterally to the region of the primary motor cortices, independent of the degree of clinical upper motor neuron involvement. Matched regional radial diffusivity increase supported the concept of anterograde degeneration of callosal fibers observed pathologically. Gray matter reductions were observed bilaterally in primary motor and supplementary motor regions, and also in the anterior cingulate and temporal lobe regions. A post hoc group comparison model incorporating significant values for fractional anisotropy, radial diffusivity, and gray matter was 92% sensitive, 88% specific, with an accuracy of 90%.

Conclusion: Callosal involvement is a consistent feature of ALS, independent of clinical upper motor neuron involvement, and may reflect independent bilateral cortical involvement or interhemispheric spread of pathology. The predominantly rostral corticospinal tract involvement further supports the concept of independent cortical degeneration even in those patients with ALS with predominantly lower motor neuron involvement clinically.

Figure 1 Regional fractional anisotropy (FA) reductions in amyotrophic lateral sclerosis group whole-brain comparison with healthy controls, alongside published postmortem observations Consistent corpus callosum (CC) and rostral corticospinal tract (CST) tract involvement was seen despite the inclusion of a large number of patients with few clinical upper motor neuron signs. Similar white matter tract degeneration sections alongside those taken from an historical pathologic study (left-side images of A–D) confirmed prominent involvement of the CC and rostral CST (A and B, thick black lines indicating primary motor cortex), with caudal CST changes seen in uncorrected FA results (A, C, and D). Images shown were corrected (red–yellow scale) and uncorrected (red-only scale) for multiple comparisons (p < 0.05; radiologic convention used for display in all images).

Figure 2 Regional fractional anisotropy (FA) reductions and radial diffusivity (RD) increases in amyotrophic lateral sclerosis (ALS) group whole-brain comparison with healthy controls The close overlap between FA reductions (top panel, red–yellow) and RD (lower panel, blue) findings suggests that involvement of the corpus callosum and rostral corticospinal tract in ALS reflects a secondary demyelinating process due to an anterograde Wallerian degeneration. Both measures were corrected for multiple comparisons (p < 0.05; radiologic convention used for display in all cases with sagittal sections specifically marked for side).

Figure 3 Gray matter (GM) and fractional anisotropy (FA) reductions in amyotrophic lateral sclerosis (ALS) group whole-brain comparison with healthy controls Widespread GM reductions (green) in the primary and supplementary motor cortices, anterior cingulate gyrus, and temporal lobes were found, many with close relation to the regional white matter changes revealed by FA reductions (red–yellow). Motor region–related GM involvement was bilateral despite correction for laterality of limb onset, with the possibility that the corpus callosum involvement reflects independent bilateral cortical processes, or interhemispheric spread of pathology in ALS. Images were corrected for multiple comparisons (p < 0.05; radiologic convention used for display in all cases with sagittal sections specifically marked for side).

Figure 4 Scatterplot of mean fractional anisotropy (FA), radial diffusivity (RD), and gray matter (GM) values in amyotrophic lateral sclerosis (ALS) and healthy control groups For each subject, the mean values for FA and RD (expressed in mm².s⁻¹), obtained in those regions found to be significantly different between the 2 groups using tract-based spatial statistics, were plotted separately against GM values obtained in those regions found to be volumetrically significantly different using voxel-based morphometry. Correlations were seen in FA vs GM (ρ = 0.64, p < 10⁻⁴) and RD vs GM (ρ = −0.61, p < 10⁻⁴) for both control (blue) and ALS (red) patient groups, with reasonable separation of the two.