Precentral degeneration and cerebellar compensation in amyotrophic lateral sclerosis: A multimodal MRI analysis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and intractable neurodegenerative disease of human motor system characterized by progressive muscular weakness and atrophy. A considerable body of research has demonstrated significant structural and functional abnormalities of the primary motor cortex in patients with ALS. In contrast, much less attention has been paid to the abnormalities of cerebellum in this disease. Using multimodal magnetic resonance imagining data of 60 patients with ALS and 60 healthy controls, we examined changes in gray matter volume (GMV), white matter (WM) fractional anisotropy (FA), and functional connectivity (FC) in patients with ALS. Compared with healthy controls, patients with ALS showed decreased GMV in the left precentral gyrus and increased GMV in bilateral cerebellum, decreased FA in the left corticospinal tract and body of corpus callosum, and decreased FC in multiple brain regions, involving bilateral postcentral gyrus, precentral gyrus and cerebellum anterior lobe, among others. Meanwhile, we found significant intermodal correlations among GMV of left precentral gyrus, FA of altered WM tracts, and FC of left precentral gyrus, and that WM microstructural alterations seem to play important roles in mediating the relationship between GMV and FC of the precentral gyrus, as well as the relationship between GMVs of the precentral gyrus and cerebellum. These findings provided evidence for the precentral degeneration and cerebellar compensation in ALS, and the involvement of WM alterations in mediating the relationship between pathologies of the primary motor cortex and cerebellum, which may contribute to a better understanding of the pathophysiology of ALS.

Keywords: amyotrophic lateral sclerosis; cerebellum; fractional anisotropy; functional connectivity; gray matter volume.

Figure 1

Brain regions showing significant GMV alterations in patients with ALS compared with healthy controls. The results were corrected for multiple comparisons using Gaussian random field theory. Cold color denotes regions with decreased GMV in patients with ALS compared with healthy controls, while warm color denotes regions with increased GMV in patients with ALS compared with healthy controls. ALS, amyotrophic lateral sclerosis; GMV, gray matter volume [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

WM alterations in patients with ALS. The upper pane displayed the three‐dimensional rendering of the WM tracts with decreased FA in patients with ALS compared with healthy controls. The lower pane displayed four sliced views (coronal) of the WM tracts with decreased FA in patients with ALS compared with healthy controls. The color bar indicates the t values. The results were corrected for multiple comparisons using Gaussian random field theory. A, anterior; ALS, amyotrophic lateral sclerosis; FC, functional connectivity; FA, fractional anisotropy; L, left; P, posterior; R, right; WM, white matter [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

Positive correlation between mean FA of the altered WM tracts and ALSFRS‐R in patients with ALS. ALS, amyotrophic lateral sclerosis; ALSFRS‐R, ALS Functional Rating Scale; FA, fractional anisotropy; WM, white matter [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 4

Brain regions showing decreased FC to the precentral ROI in patients with ALS compared with healthy controls. The color bar indicates the t values. The results were corrected for multiple comparisons using Gaussian random field theory. ALS, amyotrophic lateral sclerosis; FC, functional connectivity [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 5

Correlations among GMV, FA, and FC using data of both groups. (a) Positive correlation between GMV of the precentral ROI and ROI‐based FC. (b) Positive correlation between FA of the altered WM tracts and ROI‐based FC. (c) Positive correlation between GMV of the precentral ROI and FA of the altered WM tracts. (d) Negative correlation between GMVs of the precentral ROI and cerebellar ROI. ALS, amyotrophic lateral sclerosis; FC, functional connectivity; FA, fractional anisotropy; GMV, gray matter volume; WM, white matter [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 6

Mediation path diagrams for FA of the WM tracts using data of both groups. (a) This mediation model illustrates the direct effect of the GMV of precentral ROI on the FA of WM tracts (Path a), the direct effect of the FA of WM tracts on the FC of precentral ROI (Path b), the direct effect of the GMV and FC of the precentral ROI (Path c′), and the mediating (indirect) effect of FA of WM tracts on the relationship between GMV and FC of the precentral ROI. (b) This mediation model illustrates the direct effect of the GMV of precentral ROI on the FA of WM tracts (Path a), the direct effect of the FA of WM tracts on the GMV of cerebellar ROI (Path b), the direct effect of the GMVs of precentral ROI and cerebellar ROI (Path c′), and the mediating (indirect) effect of FA of WM tracts on the relationship between GMVs of the precentral ROI and cerebellar ROI. As indicated by the regression coefficients and p values, there were significant mediating effects of WM microstructure alterations on the association between GMV and FC of the precentral ROI or between GMVs of the precentral ROI and cerebellar ROI. FC, functional connectivity; FA, fractional anisotropy; GMV, gray matter volume; WM, white matter [Color figure can be viewed at http://wileyonlinelibrary.com]