Fiber-specific white matter reductions in amyotrophic lateral sclerosis

•Using fixel‐based analysis, we examined the WM degeneration in ALS.•Decreased FD, FC and FDC were found in the CST and CC in ALS.•FD and FDC of the CST were associated with the clinical severity in ALS.•ALS patients exhibited both microstructural and macrostructural WM abnormalities. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons. Studies using metrics derived from the diffusion tensor model have documented decreased fractional anisotropy (FA) and increased mean diffusivity in the corticospinal tract (CST) and the corpus callosum (CC) in ALS. These studies, however, only focused on microstructural white matter (WM) changes, while the macrostructural alterations of WM tracts in ALS remain unknown. Moreover, studies conducted based on the diffusion tensor model cannot provide information related to specific fiber bundles and fail to clarify which biological characteristics are changing. Using a novel fixel-based analytical method that can characterize the fiber density (FD) and the fiber-bundle cross-section (FC), this study investigated both microstructural and macrostructural changes in the WM in a large cohort of patients with ALS (N = 60) compared with demographically matched healthy controls (N = 60). Compared with healthy controls, we found decreased FD, FC and fiber density and cross-section (FDC, a combined measure of the FD and FC) values in the bilateral CST and the middle posterior body of the CC in patients with ALS, suggesting not only microstructural but also macrostructural abnormalities in these fiber bundles. Additionally, we found that the mean FD and FDC values in the bilateral CST were positively correlated with the revised ALS Functional Rating Scale, indicating that these two indices may serve as potential markers for assessing the clinical severity of ALS. Thus, these findings provide initial evidence for the existence of microstructural and macrostructural abnormalities of the fiber bundles in ALS.