Sequential alterations in diffusion metrics as correlates of disease severity in amyotrophic lateral sclerosis

Background and objective The neuropathology of amyotrophic lateral sclerosis (ALS) follows a regional distribution pattern in the brain with four stages. Using diffusion tensor imaging (DTI), this pattern can be translated into a tract-based staging scheme to assess cerebral progression in vivo. This study investigates the association between the sequential alteration pattern and disease severity in patients with ALS. Methods DTI data of 325 patients with ALS and 130 healthy controls were analyzed in a tract of interest (TOI)-based approach. Patients were categorized according to their ALS-FRS-R scores into groups with declining functionality. The fractional anisotropy (FA) values in the tracts associated with neuropathological stages were group-wise compared with healthy controls. Results The FA in the tracts associated with ALS stages showed a decrease which could be related to the disease severity stratification, i.e., at the group level, the lower the ALS-FRS-R of the categorized patient group, the higher was the effect size of the stage-related tract. In the patient group with the highest ALS-FRS-R, Cohen’s d showed a medium effect size in the corticospinal tract and small effect sizes in the other stage-related tracts. Overall, the lower the ALS-FRS-R of the categorized patient group the higher was the effect size of the comparison with healthy controls. Conclusion The progression of white matter alterations across tracts according to the model of sequential tract involvement is associated with clinical disease severity in patients with ALS, suggesting the use of staging-based DTI as a technical marker for disease progression.