Objective: To evaluate progressive white matter (WM) degeneration in ALS.

Methods: Sixty-six patients with ALS and 43 healthy controls were enrolled in a prospective, longitudinal, multicentre study in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants underwent a harmonized neuroimaging protocol across 4 centres including diffusion tensor imaging (DTI) for assessment of WM integrity. Three visits were accompanied by clinical assessments of disability (ALSFRS-R) and upper motor neuron (UMN) function. Voxel-wise whole brain and quantitative tractwise DTI assessments were done at baseline and longitudinally. Correction for site variance incorporated data from healthy controls and from healthy volunteers that underwent the DTI protocol at each centre.

Results: ALS patients had a mean progressive decline in fractional anisotropy (FA) of the corticospinal tract (CST) and frontal lobes. Tractwise analysis revealed reduced FA in the CST, corticopontine/corticorubral and corticostriatal tracts. CST FA correlated with UMN function and frontal lobe FA with the ALSFRS-R. A progressive decline in CST FA correlated with a decline in the ALSFRS-R and worsening UMN signs. Patients with fast vs slow progression had a greater reduction in FA of the CST and upper frontal lobe.

Conclusions: Progressive WM degeneration in ALS is most prominent in the CST and frontal lobes, and to a lesser degree in the corticopontine/corticorubral tracts and the corticostriatal pathways. With the use of a harmonized imaging protocol and incorporation of analytical methods to address site-related variances, this study is an important milestone towards developing DTI biomarkers for cerebral degeneration in ALS.