A prospective harmonized multicenter DTI study of cerebral white matter degeneration in ALS

Abstract

Objective To evaluate progressive white matter (WM) degeneration in amyotrophic lateral sclerosis (ALS).

 

Methods Sixty-six patients with ALS and 43 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants underwent a harmonized neuroimaging protocol across 4 centers that included diffusion tensor imaging (DTI) for assessment of WM integrity. Three visits were accompanied by clinical assessments of disability (ALS Functional Rating Scale–Revised [ALSFRS-R]) and upper motor neuron (UMN) function. Voxel-wise whole-brain and quantitative tract-wise DTI assessments were done at baseline and longitudinally. Correction for site variance incorporated data from healthy controls and from healthy volunteers who underwent the DTI protocol at each center.

 

Results Patients with ALS had a mean progressive decline in fractional anisotropy (FA) of the corticospinal tract (CST) and frontal lobes. Tract-wise analysis revealed reduced FA in the CST, corticopontine/corticorubral tract, and corticostriatal tract. CST FA correlated with UMN function, and frontal lobe FA correlated with the ALSFRS-R score. A progressive decline in CST FA correlated with a decline in the ALSFRS-R score 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 corticostriatal pathways. With the use of a harmonized imaging protocol and incorporation of analytic methods to address site-related variances, this study is an important milestone toward developing DTI biomarkers for cerebral degeneration in ALS.

 

ClinicalTrials.gov identifier NCT02405182.

 

Glossary
ALS=amyotrophic lateral sclerosis; ALSFRS-R=ALS Functional Rating Scale–Revised; CALSNIC=Canadian ALS Neuroimaging Consortium; CST=corticospinal tract; DTI=diffusion tensor imaging; FA=fractional anisotropy; FDR=false discovery rate; TFAS=tract-wise FA statistics; TOI=tract of interest; UMN=upper motor neuron; WBSS=whole brain–based spatial statistics; WM=white matter

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