Objective: To understand the progressive nature of amyotrophic lateral sclerosis (ALS) by investigating differential brain patterns of gray and white matter involvement in clinically or genetically defined subgroups of patients using cross-sectional, longitudinal and multimodal MRI.

Methods: We assessed cortical thickness, subcortical volumes and white matter connectivity from T1-weighted and diffusion-weighted MRI in 292 ALS patients (follow-up: n=150) and 156 controls (follow-up: n=72). Linear mixed-effects models were used to assess changes in structural brain measurements over time in patients compared to controls.

Results: Patients with a C9orf72 mutation (n=24) showed widespread gray and white matter involvement at baseline, and extensive loss of white matter integrity in the connectome over time. In C9orf72-negative patients, we detected cortical thinning of motor and frontotemporal regions, and loss of white matter integrity of connections linked to the motor cortex. Spinal-onset patients displayed widespread white matter involvement at baseline and gray matter atrophy over time, whereas bulbar-onset patients started out with prominent gray matter involvement. Patients with unaffected cognition or behavior displayed predominantly motor system involvement, while widespread cerebral changes, including frontotemporal regions with progressive white matter involvement over time, were associated with impaired behavior or cognition. Progressive loss of gray and white matter integrity typically occurred in patients with shorter disease durations (<13 months), independent of progression rate.

Conclusions: Heterogeneity of phenotype and C9orf72 genotype relates to distinct patterns of cerebral degeneration. We demonstrate that imaging studies have the potential to monitor disease progression and early intervention may be required to limit cerebral degeneration.

Supplemental Data corresponding to research paper 'A multimodal longitudinal study of structural brain involvement in ALS'

It contains appendices, supplemental figures and supplemental tables for this paper.