Objective: We aimed to characterize cortical macro- and micro-structure of behavioral and cognitive changes along the amyotrophic lateral sclerosis (ALS) – frontotemporal dementia (FTD) continuum.

Methods: We prospectively recruited 88 participants with a three-Tesla MRI structural and diffusion-weighted imaging sequences: 31 ALS, 20 bvFTD, and 37 cognitively normal controls. ALS participants underwent a comprehensive cognitive and behavioral assessment and were dichotomized in ALS without cognitive or behavioral impairment (ALSno-cbi, n=12) and ALS with cognitive or behavioral impairment (ALScbi, n=19). We computed cortical thickness and cortical mean diffusivity using a surface-based approach and explored the cortical correlates of cognitive impairment with the Edinburgh Cognitive and Behavioral Amyotrophic lateral sclerosis Screen (ECAS). 

Results: ALSno-cbi and ALScbi groups showed different patterns of reduced cortical thickness and increased cortical mean diffusivity. In the ALSno-cbi group, cortical thinning was mainly restricted to the dorsal motor cortex. In contrast, in the ALScbi group, cortical thinning was observed primarily on fronto-insular and temporal regions bilaterally. There were progressive cortical mean diffusivity changes along the ALSno-cbi, ALScbi, and bvFTD clinical continuum.  Importantly, ALS participants with either cognitive or behavioral impairment showed increased cortical mean diffusivity in the prefrontal cortex in the absence of cortical thickness. 

Conclusions: Cortical mean diffusivity might be a useful biomarker for the study of extra motor cortical neurodegeneration in the ALS-FTD clinical spectrum.