Cortical microstructure in the amyotrophic lateral sclerosis-frontotemporal dementia continuum

Abstract

Objective: To characterize the cortical macrostructure and microstructure of behavioral and cognitive changes along the amyotrophic lateral sclerosis (ALS)-frontotemporal dementia (FTD) continuum.

Methods: We prospectively recruited 88 participants with a 3T MRI structural and diffusion-weighted imaging sequences: 31 with ALS, 20 with the behavioral variant of FTD (bvFTD), and 37 cognitively normal controls. Participants with ALS underwent a comprehensive cognitive and behavioral assessment and were dichotomized into 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 ALS Screen.

Results: The 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 restricted mainly to the dorsal motor cortex. In contrast, in the ALScbi group, cortical thinning was observed primarily on frontoinsular and temporal regions bilaterally. There were progressive cortical mean diffusivity changes along the ALSno-cbi, ALScbi, and bvFTD clinical continuum. Participants with ALS 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 extramotor cortical neurodegeneration in the ALS-FTD clinical spectrum.

Classification of evidence: This study provides Class III evidence that the cortical microstructure correlates with cognitive impairment in the ALS-FTD continuum.

Figure 1. Diagram flow of the sample composition

Participants in the behavioral variant of frontotemporal dementia (bvFTD) and control groups have been previously reported by Illán-Gala I et al. ALS = amyotrophic lateral sclerosis; DTI = diffusion tensor imaging; PLS = primary lateral sclerosis; PMA = progressive muscular atrophy.

Figure 2. Group differences in cortical thickness and cortical mean diffusivity between participants along the ALS-FTD spectrum and controls

Group comparisons between those with amyotrophic lateral sclerosis (ALS) without cognitive or behavioral impairment (ALSno-cbi; left column), those with ALS with cognitive or behavioral impairment (ALScbi; middle column), and those with behavioral variant of frontotemporal dementia (bvFTD; right column) compared to controls for (A) cortical thickness and (B) cortical mean diffusivity. Regions in blue represent thinner cortex; regions in green represent higher cortical mean diffusivity; and regions in purple represent lower cortical mean diffusivity. All analyses were adjusted for age, sex, education, and MRI equipment. Only clusters that survived family-wise error correction p < 0.05 are shown.

Figure 3. Group differences in cortical thickness and cortical mean diffusivity in participants with ALS with behavioral impairment and abnormal ALS-specific cognitive score

(A) Group comparison between participants with amyotrophic lateral sclerosis (ALS) with behavioral impairment (n = 11) and controls. (B) Group comparison between participants with ALS with abnormal ALS-specific cognitive score (n = 9) and controls. All analyses were adjusted for age, sex, education, and MRI equipment. Only clusters that survived family-wise error correction p < 0.05 are shown.

Figure 4. Group differences in cortical thickness and cortical mean diffusivity in participants with ALS with abnormal fluency, language, and executive scores

(A) Group comparison between participants with amyotrophic lateral sclerosis (ALS) with abnormal fluency score (n = 10) and controls; (B) group comparison between participants with ALS with abnormal language score (n = 7) and controls; and (C) group comparison between participants with ALS with an abnormal executive score (n = 8) and controls. All analyses were adjusted for age, sex, education, and center. Only clusters that survived family-wise error correction p < 0.05 are shown.