Figure 1. Study Framework.

(A) Patient classification. Revised Strong criteria were applied to identify patients with amyotrophic lateral sclerosis (ALS) with and without cognitive/behavioral impairments or dementia deficits. (B) Connectome reconstruction. Connectomics was applied on diffusion tensor MRI (DTI) and resting-state fMRI after parcellating the brain into 220 regions. Structural and functional connectomes of all participants were reconstructed. (C) Regional connectivity analysis. Network-based statistics was performed, performing all possible comparisons between groups. (D) Distribution analysis. After reconstructing the structural and functional connectome of each patient and control, all connections per each patient were normalized relative to controls and grouped into 6 macro-areas. Intra-area and interarea connectivity distribution were plotted and statistically compared between groups. (E) Classification analysis. Receiver operator characteristic (ROC) curve analysis was performed to discriminate ALS with motor impairment only (ALS-cn) from behavioral variant of frontotemporal dementia (bvFTD) and vice versa, considering intra-area and interarea connectivity that resulted significantly different between these 2 groups in the distribution analysis. (F) Frequency analysis. After ROC curve analysis, the optimal cutoff was identified using the Youden index. ALS with cognitive or behavioral impairment (ALS-ci/bi) and ALS with frontotemporal dementia (ALS-FTD) cases were then subdivided into those under and above the optimal cutoff. χ² test was performed in order to identify the behavior of these 2 groups. ANOVA = analysis of variance; HC = healthy control.