Resting State Functional Connectivity Is Decreased Globally Across the C9orf72 Mutation Spectrum

A repeat expansion mutation in the C9orf72 gene causes amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or symptoms of both, and has been associated with gray and white matter changes in brain MRI scans. We used graph theory to examine the network properties of brain function at rest in a population of mixed-phenotype C9orf72 mutation carriers (C9+). Twenty-five C9+ subjects (pre-symptomatic, or diagnosed with ALS, behavioral variant FTD (bvFTD), or both ALS and FTD) and twenty-six healthy controls underwent resting state fMRI. When comparing all C9+ subjects with healthy controls, both global and connection-specific decreases in resting state connectivity were observed, with no substantial reorganization of network hubs. However, when analyzing subgroups of the symptomatic C9+ patients, those with bvFTD (with and without comorbid ALS) show remarkable reorganization of hubs compared to patients with ALS alone (without bvFTD), indicating that subcortical regions become more connected in the network relative to other regions. Additionally, network connectivity measures of the right hippocampus and bilateral thalami increased with increasing scores on the Frontal Behavioral Inventory, indicative of worsening behavioral impairment. These results indicate that while C9orf72 mutation carriers across the ALS-FTD spectrum have global decreased resting state brain connectivity, phenotype-specific effects can also be observed at more local network levels.