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

Rachel F Smallwood Shoukry,Michael G Clark,Mary Kay Floeter

doi:10.3389/fneur.2020.598474

Abstract

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.

Highlights

A repeat expansion mutation in the C9orf72 gene is the most frequent cause of familial amyotrophic lateral sclerosis (ALS) and familial frontotemporal dementia (FTD) in populations of Northern European origin [1, 2] accounting for 5–10% of sporadic cases of these disorders [3]
We hypothesized that functional imaging in C9+ carriers would show a hybrid pattern on a continuum of those seen in ALS and FTD reflecting the relative balance of motor and cognitive-behavioral dysfunction in each patient
Global Graph Metrics—C9+ vs. healthy controls (HC) Analysis of global measures revealed that the C9+ carrier group had significantly lower global network density than HC, with fewer connections with strength greater than the correlation threshold (Figures 1, 2)

Summary

Introduction

A repeat expansion mutation in the C9orf gene is the most frequent cause of familial amyotrophic lateral sclerosis (ALS) and familial frontotemporal dementia (FTD) in populations of Northern European origin [1, 2] accounting for 5–10% of sporadic cases of these disorders [3]. In individual C9+ carriers, the structural changes may represent a hybrid pattern between those described for sporadic ALS and sporadic FTD, appearing to reflect the relative balance of motor and cognitive-behavioral dysfunction [10, 19,20,21]. We hypothesized that functional imaging in C9+ carriers would show a hybrid pattern on a continuum of those seen in ALS and FTD reflecting the relative balance of motor and cognitive-behavioral dysfunction in each patient. To examine this hypothesis, we evaluated changes in network measures and their association with clinical measures of motor and cognitivebehavioral dysfunction using graph theory metrics. Graph theory allows us to quantify whole-brain network properties, as well as how regions interact with each other as part of a larger network

Methods

Results

Conclusion