Altered EEG Response of the Parietal Network in Asymptomatic C9orf72 Carriers

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron degeneration. Around 10% of cases have a genetic basis, with the C9orf72 hexanucleotide repeat expansion being the most common cause in individuals of European ancestry. Detecting early alterations in at-risk individuals could aid in identifying biomarkers for timely diagnosis and intervention. In this study, we investigated electrophysiological changes in asymptomatic C9orf72 mutation carriers using EEG, focusing on cognitive and motor networks, as these individuals are at risk of developing impairments in both domains. This study included 87 asymptomatic family members (AFM) of patients with familial C9orf72 ALS, comprising 37 individuals carrying the pathological repeat expansion (C9+) and 50 without it (C9-). High-density EEG was recorded during the sustained attention to response task (SART), which is a Go/NoGo paradigm that engages the frontoparietal and motor networks. Task performance was recorded and six behavioral measures were extracted: NoGo accuracy, Go accuracy, total accuracy, anticipation error, average response time, and response time variability. Analyses were conducted on EEG data in both sensor- and source-space, using stimulus- and response-locked data. The stimulus-locked Go and NoGo data were analysed within two time windows: 180-350 ms (N2) and 300-600 ms (P3), while response-locked Go data were analysed within a -100 to 100 ms time window. Linear mixed models were used to quantify differences between groups, incorporating familial pedigree to control for between-subject dependencies. While the two groups did not significantly differ in any SART performance measures, EEG analyses revealed differences. During the stimulus-locked N2, significant differences were observed in sensor-space, primarily in central electrodes during both NoGo and Go conditions, with C9+ AFM exhibiting an increased negative potential. Source analysis confirmed these findings and localized the increased activity in the bilateral precuneus and superior parietal regions. Further analysis of the response-locked data supported the involvement of the same posterior regions. No significant relationships were found between these EEG observations and SART performance. These findings provide the first evidence of EEG changes in AFM carrying the C9orf72 repeat expansion. The observed functional changes in the parietal regions may reflect genotype-related effects on the motor control network, potentially contributing to early pathophysiology. In contrast, clinical assessments and task performance did not differ between groups, suggesting that our EEG findings may hold promise as biomarkers for monitoring the risk of conversion to symptomatic disease and warrant further exploration to assess their predictive value for future symptom onset.

Keywords: C9orf72; ALS; EEG; amyotrophic lateral sclerosis; asymptomatic; sustained attention to response task.