Divergent Brain Network Activity in Asymptomatic <i>C9orf72</i> and <i>SOD1</i> Variant Carriers Compared With Established Amyotrophic Lateral Sclerosis

Understanding the presymptomatic biology in those at high risk of developing amyotrophic lateral sclerosis (ALS) is essential for the development of preventative therapeutic interventions. Approximately 10% of ALS is associated with a C9orf72 expansion or pathogenic variants in SOD1. Magnetoencephalography (MEG), combined with machine learning algorithms, can model brain network dynamics in such at-risk populations to develop pathogenic biomarkers. Individuals with symptomatic ALS (symALS, n = 61), asymptomatic C9orf72 carriers (aC9, n = 16), or pathological SOD1 carriers (aSOD, n = 12), and healthy controls (n = 84) underwent resting-state MEG recordings. Extracted metrics included regional oscillatory power, connectivity, and spectral shape. 'DyNeMo' was trained to identify six functional dynamic brain networks. Metrics were compared between groups. A classifier was trained to distinguish asymptomatic gene carriers from controls. Compared to controls, beta frequency power was decreased in both symALS and aC9 groups. The aC9 group showed a marked slowing of frontal oscillatory activity, while the aSOD group showed a marked acceleration. Dynamic network coactivation was dramatically disrupted in aC9, more than in both symALS and aSOD. The classifier accurately distinguished genetically at-risk groups from controls (receiver-operator-characteristic area-under-curve 0.89). The cerebral network dynamics of aC9 are markedly different from both aSOD and symALS, supporting the concept of profoundly different upstream pathways in SOD1 ALS, sparing wider cortical pathology when compared to C9orf72 ALS. aC9 changes may reflect chronic adaptive changes relating to neurodevelopmental factors or underpin aspects of system vulnerability that define penetrance variability. MEG metrics might provide important biomarkers of prevention therapy efficacy and phenoconversion in at-risk populations.