Abstract
Background
Genetic forms of frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) provide an important target for early therapeutic interventions. However, pre‐symptomatic biomarkers to monitor disease progression are lacking. Prior neuroimaging studies suggest disruption of functional and structural networks are an early feature of neurodegenerative disease. Network modularity quantifies the degree of segregation between sub‐networks. We hypothesize that structural network modularity is a marker of neurodegeneration in C9orf72 carriers.
Method
We evaluated diffusion magnetic resonance imaging (dMRI) in two independent cohorts of C9orf72 carriers and controls: University of Pennsylvania Prodromal Study (Penn‐C9) including symptomatic C9orf72 carriers (SC9; N=27; FTD=20; ALS=7), asymptomatic C9orf72 carriers (AC9; N=24), and healthy controls (HC; N=29); and Human Connectome Project‐FTD (HCP‐FTD) also including SC9 (N=12), AC9 (N=12), and HC (N=20) individuals. We quantified modularity in 7 intrinsic networks of 400 nodes from the Schaefer Atlas using participation coefficient (PC), where lower PC corresponds to higher modularity, and also investigated its constituent measures: within‐network connectivity for each network and pairwise between‐network connectivity. Modularity metrics were residualized in the Penn‐C9 dataset using linear regression to adjust for age. Statistical analyses on residualized scores were first performed in Penn‐C9 and cross‐validated in the HCP‐FTD dataset.
Result
ANCOVAs on residualized scores in Penn‐C9 revealed group differences in PC for limbic network with SC9 lower than HC (partial‐η2=0.12, p=0.011). We also observed group differences in within‐module connectivity for limbic (partial‐η2=0.16, p=0.0016) and dorsal‐attention (partial‐η2=0.1, p=0.019) networks with SC9 lower than HC. Cross‐validation in HCP‐FTD revealed group differences in modularity metrics for limbic network (PC: partial‐η2=0.29, p=0.0012 and within module connectivity:partial‐η2=0.28, p=0.0016) with both metrics lower in SC9 relative to HC. The group differences were significant between AC9 and HC in Penn‐C9 and the means of aforementioned metrics for AC9 were between HC and SC9 in both datasets, suggesting an intermediate state towards modularity.
Conclusion
We observed cross‐validated evidence of greater network modularity, in limbic network, for SC9 relative to HC and intermediate evidence of modularity in AC9. Limbic network is plausible as earliest loci of TDP‐43 pathology in FTD. We suggest that structural network modularity may be an early feature of C9orf72 disease progression.