Structural and Functional MRI Signatures of ALS Patients with C9ORF72 Hexanucleotide Repeat Expansion (P4.014)

Objective. To explore structural and functional abnormalities in C9orf72-positive (+) amyotrophic lateral sclerosis (ALS) relative to C9orf72-negative (-) cases with or without a comparable amount of cognitive deficits. Background. Previous studies suggest an extensive frontotemporal involvement as the C9orf72 structural MRI signature in ALS. However, these findings were obtained comparing C9orf72(+) with C9orf72(-) ALS patients without cognitive impairment. Methods. 21 C9orf72(+) ALS patients were compared with: 22 healthy subjects; 31 C9orf72(-) ALS patients without cognitive impairment [C9orf72(-) motor] matched for demographics, ALSFRS-r score and disease duration; 26 C9orf72(-) ALS patients matched for ALSFRS-r score and cognitive/behavioral deficits [C9orf72(-) plus]. All subjects performed 3D T1-weighted, diffusion tensor (DT), and resting state (RS) fMRI. Results. Relative to C9orf72(-) plus, C9orf72(+) ALS patients were younger and had a shorter disease duration. All patients showed cortical thinning of the precentral, middle frontal, superior temporal and inferior parietal cortices bilaterally. In the majority of regions, thinning was greater in C9orf72(+) compared to C9orf72(-) motor patients, while no areas were more affected in C9orf72(+) compared to C9orf72(-) plus. All patients showed a damage of the motor callosal fibers and corticospinal tract. C9orf72(+) patients showed an additional involvement of the right superior longitudinal fasciculus. In the motor network, C9orf72(-) patients exhibited increased functional connectivity compared to controls, while C9orf72(+) patients showed decreased functional connectivity relative to C9orf72(-) plus patients. All patients showed decreased functional connectivity within the dorsal attention network compared to controls. Conclusions. C9orf72(+) ALS patients showed a structural cortical damage similar to older C9orf72(-) patients with comparable cognitive impairment and longer disease duration, implying that frontotemporal involvement appears earlier in C9orf72(+) than in other ALS patients. C9orf72(+) ALS patients showed divergent motor functional connectivity patterns relative to C9orf72(-) plus patients suggesting altered connectivity as part of C9orf72-ALS pathogenesis. Funding: Italian Ministry of Health (#RF-2010-2313220).