Theme 8 Clinical Imaging and Electrophysiology

Background: Mutations in the C9Orf72 gene are responsible for many cases of familial ALS and FTD.Recent studies suggest that C9Orf72-related pathology may be partly linked to a neurodevelopmental disorder.This raises questions about the underlying pathogenic mechanisms and the identification of reliable biomarkers of degeneration for clinical trials.Objective of this study was to describe longitudinal cervical spinal cord (SC) pathology using MRI in a cohort of asymptomatic C9Orf72 first-degree relative subjects.Methods: 72 asymptomatic individuals were enrolled in a prospective study of first-degree relatives of ALS and FTD patients carrying the C9orf72 mutation.40 (C9) were carriers and 32 non carriers (C9).Each subject underwent a 3T cervical SC MRI.Quantitative measures of GM and WM atrophy and DTI parameters were evaluated at baseline, after 18 and after 36 months.Results: At baseline, significant WM atrophy was detected in C9 subjects older than 40 years of age (p-value <0.05) without associated changes in GM.At 18 and 36-month follow-up, no modification was observed both in WM and GM.Progressive significant fractional anisotropy (FA) reduction in the cortico-spinal tract was observed over the three time points in the C9 group (p 0.04).Discussion: Cervical SC imaging of C9orf72 hexanucleotide carriers reveals age-related WM atrophy, which remains stable over time, and no GM atrophy.Pyramidal tract FA reduction is observed in C9 subjects compared to C9 subjects and shows significant progression in follow-up scans.Stable WM atrophy might indicate a neurodevelopmental condition, which would explain the lack of progression over time, while the relation to increasing age of the subjects is similar to the one described in the general population.In contrast, changes in FA over time could be an early marker of progressive degeneration.Further studies with larger populations, including symptomatic C9 subjects, are needed to confirm this hypothesis.