Neurite density is reduced in the presymptomatic phase of <i>C9orf72</i> disease.

Abstract

To assess the added value of neurite orientation dispersion and density imaging (NODDI) compared with conventional diffusion tensor imaging (DTI) and anatomical MRI to detect changes in presymptomatic carriers of chromosome 9 open reading frame 72 (<i>C9orf72</i>) mutation. The PREV-DEMALS (Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis) study is a prospective, multicentre, observational study of first-degree relatives of individuals carrying the <i>C9orf72</i> mutation. Sixty-seven participants (38 presymptomatic <i>C9orf72</i> mutation carriers (C9+) and 29 non-carriers (C9-)) were included in the present cross-sectional study. Each participant underwent one single-shell, multishell diffusion MRI and three-dimensional T1-weighted MRI. Volumetric measures, DTI and NODDI metrics were calculated within regions of interest. Differences in white matter integrity, grey matter volume and free water fraction between <i>C9+</i> and <i>C9-</i> individuals were assessed using linear mixed-effects models. Compared with <i>C9-</i>, <i>C9+</i> demonstrated white matter abnormalities in 10 tracts with neurite density index and only 5 tracts with DTI metrics. Effect size was significantly higher for the neurite density index than for DTI metrics in two tracts. No tract had a significantly higher effect size for DTI than for NODDI. For grey matter cortical analysis, free water fraction was increased in 13 regions in <i>C9+</i>, whereas 11 regions displayed volumetric atrophy. NODDI provides higher sensitivity and greater tissue specificity compared with conventional DTI for identifying white matter abnormalities in the presymptomatic <i>C9orf72</i> carriers. Our results encourage the use of neurite density as a biomarker of the preclinical phase. NCT02590276.