Grey matter differences in genetic frontotemporal dementia: Results from the genfi study

Abstract

Frontotemporal dementia (FTD) is the second most common early onset dementia. Around a third of cases are caused by an autosomal dominant mutation in one of three genes: Chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT). In this study, we examined structural grey matter (GM) differences in these three different genetic groups using voxel based morphometry on volumetric T1 magnetic resonance images (MRI) acquired as part of the multicentre Genetic FTD Initiative (GENFI). Participants were enrolled from 12 sites within the GENFI consortium. Those that had a volumetric T1 MRI of suitable quality and known genetic status were included in the study, resulting in 272 participants. Of these, 127 were mutation negative controls, 105 were presymptomatic mutation carriers, and 40 were symptomatic carriers (see Table). All image processing was performed using SPM12 with tissue segmentation, spatial normalization to a study specific template (modulating the warped GM maps), and finally smoothing using a 6mm full width half maximum Gaussian kernel. Statistical parametric maps were generated to determine GM differences between non-carriers and groups defined by mutation and clinical status (presymptomatic or symptomatic). The model corrected for acquisition site, total intracranial volume, gender, and age. In the symptomatic carriers, frontal and temporal atrophy was present in all three genetic groups compared with controls (p<0.05 FWE corrected for multiple comparisons). However differences were seen, with MAPT mutations having predominantly anterior temporal and orbitofrontal atrophy, GRN mutations having insula, prefrontal and striatal involvement, and the C9orf72 group having more widespread cortical as well as thalamus and superior cerebellar atrophy. In the presymptomatic carriers at a significance level of p<0.001 uncorrected, involvement of similar areas was seen in all three groups, with the most significant areas being in the temporal lobe in the MAPT mutation group, the frontal lobe in the GRN mutation group and the thalamus in the C9orf72 group. Presymptomatic atrophy can be seen in all three groups in similar areas to those seen in the symptomatic carriers but to a lesser extent. Different patterns are present in the three mutation groups.