A major recent discovery was the identification of an expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene in patients with
frontotemporal dementia and
amyotrophic lateral sclerosis. Mutations in two other genes are known to account for familial
frontotemporal dementia:
microtubule-associated protein tau and
progranulin. Although imaging features have been previously reported in subjects with mutations in tau and
progranulin, no imaging features have been published in C9ORF72. Furthermore, it remains unknown whether there are differences in
atrophy patterns across these mutations, and whether regional differences could help differentiate C9ORF72 from the other two mutations at the single-subject level. We aimed to determine the regional pattern of brain
atrophy associated with the C9ORF72 gene mutation, and to determine which regions best differentiate C9ORF72 from subjects with mutations in tau and
progranulin, and from sporadic
frontotemporal dementia. A total of 76 subjects, including 56 with a clinical diagnosis of behavioural variant
frontotemporal dementia and a mutation in one of these genes (19 with C9ORF72 mutations, 25 with tau mutations and 12 with
progranulin mutations) and 20 sporadic subjects with behavioural variant
frontotemporal dementia (including 50% with
amyotrophic lateral sclerosis), with magnetic resonance imaging were included in this study. Voxel-based morphometry was used to assess and compare patterns of grey matter
atrophy. Atlas-based parcellation was performed utilizing the automated anatomical labelling atlas and Statistical Parametric Mapping software to compute volumes of 37 regions of interest. Hemispheric asymmetry was calculated. Penalized multinomial logistic regression was utilized to create a prediction model to discriminate among groups using regional volumes and asymmetry score. Principal component analysis assessed for variance within groups. C9ORF72 was associated with symmetric
atrophy predominantly involving dorsolateral, medial and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes and cerebellum. In contrast, striking anteromedial temporal
atrophy was associated with tau mutations and temporoparietal
atrophy was associated with
progranulin mutations. The sporadic group was associated with frontal and anterior temporal
atrophy. A conservative penalized multinomial logistic regression model identified 14 variables that could accurately classify subjects, including frontal, temporal, parietal, occipital and cerebellum volume. The principal component analysis revealed similar degrees of heterogeneity within all disease groups. Patterns of
atrophy therefore differed across subjects with C9ORF72, tau and
progranulin mutations and sporadic
frontotemporal dementia. Our analysis suggested that imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level.