To assess atrophy of deep grey matter (GM) and hippocampal structures using magnetic resonance imaging (MRI) in patients affected by disorders of the frontotemporal lobar degeneration (FTLD) spectrum with known genetic mutations.

Genetic heterogeneity underlying different clinical presentations of the FTLD spectrum hampers the identification of useful biomarkers that may be able to monitor disease progression.

362 patients with disorders of the FTLD spectrum were screened for known pathogenic mutations. 3D T1-weighted MRI sequences were obtained on a 3T scanner from 55 patients carrying mutations in the C9ORF72, GRN, TARDBP or SOD1 genes, including 38 with pure motor neuron disease (MND) and 17 with frontotemporal dementia (FTD). 57 age- and sex-matched healthy controls (HC) were also enrolled. GM volumes of the basal ganglia, thalami and hippocampi were obtained using FIRST in FSL and normalized for head size. MRI measures were compared between groups using Kruskal-Wallis tests.

The 32 patients carrying a C9ORF72 expansion were divided into two groups of 21 C9-MND and 11 C9-FTD. All 6 GRN-positive patients had an FTD clinical presentation, whereas patients showing TARDBP (n=10) and SOD1 (n=7) mutations had pure MND. Compared with HC, C9-MND patients showed atrophy of the bilateral pallidi, left caudate, and right hippocampus (p ranging 0.001-0.007); C9-FTD patients showed atrophy in the same structures, as well as in the right caudate, right putamen, left thalamus and left hippocampus (p<0.001-0.02); GRN-FTD patients showed a severe involvement of all basal ganglia and bilateral hippocampi (p<0.001-0.05). TARDBP-MND and SOD1-MND patients showed GM volume values that overlapped with those of HC.

Our data suggest that measures of deep GM and hippocampal involvement might be useful markers of C9ORF72-related disorders, regardless of the clinical presentation within the FTLD spectrum.