Patterns of gray matter atrophy in genetic frontotemporal dementia: results from the GENFI study

Abstract

Frontotemporal dementia (FTD) is a highly heritable condition with multiple genetic causes. In this study, similarities and differences of gray matter (GM) atrophy patterns were assessed among 3 common forms of genetic FTD (mutations in C9orf72, GRN, and MAPT). Participants from the Genetic FTD Initiative (GENFI) cohort with a suitable volumetric T1 magnetic resonance imaging scan were included (319): 144 nonmutation carriers, 128 presymptomatic mutation carriers, and 47 clinically affected mutation carriers. Cross-sectional differences in GM volume between noncarriers and carriers were analyzed using voxel-based morphometry. In the affected carriers, each genetic mutation group exhibited unique areas of atrophy but also a shared network involving the insula, orbitofrontal lobe, and anterior cingulate. Presymptomatic GM atrophy was observed particularly in the thalamus and cerebellum in the C9orf72 group, the anterior and medial temporal lobes in MAPT, and the posterior frontal and parietal lobes as well as striatum in GRN. Across all presymptomatic carriers, there were significant decreases in the anterior insula. These results suggest that although there are important differences in atrophy patterns for each group (which can be seen presymptomatically), there are also similarities (a fronto-insula-anterior cingulate network) that help explain the clinical commonalities of the disease.

Keywords: Atrophy; Frontotemporal dementia; Magnetic resonance imaging; Preclinical dementia; Voxel-based morphometry.

Fig. 1

Gray-matter (GM) differences by mutation and clinical status. GM differences in affected (odd rows, p < 0.05 FWE-corrected) and presymptomatic (even rows, p < 0.001 uncorrected) carriers compared to noncarriers. Comparisons to the C9orf72 carriers are in the top 2 rows (with findings at p < 0.05, FWE-corrected circled in the presymptomatic group), the GRN carriers in the middle 2 rows, and MAPT carriers in the bottom 2 rows.

Fig. 2

Comparison of gray matter atrophy patterns across the 3 genetic mutations. Comparison of atrophy patterns across the 3 genetic groups (symptomatic carriers). On the left hand of the figure, masks of the regions where there are significant differences (p < 0.05, FWE-corrected) are shown, color coded by mutation, along with areas where the patterns intersect within 2 or more mutations. The region satisfying the compound hypothesis of all 3 contrasts being true, indicating the intersection of atrophy in these mutations, is coded in light pink. A surface rendering of this intersection is shown on the right. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)