It is important to characterize the longitudinal imaging features in f-FTD in mutation carriers in order to plan for future disease-modifying trials.

To characterize the longitudinal volumetric changes in familial frontotemporal dementia (f-FTD).

Using MRI we compared rates of atrophy between 4 microtubule associated protein tau (MAPT) mutation carriers (N279K mutation) who transitioned from asymptomatic to symptomatic (converter) to 8 asymptomatic (asym) and 8 non-mutation carrier family controls (noncarrier). MRI was analyzed using the TBM-SyN methodology to quantify lobar volumes at baseline and longitudinally.

There were no differences between the 3 groups at baseline based on sex, education, age at initial MRI scan and cognitive scores. Baseline temporal (P=0.01) and parietal (P=0.02) lobe volumes were less in the converter group compared to asym and noncarrier groups. Using mixed effect models with the noncarriers as the reference, the annual change estimates (95% CI) were greatest in the temporal lobes [converter x age at MRI= -1.26 (-1.83, -0.69), P<0.001, and asym x age at MRI= -0.73 (-1.21, -0.26), P=0.003].  The annual change estimates in the frontal and parietal lobes were lower but still significant [frontal: converter x age at MRI= -0.76 (-1.33, -0.18), P=0.01, and parietal: converter x age at MRI= -0.19 (-0.35, -0.03), P=0.02]. The annual changes for frontotemporal lobe volume compared to non-carrier were: converter x age at MRI= -2.02 (-3.06, -0.97), P<0.001, and asym x age at MRI= -1.20 (-2.08, -0.32), P=0.008.

These findings suggest that among this cohort of MAPT mutation carriers, a) the temporal lobe volumes decline earliest (asymptomatic phase) and the changes are most dramatic during the symptomatic phase, b) frontal and parietal lobe volumes also decline during the early symptomatic phase, and c) the composite frontotemporal volume appears to show the most robust change in the asymptomatic as well as symptomatic phases.