Longitudinal brain atrophy rates in presymptomatic genetic frontotemporal dementia

Background In light of upcoming clinical trials for genetic frontotemporal dementia (FTD), it is important to identify at what age brain atrophy rates start to accelerate and deviate from normal aging effects to find the optimal starting point for treatment. We aimed to investigate longitudinal brain atrophy rates in the presymptomatic stage of genetic FTD, using normative brain volumetry software. Method 34 GRN, eight MAPT, and 14 C9orf72 presymptomatic mutation carriers underwent longitudinal volumetric T1‐weighted MRI of the brain with a one‐ to two‐year interval (mean number of scans = 3.5, SD = 1.6). Images were automatically analyzed with Quantib ® ND which consisted of volume measurements (CSF and grey + white matter) of lobes (left, right, and combined), cerebellum, and hippocampus. All volumes were compared to reference centile curves based on a large population‐derived sample of non‐demented individuals (n = 4951). Mixed‐effects models were fitted to analyze atrophy rates of the different gene groups as a function of age, and were corrected for sex, head coil, and scanner software version. Result Atrophy rates of the total brain, frontal lobe, and temporal lobe differed between gene groups (all p<0.002). GRN mutation carriers declined faster than the reference centile curves for all brain areas, though relative volumes remained between 5 th and 75 th percentile between the ages of 45 – 70. In MAPT mutation carriers, frontal lobe volume was already at the 5 th percentile at age 45, and showed further decline between the ages 50‐60. Temporal lobe volume started in the 50 th percentile at age 45, but showed fastest decline over time compared to other brain structures. Frontal, temporal, parietal and cerebellar volume already started below the 5 th percentile compared to the reference centile curves at age 45 for C9orf72 mutation carriers, but there was minimal decline over time until the age of 60. Conclusion We provide evidence for longitudinal brain atrophy in the presymptomatic stage of genetic FTD. The affected brain areas and the age after which atrophy rates start to accelerate and diverge from normal aging slopes differed between gene groups. These results highlight the value of normative volumetry software for disease‐tracking and staging biomarkers in genetic FTD.