Trajectory of lobar atrophy in asymptomatic and symptomatic GRN mutation carriers: a longitudinal MRI study

Abstract

Loss-of-function mutations in the progranulin gene (GRN) are one of the major causes of familial frontotemporal lobar degeneration. Our objective was to determine the rates and trajectories of lobar cortical atrophy from longitudinal structural magnetic resonance imaging in both asymptomatic and symptomatic GRN mutation carriers. Individuals in this study were from the ADRC and LEFFTDS studies at the Mayo Clinic. We identified 13 GRN mutation carriers (8 asymptomatic, 5 symptomatic) and noncarriers (n = 10) who had at least 2 serial T1-weighted structural magnetic resonance images and were followed annually with a median of 3 years (range 1.0-9.8 years). Longitudinal changes in lobar cortical volume were analyzed using the tensor-based morphometry with symmetric normalization (TBM-SyN) algorithm. Linear mixed-effect models were used to model cortical volume change over time among 3 groups. The annual rates of frontal (p < 0.05) and parietal (p < 0.01) lobe cortical atrophy were higher in asymptomatic GRN mutation carriers than noncarriers. The symptomatic GRN mutation carriers also had increased rates of atrophy in the frontal (p < 0.01) and parietal lobe (p < 0.01) cortices than noncarriers. In addition, greater rates of cortical atrophy were observed in the temporal lobe cortices of symptomatic GRN mutation carriers than noncarriers (p < 0.001). We found that a decline in frontal and parietal lobar cortical volume occurs in asymptomatic GRN mutation carriers and continues in the symptomatic GRN mutation carriers, whereas an increased rate of temporal lobe cortical atrophy is observed only in symptomatic GRN mutation carriers. This sequential pattern of cortical involvement in GRN mutation carriers has important implications for using imaging biomarkers of neurodegeneration as an outcome measure in potential treatment trials involving GRN mutation carriers.

Keywords: Asymptomatic; Frontotemporal dementia; GRN; Longitudinal; Magnetic resonance image.

Copyright © 2019 Elsevier Inc. All rights reserved.

Figures

Figure 1:

Brain MRIs (coronal T1-weighted images) of one GRN mutation carriers who progressed from the asymptomatic to the symptomatic stage are shown in the timeline with proximity to symptom onset against the combined fronto-parietal lobe volume. 0 indicates the actual symptom onset time point. This is a female GRN mutation carrier who was diagnosed as behavior type of mild cognitive impairment at age 53 and progressed to bvFTD one year later. The fronto-parietal lobe volume started to decline years before symptom onset and progressively deteriorated.

Figure 2:

Lobar cortical volumes plotted against age at MRI. The observed trajectories are plotted in the top panel; each line shows the repeated measures for one individual in the raw data. The predicted volumes for ages 50–70 from the mixed models are plotted in the bottom panel. The lines come from the models in Table 2; each shows what we would expect per group in the age range. The blue line represents the asymptomatic GRN mutation carriers; the red line represents the symptomatic GRN mutation carriers; the black line represents the non-carriers.

Figure 3

Voxel-based analyses showed greater annualized rates of cortical atrophy in symptomatic GRN mutation carriers compared to non-carriers. The results are shown at p<0.05 after using the false discovery rate (FDR) correction for multiple comparisons.