White matter abnormalities in presymptomatic GRN and C9orf72 mutation carriers

Abstract A large proportion of familial frontotemporal dementia is caused by TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa) proteinopathies. Accordingly, carriers of autosomal dominant mutations in the genes associated with TAR DNA binding protein 43 aggregation, such as chromosome 9 open reading frame 72 (C9orf72) or progranulin (GRN), are at risk of later developing frontotemporal dementia. Brain imaging abnormalities that develop before dementia onset in mutation carriers may serve as proxies for the presymptomatic stages of familial frontotemporal dementia due to genetic cause. Our study objective was to investigate brain MRI-based white matter changes in predementia participants carrying mutations in C9orf72 or GRN genes. We analyzed mutation carriers and their family member controls (Noncarriers) from the University of British Columbia Familial frontotemporal dementia study. First, a total of 42 participants (8 GRN carriers; 11 C9orf72 carriers; 23 Noncarriers) had longitudinal T1-weighted MRI over approximately two years. White matter signal hypointensities were segmented and volumes were calculated for each participant. General linear models were applied to compare the baseline burden and the annualized rate of accumulation of signal abnormalities among mutation carriers and Noncarriers. Second, a total of 60 participants (9 GRN carriers; 17 C9orf72 carriers; 34 Noncarriers) had cross-sectional diffusion tensor MRI available. For each participant, we calculated the average fractional anisotropy and mean, radial, and axial diffusivity parameter values within the normal-appearing white matter tissues. General linear models were applied to compare whether mutation carriers and Noncarriers had different trends of diffusion tensor imaging parameter values as they neared the expected age of onset. Baseline volumes of white matter signal abnormalities were not significantly different among mutation carriers and Noncarriers. Longitudinally, GRN carriers had significantly higher annualized rates of accumulation (estimated mean: 15.87%/y) compared to C9orf72 carriers (3.69%/y) or Noncarriers (2.64%/y). A significant relationship between diffusion tensor imaging parameter values and increasing expected age of onset was found in periventricular normal-appearing white matter region. Specifically, GRN carriers had a tendency of faster increase of mean and radial diffusivity values and C9orf72 carriers had a tendency of faster decline of fractional anisotropy values as they reached closer to the expected age of dementia onset. These findings suggest that white matter changes may represent early markers of familial frontotemporal dementia due to genetic cause. However, GRN and C9orf72 mutation carriers may have different mechanisms leading to tissue abnormalities.