White matter hyperintensities are seen only in mutation carriers in the GENFI cohort.

Genetic frontotemporal dementia is most commonly caused by mutations in the progranulin , microtubule-associated protein tau ( and chromosome 9 open reading frame 72 ) genes. Previous small studies have reported the presence of cerebral white matter hyperintensities (WMH) in genetic FTD but this has not been systematically studied across the different mutations. In this study WMH were assessed in 180 participants from the Genetic FTD Initiative (GENFI) with 3D T1- and T2-weighed magnetic resonance images: 43 symptomatic (7 , 13 and 23 ), 61 presymptomatic mutation carriers (25 , 8 and 28 ) and 76 mutation negative non-carrier family members. An automatic detection and quantification algorithm was developed for determining load, location and appearance of WMH. Significant differences were seen only in the symptomatic group compared with the other groups with no differences in the or groups: increased global load of WMH was seen, with WMH located in the frontal and occipital lobes more so than the parietal lobes, and nearer to the ventricles rather than juxtacortical. Although no differences were seen in the presymptomatic group as a whole, in the cohort only there was an association of increased WMH volume with expected years from symptom onset. The appearance of the WMH was also different in the group compared with the other groups, with the lesions in the group being more similar to each other. The presence of WMH in those with progranulin deficiency may be related to the known role of progranulin in neuroinflammation, although other roles are also proposed including an effect on blood-brain barrier permeability and the cerebral vasculature. Future studies will be useful to investigate the longitudinal evolution of WMH and their potential use as a biomarker as well as post-mortem studies investigating the histopathological nature of the lesions.