Abstract
Genetic frontotemporal dementia is most commonly caused by mutations in the progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) 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 GRN, 13 MAPT and 23 C9orf72), 61 presymptomatic mutation carriers (25 GRN, 8 MAPT and 28 C9orf72) 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 GRN group compared with the other groups with no differences in the MAPT or C9orf72 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 GRN 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 GRN group compared with the other groups, with the lesions in the GRN 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.
Highlights
Frontotemporal dementia (FTD) is an umbrella term used to denote a group of neurodegenerative disorders affecting principally the frontal and temporal lobes
Mean adjusted back-transformed results with confidence intervals and p-values for group comparisons are shown in Table 2: symptomatic genes: progranulin (GRN) subjects had a significantly higher mean global white matter hyperintensities (WMH) volume than presymptomatic GRN cases and noncarriers, as well as more than the symptomatic microtubule associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) groups
Through the use of a lesion segmentation algorithm adapted to segment WMH from 3D T1- and T2- weighted scans this study extends previous work on WMH in genetic FTD to show their presence in a symptomatic GRN mutation group only, and not in presymptomatic participants nor in those with MAPT or C9orf72 mutations
Summary
Frontotemporal dementia (FTD) is an umbrella term used to denote a group of neurodegenerative disorders affecting principally the frontal and temporal lobes. It is a highly heritable disorder with approximately a third of cases being caused by mutations in predominantly three genes: progranulin (GRN), microtubule associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) (Rohrer et al, 2015; Rohrer and Warren, 2011). Most antemortem studies of familial FTD have focused on changes in gray matter, but some types of FTD are known to be associated with white matter pathology Such changes may be seen by magnetic resonance imaging (MRI) e.g. cerebral white matter hyperintensities (WMH). A detailed investigation in a large cohort has yet to be performed
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