Patterns of brain atrophy in frontotemporal dementia with mutations in MAPT or PGRN

Background: Approximately 40% of subjects with frontotemporal dementia have a positive family history with an autosomal dominant pattern of inheritance. The two most commonly mutated genes in frontotemporal dementia are microtubule associated protein tau (MAPT) and progranulin (PGRN), both located on chromosome 17q21. The objectives of this study were first to compare patterns of grey matter loss in subjects with mutations in PGRN to subjects with mutations in MAPT, and secondly to assess patterns of atrophy in different MAPT mutations. Methods: We identified 12 subjects with a mutation in PGRN and 19 subjects with a mutation in MAPT that had volumetric MRI. In order to compare the PGRN and MAPT groups we selected 12 of the MAPT subjects, matched by time from disease onset-to-scan to the PGRN subjects. Voxel-based morphometry (VBM) was used to assess patterns of grey matter loss in these PGRN and MAPT groups compared to controls, and compared to each other. In addition, we used VBM to assess patterns of loss in groups of subjects with the IVS10 + 3, IVS10 + 16, S305 N and N279 K mutations which influence the splicing of tau RNA, and the P301L and V337 M mutations that affect the structure of the tau protein. Results: Both PGRN and MAPT groups showed frontal, temporal and parietal lobe grey matter loss compared to controls, although loss was predominantly identified in posterior temporal and parietal lobes in PGRN and anteromedial temporal lobes in MAPT (Figure). The MAPT subjects showed greater loss in the medial temporal lobes than the PGRN subjects. The different MAPT mutations all showed predominant anterior temporal lobe atrophy. Subjects with IVS10 + 3, IVS10 + 16, S305 N and N279 K mutations showed most significant loss in anteromedial temporal lobes, whereas subjects with P301L and V337 M mutations showed most significant loss in the lateral temporal lobes (Figure). Conclusions: Patterns of atrophy on MRI differ between PGRN and MAPT mutation carriers. Furthermore, while all MAPT mutations were associated with temporal atrophy the P301L and V337 M mutations showed a different pattern of temporal involvement to the IVS10 + 3, IVS10 + 16, S305 N and N279 K mutations. Patterns of atrophy may therefore aid in the differentiation of these different mutations.

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