Clinical heterogeneity of frontotemporal dementia and Parkinsonism linked to chromosome 17 caused by MAPT N279K mutation in relation to tau positron emission tomography features

Background: While mechanistic links between tau abnormalities and neurodegeneration have been proven in frontotemporal dementia and parkinsonism linked to chromosome 17 caused by MAPT mutations, variability of the tau pathogenesis and its relation to clinical progressions in the same MAPT mutation carriers are yet to be clarified. Objectives: The present study aimed to analyze clinical profiles, tau accumulations, and their correlations in 3 kindreds with frontotemporal dementia and parkinsonism linked to chromosome 17 attributed to the MAPT N279K mutation. Methods: Four patients with N279K mutant frontotemporal dementia and parkinsonism linked to chromosome 17/MAPT underwent [ ¹¹ C]PBB3-PET to estimate regional tau loads. Results: Haplotype assays revealed that these kindreds originated from a single founder. Despite homogeneity of the disease-causing MAPT allele, clinical progression was more rapid in 2 kindreds than in the other. The kindred with slow progression showed mild tau depositions, mostly confined to the midbrain and medial temporal areas. In contrast, kindreds with rapid progression showed profoundly increased [ ¹¹ C]PBB3 binding in widespread regions from an early disease stage. Conclusions: [ ¹¹ C]PBB3-PET can capture four-repeat tau pathologies characteristic of N279K mutant frontotemporal dementia and parkinsonism linked to chromosome 17/MAPT. Our findings indicate that, in addition to the mutated MAPT allele, genetic and/or epigenetic modifiers of tau pathologies lead to heterogeneous clinicopathological features.