Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging

Abstract

Hereditary frontotemporal dementia associated with mutations in the microtubule-associated protein tau gene (MAPT) is a protean disorder. Three neuropathologic subtypes can be recognized, based on the presence of inclusions made of tau isoforms with three and four repeats, predominantly three repeats and mostly four repeats. This is relevant for establishing a correlation between structural magnetic resonance imaging and positron emission tomography using tracers specific for aggregated tau. Longitudinal studies will be essential to determine the evolution of anatomical alterations from the asymptomatic stage to the various phases of disease following the onset of symptoms.

Keywords: FTDP-17 MAPT; Pick body; [F18]-T807; neurofibrillary tangle; tau; tau aggregation.

Figure 1

Schematic representation of the six tau isoforms generated by alternative mRNA splicing of exons 2, 3 and 10.

Figure 2

Schematic representation of the exons and introns of the MAPT gene, where 53 mutations causing FTDP-17 have been found. Intronic mutations −15 and +4 occur together.

Figure 3

Tau pathology in the hippocampus of a patient carrying the R406W mutation. Dentate gyrus (a, c, e) and pyramidal layers (b, d, f) of the hippocampus are immunolabeled with anti-tau antibodies, showing tau-immunoreactive neuropil threads and neurofibrillary tangles with antibodies AT8 (a, b), 3R tau (c, d) and 4R tau (e, f).

Figure 4

Tau immunohistochemistry in the frontal cortex from a case with the G389R mutation. AT8 labelling demonstrates tau-immunoreactive deposits or Pick bodies in neurons of layers II-VI (a, b). The tau deposits are positive for 3R (c, d) and 4R (e, f) tau.

Figure 5

Tau pathology in the hippocampus of a patient carrying the IVS10+16 mutation. Dentate gyrus (a, c, e) and pyramidal layers (b, d, f) of the hippocampus are immunolabeled with anti-tau antibodies, showing tau-immunoreactive inclusions with antibodies AT8 (a, b) and 4R tau (e, f), but not 3R tau (c, d).

Figure 6

Tau pathology in the hippocampus of a patient carrying the P301L mutation. The dentate gyrus of the hippocampus is labeled with AT8 (a) and 4R tau (c), but not 3R tau (b).

Figure 7

Coronal T1-weighted magnetic resonance imaging (MRI). Panel a is from a 65-year-old male with behavioural-variant frontotemporal dementia associated with the V337M MAPT mutation. Symptoms evolved over 20 years. Note the moderate to marked bilateral frontal and temporal cortical atrophy, with a severe anterior temporal lobe atrophy. Panel b is from a 25-year-old male with frontotemporal dementia and primary progressive aphasia associated with the G389R MAPT mutation. Symptoms rapidly developed over 1 year. Note the mild bilateral frontal and temporal cortical atrophy, with more pronounced medial and inferolateral anterior temporal atrophy. Panel c is from a 51-year-old male with behavioural-variant frontotemporal dementia associated with the IVS10+3 MAPT mutation. Symptoms evolved over 3 years. Note the mild bilateral frontal and temporal cortical atrophy with more pronounced mesial temporal atrophy. Panel d is from a 62-year-old female with severe behavioural-variant frontotemporal dementia associated with the P301L MAPT mutation. Symptoms evolved over 6 years. Note the striking bilateral prefrontal and anterior temporal atrophy with white matter changes.

Figure 8

[F18]-T807 PET images from a 56-year-old individual with frontotemporal dementia and the P301L MAPT mutation. Coronal (top row), sagittal (middle row) and axial (bottom row) views of prefrontal and anterior temporal atrophy with white matter signal change on MRI (left column) and [F18]-T807 images (right column) showing elevated signal in frontal, anterior temporal and parietal cortex, as well as in basal ganglia, consistent with expected tau inclusions. The PET reference region was the cerebellar grey matter.

Figure 9

Post-mortem tau immunohistochemistry using AT8 (a) and in vivo [F-18]-T807 imaging (b) from two individuals with the P301L MAPT mutation. Tau-immunoreactivity is observed in the middle temporal gyrus, inferior temporal gyrus, fusiform gyrus, parahippocampus, entorhinal cortex and hippocampus. The superior temporal gyrus is spared (a). In vivo imaging using T807 demonstrates tau binding in the middle temporal gyrus, inferior temporal gyrus, fusiform gyrus, parahippocampus, entorhinal cortex and hippocampus, with no binding in the superior temporal gyrus (b).