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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. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

We report a Japanese man with familial parkinsonism who died at age 54. His younger brother, his mother, the mother's 4 brothers, and their mother were also affected with similar parkinsonism. The patient had had nystagmus since adolescence. He noticed difficulty in walking and micrographia at age 42. Neurological examination at age 45 in our hospital revealed pendular nystagmus, moderate rigidity in his neck and upper limbs, postural tremor in hands and shuffling gait. He received L-dopa/benzerazide 200 mg and his movement was mildly improved. Then he developed forced closing of eyelids suggesting either blepharospasms or apraxia of eye lid opening. He became apathetic at age 48. He was admitted to our hospital at age 49. On admission, he showed mild dementia and sexually disinhibited behaviours. Moderate downward gaze palsy and rigidity were seen. Increase of L-dopa/benzerazide and pergolide did not improve his parkinsonism and his disinhibited behaviors became worse. L-dopa/benzerazide and pergolide were decreased and he received electroconvulsive therapy at a psychiatric hospital with temporally improvement in his movement. He became unable to walk at age 52 and he was mutic and bedridden. He died of pneumonia at age 54. The patient was discussed in a neurological CPC, and a chief discussant arrived at the conclusion that the patient had a familial form of dementia with Lewy bodies. Many participants thought that he had frontotemporal dementia and parkinsonism linked to chromosome 17. The pathological examination of his brain showed severe neuronal loss in the substantia nigra, subthalamus, and pallidum. Ballooned neurons were observed in the cerebral cortex. Immunohistochemistry using anti-tau antibodies revealed tau-positive neurons, glial cells and threads in the cerebral cortex, white matter and subcortical nuclei; these tau deposition reacted with an anti-4-repeat tau antibody, but not reacted to an anti-3-repeat tau antibody. Sequencing of genomic DNA of the patient showed a missense mutation in exon 10 of tau that caused a substitution at codon N279K. These neuropathological and molecular studies revealed the diagnosis of the patient was FTDP-17 with N279K mutation.