A Japanese male in his late 40s, with no obvious neuropsychiatric family history, presented stereotyped behavior, disinhibition, and loss of sympathy, which gradually became more apparent. Hyperorality, dietary changes, repetitive speech, hoarding, and apathy followed within a few years. Donepezil was not effective, and at age 51, he was admitted to our hospital. Neurological examination and blood test findings were normal. The Cognistat test showed normal orientation but impaired memory, language, and reasoning function, and the Frontal Assessment Battery (FAB) score was 14/18, indicating slight frontal lobe dysfunction. Brain MR imaging revealed marked atrophy of the bilateral hippocampus, amygdala, and frontal and anterior temporal lobes (Fig. 1). The patient was diagnosed as probable behavioral variant FTD (bvFTD) [5]. The behavioral symptoms improved slightly on treatment with carbamazepine and valproic acid, but the cognitive dysfunction progressed. The patient's spontaneous activity gradually decreased, followed by muscle wasting, although other motor symptoms including parkinsonism were not apparent in the advanced stages. The patient eventually became bedridden and died of aspiration pneumonia at age 58.

Postmortem examination showed macroscopically severe brain atrophy in the bilateral cerebral frontotemporal lobes (Fig. 2A). The temporal lobe showed severer atrophy in the lower parts (T3-4) than in the upper parts (T1-2) (Fig. 2B), and atrophy of the caudate nuclei, amygdala, and hippocampus was also apparent. The brainstem was preserved, and the substantia nigra and locus coeruleus showed mildly reduced pigmentation. Histologically, neuronal loss and gliosis were the most pronounced in the middle and inferior temporal cortices (Fig. 2C), entorhinal cortex, hippocampus, and striatum. In the locus coeruleus and substantia nigra, some free melanin was found, but neuronal loss was not apparent. Degeneration of precentral gyrus and pyramidal tract was not evident. Gallyas-Braak (GB) staining revealed diffuse neuronal and glial staining in the cerebral neocortex, limbic regions, subcortical nuclei, and white matter (Fig. 2D–F). Immunostaining revealed phosphorylated 4-repeat tau inclusions (Fig. 2G–M), as summarized in Table 1. The major neuronal tau inclusions were GB-positive dots and thread-like dystrophic neurites. Pretangles were also seen but were not very frequent (Fig. 2E, G, H). Glial deposits were mostly GB-positive oligodendroglial inclusions and coiled bodies (Fig. 2F). Astrocytic inclusions, observed as tuft-shaped (Fig. 2I) or globular inclusions (Fig. 2J, K), were considerably fewer and were GB-negative. The accumulation of tau deposits was less in the brainstem and cerebellum. The pathological hallmarks of CBD, such as prominent ballooned neurons and astrocytic plaques, were absent. Argyrophilic grains were moderately seen in amygdala and related limbic cortexes. Anti-phosphorylated synuclein immunostaining detected only a few Lewy neurites in the hippocampus and temporal cortex, and methenamine‑silver staining and anti-phosphorylated TDP-43 immunostaining were consistently negative. Immunoblotting of the sarkosyl-insoluble fraction from the temporal lobes revealed a 4-repeat tau banding pattern with predominant 37 kDa fragments (Fig. 2N). Electron micrographs of sarkosyl-insoluble fraction from the temporal lobes with AT8 antibody labeling revealed ribbon-like filamentous structures with a regular twist at approximately every 200 nm (Fig. 2O). The DNA sequence analysis revealed the presence of MAPT IVS 10 + 14C > T heterozygous mutation in the frontal cortex (Fig. 2P).