Although Pick’s disease had been considered as threerepeat (3R) tauopathy [3], recent studies have reported that 3R tau, four-repeat (4R) tau or both is accumulated in Pick’s disease brains [6]. We present an unusual case with frontotemporal dementia (FTD) and parkinsonism with 4R tau-positive Pick body (PiB)-like inclusions. A 66-year-old woman presented with a 3-year history of personality and behavior changes and a shuffling gait with small steps: she had no family history. Levodopa slightly relieved her parkinsonism. On the Wechsler Adult Intelligence Scale (WAIS) she achieved a verbal IQ score of 115. Her postural reflex was disturbed. Other neurological examinations were normal. An MRI scan showed mild diffuse brain atrophy. She gradually deteriorated and was mute and bed-bound at the age of 73. She died at the age of 76. Her brain weighed 825 g. Macroscopically, the cerebral hemisphere showed a severe degree of atrophy of the frontal lobe and the anterior parts of the temporal lobe and hippocampus (Fig. 1a). Microscopically, neuronal loss with gliosis was found in the upper cortical layer of the frontotemporal cortex, globus pallidus, thalamus, hippocampal formation and substantia nigra, while the caudate nucleus and putamen were mildly affected. The most prominent histological features were numerous basophilic intracytoplasmic inclusions, which were sharply circumscribed, resembling PiBs in the lower cortical layers of the frontal, temporal, parietal, insular, and cingulated cortex (Fig. 1h, inset). Ballooned neurons were present in the same area. Bodian staining showed argyrophilic PiB-like inclusions (Fig. 1b) and glial inclusions (Fig. 1c) in the same area, and globose neurofibrillary tangles (NFTs) (Fig. 1d) in the brain stem nuclei. A few neuronal and glial inclusions were stained by the Gallyas-Braak method. PiB-like inclusions were not observed in the dentate gyrus. The selected paraffin-embedded sections from the temporal cortex were immunostained using the following primary antibodies: anti-tau (AT8, monoclonal, mouse, 1:800, Innogenetics, Belgium), anti-ubiquitin (DF2, monoclonal, mouse, 1:20, donated by Dr. H. Mori), anti-a-synuclein (polyclonal, rabbit, 1:1,000, Chemicon, USA), anti-Ab (polyclonal, rabbit, 1:200, IBL, Japan), antiphosphorylated neurofilament (SMI, monoclonal, mouse, 1:1,000, Sigma, USA), anti-3R tau (RD3: monoclonal, mouse, 1:100, Upstate, USA) and anti-4R tau (RD4: monoclonal, mouse, 1:100, Upstate). RD3 and RD4 were applied after pretreatment of the sections with formic acid for 30 min. AT8 immunostaining showed numerous neuronal and glial inclusions in the cortex (Fig. 1e). Threads and oligodendroglial coiled bodies in the white matter were also stained by AT8. These inclusions were positive for RD4 (Fig. 1f) but negative for RD3 (Fig. 1g), DF2, SMI and a-synuclein. For electron microscopy, a block of the left temporal cortex was fixed in 4% paraformaldehyde, and then transferred to a maintenance solution of 20% sucrose in 0.01 M phosphate-buffered saline, pH 7.4. One-mmthick blocks were embedded in LR white Resin (Reading, UK). For immunoelectron microscopy, ultrathin Y. Motoi (&) AE M. Itaya AE Y. Mizuno AE H. Mori Department of Neurology, Juntendo University School of Medicine, 3-1-3 Hongo Bunkyo-ku, 113-8431 Tokyo, Japan E-mail: motoi@med.juntendo.ac.jp Tel.: +81-3-38133111 Fax: +81-3-56840476