These results suggest that ubiquitin-related cytoskeletal abnormalities are common in cerebral non-motor small neurons in these patients. In the following year, Wightman et al.7 confirmed our findings. In 1994,

the Lund and Manchester Groups proposed clinical and neuropathological criteria for frontotemporal dementia, dividing it into three subgroups: the frontal lobe degeneration type, the Pick type and the MND type.8 The BGB324 nmr inclusions were described as a neuropathological marker of the MND type, in which “hippocampal dentate gyrus neurons show inclusions that are ubiquitin-positive but not silver or tau reactive”. In 1998, Neary et al.9 proposed a consensus on the clinical diagnostic criteria for frontotemporal lobar degeneration (FTLD). However, FTLD is a heterogeneous entity, and the pathological diagnosis of FTLD includes tau-positive FTLD and tau-negative FTLD.10 Two variants of tau-negative FTLD are FTLD with and without MND. FTLD with ubiquitin-positive tau-negative neuronal inclusions was grouped as FTLD-U. In 1996, we examined the inclusions using paired routine electron-microscopic ultrathin sections and adjacent semithin sections.11 After the removal of the epon, the semithin sections were stained

with anti-ubiquitin antiserum. In the ubiquitin-stained semithin sections, the inclusions formed a crescent or circular pattern around the nucleus (Fig. 2). The

PI-1840 adjacent ultrathin sections were examined by electron microscopy, and there was no limiting membrane around the area (Fig. 3). The area seemed to consist of ordinary cytoplasmic organelles, this website including lipofuscin, mitochondria, cytoplasmic reticulum, and many ribosome-like granules. There were a few filamentous structures. When the findings from immunoelectron-microscopic and semithin sections were compared, the ubiquitin-positive structures seemed to correspond to ribosome-like granules and filaments. The granules were less electron-dense and more irregular, with amorphous outlines, than the ribosomes in the non-ubiquitinated cytoplasm. These findings suggest the development of ribosome-associated and ubiquitin-related abnormalities in the neurons of the extra-motor cortices of these patients. The inclusions were positive for ubiquitin-binding protein p6212,13 and vacuole-creating protein.14 However, their main components were unknown. In 2006, Neumann et al.15 and Arai et al.16 found that the ubiquitin-positive tau-negative inclusions are composed of the 43-kDa TAR DNA-binding protein (TDP-43). Diseases that include TDP-43-positive inclusions have recently been classified as TDP-43 proteinopathy.17 This work was supported by Grants-in-Aid from the Ministry of Health, Labour and Welfare of Japan, and also from the Ministry of Education, Culture, Sports, Science and Technology of Japan.