Urwin, H. (Hazel); Josephs, K.A. (Keith); Rohrer, J.D. (Jonathan Daniel); Mackenzie, I.R.A. (Ian); Neumann, H.A.M. (Martino); Authier, A. (Astrid); Seelaar, H. (Harro); Swieten, van J.C.; Brown, J.M. (Jeremy); Johannsen, P. (Peter); Nielsen, J.E. (Jorgen); Holm, I.E. (Ida); Dickson, D. (Dennis); Rademakers, R. (Rosa); Graff-Radford, N.R. (Neill); Parisi, J.E. (Joseph); Petersen, R.C. (Ronald); Hatanpaa, K.J. (Kimmo); White Iii, C.L. (Charles); Weiner, M.F. (Myron); Geser, F. (Felix); Deerlin, V.M. (Vivianna); Trojanowski, J.Q. (John); Miller, B.L. (Bruce Lars); Seeley, W. (William); Zee, van der J. (Jill); Kumar-Singh, S. (Samir); Engelborghs, S. (Sebastiaan); Deyn, de P.P. (Peter); Broeckhoven, van C. (Christine); Bigio, E.H. (Eileen); Deng, H-X. (Han-Xiang); Halliday, G.M. (Glenda Margaret); Kril, J.J. (Jillian); Munoz, D.G. (David); Mann, D. (David); Pickering-Brown, S. (Stuart); Doodeman, V. (Valerie); Adamson, G. (Gary); Ghazi-Noori, S. (Shabnam); Fisher, E.M.C. (Elizabeth); Holton, J.L. (Janice); Revesz, T. (Tamas); Rossor, M.N. (Martin); Collinge, J. (John); Mead, S. (Simon); Isaacs, A.M. (Adrian)
Through an international consortium, we have collected 37 tau-and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43-and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.