FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration

H Urwin, KA Josephs, JD Rohrer, IR Mackenzie, M (Manuela) Neumann, A Authier, Harro Seelaar, J.C. van Swieten, JM Brown, P Johannsen, JE Nielsen, IE Holm, DW Dickson, R Rademakers, NR Graff-Radford, JE Parisi, RC Petersen, KJ Hatanpaa, CL White, MF WeinerF Geser, VM Van Deerlin, JQ Trojanowski, BL Miller, WW Seeley, JA Zee, S Kumar-Singh, S Engelborghs, PP de Deyn, C van Broeckhoven, EH Bigio, HX Deng, GM Halliday, JJ Kril, DG Munoz, DM Mann, SM Pickering-Brown, V Doodeman, G Adamson, S Ghazi-Noori, EMC Fisher, JL Holton, T Revesz, MN Rossor, J Collinge, S Mead, AM Isaacs

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Abstract

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.
Original languageUndefined/Unknown
Pages (from-to)33-41
Number of pages9
JournalActa Neuropathologica
Volume120
Issue number1
DOIs
Publication statusPublished - 2010

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