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.

Additional Metadata
Keywords FTD, FTLD, FTLD-UPS, FUS, Frontotemporal
Persistent URL dx.doi.org/10.1007/s00401-010-0698-6, hdl.handle.net/1765/20260
Citation
Urwin, H., Josephs, K.A., Rohrer, J.D., Mackenzie, I.R.A., Neumann, H.A.M., Authier, A., … Isaacs, A.M.. (2010). FUS pathology defines the majority of tau-and TDP-43-negative frontotemporal lobar degeneration. Acta Neuropathologica, 120(1), 33–41. doi:10.1007/s00401-010-0698-6