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

  • Author(s): Urwin, Hazel;
  • Josephs, Keith A;
  • Rohrer, Jonathan D;
  • Mackenzie, Ian R;
  • Neumann, Manuela;
  • Authier, Astrid;
  • Seelaar, Harro;
  • Van Swieten, John C;
  • Brown, Jeremy M;
  • Johannsen, Peter;
  • Nielsen, Jorgen E;
  • Holm, Ida E;
  • FReJA Consortium;
  • Dickson, Dennis W;
  • Rademakers, Rosa;
  • Graff-Radford, Neill R;
  • Parisi, Joseph E;
  • Petersen, Ronald C;
  • Hatanpaa, Kimmo J;
  • White, Charles L;
  • Weiner, Myron F;
  • Geser, Felix;
  • Van Deerlin, Vivianna M;
  • Trojanowski, John Q;
  • Miller, Bruce L;
  • Seeley, William W;
  • van der Zee, Julie;
  • Kumar-Singh, Samir;
  • Engelborghs, Sebastiaan;
  • De Deyn, Peter P;
  • Van Broeckhoven, Christine;
  • Bigio, Eileen H;
  • Deng, Han-Xiang;
  • Halliday, Glenda M;
  • Kril, Jillian J;
  • Munoz, David G;
  • Mann, David M;
  • Pickering-Brown, Stuart M;
  • Doodeman, Valerie;
  • Adamson, Gary;
  • Ghazi-Noori, Shabnam;
  • Fisher, Elizabeth MC;
  • Holton, Janice L;
  • Revesz, Tamas;
  • Rossor, Martin N;
  • Collinge, John;
  • Mead, Simon;
  • Isaacs, Adrian M
  • et al.
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.

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