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

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

Research output: Contribution to journalArticle

171 Scopus citations

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 languageEnglish (US)
Pages (from-to)33-41
Number of pages9
JournalActa Neuropathologica
Volume120
Issue number1
DOIs
StatePublished - Jul 2010

Keywords

  • FTD
  • FTLD
  • FTLD-UPS
  • FUS
  • Frontotemporal

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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  • Cite this

    Urwin, H., Josephs, K. A., Rohrer, J. D., MacKenzie, I. R., Neumann, M., Authier, A., Seelaar, H., Van Swieten, J. C., Brown, J. M., Johannsen, P., Nielsen, J. E., Holm, I. E., Dickson, D. W., Rademakers, R., Graff-Radford, N. R., Parisi, J. E., Petersen, R. C., Hatanpaa, K. J., White, C. L., ... Isaacs, A. M. (2010). FUS pathology defines the majority of tau-and TDP-43-negative frontotemporal lobar degeneration. Acta Neuropathologica, 120(1), 33-41. https://doi.org/10.1007/s00401-010-0698-6