title: FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration.
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.
authors.affiliation: UCL Institute of Neurology, London, UK.
authors.forename: Hazel
authors.initials: H
authors.lastname: Urwin
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rohrer
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Astrid
authors.initials: A
authors.lastname: Authier
authors.forename: Harro
authors.initials: H
authors.lastname: Seelaar
authors.forename: John C
authors.initials: JC
authors.lastname: Van Swieten
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Brown
authors.forename: Peter
authors.initials: P
authors.lastname: Johannsen
authors.forename: Jorgen E
authors.initials: JE
authors.lastname: Nielsen
authors.forename: Ida E
authors.initials: IE
authors.lastname: Holm
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Kimmo J
authors.initials: KJ
authors.lastname: Hatanpaa
authors.forename: Charles L
authors.initials: CL
authors.lastname: White
authors.forename: Myron F
authors.initials: MF
authors.lastname: Weiner
authors.forename: Felix
authors.initials: F
authors.lastname: Geser
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.forename: Julie
authors.initials: J
authors.lastname: van der Zee
authors.forename: Samir
authors.initials: S
authors.lastname: Kumar-Singh
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: Deng
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
authors.forename: Jillian J
authors.initials: JJ
authors.lastname: Kril
authors.forename: David G
authors.initials: DG
authors.lastname: Munoz
authors.forename: David M
authors.initials: DM
authors.lastname: Mann
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pickering-Brown
authors.forename: Valerie
authors.initials: V
authors.lastname: Doodeman
authors.forename: Gary
authors.initials: G
authors.lastname: Adamson
authors.forename: Shabnam
authors.initials: S
authors.lastname: Ghazi-Noori
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.forename: Martin N
authors.initials: MN
authors.lastname: Rossor
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Isaacs
mesh_terms: D000328:Adult; D017668:Age of Onset; D004268:DNA-Binding Proteins / Q000378:metabolism; D020820:Dyskinesias / Q000453:epidemiology; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D057174:Frontotemporal Lobar Degeneration / Q000453:epidemiology* / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000453:epidemiology; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D016875:tau Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C054369:MAPT protein, human; D034702:RNA-Binding Protein FUS; D016875:tau Proteins