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; Jørgen Erik Nielsen; Ida E Holm; FReJA Consortium; Dennis W Dickson; Rosa Rademakers; Neill R Graff-Radford; Joseph E Parisi; Ronald C Petersen; Kimmo J Hatanpaa; Charles L White; Myron F Weiner; Felix 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

doi:10.1007/s00401-010-0698-6

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, Jørgen Erik Nielsen, Ida E Holm, FReJA Consortium, Dennis W Dickson, Rosa Rademakers, Neill R Graff-Radford, Joseph E Parisi, Ronald C Petersen, Kimmo J Hatanpaa, Charles L WhiteMyron F Weiner, Felix 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

Medical Genetics Program

175 Citations (Scopus)

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 language	English
Journal	Acta Neuropathologica
Volume	120
Issue number	1
Pages (from-to)	33-41
Number of pages	8
ISSN	0001-6322
DOIs	https://doi.org/10.1007/s00401-010-0698-6
Publication status	Published - Jul 2010

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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., FReJA Consortium, Dickson, D. W., Rademakers, R., Graff-Radford, N. R., Parisi, J. E., Petersen, R. C., Hatanpaa, K. J., ... 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

Urwin, H, Josephs, KA, Rohrer, JD, Mackenzie, IR, Neumann, M, Authier, A, Seelaar, H, Van Swieten, JC, Brown, JM, Johannsen, P, Nielsen, JE, Holm, IE, FReJA Consortium, Dickson, DW, Rademakers, R, Graff-Radford, NR, Parisi, JE, Petersen, RC, Hatanpaa, KJ, White, CL, Weiner, MF, Geser, F, Van Deerlin, VM, Trojanowski, JQ, Miller, BL, Seeley, WW, van der Zee, J, Kumar-Singh, S, Engelborghs, S, De Deyn, PP, Van Broeckhoven, C, Bigio, EH, Deng, H-X, Halliday, GM, Kril, JJ, Munoz, DG, Mann, DM, Pickering-Brown, SM, Doodeman, V, Adamson, G, Ghazi-Noori, S, Fisher, EMC, Holton, JL, Revesz, T, Rossor, MN, Collinge, J, Mead, S & Isaacs, AM 2010, 'FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration', Acta Neuropathologica, vol. 120, no. 1, pp. 33-41. https://doi.org/10.1007/s00401-010-0698-6

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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.",

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

year = "2010",

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doi = "10.1007/s00401-010-0698-6",

language = "English",

volume = "120",

pages = "33--41",

journal = "Acta Neuropathologica",

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TY - JOUR

T1 - FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration

AU - Urwin, Hazel

AU - Josephs, Keith A

AU - Rohrer, Jonathan D

AU - Mackenzie, Ian R

AU - Neumann, Manuela

AU - Authier, Astrid

AU - Seelaar, Harro

AU - Van Swieten, John C

AU - Brown, Jeremy M

AU - Johannsen, Peter

AU - Nielsen, Jørgen Erik

AU - Holm, Ida E

AU - FReJA Consortium

AU - Dickson, Dennis W

AU - Rademakers, Rosa

AU - Graff-Radford, Neill R

AU - Parisi, Joseph E

AU - Petersen, Ronald C

AU - Hatanpaa, Kimmo J

AU - White, Charles L

AU - Weiner, Myron F

AU - Geser, Felix

AU - Van Deerlin, Vivianna M

AU - Trojanowski, John Q

AU - Miller, Bruce L

AU - Seeley, William W

AU - van der Zee, Julie

AU - Kumar-Singh, Samir

AU - Engelborghs, Sebastiaan

AU - De Deyn, Peter P

AU - Van Broeckhoven, Christine

AU - Bigio, Eileen H

AU - Deng, Han-Xiang

AU - Halliday, Glenda M

AU - Kril, Jillian J

AU - Munoz, David G

AU - Mann, David M

AU - Pickering-Brown, Stuart M

AU - Doodeman, Valerie

AU - Adamson, Gary

AU - Ghazi-Noori, Shabnam

AU - Fisher, Elizabeth M C

AU - Holton, Janice L

AU - Revesz, Tamas

AU - Rossor, Martin N

AU - Collinge, John

AU - Mead, Simon

AU - Isaacs, Adrian M

PY - 2010/7

Y1 - 2010/7

N2 - 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.

AB - 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.

U2 - 10.1007/s00401-010-0698-6

DO - 10.1007/s00401-010-0698-6

M3 - Journal article

C2 - 20490813

SN - 0001-6322

VL - 120

SP - 33

EP - 41

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 1

ER -

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

Abstract

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