Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: Consensus of the Consortium for Frontotemporal Lobar Degeneration

Nigel J. Cairns, Eileen H. Bigio, Ian R A Mackenzie, Manuela Neumann, Virginia M Y Lee, Kimmo J. Hatanpaa, Charles L. White, Julie A. Schneider, Lea Tenenholz Grinberg, Glenda Halliday, Charles Duyckaerts, James S. Lowe, Ida E. Holm, Markus Tolnay, Koichi Okamoto, Hideaki Yokoo, Shigeo Murayama, John Woulfe, David G. Munoz, Dennis W DicksonPaul G. Ince, John Q. Trojanowski, David M A Mann

Research output: Contribution to journalArticle

753 Citations (Scopus)

Abstract

The aim of this study was to improve the neuropathologic recognition and provide criteria for the pathological diagnosis in the neurodegenerative diseases grouped as frontotemporal lobar degeneration (FTLD); revised criteria are proposed. Recent advances in molecular genetics, biochemistry, and neuropathology of FTLD prompted the Midwest Consortium for Frontotemporal Lobar Degeneration and experts at other centers to review and revise the existing neuropathologic diagnostic criteria for FTLD. The proposed criteria for FTLD are based on existing criteria, which include the tauopathies [FTLD with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, sporadic multiple system tauopathy with dementia, argyrophilic grain disease, neurofibrillary tangle dementia, and FTD with microtubule-associated tau (MAPT) gene mutation, also called FTD with parkinsonism linked to chromosome 17 (FTDP-17)]. The proposed criteria take into account new disease entities and include the novel molecular pathology, TDP-43 proteinopathy, now recognized to be the most frequent histological finding in FTLD. TDP-43 is a major component of the pathologic inclusions of most sporadic and familial cases of FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Molecular genetic studies of familial cases of FTLD-U have shown that mutations in the progranulin (PGRN) gene are a major genetic cause of FTLD-U. Mutations in valosin-containing protein (VCP) gene are present in rare familial forms of FTD, and some families with FTD and/or MND have been linked to chromosome 9p, and both are types of FTLD-U. Thus, familial TDP-43 proteinopathy is associated with defects in multiple genes, and molecular genetics is required in these cases to correctly identify the causative gene defect. In addition to genetic heterogeneity amongst the TDP-43 proteinopathies, there is also neuropathologic heterogeneity and there is a close relationship between genotype and FTLD-U subtype. In addition to these recent significant advances in the neuropathology of FTLD-U, novel FTLD entities have been further characterized, including neuronal intermediate filament inclusion disease. The proposed criteria incorporate up-to-date neuropathology of FTLD in the light of recent immunohistochemical, biochemical, and genetic advances. These criteria will be of value to the practicing neuropathologist and provide a foundation for clinical, clinico-pathologic, mechanistic studies and in vivo models of pathogenesis of FTLD.

Original languageEnglish (US)
Pages (from-to)5-22
Number of pages18
JournalActa Neuropathologica
Volume114
Issue number1
DOIs
StatePublished - Jul 2007

Fingerprint

Frontotemporal Lobar Degeneration
Consensus
TDP-43 Proteinopathies
Molecular Biology
Tauopathies
Motor Neuron Disease
Genes
Mutation
Dementia
Progressive Supranuclear Palsy
Frontotemporal Dementia
Chromosomes, Human, Pair 17
Neurofibrillary Tangles

Keywords

  • Charged multivesicular body protein 2B
  • Frontotemporal dementia
  • Frontotemporal lobar degeneration
  • Motor neuron disease
  • Neuronal intermediate filament inclusion disease
  • Neuropathologic diagnosis
  • Progranulin
  • Progressive non-fluent aphasia
  • Semantic dementia
  • Tauopathy
  • TDP-43 proteinopathy
  • Ubiquitin
  • Valosin-containing protein

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Neuroscience(all)

Cite this

Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration : Consensus of the Consortium for Frontotemporal Lobar Degeneration. / Cairns, Nigel J.; Bigio, Eileen H.; Mackenzie, Ian R A; Neumann, Manuela; Lee, Virginia M Y; Hatanpaa, Kimmo J.; White, Charles L.; Schneider, Julie A.; Grinberg, Lea Tenenholz; Halliday, Glenda; Duyckaerts, Charles; Lowe, James S.; Holm, Ida E.; Tolnay, Markus; Okamoto, Koichi; Yokoo, Hideaki; Murayama, Shigeo; Woulfe, John; Munoz, David G.; Dickson, Dennis W; Ince, Paul G.; Trojanowski, John Q.; Mann, David M A.

In: Acta Neuropathologica, Vol. 114, No. 1, 07.2007, p. 5-22.

Research output: Contribution to journalArticle

Cairns, NJ, Bigio, EH, Mackenzie, IRA, Neumann, M, Lee, VMY, Hatanpaa, KJ, White, CL, Schneider, JA, Grinberg, LT, Halliday, G, Duyckaerts, C, Lowe, JS, Holm, IE, Tolnay, M, Okamoto, K, Yokoo, H, Murayama, S, Woulfe, J, Munoz, DG, Dickson, DW, Ince, PG, Trojanowski, JQ & Mann, DMA 2007, 'Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: Consensus of the Consortium for Frontotemporal Lobar Degeneration', Acta Neuropathologica, vol. 114, no. 1, pp. 5-22. https://doi.org/10.1007/s00401-007-0237-2
Cairns, Nigel J. ; Bigio, Eileen H. ; Mackenzie, Ian R A ; Neumann, Manuela ; Lee, Virginia M Y ; Hatanpaa, Kimmo J. ; White, Charles L. ; Schneider, Julie A. ; Grinberg, Lea Tenenholz ; Halliday, Glenda ; Duyckaerts, Charles ; Lowe, James S. ; Holm, Ida E. ; Tolnay, Markus ; Okamoto, Koichi ; Yokoo, Hideaki ; Murayama, Shigeo ; Woulfe, John ; Munoz, David G. ; Dickson, Dennis W ; Ince, Paul G. ; Trojanowski, John Q. ; Mann, David M A. / Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration : Consensus of the Consortium for Frontotemporal Lobar Degeneration. In: Acta Neuropathologica. 2007 ; Vol. 114, No. 1. pp. 5-22.
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AU - Mackenzie, Ian R A

AU - Neumann, Manuela

AU - Lee, Virginia M Y

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AU - Schneider, Julie A.

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AU - Yokoo, Hideaki

AU - Murayama, Shigeo

AU - Woulfe, John

AU - Munoz, David G.

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N2 - The aim of this study was to improve the neuropathologic recognition and provide criteria for the pathological diagnosis in the neurodegenerative diseases grouped as frontotemporal lobar degeneration (FTLD); revised criteria are proposed. Recent advances in molecular genetics, biochemistry, and neuropathology of FTLD prompted the Midwest Consortium for Frontotemporal Lobar Degeneration and experts at other centers to review and revise the existing neuropathologic diagnostic criteria for FTLD. The proposed criteria for FTLD are based on existing criteria, which include the tauopathies [FTLD with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, sporadic multiple system tauopathy with dementia, argyrophilic grain disease, neurofibrillary tangle dementia, and FTD with microtubule-associated tau (MAPT) gene mutation, also called FTD with parkinsonism linked to chromosome 17 (FTDP-17)]. The proposed criteria take into account new disease entities and include the novel molecular pathology, TDP-43 proteinopathy, now recognized to be the most frequent histological finding in FTLD. TDP-43 is a major component of the pathologic inclusions of most sporadic and familial cases of FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Molecular genetic studies of familial cases of FTLD-U have shown that mutations in the progranulin (PGRN) gene are a major genetic cause of FTLD-U. Mutations in valosin-containing protein (VCP) gene are present in rare familial forms of FTD, and some families with FTD and/or MND have been linked to chromosome 9p, and both are types of FTLD-U. Thus, familial TDP-43 proteinopathy is associated with defects in multiple genes, and molecular genetics is required in these cases to correctly identify the causative gene defect. In addition to genetic heterogeneity amongst the TDP-43 proteinopathies, there is also neuropathologic heterogeneity and there is a close relationship between genotype and FTLD-U subtype. In addition to these recent significant advances in the neuropathology of FTLD-U, novel FTLD entities have been further characterized, including neuronal intermediate filament inclusion disease. The proposed criteria incorporate up-to-date neuropathology of FTLD in the light of recent immunohistochemical, biochemical, and genetic advances. These criteria will be of value to the practicing neuropathologist and provide a foundation for clinical, clinico-pathologic, mechanistic studies and in vivo models of pathogenesis of FTLD.

AB - The aim of this study was to improve the neuropathologic recognition and provide criteria for the pathological diagnosis in the neurodegenerative diseases grouped as frontotemporal lobar degeneration (FTLD); revised criteria are proposed. Recent advances in molecular genetics, biochemistry, and neuropathology of FTLD prompted the Midwest Consortium for Frontotemporal Lobar Degeneration and experts at other centers to review and revise the existing neuropathologic diagnostic criteria for FTLD. The proposed criteria for FTLD are based on existing criteria, which include the tauopathies [FTLD with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, sporadic multiple system tauopathy with dementia, argyrophilic grain disease, neurofibrillary tangle dementia, and FTD with microtubule-associated tau (MAPT) gene mutation, also called FTD with parkinsonism linked to chromosome 17 (FTDP-17)]. The proposed criteria take into account new disease entities and include the novel molecular pathology, TDP-43 proteinopathy, now recognized to be the most frequent histological finding in FTLD. TDP-43 is a major component of the pathologic inclusions of most sporadic and familial cases of FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Molecular genetic studies of familial cases of FTLD-U have shown that mutations in the progranulin (PGRN) gene are a major genetic cause of FTLD-U. Mutations in valosin-containing protein (VCP) gene are present in rare familial forms of FTD, and some families with FTD and/or MND have been linked to chromosome 9p, and both are types of FTLD-U. Thus, familial TDP-43 proteinopathy is associated with defects in multiple genes, and molecular genetics is required in these cases to correctly identify the causative gene defect. In addition to genetic heterogeneity amongst the TDP-43 proteinopathies, there is also neuropathologic heterogeneity and there is a close relationship between genotype and FTLD-U subtype. In addition to these recent significant advances in the neuropathology of FTLD-U, novel FTLD entities have been further characterized, including neuronal intermediate filament inclusion disease. The proposed criteria incorporate up-to-date neuropathology of FTLD in the light of recent immunohistochemical, biochemical, and genetic advances. These criteria will be of value to the practicing neuropathologist and provide a foundation for clinical, clinico-pathologic, mechanistic studies and in vivo models of pathogenesis of FTLD.

KW - Charged multivesicular body protein 2B

KW - Frontotemporal dementia

KW - Frontotemporal lobar degeneration

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KW - Progranulin

KW - Progressive non-fluent aphasia

KW - Semantic dementia

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KW - Valosin-containing protein

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