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Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration
Open accessAbstract
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.
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“Frontotemporal dementia is caused by frontotemporal lobar degeneration (FTLD), which features abnormal aggregation of the microtubule associated protein consisting of tau (FTLD-tau) or the transactivating DNA-binding protein 43.16,18–20”
From Association of Cognitive and Behavioral Features Between Adults With Tuberous Sclerosis and Frontotemporal Dementia (2020) · cites this paper as [18]
Experimental — accuracy not yet measuredIn the citing paper
“Older studies that reported cases with dementia and no other known pathologic substrate lacked insights into more recently defined pathologies, such as those with aberrant TDP-43, valosin-containing protein, and fused in sarcoma inclusions (37, 167).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [37]
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Metadata
- Authors
- Cairns, N. J., Bigio, E. H., Mackenzie, I. R. A., Neumann, M., Lee, V. M.-Y., Hatanpaa, K. J., White, C. L., Schneider, J. A., Grinberg, L. T., Halliday, G., Duyckaerts, C., Lowe, J. S., Holm, I. E., Tolnay, M., Okamoto, K., Yokoo, H., Murayama, S., Woulfe, J., Munoz, D. G., Dickson, D. W., Ince, P. G., Trojanowski, J. Q., & Mann, D. M. A.
- Affiliations
- Washington University in St. Louis (US)
- Northwestern University (US)
- Vancouver General Hospital (CA)
- Institut für Neuropathologie (DE)
- University of Pennsylvania (US)
- The University of Texas Southwestern Medical Center (US)
- Rush University Medical Center (US)
- Universidade de São Paulo (BR)
- Neuroscience Research Australia (AU)
- Pitié-Salpêtrière Hospital (FR)
- Nottingham University Hospitals NHS Trust (GB)
- Aalborg University Hospital (DK)
- University Hospital of Basel (CH)
- Gunma University (JP)
- Tokyo Metropolitan Institute of Gerontology (JP)
- University of Ottawa (CA)
- Mayo Clinic (US)
- University of Sheffield (GB)
- University of Manchester (GB)
- Corresponding author
- Cairns, Nigel J.
- ORCID
- 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.
- Tolnay, Markus
- Okamoto, Koichi
- Yokoo, Hideaki
- Murayama, Shigeo
- Woulfe, John
- Dickson, Dennis W.
- Ince, Paul G.
- Trojanowski, John Q.
- Mann, David M. A.
- Venue
- Acta Neuropathologica
- Published
- 2007-06-20
- Volume
- 114
- Issue
- 1
- Pages
- 5-22
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC2827877
- OpenAlex
- W2091173932
- Cited by
- 1,110
- References
- 85
- Citations by year
- 2026: 22 · 2025: 27 · 2024: 46 · 2023: 40 · 2022: 52 · 2021: 42 · 2020: 54 · 2019: 60 · 2018: 51 · 2017: 49 · 2016: 43 · 2015: 50 · 2014: 51 · 2013: 65 · 2012: 70
- FWCI
- 65.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AG 10 124, AG05681, AG 17586, AG13854, AG 03991, NS057105)
- National Institute on Aging (AG13854, AG03991, U01AG016976, P30AG010124, P01AG017586, AG 05681, AG17586, U01-AG 16976, AG-10124, P30AG13854, P 50 AG05681, P50AG005681, P01 AG0 3991, P01AG003991, P30AG013854)
- National Institute of Neurological Disorders and Stroke (P30NS057105)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- frontotemporal lobar degeneration, nosologic classification, TDP-43 proteinopathy, tauopathy, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease
- MeSH terms
- Algorithms, Dementia, Frontal Lobe, Humans, Temporal Lobe, tau Proteins, Ubiquitin
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