Consensus Paper

Acta Neuropathologica

, Volume 114, Issue 1, pp 5-22

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

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

  • Nigel J. CairnsAffiliated withDepartment of Neurology, Washington University School of MedicineDepartment of Pathology and Immunology, Washington University School of MedicineAlzheimer’s Disease Research Center, Washington University School of Medicine Email author 
  • , Eileen H. BigioAffiliated withDepartment of Pathology, Northwestern University Feinberg School of MedicineCognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine
  • , Ian R. A. MackenzieAffiliated withDepartment of Pathology and Laboratory Medicine, Vancouver General Hospital
  • , Manuela NeumannAffiliated withCenter for Neuropathology and Prion Research, Ludwig-Maximilians University
  • , Virginia M.-Y. LeeAffiliated withDepartment of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine
  • , Kimmo J. HatanpaaAffiliated withNeuropathology Laboratory, Department of Pathology, University of Texas Southwestern Medical School
  • , Charles L. WhiteIIIAffiliated withNeuropathology Laboratory, Department of Pathology, University of Texas Southwestern Medical School
  • , Julie A. SchneiderAffiliated withRush Alzheimer’s Disease Center, Rush University Medical School
  • , Lea Tenenholz GrinbergAffiliated withDepartment of Pathology and Instituto Israelita de Ensino e Pesquisa Albert Einstein, Faculdade de Medicina, Universidade de São Paulo
    • , Glenda HallidayAffiliated withPrince of Wales Medical Research Institute
    • , Charles DuyckaertsAffiliated withLaboratoire de Neuropathologie Escourolle, Hôpital de La Salpêtrière
    • , James S. LoweAffiliated withDepartment of Neuropathology, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust
    • , Ida E. HolmAffiliated withDepartment of Pathology, Aalborg Hospital, Aarhus University Hospital
    • , Markus TolnayAffiliated withDepartment of Neuropathology, Institute of Pathology, University Hospital Basel
    • , Koichi OkamotoAffiliated withDepartment of Neurology, Gunma University Graduate School of Medicine
    • , Hideaki YokooAffiliated withDepartment of Human Pathology, Gunma University Graduate School of Medicine
    • , Shigeo MurayamaAffiliated withGeriatric Neuroscience (Neuropathology), Tokyo Metropolitan institute of Gerontology
    • , John WoulfeAffiliated withDepartment of Pathology, Ottawa Hospital and University of Ottawa
    • , David G. MunozAffiliated withDepartment of Pathology, Saint Michael’s Hospital and University of Toronto
    • , Dennis W. DicksonAffiliated withNeuropathology Laboratory, Mayo Clinic College of Medicine
    • , Paul G. InceAffiliated withNeuropathology Group, Academic Unit of Pathology, University of Sheffield Medical School
    • , John Q. TrojanowskiAffiliated withDepartment of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of MedicineInstitute on Aging, University of Pennsylvania School of Medicine
    • , David M. A. MannAffiliated withClinical Neuroscience Research Group, School of Translational Medicine, Greater Manchester Neurosciences Centre, University of Manchester


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.


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