Original Paper

Acta Neuropathologica

, Volume 111, Issue 4, pp 329-340

An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies

  • Rohan de SilvaAffiliated withReta Lila Weston Institute of Neurological Studies, University College London
  • , Tammaryn LashleyAffiliated withDepartment of Molecular Neuroscience, Queen Square Brain Bank, Institute of Neurology, University College London
  • , Catherine StrandAffiliated withDepartment of Molecular Neuroscience, Queen Square Brain Bank, Institute of Neurology, University College London
  • , Anna-Maria ShiarliAffiliated withCentre for Clinical Neurosciences, University of Manchester, Greater Manchester Neurosciences Centre, Hope Hospital
  • , Jing ShiAffiliated withCentre for Clinical Neurosciences, University of Manchester, Greater Manchester Neurosciences Centre, Hope HospitalDepartment of Care of the Elderly, Dongzhimen Hospital
  • , Jinzhou TianAffiliated withCentre for Clinical Neurosciences, University of Manchester, Greater Manchester Neurosciences Centre, Hope HospitalDepartment of Care of the Elderly, Dongzhimen Hospital
  • , Kathryn L. BaileyAffiliated withCentre for Clinical Neurosciences, University of Manchester, Greater Manchester Neurosciences Centre, Hope Hospital
  • , Peter DaviesAffiliated withDepartment of Pathology, Albert Einstein College of Medicine
  • , Eileen H. BigioAffiliated withNorthwestern University Alzheimer’s Disease Center
    • , Kunimasa ArimaAffiliated withNational Centre of Neurology and Psychiatry, Musashi Hospital
    • , Eizo IsekiAffiliated withJuntendo Tokyo Koto Geriatric Medical Center, Juntendo University School of Medicine
    • , Shigeo MurayamaAffiliated withDepartment of Neuropathology, Tokyo Metropolitan Institute of Gerontology
    • , Hans KretzschmarAffiliated withReta Lila Weston Institute of Neurological Studies, University College LondonReference Centre for Prion Diseases and Neurodegenerative Diseases, Institute of Neuropathology
    • , Manuela NeumannAffiliated withReta Lila Weston Institute of Neurological Studies, University College LondonReference Centre for Prion Diseases and Neurodegenerative Diseases, Institute of Neuropathology
    • , Carol LippaAffiliated withReta Lila Weston Institute of Neurological Studies, University College LondonMemory Disorders Centre, Drexel University College of Medicine
    • , Glenda HallidayAffiliated withReta Lila Weston Institute of Neurological Studies, University College LondonDepartment of Neuropathology, Prince of Wales Medical Research Institute, University of New South Wales
    • , James MacKenzieAffiliated withReta Lila Weston Institute of Neurological Studies, University College LondonThe Royal Infirmary, Foresterhill
    • , Rivka RavidAffiliated withReta Lila Weston Institute of Neurological Studies, University College LondonNetherlands Brain Bank
    • , Dennis DicksonAffiliated withReta Lila Weston Institute of Neurological Studies, University College LondonMayo Clinic
    • , Zbigniew WszolekAffiliated withReta Lila Weston Institute of Neurological Studies, University College LondonMayo Clinic
    • , Takeshi IwatsuboAffiliated withReta Lila Weston Institute of Neurological Studies, University College LondonDepartment of Neuropathology and Neuroscience, University of Tokyo
    • , Stuart M. Pickering-BrownAffiliated withReta Lila Weston Institute of Neurological Studies, University College LondonCentre for Clinical Neurosciences, University of Manchester, Greater Manchester Neurosciences Centre, Hope HospitalMayo Clinic
    • , Janice HoltonAffiliated withDepartment of Molecular Neuroscience, Queen Square Brain Bank, Institute of Neurology, University College London
    • , Andrew LeesAffiliated withReta Lila Weston Institute of Neurological Studies, University College London
    • , Tamas ReveszAffiliated withDepartment of Molecular Neuroscience, Queen Square Brain Bank, Institute of Neurology, University College London
    • , David M. A. MannAffiliated withCentre for Clinical Neurosciences, University of Manchester, Greater Manchester Neurosciences Centre, Hope Hospital Email author 

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Abstract

The pathological distinctions between the various clinical and pathological manifestations of frontotemporal lobar degeneration (FTLD) remain unclear. Using monoclonal antibodies specific for 3- and 4-repeat isoforms of the microtubule associated protein, tau (3R- and 4R-tau), we have performed an immunohistochemical study of the tau pathology present in 14 cases of sporadic forms of FTLD, 12 cases with Pick bodies and two cases without and in 27 cases of familial FTLD associated with 12 different mutations in the tau gene (MAPT), five cases with Pick bodies and 22 cases without. In all 12 cases of sporadic FTLD where Pick bodies were present, these contained only 3R-tau isoforms. Clinically, ten of these cases had frontotemporal dementia and two had progressive apraxia. Only 3R-tau isoforms were present in Pick bodies in those patients with familial FTLD associated with L266V, Q336R, E342V, K369I or G389R MAPT mutations. Patients with familial FTLD associated with exon 10 N279K, N296H or +16 splice site mutations showed tau pathology characterised by neuronal neurofibrillary tangles (NFT) and glial cell tangles that contained only 4R-tau isoforms, as did the NFT in P301L MAPT mutation. With the R406W mutation, NFT contained both 3R- and 4R-tau isoforms. We also observed two patients with sporadic FTLD, but without Pick bodies, in whom the tau pathology comprised only of 4R-tau isoforms. We have therefore shown by immunohistochemistry that different specific tau isoform compositions underlie the various kinds of tau pathology present in sporadic and familial FTLD. The use of such tau isoform specific antibodies may refine pathological criteria underpinning FTLD.