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Globular glial tauopathies (GGT): consensus recommendations

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Abstract

Recent studies have highlighted a group of 4-repeat (4R) tauopathies that are characterised neuropathologically by widespread, globular glial inclusions (GGIs). Tau immunohistochemistry reveals 4R immunoreactive globular oligodendroglial and astrocytic inclusions and the latter are predominantly negative for Gallyas silver staining. These cases are associated with a range of clinical presentations, which correlate with the severity and distribution of underlying tau pathology and neurodegeneration. Their heterogeneous clinicopathological features combined with their rarity and under-recognition have led to cases characterised by GGIs being described in the literature using various and redundant terminologies. In this report, a group of neuropathologists form a consensus on the terminology and classification of cases with GGIs. After studying microscopic images from previously reported cases with suspected GGIs (n = 22), this panel of neuropathologists with extensive experience in the diagnosis of neurodegenerative diseases and a documented record of previous experience with at least one case with GGIs, agreed that (1) GGIs were present in all the cases reviewed; (2) the morphology of globular astrocytic inclusions was different to tufted astrocytes and finally that (3) the cases represented a number of different neuropathological subtypes. They also agreed that the different morphological subtypes are likely to be part of a spectrum of a distinct disease entity, for which they recommend that the overarching term globular glial tauopathy (GGT) should be used. Type I cases typically present with frontotemporal dementia, which correlates with the fronto-temporal distribution of pathology. Type II cases are characterised by pyramidal features reflecting motor cortex involvement and corticospinal tract degeneration. Type III cases can present with a combination of frontotemporal dementia and motor neuron disease with fronto-temporal cortex, motor cortex and corticospinal tract being severely affected. Extrapyramidal features can be present in Type II and III cases and significant degeneration of the white matter is a feature of all GGT subtypes. Improved detection and classification will be necessary for the establishment of neuropathological and clinical diagnostic research criteria in the future.

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Acknowledgments

Grant supports: BG—PHS P30 AG010133; CLW and KJH—NIH P30 AG12300, and CLW—Winspear Family Center for Research on the Neuropathology of Alzheimer Disease, and McCune Foundation; EHB—AG13854; GG—Italian Ministry of Health; HT—Research Committee for CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare, Japan; KAJ—NIH R01 AG37491; GGK-DEVELAGE (FP7/2007–2013, N° 278486); TR and JLH—the Multiple System Atrophy Trust, The Alzheimer’s Research Trust and Parkinson’s UK and JLH—the Reta Lila Weston Institute for Neurological Studies. The Queen Square Brain Bank is supported by the Reta Lila Weston Institute for Neurological Studies and the PSP (Europe) Association. Part of this work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme and, in part, funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Unit in Dementia based at University College London Hospitals (UCLH), University College London (UCL). Zeshan Ahmed is currently a post-doctoral research fellow at Eli Lilly and Company.

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Authors and Affiliations

  1. Department of Molecular Neuroscience, Queen Square Brain Bank, Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK

    Zeshan Ahmed, Janice L. Holton & Tamas Revesz

  2. Department of Pathology, Northwestern Alzheimer Disease Center, Northwestern Feinberg School of Medicine, Chicago, IL, USA

    Eileen H. Bigio

  3. Institute of Neurology, Medical University of Vienna, Vienna, Austria

    Herbert Budka & Gabor G. Kovacs

  4. Mayo Clinic, Jacksonville, FL, USA

    Dennis W. Dickson

  5. Institute of Neuropathology, University Hospital Bellvitge, University of Barcelona, CIBERNED, Hospitalet de LLobregat, Spain

    Isidro Ferrer

  6. Department of Pathology and Laboratory Medicine, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA

    Bernardino Ghetti & Salvatore Spina

  7. Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

    Giorgio Giaccone

  8. Department of Pathology, Alzheimer’s Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Kimmo J. Hatanpaa & Charles L. White III

  9. Mayo Clinic, Rochester, MN, USA

    Keith A. Josephs

  10. University of Rochester, School of Medicine and Dentistry, Rochester, NY, USA

    James Powers

  11. Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan

    Hitoshi Takahashi

  12. Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland

    Herbert Budka

Authors
  1. Zeshan Ahmed
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  2. Eileen H. Bigio
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  3. Herbert Budka
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  4. Dennis W. Dickson
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  5. Isidro Ferrer
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  6. Bernardino Ghetti
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  7. Giorgio Giaccone
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  8. Kimmo J. Hatanpaa
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  9. Janice L. Holton
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  10. Keith A. Josephs
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  11. James Powers
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  12. Salvatore Spina
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  13. Hitoshi Takahashi
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  14. Charles L. White III
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  15. Tamas Revesz
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  16. Gabor G. Kovacs
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Corresponding author

Correspondence to Tamas Revesz.

Additional information

Z. Ahmed and G. G. Kovacs contributed equally to this article.

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Ahmed, Z., Bigio, E.H., Budka, H. et al. Globular glial tauopathies (GGT): consensus recommendations. Acta Neuropathol 126, 537–544 (2013). https://doi.org/10.1007/s00401-013-1171-0

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  • DOI: https://doi.org/10.1007/s00401-013-1171-0

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