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Globular glial tauopathies (GGT) presenting with motor neuron disease or frontotemporal dementia: an emerging group of 4-repeat tauopathies

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Abstract

A number of recent studies have described cases with tau-positive globular oligodendroglial inclusions (GOIs) and such cases have overlapping pathological features with progressive supranuclear palsy (PSP), but present with clinical features of motor neuron disease (MND) and/or frontotemporal dementia (FTD). These two clinical phenotypes have been published independently and as a result, have come to be considered as distinct disease entities. We describe the clinicopathological and biochemical features of two cases with GOIs: one with clinical symptoms suggestive of MND and the other with FTD. Histological changes in our two cases were consistent with their clinical symptoms; the MND case had severe neurodegeneration in the primary motor cortex and corticospinal tract, whereas the FTD case had severe involvement of the frontotemporal cortices and associated white matter. Immunohistochemistry in both cases revealed significant 4-repeat (4R) tau pathology primarily in the form of GOIs, but also in astrocytes and neurons. Astrocytic tau pathology was morphologically similar to that seen in PSP, but in contrast was consistently negative for Gallyas silver staining. Tau-specific western blotting revealed 68, 64 and 35 kDa bands, showing further overlap with PSP. The underlying neuropathological features of these two cases were similar, with the major difference relating to the regional distribution of pathology and resulting clinical symptoms and signs. The globular nature of glial inclusions and the non-fibrillar properties of tau in astrocytes are characteristic features that allow them to be distinguished from PSP and other tauopathies. We, therefore, propose the term globular glial tauopathy as an encompassing term to classify this emerging class of 4R tauopathy.

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Abbreviations

AD:

Alzheimer’s disease

AGD:

Argyrophillic grain disease

ALS:

Amyotrophic lateral sclerosis

CBD:

Corticobasal degeneration

CBS:

Corticobasal syndrome

CST:

Corticospinal tract

FTD:

Frontotemporal dementia

FTDP-17:

Frontotemporal dementia with parkinsonism linked to chromosome 17

FTD-P-MND:

Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, parkinsonism, and motor neuron disease

FTLD:

Frontotemporal lobar degeneration

FUS:

Fused in sarcoma protein

GGT:

Globular glial tauopathy

GOIs:

Globular oligodendroglial inclusions

IHC:

Immunohistochemistry

MND:

Motor neuron disease

MSA:

Multiple system atrophy

MSTD:

Multiple system tauopathy with dementia

NFT:

Neurofibrillary tangles

PiD:

Pick’s disease

PLS:

Primary lateral sclerosis

PSP:

Progressive supranuclear palsy

PSP-CST:

Atypical PSP with corticospinal tract degeneration

TDP-43:

TAR DNA-binding protein 43

WMT-GGI:

White matter tauopathy with globular glial inclusions

27 kP:

27,000×g pellet

3R:

3-repeat tau

4R:

4-repeat tau

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Acknowledgments

Professor Revesz, Dr Holton and Dr Ahmed are supported by the Multiple System Atrophy Trust (formerly known as the Sarah Matheson Trust for Multiple System Atrophy). Dr Silveira-Moriyama, Dr Holton, Dr de Silva and Dr Doherty are supported by the Reta Lila Weston Trust for Medical Research. Dr de Silva is funded by grants by the Medical Research Council (G0501560) and Cure PSP+. 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.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK

    Zeshan Ahmed, Rina Bandopadhyay, Tammaryn Lashley, Adamantios Mamais, Selina Wray, Janice L. Holton, Andrew J. Lees & Tamas Revesz

  2. Reta Lila Weston Institute for Neurological Studies, Department of Molecular Neuroscience, UCL Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK

    Zeshan Ahmed, Karen M. Doherty, Laura Silveira-Moriyama, Rina Bandopadhyay, Adamantios Mamais, Geshanthi Hondhamuni, Sean S. O’Sullivan, Rohan de Silva, Janice L. Holton & Andrew J. Lees

  3. The National Hospital for Neurology and Neurosurgery, UCL, London, UK

    Stephen Wroe

  4. NeuroResource, UCL Institute of Neurology, London, UK

    Jia Newcombe

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  1. Zeshan Ahmed
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  2. Karen M. Doherty
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  15. Tamas Revesz
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Corresponding author

Correspondence to Tamas Revesz.

Additional information

Z. Ahmed and K. Doherty contributed equally to this paper.

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Ahmed, Z., Doherty, K.M., Silveira-Moriyama, L. et al. Globular glial tauopathies (GGT) presenting with motor neuron disease or frontotemporal dementia: an emerging group of 4-repeat tauopathies. Acta Neuropathol 122, 415–428 (2011). https://doi.org/10.1007/s00401-011-0857-4

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