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Distinct pathological subtypes of FTLD-FUS

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Abstract

Most cases of frontotemporal lobar degeneration (FTLD) are characterized by abnormal intracellular accumulation of either tau or TDP-43 protein. However, in ~10% of cases, composed of a heterogenous collection of uncommon disorders, the molecular basis remains to be uncertain. We recently discovered that the pathological changes in several tau/TDP-43-negative FTLD subtypes are immunoreactive (ir) for the fused in sarcoma (FUS) protein. In this study, we directly compared the pattern of FUS-ir pathology in cases of atypical FTLD-U (aFTLD-U, N = 10), neuronal intermediate filament inclusion disease (NIFID, N = 5) and basophilic inclusion body disease (BIBD, N = 8), to determine whether these are discrete entities or represent a pathological continuum. All cases had FUS-ir pathology in the cerebral neocortex, hippocampus and a similar wide range of subcortical regions. Although there was significant overlap, each group showed specific differences that distinguished them from the others. Cases of aFTLD-U consistently had less pathology in subcortical regions. In addition, the neuronal inclusions in aFTLD-U usually had a uniform, round shape, whereas NIFID and BIBD were characterized by a variety of inclusion morphologies. In all cases of aFTLD-U and NIFID, vermiform neuronal intranuclear inclusions (NII) were readily identified in the hippocampus and neocortex. In contrast, only two cases of BIBD had very rare NII in a single subcortical region. These findings support aFTLD-U, NIFID and BIBD as representing closely related, but distinct entities that share a common molecular pathogenesis. Although cases with overlapping pathology may exist, we recommend retaining the terms aFTLD-U, NIFID and BIBD for specific FTLD-FUS subtypes.

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Acknowledgments

We thank Margaret Luk and Mareike Schroff for their excellent technical assistance. This work was supported by grants from Canadian Institutes of Health Research (grant number 74580, IM); the Pacific Alzheimer Research Foundation (IM); the German Federal Ministry of Education and Research (grant number 01GI0704, MN); the Stavros-Niarchos Foundation (MN); the Synapsis Foundation (MN); and the German Brain Bank “BrainNet” (HK).

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Authors and Affiliations

  1. Department of Pathology, Vancouver General Hospital, University of British Columbia, 855 West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada

    Ian R. A. Mackenzie

  2. Department of Laboratory Medicine and Pathobiology, St., Michael’s Hospital, University of Toronto, Toronto, Canada

    David G. Munoz

  3. Department of Neurology, Kansai Medical University, Osaka, Japan

    Hirofumi Kusaka

  4. Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Osamu Yokota

  5. Department of Neurology, Showa University School of Medicine, Tokyo, Japan

    Kenji Ishihara

  6. Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany

    Sigrun Roeber & Hans A. Kretzschmar

  7. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    Nigel J. Cairns

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

    Manuela Neumann

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  1. Ian R. A. Mackenzie
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Mackenzie, I.R.A., Munoz, D.G., Kusaka, H. et al. Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol 121, 207–218 (2011). https://doi.org/10.1007/s00401-010-0764-0

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