Distinct pathological subtypes of FTLD-FUS

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 aFTLDU, 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. I. R. A. Mackenzie (&) Department of Pathology, Vancouver General Hospital, University of British Columbia, 855 West 12th Avenue, Vancouver, BC V5Z 1M9, Canada e-mail: ian.mackenzie@vch.ca D. G. Munoz Department of Laboratory Medicine and Pathobiology, St., Michael’s Hospital, University of Toronto, Toronto, Canada H. Kusaka Department of Neurology, Kansai Medical University, Osaka, Japan O. Yokota Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan K. Ishihara Department of Neurology, Showa University School of Medicine, Tokyo, Japan S. Roeber  H. A. Kretzschmar Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany N. J. Cairns Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA M. Neumann Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland