Distinct pathological subtypes of FTLD-FUS

Acta Neuropathol. 2011 Feb;121(2):207-18. doi: 10.1007/s00401-010-0764-0. Epub 2010 Oct 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basophils / pathology
  • Brain / metabolism*
  • Brain / pathology*
  • DNA-Binding Proteins / metabolism
  • Female
  • Frontotemporal Lobar Degeneration* / classification
  • Frontotemporal Lobar Degeneration* / metabolism
  • Frontotemporal Lobar Degeneration* / pathology
  • Humans
  • Intranuclear Inclusion Bodies / metabolism
  • Intranuclear Inclusion Bodies / pathology
  • Male
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • RNA-Binding Protein FUS / metabolism*
  • Statistics, Nonparametric
  • tau Proteins / metabolism

Substances

  • DNA-Binding Proteins
  • RNA-Binding Protein FUS
  • tau Proteins

Supplementary concepts

  • Neuronal intranuclear inclusion disease