Acta Neuropathologica

, 116:147

TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD


  • Sigrun Roeber
    • Center for Neuropathology and Prion ResearchLudwig-Maximilians University Munich
  • Ian R. A. Mackenzie
    • Department of Pathology and Laboratory MedicineUniversity of British Columbia
  • Hans A. Kretzschmar
    • Center for Neuropathology and Prion ResearchLudwig-Maximilians University Munich
    • Center for Neuropathology and Prion ResearchLudwig-Maximilians University Munich
Original Paper

DOI: 10.1007/s00401-008-0395-x

Cite this article as:
Roeber, S., Mackenzie, I.R.A., Kretzschmar, H.A. et al. Acta Neuropathol (2008) 116: 147. doi:10.1007/s00401-008-0395-x


Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is the most common neuropathological subtype of frontotemporal dementias. While TDP-43 is the pathologic protein in the majority of FTLD-U cases, small numbers of cases have recently been reported with TDP-43-negative FTLD-U pathology. To determine the frequency and to define the clinico-pathological spectrum of TDP-43-negative FTLD-U, we re-evaluated 44 cases with a previous diagnosis of FTLD-U or dementia lacking distinctive histopathology. We identified nine cases (20%) with TDP-43-negative FTLD-U pathology by immunohistochemistry and confirmed the absence of pathological TDP-43 by biochemical analysis. All patients presented with sporadic early-onset frontotemporal dementia with predominant behavioral and personality changes. Besides ubiquitin-positive neuronal cytoplasmic inclusions, the most intriguing neuropathological feature was the presence of ubiquitin-positive neuronal intranuclear inclusions (NIIs), often with curved or twisted morphology, in the neocortex, hippocampus, brainstem, and spinal cord. Double-label immunofluorescence revealed an unusual and distinct immunoreactivity profile for these NIIs, with ubiquitin-immunoreactivity, but absence of p62 labeling. The highly consistent clinical and neuropathological phenotype supports the concept that TDP-43-negative FTLD-U should be considered as a new clinicopathological FTLD entity.


TDP-43p62UbiquitinIntranuclear inclusionsFrontotemporal dementiaFrontotemporal lobar degeneration

Copyright information

© Springer-Verlag 2008