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

Acta Neuropathol. 2008 Aug;116(2):147-57. doi: 10.1007/s00401-008-0395-x. Epub 2008 Jun 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Brain / metabolism
  • Brain / pathology
  • DNA-Binding Proteins / metabolism*
  • Dementia / classification*
  • Dementia / metabolism*
  • Dementia / pathology*
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Immunohistochemistry
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology*
  • Male
  • Middle Aged
  • Ubiquitin / metabolism*


  • DNA-Binding Proteins
  • Ubiquitin