TAR DNA-binding protein 43 immunohistochemistry reveals extensive neuritic pathology in FTLD-U: A midwest-southwest consortium for FTLD study

Kimmo J. Hatanpaa, Eileen H. Bigio, Nigel J. Cairns, Kyle B. Womack, Sandra Weintraub, John C. Morris, Chan Foong, Guanghua Xiao, Christa Hladik, Tina Y. Mantanona, Charles L. White

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48 Scopus citations

Abstract

TAR DNA-binding protein 43 (TDP-43) is a major component of the inclusions in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). We studied TDP-43 pathology in the hippocampus and frontal cortex of autopsy brains from patients with FTLD-U (n = 68), dementia lacking distinctive histopathology (n = 4), other neurodegenerative diseases (n = 23), and controls (n = 12) using a sensitive immunohistochemistry protocol. Marked enhancement of staining of TDP-43-positive dystrophic neurites (DNs) was obtained, and we observed 2 previously unrecognized pathologic patterns (i.e. frequent long DNs in the CA1 region and frequent dot-like DNs in the neocortical layer 2) in 39% and 15% of the FTLD-U cases, respectively. Frequent long DNs, but not dot-like DNs, were significantly associated with progranulin mutations. Based on this evaluation, 4 FTLD-U cases showed no TDP-43 pathology and were reclassified as "FTLD-U, non-TDP-43 proteinopathy," and 3 cases of dementia lacking distinctive histopathology were reclassified as FTLD-U. Of the cases with other neurodegenerative diseases, 43% showed TDP-43 pathology in the hippocampus, but only 4% showed TDP-43 pathology in the frontal cortex. No TDP-43 pathology was seen in controls. These results indicate that the sensitivity of the TDP-43 immunohistochemistry method affects both the extent and type of abnormalities detected. Moreover, assessment of abnormalities in both the hippocampus and frontal cortex may be diagnostically important in FTLD-U.

Original languageEnglish
Pages (from-to)271-279
Number of pages9
JournalJournal of neuropathology and experimental neurology
Volume67
Issue number4
DOIs
StatePublished - Apr 2008

Keywords

  • Dementia lacking distinctive histopathology
  • Dystrophic neurites
  • Frontotemporal lobar degeneration with motor neuron disease
  • Frontotemporal lobar degeneration with ubiquitinated inclusions
  • Immunohistochemistry
  • Progranulin
  • TAR DNA-binding protein 43

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