TAR DNA-binding protein 43 immunohistochemistry reveals extensive neuritic pathology in FTLD-U: a midwest-southwest consortium for FTLD study.
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.
Hatanpaa
Kimmo J
KJ
Department of Pathology, University of Texas Southwestern School of Medicine, Dallas, Texas 75390, USA. Kimmo.Hatanpaa@UTSouthwestern.edu
Bigio
Eileen H
EH
Cairns
Nigel J
NJ
Womack
Kyle B
KB
Weintraub
Sandra
S
Morris
John C
JC
Foong
Chan
C
Xiao
Guanghua
G
Hladik
Christa
C
Mantanona
Tina Y
TY
White
Charles L
CL
D000368:Aged; D001344:Autopsy; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003704:Dementia / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D016501:Neurites / Q000378:metabolism* / Q000473:pathology*; D058225:Plaque, Amyloid / Q000473:pathology; D025801:Ubiquitin; D016875:tau Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; D025801:Ubiquitin; D016875:tau Proteins