title: Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease.
abstract: Recently, TDP-43, a 43 kDa nuclear TAR DNA-binding protein, was identified as the major disease protein in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), FTLD-U with motor neuron disease (FTLD-MND), and amyotrophic lateral sclerosis. To date, TDP-43 pathology in sporadic FTLD-MND has been reported only in select central nervous system areas. However, this distribution of lesions is insufficient to explain all clinical signs of FTLD-MND and the extent of TDP-43 pathology, throughout the brain, remains unknown. Therefore, as a pilot study, we performed an immunohistochemical whole brain scan of two cases diagnosed clinically as FTLD-MND and two control subjects. We found evidence of both neuronal and glial TDP-43 pathology in multiple brain areas including the nigro-striatal system, neo- and allocortical brain areas, with varying frequency, morphology, and degree, and nowhere in control tissue. The finding of a distinct cytopathological profile consisting of a cell nucleus devoid of endogenous TDP-43 staining coupled with diffuse/granular cytoplasmic staining ("pre-inclusion") was prominent in a couple of brain areas. These pre-inclusions were not or only weakly ubiquitin-immunoreactive. While the findings of severe involvement of extracortical or extrapyramidal areas are strongly suggestive for FTLD-MND being a TDP-43 multisystem proteinopathy rather than a disease predominantly affecting the cortex and spinal cord, more detailed clinicopathological studies of larger cohorts are needed to fully elucidate the distribution and severity of pathological TDP-43 in this disease.
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Alzheimer's Disease Core Center, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandmeir
authors.forename: Felix
authors.initials: F
authors.lastname: Geser
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.forename: Earl
authors.initials: E
authors.lastname: Zimmerman
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003704:Dementia / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010865:Pilot Projects
chemical_list: D004268:DNA-Binding Proteins