title: TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease.
abstract: The clinical syndrome of primary progressive aphasia (PPA) can be associated with a variety of neuropathologic diagnoses at autopsy. Thirty percent of cases have Alzheimer disease (AD) pathology, most often in the usual distribution, which defies principles of brain-behavior organization, in that aphasia is not symptomatic of limbic disease. The present study investigated whether concomitant TDP-43 pathology could resolve the lack of clinico-anatomic concordance. In this paper, 16 cases of clinical PPA and 10 cases of primarily non-aphasic frontotemporal dementia (FTD), all with AD pathology, were investigated to determine whether their atypical clinical phenotypes reflected the presence of additional TDP-43 pathology. A comparison group consisted of 27 cases of pathologic AD with the typical amnestic clinical phenotype of probable AD. Concomitant TDP-43 pathology was discovered in only three of the FTD and PPA but in more than half of the typical amnestic clinical phenotypes. Hippocampal sclerosis (HS) was closely associated with TDP-43 pathology when all groups were combined for analysis. Therefore, the clinical phenotypes of PPA and FTD in cases with pathologic AD are only rarely associated with TDP-43 proteinopathy. Furthermore, medial temporal TDP-43 pathology is more tightly linked to HS than to clinical phenotype. These findings challenge the current notions about clinicopathologic correlation, especially about the role of multiple pathologies.
authors.affiliation: Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. e-bigio@northwestern.edu
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.forename: Manjari
authors.initials: M
authors.lastname: Mishra
authors.forename: Kimmo J
authors.initials: KJ
authors.lastname: Hatanpaa
authors.forename: Charles L
authors.initials: CL
authors.lastname: White
authors.forename: Nancy
authors.initials: N
authors.lastname: Johnson
authors.forename: Alfred
authors.initials: A
authors.lastname: Rademaker
authors.forename: Bing Bing
authors.initials: BB
authors.lastname: Weitner
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: Deng
authors.forename: Steven D
authors.initials: SD
authors.lastname: Dubner
authors.forename: Sandra
authors.initials: S
authors.lastname: Weintraub
authors.forename: Marsel
authors.initials: M
authors.lastname: Mesulam
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018888:Aphasia, Primary Progressive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D010641:Phenotype; D012598:Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology
chemical_list: D053327:Apolipoprotein E4; D004268:DNA-Binding Proteins