TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease.
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.
Bigio
Eileen H
EH
Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. e-bigio@northwestern.edu
Mishra
Manjari
M
Hatanpaa
Kimmo J
KJ
White
Charles L
CL
Johnson
Nancy
N
Rademaker
Alfred
A
Weitner
Bing Bing
BB
Deng
Han-Xiang
HX
Dubner
Steven D
SD
Weintraub
Sandra
S
Mesulam
Marsel
M
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
D053327:Apolipoprotein E4; D004268:DNA-Binding Proteins