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TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease

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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.

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Acknowledgments

We are grateful to John Trojanowski and Virginia Lee for their helpful discussions and for sharing their TDP-43 immunoprotocol with us. We are most grateful to those patients and family members who so willingly participated in our research programs, without whom our studies are not possible. The study was supported in part by NIH grants AG13854, AG12300, P30 AG012300, Winspear Family Center for Research on the Neuropathology of Alzheimer Disease, and McCune Foundation.

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Authors and Affiliations

  1. Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Eileen H. Bigio, Manjari Mishra, Nancy Johnson, Alfred Rademaker, Steven D. Dubner, Sandra Weintraub & Marsel Mesulam

  2. Department of Pathology, Northwestern University Feinberg School of Medicine, 710 N. Fairbanks Ct., Olson 2-459, Chicago, IL, 60611, USA

    Eileen H. Bigio & Steven D. Dubner

  3. Department of Pathology, Alzheimer Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Kimmo J. Hatanpaa & Charles L. White III

  4. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Nancy Johnson, Han-Xiang Deng & Marsel Mesulam

  5. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Alfred Rademaker & Bing Bing Weitner

  6. Department of Psychiatry, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Sandra Weintraub

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  1. Eileen H. Bigio
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Correspondence to Eileen H. Bigio.

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Bigio, E.H., Mishra, M., Hatanpaa, K.J. et al. TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease. Acta Neuropathol 120, 43–54 (2010). https://doi.org/10.1007/s00401-010-0681-2

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  • DOI: https://doi.org/10.1007/s00401-010-0681-2

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