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Primary progressive aphasia: clinicopathological correlations

Abstract

Primary progressive aphasia (PPA) is a disorder of declining language that is a frequent presentation of neurodegenerative diseases such as frontotemporal lobar degeneration. Three variants of PPA are recognized: progressive nonfluent aphasia, semantic dementia, and logopenic progressive aphasia. In an era of etiology-specific treatments for neurodegenerative conditions, determining the histopathological basis of PPA is crucial. Clinicopathological correlations in PPA emphasize the contributory role of dementia with Pick bodies and other tauopathies, TDP-43 proteinopathies, and Alzheimer disease. These data suggest an association between a specific PPA variant and an underlying pathology, although many cases of PPA are associated with an unexpected pathology. Neuroimaging and biofluid biomarkers are now emerging as important adjuncts to clinical diagnosis. There is great hope that the addition of biomarker assessments to careful clinical examination will enable accurate diagnosis of the pathology associated with PPA during a patient's life, and that such findings will serve as the basis for clinical trials in this spectrum of disease.

Key Points

  • Primary progressive aphasia (PPA) is a major clinical presentation of frontotemporal lobar degeneration, a frequent neurodegenerative condition presenting in the presenium

  • PPA has several distinct presentations, including progressive nonfluent aphasia, semantic dementia, and logopenic progressive aphasia

  • Autopsy studies show that these syndromes are associated preferentially with a particular underlying pathology, but are not diagnostic of these pathologies

  • Advances in imaging and biofluid biomarkers in the coming years should facilitate the diagnosis of specific pathology in patients with PPA

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Figure 1: Tau-positive pathology: dementia with Pick bodies.
Figure 2: Alzheimer disease pathology.
Figure 3: Frontotemporal lobar degeneration TAR DNA-binding protein 43 proteinopathy.
Figure 4: Brain of a patient who had progressive nonfluent aphasia associated with corticobasal degeneration.
Figure 5: Distribution of cortical atrophy in three primary progressive aphasia syndromes.

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Acknowledgements

The author's work is supported in part by the NIH (AG17586, AG15116, NS44266 and NS53488). The author would also like to express his appreciation to John Q. Trojanowski and William T. Hu for their thoughtful comments on an early version of this paper, and to the patients with primary progressive aphasia and their families who contribute enthusiastically to our work.

Désirée Lie, University of California, Orange, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

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M. Grossman has acted as a consultant for Allon Therapeutics and Pfizer. The Journal Editor H. Wood and the CME questions author D. Lie declare no competing interests.

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Grossman, M. Primary progressive aphasia: clinicopathological correlations. Nat Rev Neurol 6, 88–97 (2010). https://doi.org/10.1038/nrneurol.2009.216

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