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Primary progressive aphasia and the evolving neurology of the language network

Key Points

  • Primary progressive aphasia (PPA) is a clinical syndrome caused by selective neurodegeneration of the language-dominant cerebral hemisphere, thus affecting the language network

  • The language disorder manifest in patients with PPA can take the form of agrammatic, logopenic or semantic aphasia, depending on the anatomical distribution of cortical atrophy

  • PPA can be caused by several types of neuropathology, including Alzheimer disease and frontotemporal lobar degeneration; these diseases tend to be associated with specific variants of PPA

  • Concepts relating to Wernicke's area and anterior temporal lobe function need to be revised on the basis of the relationships identified between the clinical characteristics and neuroanatomy of peak atrophy sites in PPA

  • PPA susceptibility, aetiology and pathogenesis, and the asymmetry of cerebral atrophy in particular, are poorly understood and require further elucidation

  • Effective PPA treatments are urgently needed; development of such treatments should be considered a research area of importance

Abstract

Primary progressive aphasia (PPA) is caused by selective neurodegeneration of the language-dominant cerebral hemisphere; a language deficit initially arises as the only consequential impairment and remains predominant throughout most of the course of the disease. Agrammatic, logopenic and semantic subtypes, each reflecting a characteristic pattern of language impairment and corresponding anatomical distribution of cortical atrophy, represent the most frequent presentations of PPA. Such associations between clinical features and the sites of atrophy have provided new insights into the neurology of fluency, grammar, word retrieval, and word comprehension, and have necessitated modification of concepts related to the functions of the anterior temporal lobe and Wernicke's area. The underlying neuropathology of PPA is, most commonly, frontotemporal lobar degeneration in the agrammatic and semantic forms, and Alzheimer disease (AD) pathology in the logopenic form; the AD pathology often displays atypical and asymmetrical anatomical features consistent with the aphasic phenotype. The PPA syndrome reflects complex interactions between disease-specific neuropathological features and patient-specific vulnerability. A better understanding of these interactions might help us to elucidate the biology of the language network and the principles of selective vulnerability in neurodegenerative diseases. We review these aspects of PPA, focusing on advances in our understanding of the clinical features and neuropathology of PPA and what they have taught us about the neural substrates of the language network.

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Figure 1: The unusual complexity of clinicopathological correlations in PPA.
Figure 2: Template approach to the classification of PPA.
Figure 3: Atrophy maps of the brain in PPA subtypes.
Figure 4: Resting state functional connectivity of the ATL.
Figure 5: Asymmetry of brain atrophy in PPA.
Figure 6: Atypical distribution of AD pathology in PPA.
Figure 7: Biomarker assessments to gauge the likelihood of Alzheimer pathology in PPA.
Figure 8: Differential patterns of neuropathology in PPA-G and PPA-L.
Figure 9: Artwork by R.S., a patient with agrammatic primary progressive aphasia.

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Acknowledgements

The work of the authors is supported by the National Institute on Deafness and Communication Disorders (grants DC008552 to M.-M.M. and DC01948 to C.K.T.), the NIH National Institute on Aging (grant AG13854 for the Alzheimer Disease Centre to M.-M.M.), and the NIH National Institute on Neurological Disease and Stroke (grant NS075075 to E.J.R.) Imaging was performed at the Northwestern University Centre for Translational Imaging.

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All authors researched literature for the article and reviewed and/or edited the manuscript before submission. M.-M.M. wrote the article.

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Correspondence to M.-Marsel Mesulam.

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Mesulam, MM., Rogalski, E., Wieneke, C. et al. Primary progressive aphasia and the evolving neurology of the language network. Nat Rev Neurol 10, 554–569 (2014). https://doi.org/10.1038/nrneurol.2014.159

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