Primary Progressive Aphasia: Toward a Pathophysiological Synthesis

Abstract

Purpose of review: The term primary progressive aphasia (PPA) refers to a diverse group of dementias that present with prominent and early problems with speech and language. They present considerable challenges to clinicians and researchers.

Recent findings: Here, we review critical issues around diagnosis of the three major PPA variants (semantic variant PPA, nonfluent/agrammatic variant PPA, logopenic variant PPA), as well as considering 'fragmentary' syndromes. We next consider issues around assessing disease stage, before discussing physiological phenotyping of proteinopathies across the PPA spectrum. We also review evidence for core central auditory impairments in PPA, outline critical challenges associated with treatment, discuss pathophysiological features of each major PPA variant, and conclude with thoughts on key challenges that remain to be addressed. New findings elucidating the pathophysiology of PPA represent a major step forward in our understanding of these diseases, with implications for diagnosis, care, management, and therapies.

Keywords: Alzheimer’s disease; Frontotemporal dementia; Logopenic aphasia; Physiology; Primary progressive aphasia; Progressive nonfluent aphasia; Semantic dementia.

Fig. 1

Neuroanatomical profiles of the major syndromes of primary progressive aphasia. Panels present T1-weighted coronal brain MRI sections of patients with typical syndromes of semantic variant primary progressive aphasia (svPPA), nonfluent/agrammatic primary progressive aphasia (nfvPPA), and logopenic variant primary progressive aphasia (lvPPA). Brain images are presented with the left hemisphere on the right. The svPPA scan shows asymmetric (predominantly left-sided) anterior inferior and mesial temporal lobe atrophy; the nfvPPA scan shows asymmetric (predominantly left-sided) inferior frontal, insular, and anterior-superior temporal gyrus atrophy, while the lvPPA scan shows asymmetric (predominantly left-sided) temporo-parietal junction atrophy

Fig. 2

Proposed pathophysiological synthesis of primary progressive aphasias. The figure diagrams core neural processes proposed to be targeted in each of the canonical syndromes of primary progressive aphasia, projected on a lateral view of the left cerebral hemisphere. Oblongs signify core neural processing modules or circuits within the language network: each instantiates a key template-matching operation in which incoming data (represented by black hatching) is iteratively reconciled with prior predictions and transformed into an output (predictive decoding; see text). The bidirectional arrows represent the reciprocal exchange of data and predictions between core processing modules. Processing modules are organised hierarchically, in that incoming sensory representations arriving at temporoparietal junctional cortex (blue) are transformed into increasingly abstract conceptual representations in anterior temporal cortex (green) and may ultimately be used in generating a motor output via anterior peri-Sylvian mechanisms (red). However, extensive dynamic interactions between processing modules are essential to the normal operation of the language system. Note that the neuroanatomical loci of the processing modules designated here correspond only loosely to ‘Broca’s area’, ‘Wernicke’s area’, and other structures emphasised in classical (vascular) aphasiology; the primary progressive aphasia are essentially network-based disorders. lvPPA, logopenic variant of primary progressive aphasia; nfvPPA, nonfluent-agrammatic variant of primary progressive aphasia; svPPA, semantic variant of primary progressive aphasia