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.

Figure 1

Tau-positive pathology: dementia with Pick bodies. a | Hemotoxylin and eosin preparation of Pick bodies. b | Tau-immunoreactive Pick bodies. Pick bodies are indicated by arrows; ×200 magnification. Images courtesy of Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.

Figure 2

Alzheimer disease pathology. a | Neurofibrillary tangle (arrow). b | Neuritic plaque (arrow). ×400 magnification. Images courtesy of Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.

Figure 3

Frontotemporal lobar degeneration TAR DNA-binding protein 43 proteinopathy. a | Dystrophic neurites, indicated by arrow (Sampathu type 1, Mackenzie type 2 pathology). b | Dystrophic neurites and neuronal cytoplasmic inclusions. Arrows indicate cytoplasmic inclusions (Sampathu type 2, Mackenzie type 3 pathology). c | Dystrophic neurites, neuronal cytoplasmic inclusions and neuronal intranuclear inclusions. Arrow indicates intranuclear inclusion (Sampathu type 3, Mackenzie type 1 pathology). ×100 magnification. Images courtesy of Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.

Figure 4

Brain of a patient who had progressive nonfluent aphasia associated with corticobasal degeneration. During life, this patient had hesitant, effortful speech with grammatical errors and some phonological errors, as well as impaired grammatical comprehension, consistent with progressive nonfluent aphasia. Inspection of this left hemisphere specimen at autopsy revealed considerable atrophy in inferior frontal and anterior superior temporal regions, as well as superior parietal and frontal cortices. Arrowhead indicates insula revealed by marked atrophy in inferior frontal and superior temporal portions of the left hemisphere. Large arrow indicates atrophy of the superior parietal lobule; small arrow indicates superior frontal atrophy. Histopathological examination revealed tau-positive ballooned cells and other histopathological features consistent with corticobasal degeneration. Image courtesy of Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA.

Figure 5

Distribution of cortical atrophy in three primary progressive aphasia syndromes. This image is based on a quantitative cortical thickness analysis of high-resolution 3T MRI studies in patients with primary progressive aphasia. Statistically significant cortical thinning is observed in inferior, dorsolateral prefrontal and insular regions of the left frontal lobe in progressive nonfluent aphasia (red, n = 12 patients), in the left lateral temporal and inferior parietal regions in logopenic progressive aphasia (green, n = 9 patients), and in the left anterior temporal lobe in semantic dementia (blue, n = 11 patients) relative to age-matched healthy adults.