Primary progressive aphasia and the evolving neurology of the language network

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.

Figure 1

The unusual complexity of clinicopathological correlations in PPA. a | Drawing of an axial section of a structural MRI scan from a 57-year-old familial left-handed man with right-hemisphere language dominance and logopenic PPA; the right cerebral hemisphere is on the left-hand side. Areas of substantial atrophy can be observed in the right perisylvian cortex, including the posterior STG (arrow). b | Illustration of findings based on fMRI evaluation of the same patient performed soon after the structural scan, revealing that the atrophic area of the right hemisphere was activated (arrow) during a task in which the patient was asked to determine whether two words had the same meaning. c | The patient died 8 years later; pathology of autopsy tissue demonstrated features consistent with frontotemporal lobar degeneration with TAR DNA-binding protein 43 pathology. In particular, despite the severe atrophy at the time of the structural MRI scan and progressive neuronal loss over the subsequent 8 years before death, the photomicrograph of a cresyl violet-stained region of the right STG demonstrates identifiable neurons (arrows), some of which might have contributed to the activation of this region during the fMRI assessment. Abbreviations: fMRI, functional MRI; PPA, primary progressive aphasia; STG, superior temporal gyrus.

Figure 2

Template approach to the classification of PPA. This simplified approach is based on the integrity of single-word comprehension and grammaticality of sentences. The patient must fulfil the root diagnosis of PPA before undergoing classification according to this system. The performance of the classification system is optimal if conducted neither too early nor too late in the course of the disease. The individual tests and cut-off scores must be determined empirically, and depend on the severity of the aphasia.^, The broken boundary line between the PPA-G and PPA-L quadrants represents the challenge that is frequently faced in differentiating these two aphasia subtypes. The upper right quadrant can potentially contain the most heterogeneous population. In practice, however, it becomes populated almost exclusively by patients who are clinically logopenic, either with or without phrase and sentence repetition impairments. Abbreviations: ATL, anterior temporal lobe; FTLD, frontotemporal lobar degeneration; FTLD-TDP, FTLD with TAR DNA-binding protein 43 pathology; IFG, inferior frontal gyrus; PPA, primary progressive aphasia; PPA-G, agrammatic PPA; PPA-L, logopenic PPA; PPA-M, mixed PPA; PPA-S, semantic PPA.

Figure 3

Atrophy maps of the brain in PPA subtypes. Atrophy maps of the brain were generated by comparing MRI-based cortical thickness data from a single patient with ‘normal’ measurements derived from a control group of 27 healthy individuals using FreeSurfer software, which presents the peak atrophic sites in red and yellow.^, The maps were produced using a threshold false discovery rate of P <0.05. a | Map based on an MRI scan from a right-handed man with PPA-G aged 59 years, 3 years after symptom onset at the age of 56 years. b | Atrophy map associated with PPA-L in a right-handed woman with symptom onset at the age of 60 years; the scan was obtained 5 years after symptom onset. c | Atrophy map of a 72-year-old right-handed woman with PPA-L, 4 years after symptom onset. d | Map of atrophy in a right-handed woman with PPA-S based on a scan performed 2 years after symptom onset at the age of 59 years. Abbreviations: 37, Brodmann area 37; AG, angular gyrus; ATL, anterior temporal lobe; IFG, inferior frontal gyrus; MTG, middle temporal gyrus; PPA, primary progressive aphasia; PPA-G, agrammatic PPA; PPA-L, logopenic PPA; PPA-M, mixed PPA; PPA-S, semantic PPA; SMG, supramarginal gyrus; STG, superior temporal gyrus; TP, temporopolar cortex; TPJ, temporoparietal junction.

Figure 4

Resting state functional connectivity of the ATL. 33 right-handed neurologically intact patients underwent MRI, and the task-free functional connectivity of a 10 mm seed in the ATL (blue circle) with all other voxels in the brain was computed by correlating the averaged haemodynamic time series data.^, Areas in red and yellow contain voxels that have statistically significant functional connectivity with the seed area at a false discovery rate threshold of P <0.001.^, a | The left ATL has functional connectivity with the IFG and TPJ in the ipsilateral and, to a lesser extent, in the contralateral hemisphere. The TPJ area includes parts of the inferior parietal lobule and posterior tip of the superior temporal gyrus. b | The right ATL has almost no significant functional connectivity at this threshold with the IFG or TPJ area in either hemisphere. The ATL is, therefore, asymmetrically organized. Abbreviations: ATL, anterior temporal lobe; IFG, inferior frontal gyrus; TPJ, temporoparietal junction.

Figure 5

Asymmetry of brain atrophy in PPA. These photographs demonstrate the asymmetric atrophy of the left-hemisphere language network associated with three different types of neuropathology in three right-handed patients with PPA. a | Alzheimer disease pathology in a woman who died at the age of 80 years, 7 years after the onset of PPA; the left IFG (arrow) is atrophic, but the right IFG is not. b | FTLD-tau pathology of the corticobasal degeneration type in a woman with PPA onset at the age of 72 years, who subsequently died at the age of 78 years; again, the left IFG (arrow) is atrophic, but the right IFG is not. c | Type B FTLD-TDP in a man with onset of PPA at the age of 66 years, who died 6 years later; the left TP and ATL are atrophic, but the homologous areas of the right hemisphere are not. Asterisks indicate brain regions that were removed for biochemical analyses. Abbreviations: ATL, anterior temporal lobe; FTLD-tau, frontotemporal lobar degeneration with tau protein pathology; FTLD-TDP, frontotemporal lobar degeneration with TAR DNA-binding protein 43 pathology; IFG, inferior frontal gyrus; PPA, primary progressive aphasia; TP, temporal pole. Permission obtained from Oxford University Press © Mesulam, M.-M. et al. Brain 137, 1176–1192 (2014).

Figure 6

Atypical distribution of AD pathology in PPA. Photomicrographs show fluorescent thioflavin-S-stained tissue from different regions of the brain of a man with PPA, with onset at age 61 years. The patient died aged 71 years and the autopsy revealed AD pathology. Plaques (arrow) and neurofibrillary tangles (asterisk) were detected in the a | CA1 area of the hippocampus, b | entorhinal cortex, c | STG of the left hemisphere and d | STG of the right hemisphere. Panels a and b show that the lesion density is lower in the CA1 and entorhinal cortex than in neocortical areas such as the STG. This pattern of lesion distribution does not conform to the principles of Braak staging in Alzheimer disease. Panels c and d demonstrate a higher density of plaques and neurofibrillary tangles in the STG of the left hemisphere than in the homologous region on the right side. Magnification was 100×, except in the entorhinal cortex (40× magnification). Abbreviations: AD, Alzheimer disease; PPA, primary progressive aphasia; STG, superior temporal gyrus. Permission obtained from Oxford University Press © Mesulam, M.-M. et al. Brain 137, 1176–1192 (2014).

Figure 7

Biomarker assessments to gauge the likelihood of Alzheimer pathology in PPA. Data from biomarker evaluations in two patients with a logopenic pattern of PPA at the initial clinical visit. Axial scans on the left show the results of PET imaging using an Aβ-binding tracer, ¹⁸F-florbetapir. Intense red areas on scan from Patient A are indicative of a positive PET result for Aβ plaques, indicating AD pathology, whereas the scan from Patient B demonstrates a negative result of this biomarker test. Right-hand panels show CSF levels of phospho-tau on the x-axis and a proprietary ratio of CSF Aβ:total tau on the y-axis (test performed by Athena Diagnostics). The diagnostic implications of values plotted on this graph have been determined empirically. Asterisks in the right-hand panels denote these values measured in CSF samples from the two patients. Patient A had high CSF levels of phospho-tau and a low CSF Aβ:total tau ratio, consistent with AD pathology, confirmed at postmortem examination. Both the CSF and PET results for Patient B are inconsistent with AD pathology and lead us to predict that the autopsy will reveal a form of frontotemporal lobar degeneration underlying PPA in this individual. Abbreviations: Aβ, amyloid-β; AD, Alzheimer disease; CSF, cerebrospinal fluid; PPA, primary progressive aphasia.

Figure 8

Differential patterns of neuropathology in PPA-G and PPA-L. 49 PPA patients without word comprehension impairments, most of whom would fit the ‘progressive nonfluent aphasia’ designation, were divided into two groups on the basis of grammaticality. The two groups had significantly different proportions of neuropathology types (Fisher’s exact test, P = 0.001). The group of patients with preserved grammar (consisting of PPA-L patients with and without impairment in repetition of phrases and sentences) mostly had Alzheimer pathology, whereas the group with impaired grammar (PPA-G) had mostly FTLD-tau pathology. Abbreviation: FTLD-tau, frontotemporal lobar degeneration with tau protein pathology; FTLD-TDP, frontotemporal lobar degeneration with TAR DNA-binding protein 43 pathology; PPA, primary progressive aphasia; PPA-G, agrammatic PPA; PPA-L, logopenic PPA.

Figure 9

Artwork by R.S., a patient with agrammatic primary progressive aphasia. She was 60 years of age at the time of diagnosis and started painting 2 years later. Image reproduced with permission of the artist.