Primary progressive aphasias (PPA) are neurodegenerative diseases clinically characterized by an early and relatively isolated language impairment. Three main clinical variants, namely the nonfluent/agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA) have been described, each with specific linguistic/cognitive deficits, corresponding anatomical and most probable pathological features. Since the discovery and the development of diagnostic criteria for the PPA variants by the experts in the field, significant progress has been made in the understanding of these diseases. This review aims to provide an overview of the literature on each of the PPA variant in terms of their clinical, anatomical and pathological features, with a specific focus on recent findings. In terms of clinical advancements, recent studies have allowed a better characterization and differentiation of PPA patients based on both their linguistic and non-linguistic profiles. In terms of neuroimaging, techniques such as diffusion imaging and resting-state fMRI have allowed a deeper understanding of the impact of PPA on structural and functional connectivity alterations beyond the well-defined pattern of regional gray matter atrophy. Finally, in terms of pathology, despite significant advances, clinico-pathological correspondence in PPA remains far from absolute. Nonetheless, the improved characterization of PPA has the potential to have a positive impact on the management of patients. Improved reliability of diagnoses and the development of reliable in vivo biomarkers for underlying neuropathology will also be increasingly important in the future as trials for etiology-specific treatments become available.

Introduction

Positron emission tomography (PET) amyloid imaging has become an important part of the diagnostic workup for patients with primary progressive aphasia (PPA) and uncertain underlying pathology. Here, we employ a semi-automated analysis of connected speech (CS) with a twofold objective. First, to determine if quantitative CS features can help select primary progressive aphasia (PPA) patients with a higher probability of a positive PET amyloid imaging result. Second, to examine the relevant group differences from a clinical perspective.

Methods

117 CS samples from a well-characterised cohort of PPA patients who underwent PET amyloid imaging were collected. Expert consensus established PET amyloid status for each patient, and 40% of the sample was amyloid positive.

Results

Leave-one-out cross-validation yields 77% classification accuracy (sensitivity: 74%, specificity: 79%).

Discussion

Our results confirm the potential of CS analysis as a screening tool. Discriminant CS features from lexical, syntactic, pragmatic, and semantic domains are discussed.

Background

Increasing evidence shows that the semantic variant of primary progressive aphasia (svPPA) is characterized by hippocampal atrophy. However, less is known about disease-related morphological hippocampal changes. The goal of the present study is to conduct a detailed characterization of the impact of svPPA on global hippocampus volume and morphology compared with control subjects and patients with Alzheimer's disease (AD).

Methods

We measured hippocampal volume and deformation-based shape differences in 22 patients with svPPA compared with 99 patients with AD and 92 controls. Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeT-Brain) was used on MRI images obtained at the diagnostic visit.

Results

Comparable left and right hippocampal atrophy were observed in svPPA and AD. Deformation-based shape analysis showed a common pattern of morphological deformation in svPPA and AD compared with controls. More specifically, both svPPA and AD showed inward deformations in the dorsal surface of the hippocampus, from head to tail on the left side, and more limited to the anterior portion of the body in the right hemisphere. These results also pointed out that both diseases are characterized by a lateral displacement of the central part (body) of the hippocampus.

Discussion

Our study provides critical new evidence of hippocampal morphological changes in svPPA, similar to those found in AD. These findings highlight the importance of considering morphological hippocampal changes as part of the anatomical profile of patients with svPPA.

Intrinsic connectivity networks (ICNs) identified through task-free fMRI (tf-fMRI) offer the opportunity to investigate human brain circuits involved in language processes without requiring participants to perform challenging cognitive tasks. In this study, we assessed the ability of tf-fMRI to isolate reproducible networks critical for specific language functions and often damaged in primary progressive aphasia (PPA). First, we performed whole-brain seed-based correlation analyses on tf-fMRI data to identify ICNs anchored in regions known for articulatory, phonological, and semantic processes in healthy male and female controls (HCs). We then evaluated the reproducibility of these ICNs in an independent cohort of HCs, and recapitulated their functional relevance with a post hoc meta-analysis on task-based fMRI. Last, we investigated whether atrophy in these ICNs could inform the differential diagnosis of nonfluent/agrammatic, semantic, and logopenic PPA variants. The identified ICNs included a dorsal articulatory-phonological network involving inferior frontal and supramarginal regions; a ventral semantic network involving anterior middle temporal and angular gyri; a speech perception network involving superior temporal and sensorimotor regions; and a network between posterior inferior temporal and intraparietal regions likely linking visual, phonological, and attentional processes for written language. These ICNs were highly reproducible across independent groups and revealed areas consistent with those emerging from task-based meta-analysis. By comparing ICNs' spatial distribution in HCs with patients' atrophy patterns, we identified ICNs associated with each PPA variant. Our findings demonstrate the potential use of tf-fMRI to investigate the functional status of language networks in patients for whom activation studies can be methodologically challenging.SIGNIFICANCE STATEMENT We showed that a single, short, task-free fMRI acquisition is able to identify four reproducible and relatively segregated intrinsic left-dominant networks associated with articulatory, phonological, semantic, and multimodal orthography-to-phonology processes, in HCs. We also showed that these intrinsic networks relate to syndrome-specific atrophy patterns in primary progressive aphasia. Collectively, our results support the application of task-free fMRI in future research to study functionality of language circuits in patients for whom tasked-based activation studies might be methodologically challenging.

Semantic variant primary progressive aphasia is a clinical syndrome characterized by marked semantic deficits, anterior temporal lobe atrophy and reduced connectivity within a distributed set of regions belonging to the functional network associated with semantic processing. However, to fully depict the clinical signature of semantic variant primary progressive aphasia, it is necessary to also characterize preserved neural networks and linguistic abilities, such as those subserving speech production. In this case-control observational study, we employed whole-brain seed-based connectivity on task-free MRI data of 32 semantic variant primary progressive aphasia patients and 46 healthy controls to investigate the functional connectivity of the speech production network and its relationship with the underlying grey matter. We investigated brain-behaviour correlations with speech fluency measures collected through clinical tests (verbal agility) and connected speech (speech rate and articulation rate). As a control network, we also investigated functional connectivity within the affected semantic network. Patients presented with increased connectivity in the speech production network between left inferior frontal and supramarginal regions, independent of underlying grey matter volume. In semantic variant primary progressive aphasia patients, preserved (verbal agility) and increased (articulation rate) speech fluency measures correlated with increased connectivity between inferior frontal and supramarginal regions. As expected, patients demonstrated decreased functional connectivity in the semantic network (dependent on the underlying grey matter atrophy) associated with average nouns' age of acquisition during connected speech. Collectively, these results provide a compelling model for studying compensation mechanisms in response to disease that might inform the design of future rehabilitation strategies in semantic variant primary progressive aphasia.