Purpose of review

Knowledge on primary progressive aphasia (PPA) has expanded rapidly in the past few decades. Clinical characteristics, neuroimaging correlates, and neuropathological features of PPA are better delineated. This facilitates scientific studies on the disease pathophysiology and allows speech and language therapy to be more precisely targeted. This review article begins with a summary of the current understanding of PPA and discusses how PPA can serve as a model to promote scientific discovery in neurodegenerative diseases.

Recent findings

Studies on the different variants of PPA have demonstrated the high compatibility between clinical presentations and neuroimaging features, and in turn, enhances the understanding of speech and language neuroanatomy. In addition to the traditional approach of lesion-based or voxel-based mapping, scientists have also adopted functional connectivity and network topology approaches that permits a more multidimensional understanding of neuroanatomy. As a result, pharmacological and cognitive therapeutic strategies can now be better targeted towards specific pathological/molecular and cognitive subtypes.

Summary

Recent scientific advancement in PPA potentiates it to be an optimal model for studying brain network vulnerability, neurodevelopment influences and the effects of nonpharmacological intervention in neurodegenerative diseases.

Advances in automatic text classification have been necessitated by the rapid increase in the availability of digital documents. Machine learning (ML) algorithms can 'learn' from data: for instance a ML system can be trained on a set of features derived from written texts belonging to known categories, and learn to distinguish between them. Such a trained system can then be used to classify unseen texts. In this paper, we explore the potential of the technique to classify transcribed speech samples along clinical dimensions, using vocabulary data alone. We report the accuracy with which two related ML algorithms [naive Bayes Gaussian (NBG) and naive Bayes multinomial (NBM)] categorized picture descriptions produced by: 32 semantic dementia (SD) patients versus 10 healthy, age-matched controls; and SD patients with left- (n = 21) versus right-predominant (n = 11) patterns of temporal lobe atrophy. We used information gain (IG) to identify the vocabulary features that were most informative to each of these two distinctions. In the SD versus control classification task, both algorithms achieved accuracies of greater than 90%. In the right- versus left-temporal lobe predominant classification, NBM achieved a high level of accuracy (88%), but this was achieved by both NBM and NBG when the features used in the training set were restricted to those with high values of IG. The most informative features for the patient versus control task were low frequency content words, generic terms and components of metanarrative statements. For the right versus left task the number of informative lexical features was too small to support any specific inferences. An enriched feature set, including values derived from Quantitative Production Analysis (QPA) may shed further light on this little understood distinction.

In the field of neurodegeneration, speech and language assessments are useful for diagnosing aphasic syndromes and for characterizing other disorders. As a complement to classic tests, scalable and low-cost digital tools can capture relevant anomalies automatically, potentially supporting the quest for globally equitable markers of brain health. However, this promise remains unfulfilled due to limited linguistic diversity in scientific works and clinical instruments. Here we argue for cross-linguistic research as a core strategy to counter this problem. First, we survey the contributions of linguistic assessments in the study of primary progressive aphasia and the three most prevalent neurodegenerative disorders worldwide-Alzheimer's disease, Parkinson's disease, and behavioural variant frontotemporal dementia. Second, we address two forms of linguistic unfairness in the literature: the neglect of most of the world's 7000 languages and the preponderance of English-speaking cohorts. Third, we review studies showing that linguistic dysfunctions in a given disorder may vary depending on the patient's language and that English speakers offer a suboptimal benchmark for other language groups. Finally, we highlight different approaches, tools and initiatives for cross-linguistic research, identifying core challenges for their deployment. Overall, we seek to inspire timely actions to counter a looming source of inequity in behavioural neurology.

The logopenic variant of primary progressive aphasia is characterized by early deficits in language production and phonological short-term memory, attributed to left-lateralized temporoparietal, inferior parietal and posterior temporal neurodegeneration. Despite patients primarily complaining of language difficulties, emerging evidence points to performance deficits in non-linguistic domains. Temporoparietal cortex, and functional brain networks anchored to this region, are implicated as putative neural substrates of non-linguistic cognitive deficits in logopenic variant primary progressive aphasia, suggesting that degeneration of a shared set of brain regions may result in co-occurring linguistic and non-linguistic dysfunction early in the disease course. Here, we provide a Review aimed at broadening the understanding of logopenic variant primary progressive aphasia beyond the lens of an exclusive language disorder. By considering behavioural and neuroimaging research on non-linguistic dysfunction in logopenic variant primary progressive aphasia, we propose that a significant portion of multidimensional cognitive features can be explained by degeneration of temporal/inferior parietal cortices and connected regions. Drawing on insights from normative cognitive neuroscience, we propose that these regions underpin a combination of domain-general and domain-selective cognitive processes, whose disruption results in multifaceted cognitive deficits including aphasia. This account explains the common emergence of linguistic and non-linguistic cognitive difficulties in logopenic variant primary progressive aphasia, and predicts phenotypic diversification associated with progression of pathology in posterior neocortex.

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.

Previous evidence from neuropsychological and neuroimaging studies suggests functional specialization for tools and related semantic knowledge in a left frontoparietal network. It is still debated whether these areas are involved in the representation of rudimentary movement-relevant knowledge regardless of semantic domains (animate vs. inanimate) or categories (tools vs. nontool objects). Here, we used fMRI to record brain activity while 13 volunteers performed two semantic judgment tasks on visually presented items from three different categories: animals, tools, and nontool objects. Participants had to judge two distinct semantic features: whether two items typically move in a similar way (e.g., a fan and a windmill move in circular motion) or whether they are usually found in the same environment (e.g., a seesaw and a swing are found in a playground). We investigated differences in overall activation (which areas are involved) as well as representational content (which information is encoded) across semantic features and categories. Results of voxel-wise mass univariate analysis showed that, regardless of semantic category, a dissociation emerges between processing information on prototypical location (involving the anterior temporal cortex and the angular gyrus) and movement (linked to left inferior parietal and frontal activation). Multivoxel pattern correlation analyses confirmed the representational segregation of networks encoding task- and category-related aspects of semantic processing. Taken together, these findings suggest that the left frontoparietal network is recruited to process movement properties of items (including both biological and nonbiological motion) regardless of their semantic category.

Objective

To determine the effect of three psycholinguistic variables-lexical frequency, age of acquisition (AoA), and neighborhood density (ND)-on lexical-semantic processing in individuals with non-fluent (nfvPPA), logopenic (lvPPA), and semantic primary progressive aphasia (svPPA). Identifying the scope and independence of these features can provide valuable information about the organization of words in our mind and brain.

Method

We administered a lexical decision task-with words carefully selected to permit distinguishing lexical frequency, AoA, and orthographic ND effects-to 41 individuals with PPA (13 nfvPPA, 14 lvPPA, 14 svPPA) and 25 controls.

Results

Of the psycholinguistic variables studied, lexical frequency had the largest influence on lexical-semantic processing, but AoA and ND also played an independent role. The results reflect a brain-language relationship with different proportional effects of frequency, AoA, and ND in the PPA variants, in a pattern that is consistent with the organization of the mental lexicon. Individuals with nfvPPA and lvPPA experienced an ND effect consistent with the role of inferior frontal and temporoparietal regions in lexical analysis and word form processing. By contrast, individuals with svPPA experienced an AoA effect consistent with the role of the anterior temporal lobe in semantic processing.

Conclusions

The findings are in line with a hierarchical mental lexicon structure with a conceptual (semantic) and a lexeme (word-form) level, such that a selective deficit at one of these levels of the mental lexicon manifests differently in lexical-semantic processing performance, consistent with the affected language-specific brain region in each PPA variant.

Syntactic processing deficits are highly variable in individuals with primary progressive aphasia. Damage to left inferior frontal cortex has been associated with syntactic deficits in primary progressive aphasia in a number of structural and functional neuroimaging studies. However, a contrasting picture of a broader syntactic network has emerged from neuropsychological studies in other aphasic cohorts, and functional imaging studies in healthy controls. To reconcile these findings, we used functional magnetic resonance imaging to investigate the functional neuroanatomy of syntactic comprehension in 51 individuals with primary progressive aphasia, composed of all clinical variants and a range of degrees of syntactic processing impairment. We used trial-by-trial reaction time as a proxy for syntactic processing load, to determine which regions were modulated by syntactic processing in each patient, and how the set of regions recruited was related to whether syntactic processing was ultimately successful or unsuccessful. Relationships between functional abnormalities and patterns of cortical atrophy were also investigated. We found that the individual degree of syntactic comprehension impairment was predicted by left frontal atrophy, but also by functional disruption of a broader syntactic processing network, comprising left posterior frontal cortex, left posterior temporal cortex, and the left intraparietal sulcus and adjacent regions. These regions were modulated by syntactic processing in healthy controls and in patients with primary progressive aphasia with relatively spared syntax, but they were modulated to a lesser extent or not at all in primary progressive aphasia patients whose syntax was relatively impaired. Our findings suggest that syntactic comprehension deficits in primary progressive aphasia reflect not only structural and functional changes in left frontal cortex, but also disruption of a wider syntactic processing network.

Semantic dementia (SD) is a clinical variant of frontotemporal lobar degeneration (FTLD) characterized by progressive deterioration of semantic memory with relative sparing of other cognitive functions. It is associated with mainly left anterior temporal atrophy, and is also referred to as "left-temporal lobe variant" of FTLD. Recently, patients with mainly right-sided atrophy, or "right-temporal lobe variant"(RTLV), have been described. While some authors have reported that the initial and most significant deficit in these right-sided cases is a difficulty in recognizing famous people, others have observed that major behavioral abnormalities are the presenting symptoms. Here we report a detailed neuropsychological, language, behavioral and neuroimaging assessment of JT, a case of right temporal lobe variant of FTLD. JT showed early and prominent behavioral changes accompanied by a severe impairment in recognizing foods by their look, flavor or name. Later she also developed a difficulty in recognizing familiar people and objects. Standardized caregiver questionnaires of JT's pre- and post-morbid personality and interpersonal functioning showed that she went from being a flexible, dominant, extraverted, person to showing rigid, submissive and introverted behaviors. Her levels of neuroticism significantly increased, while her scores on agreeableness and cognitive and emotional empathy dropped. Voxel-based morphometry (VBM) showed most significant atrophy in the right amygdala/anterior hippocampal complex and collateral sulcus, extending to the right insula. We discuss the atypical cognitive and behavioral features of this case of RTLV of FTLD and stress the importance of behavioral changes and atypical semantic deficits for early diagnosis.