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The primary progressive aphasias are a heterogeneous group of focal ‘language-led’ dementias that pose substantial challenges for diagnosis and management. Here we present a clinical approach to the progressive aphasias, based on our experience of these disorders and directed at non-specialists. We first outline a framework for assessing language, tailored to the common presentations of progressive aphasia. We then consider the defining features of the canonical progressive nonfluent, semantic and logopenic aphasic syndromes, including ‘clinical pearls’ that we have found diagnostically useful and neuroanatomical and other key associations of each syndrome. We review potential diagnostic pitfalls and problematic presentations not well captured by conventional classifications and propose a diagnostic ‘roadmap’. After outlining principles of management, we conclude with a prospect for future progress in these diseases, emphasising generic information processing deficits and novel pathophysiological biomarkers.

INTRODUCTION Primary progressive aphasia (PPA), a language‐based neurodegenerative dementia, negatively impacts communication and quality of life. Previous non‐pharmacologic interventions show promise but lack efficacy trials. Here, outcomes are provided from Communication Bridge‐2 (CB2), a speech‐language randomized controlled trial (RCT) for PPA. METHODS CB2 is the first Phase 2, Stage II, parallel‐group RCT delivered via video chat with global enrollment. Ninety‐five dyads were randomized into one of two speech‐language intervention arms. Primary outcomes included communication confidence and participation measures. Marginal linear models assessed efficacy across ≈12 months. RESULTS Ninety‐five dyads were randomized from four countries. Experimental arm superiority in communication‐participation measurement of goal attainment was demonstrated (66.7% vs 49.1%, respectively, p = 0.006), and corroborated by post‐study interviews. DISCUSSION Outcomes demonstrate the feasibility and initial efficacy of a person‐centered telemedicine intervention for maximizing communication participation for mild‐to‐moderate PPA, providing a pathway for developing and implementing clinically meaningful interventions for Alzheimer's disease and related dementias. Highlights Primary progressive aphasia (PPA) negatively impacts communication participation. Communication Bridge‐2 (CB2) is a telemedicine‐delivered randomized controlled trial (RCT). Global recruitment of 95 PPA participant dyads into an RCT with low dropout. First international superiority trial for PPA using video chat shows efficacy. The study provides a model for rigorous non‐pharmacologic trials for Alzheimer's disease/Alzheimer's disease and related dementias (AD/ADRD).

Primary progressive aphasias (PPA) are a group of neurodegenerative syndromes primarily characterized by the progressive loss of language. Despite established diagnostic criteria, identification can be challenging, especially in regions with limited resources and few studies, such as Latin America. This study aims to describe the clinical, neuropsychological, and radiological characteristics of a cohort of Peruvian patients diagnosed with PPA. A retrospective study was conducted on patients diagnosed with PPA at a reference center in Lima, Peru. The 2011 international consensus criteria for PPA were applied. Neuropsychological and clinical assessments, along with magnetic resonance imaging (MRI), were used to confirm the diagnosis. Descriptive statistical analyses were performed for sociodemographic, clinical, and radiological variables. ANOVA was used to assess differences in the neuropsychological battery scores between PPA syndrome groups. IRB approval was obtained for this study RESULT: A total of 22 patients were included in the study. The average age of participants was 65.3 (SD 8.7), and 77.3% were male. Semantic and non-fluent variants were the most frequent PPA subtype with 9 patients respectively. The UDS assessment revealed significant differences were observed in the Letters: P task, where the svPPA and nfvPPA groups performed significantly better than the lvPPA group (p = 0.0415). Regarding MRI findings, a high proportion of patients (60%) with nfvPPA presented diffuse atrophy, without predominance. This study highlights the clinical, neuropsychological, and radiological characteristics of Peruvian patients with PPA, contributing valuable data from a region with limited research in this field. Comprehensive evaluations in resource-limited settings to improve diagnostic accuracy and understanding of PPA in diverse populations are needed. Further studies are needed for better characterization of these patients in the region.

Background This study aimed at assessing the applicability of a symptom‐led staging system for primary progressive aphasia (PPA) based on retrospective medical records, as well as at exploring their demographic and clinical correlates. Methods 75 PPA patients (10 semantic, 28 non‐fluent, 22 logopenic, and 16 mixed variants) were retrospectively staged according to the PPA Progression Planning Aid (PPA‐Squared) system, which stages the disease by accounting for clinical features along three axes: (1) Communication; (2) Non‐Verbal Thinking and Personality; (3) Personal Care and Well‐Being. The percentage of successfully staged patients was computed. The association between PPA‐Squared scores and demographic and clinical data was tested via non‐parametric tests. The predictive capability of PPA‐Squared scores towards survival was explored via a Mantel‐Cox test. Results 89.3% of patients were successfully staged based on retrospective medical records. The PPA‐Squared was associated with the MMSE (p < 0.001), ADL (p = 0.021), and IADL scores (p < 0.001) and a set of second‐level cognitive measures tapping on attention, executive functions, language, long‐term memory, and visuo‐spatial abilities (p ≤ 0.049). No association was found between the PPA‐Squared and demographic features, symptom duration, PPA phenotype, the presence of motor involvement, and survival. Discussion The PPA‐Squared is a feasible and clinically valid tool for staging PPA patients based on their cognitive and functional status.

Primary progressive aphasia (PPA) and primary progressive apraxia of speech (PPAOS) are neurodegenerative syndromes characterized by progressive decline in language or speech. There is a growing number of studies investigating speech-language interventions for PPA/PPAOS. An updated systematic evaluation of the treatment evidence is warranted to inform best clinical practice and guide future treatment research. We systematically reviewed the evidence for behavioral treatment for speech and language in this population. Reviewed articles were published in peer-reviewed journals through 31 May 2021. We evaluated level of evidence, reporting quality, and risk of bias using a modified version of the American Speech-Language Hearing Association (ASHA) Levels of Evidence, an appraisal point system, additional reporting quality and internal/external validity items, and, as appropriate, the Single Case Experimental DesignScale or the Physiotherapy Evidence Database – PsycBITERating Scale for Randomized and Non-Randomized Controlled Trials. Results were synthesized using quantitative summaries and narrative review. A total of 103 studies reported treatment outcomes for 626 individuals with PPA; no studies used the diagnostic label PPAOS. Most studies evaluated interventions for word retrieval. The highest-quality evidence was provided by 45 experimental and quasi-experimental studies (16 controlled group studies, 29 single-subject designs). All (k = 45/45) reported improvement on a primary outcome measure; most reported generalization (k = 34/43), maintenance (k = 34/39), or social validity (k = 17/19) of treatment for at least one participant. The available evidence supports speech-language intervention for persons with PPA; however, treatment for PPAOS awaits systematic investigation. Implications and limitations of the evidence and the review are discussed.

Background Primary progressive aphasia (PPA) is a clinical dementia syndrome. Impairments in language (speaking, reading, writing, and understanding) are the primary and persistent symptoms. These impairments progress insidiously and devastate communication confidence, participation, and quality of life for persons living with PPA. Currently, there are no effective disease modifying treatments for PPA. Speech-language interventions hold promise for mitigating communication challenges and language symptoms. However, evidence regarding their efficacy in PPA is of low quality and there are currently no rigorous randomized trials. Method Communication Bridge™-2 (CB2) is a Stage 2, superiority, single-blind, randomized, parallel group, active-control, behavioral clinical trial delivered virtually within a telehealth service delivery model to individuals with PPA. Ninety carefully characterized participants with clinically confirmed PPA will be randomized to one of two speech-language intervention arms: (1) Communication Bridge™ a dyadic intervention based in communication participation therapy models that incorporates salient training stimuli or (2) the control intervention a non-dyadic intervention based in impairment therapy models addressing word retrieval and language production that incorporates fixed stimuli. The superiority of Communication Bridge™ over the Control arm will be evaluated using primary outcomes of communication confidence and participation. Other outcomes include accuracy for trained words and scripts. Participants complete two therapy blocks over a 12-month period. Outcomes will be measured at baseline, at each therapy block, and at 12 months post enrollment. Discussion The CB2 trial will supply Level 2 evidence regarding the efficacy of the Communication Bridge™ intervention delivered in a telehealth service delivery model for individuals with mild to moderate PPA. An important by-product of the CB2 trial is that these data can be used to evaluate the efficacy of speech-language interventions delivered in both trial arms for persons with PPA. The impact of these data should not be overlooked as they will yield important insights examining why interventions work and for whom, which will advance effectiveness trials for speech-language interventions in PPA. Trial Registration ClinicalTrials.gov NCT03371706 . Registered prospectively on December 13, 2017.

The diverse typology of languages often precipitates distinct language-specific symptomatologies. While dyslexia and dysgrahia are included in the diagnostic criteria of Primary Progressive Aphasia (PPA), the descriptions predominantly pertain to alphabetic scripts, with a lack of insight into their manifestations in logographic systems. This study examines the dyslexia phenotypes of Chinese-speaking PPA patients. The Chinese Language Assessment for PPA (CLAP) study recruited Mandarin and Cantonese-speaking participants [cognitively normal (CN, n = 68) and individuals with PPA (16 semantic variant (sv)PPA, 16 nonfluent/aggramatic variant (nfv)PPA ), 21 logopenic variant (lv)PPA] using a neurolinguistic tailored battery for Chinese languages. In the CLAP character reading test, participants are required to read 250 Chinese characters, encompassing a range of lexical types (pictographic, regular compound, and irregular compound characters), frequencies, and levels of concreteness. Participants are also tasked to read aloud pairs of compound words that include heteronyms (i.e., words with same spelling but pronounced differently; e.g., 'bow tie' versus 'bow down'). Additionally, voxel-based morphometry was utilized to investigate the neural basis of reading performance. In the character reading test, svPPA participants demonstrated significantly lower performance than other study groups, even after adjusting for age, education, and testing language (pictographic: p <0.001; regular compound: p <0.001; irregular compound characters: p <0.001). While over-regularization errors (i.e., surface dyslexia) were prevalent across control and PPA groups, they were not specific to svPPA (p = 0.495). In contrast, on the heteronym word reading test, both svPPA and lvPPA showed significantly lower accuracy (both p <0.001), with over-regularization errors occurring more frequently in the svPPA group (p <0.001). Across all lexical categories, character reading scores were significantly correlated with volumetric changes in the left middle and inferior temporal regions while heteronym reading accuracy were positively correlated with left temporal pole and inferior temporal areas. Contrary to English svPPA patients who primarily struggled with irregular word reading and frequently exhibit surface dyslexia, Chinese PPA patients showed no variant-specific differences across lexicality, and svPPA-specific over-regularization phenomenon were found at the lexical (i.e., heteronym-reading) and not sub-lexical reading. These findings underscore that diagnostic criteria for PPA syndromes should be linguistically tailored to accommodate language topology effect.

Although most cases of logopenic variant primary progressive aphasia (lvPPA) are caused by Alzheimer’s disease (AD), Lewy body disease (LBD) has also been reported. We assessed brain perfusion, atrophy, dopamine transporter (DAT) uptake, and language function among patients with lvPPA based on beta-amyloid. Thirty-three patients with lvPPA and 28 healthy controls (HCs) underwent MRI, 18 F-florbetaben PET, and early- and late-phase DAT PET. All patients completed a language test. General linear models were applied to investigate the association of brain imaging with the aphasia quotient (AQ) and repetition scores. 20 (60.6%) and 13 (39.4%) of the lvPPA patients were amyloid-positive (lvPPA A+ ) and -negative (lvPPA A− ), respectively. Language function was comparable between groups. Compared to HCs, the lvPPA A+ had lower perfusion across widespread brain regions, the lvPPA A− had lower perfusion in the left supramarginal and angular gyri, and both groups had lower DAT in the left caudate and bilateral substantia nigra. In the lvPPA A− , AQ and repetition scores were positively correlated with perfusion in the left temporal and inferior parietal cortices, with perfusion in the left supramarginal gyrus mediating the effect of left substantia nigra DAT. Although AD is the most common underlying pathology of lvPPA, LBD may contribute to the logopenic phenotype.

Here, we review recent progress in the diagnosis and management of primary progressive aphasia—the language-led dementias. We pose six key unanswered questions that challenge current assumptions and highlight the unresolved difficulties that surround these diseases. How many syndromes of primary progressive aphasia are there—and is syndromic diagnosis even useful? Are these truly ‘language-led’ dementias? How can we diagnose (and track) primary progressive aphasia better? Can brain pathology be predicted in these diseases? What is their core pathophysiology? In addition, how can primary progressive aphasia best be treated? We propose that pathophysiological mechanisms linking proteinopathies to phenotypes may help resolve the clinical complexity of primary progressive aphasia, and may suggest novel diagnostic tools and markers and guide the deployment of effective therapies.

INTRODUCTION Here we set out to create a symptom‐led staging system for the canonical semantic and non‐fluent/agrammatic variants of primary progressive aphasia (PPA), which present unique diagnostic and management challenges not well captured by functional scales developed for Alzheimer's disease and other dementias. METHODS An international PPA caregiver cohort was surveyed on symptom development under six provisional clinical stages and feedback was analyzed using a mixed‐methods sequential explanatory design. RESULTS Both PPA syndromes were characterized by initial communication dysfunction and non‐verbal behavioral changes, with increasing syndromic convergence and functional dependency at later stages. Milestone symptoms were distilled to create a prototypical progression and severity scale of functional impairment: the PPA Progression Planning Aid (“PPA‐Squared”). DISCUSSION This work introduces a symptom‐led staging scheme and functional scale for semantic and non‐fluent/agrammatic variants of PPA. Our findings have implications for diagnostic and care pathway guidelines, trial design, and personalized prognosis and treatment for PPA. Highlights We introduce new symptom‐led perspectives on primary progressive aphasia (PPA). The focus is on non‐fluent/agrammatic (nfvPPA) and semantic (svPPA) variants. Foregrounding of early and non‐verbal features of PPA and clinical trajectories is featured. We introduce a symptom‐led staging scheme for PPA. We propose a prototype for a functional impairment scale, the PPA Progression Planning Aid.