Primary progressive aphasia in Italian and English: a cross-linguistic cohort study

Background and objectives Primary progressive aphasia (PPA) signifies a diverse group of neurodegenerative disorders principally affecting language functions. The major syndromic variants of PPA present with distinct profiles of linguistic deficits. However, current concepts and diagnosis of PPA are largely based on English-speaking patients, while few studies have explored how PPA syndromes might vary between languages. Here we undertook a comprehensive neuropsychological comparison of all major PPA syndromes in two languages with contrasting characteristics: Italian and English. Methods We retrospectively compared the PPA cohorts attending our specialist referral centres on neuropsychological tests sampling a range of linguistic and general cognitive domains. The cohorts comprised 106 native Italian-speakers with PPA (14 nonfluent/agrammatic variant [nfvPPA], 20 semantic variant [svPPA], 41 logopenic variant [lvPPA], 31 mixed PPA [mPPA]) and 166 native English-speakers with PPA (70 nfvPPA, 45 svPPA, 42 lvPPA, 9 mPPA). Neuropsychological scores were normalised to healthy older native speakers (adjusted for age and years of education) and dichotomised (impaired/unimpaired) to identify the proportion of each cohort showing impairment on each test. Cohorts were compared in logistic regression models, covarying for symptom duration and overall cognitive severity. Results The English PPA cohort was significantly younger (mean 62.7 years) than the Italian cohort (mean 65.9 years; p=0.003), with longer symptom duration (mean 4.6 vs 3.1 years; p=0.048), a higher proportion of nfvPPA cases (42% vs. 13%, p<0.001) and lower proportions of lvPPA (25% vs. 38%, p=0.019) and mPPA (5% vs. 29%, p<0.001). Compared with Italian-speaking patients, English-speaking nfvPPA patients had less frequent expressive agrammatism (p=0.015) and more frequently impaired single-word comprehension (p=0.013) and nonverbal working memory (p=0.041). English svPPA patients had more frequent surface dyslexia (p=0.046) and dysgraphia (p=0.021), while English lvPPA patients had more frequently impaired single-word comprehension (p<0.001), word repetition (p=0.02), nonverbal working memory (p=0.005) and visuospatial perception (p<0.001). Discussion Language-specific characteristics importantly influence PPA phenotypes: degeneration of language networks may predispose to expressive agrammatism in Italian (reflecting its morphological complexity) and to impaired spoken word processing and regularisation errors in English (reflecting its articulatory, acoustic and orthographic complexity). These findings have implications for diagnosis, management and cross-linguistic collaborative initiatives in PPA. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Alzheimer's Society, Alzheimer's Research UK, the UK Dementia Research Institute at UCL, the National Institute for Health Research University College London Hospitals Biomedical Research Centre and RICATEN24 (BN, Ateneo Universita di Firenze, fondi Ateneo 2024). CJDH is supported by a NIHR [Invention for Innovation (NIHR204280)] grant and received a Wellcome Institutional Strategic Support Fund Award (204841/Z/16/Z). JJ was supported by the National Brain Appeal (Frontotemporal Dementia Research Studentship in Memory of David Blechner). CM and VM are supported by a Tuscany Region grant (CUP. D18D20001300002). JCSJ was supported by an Association of British Neurologists Clinical Research Training Fellowship. AV is supported by a NIHR Advanced Fellowship NIHR302240. JDR has been supported by a Miriam Marks Brain Research UK Senior Fellowship, a Medical Research Council Clinician Scientist Fellowship (MR/M008525/1) and the National Institute for Health Research Rare Disease Translational Research Collaboration (BRC149/NS/MH). JDW is supported by the Alzheimer's Society, Alzheimer's Research UK, the Royal National Institute for Deaf People (Discovery Grant G105_WARREN) and the National Institute for Health Research University College London Hospitals Biomedical Research Centre. This research was funded in part by UKRI and Wellcome Trust (Grant 204841/Z/16/Z). For the purpose of Open Access, the authors have applied a Creative Commons Attribution (CC BY) public copyright licence to any Author Accepted Manuscript version arising from this submission. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All participants gave informed consent to take part in the relevant cohort study and ethical approval was granted by the local institutional ethics committee (the UCL-NHNN Joint Research Ethics Committee or the Institutional Review Board of Careggi University Hospital, Florence, Italy, reference 15691oss), in accordance with Declaration of Helsinki guidelines. 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