Multi-level language deficits in behavioural frontotemporal degeneration and related disorders

Language is essential to social communication. Its complexity and hierarchical organization, from low-level operations to high-order integrative processes, may provide valuable diagnostic insights in neurodegeneration beyond classical aphasia syndromes. However, systematic investigations in these conditions, particularly in behavioural variant frontotemporal degeneration (bvFTD), remain scarce. To refine differential diagnosis, an exhaustive characterization of language functions is required. We systematically compared multi-level language functioning across bvFTD, Alzheimer's disease (AD) and primary psychiatric disorders (PPD), within an integrative neurolinguistic framework distinguishing lexical, syntactic and discursive levels, together with a cross-modal transposition/transcoding dimension. A total of 85 patients (including 34 with bvFTD, 30 with AD, 21 with PPD) and 40 matched healthy controls underwent an extensive language assessment using the GREMOTs battery. Composite, quantitative as well as qualitative indices were computed for each linguistic level. Structural MRI data were analysed using voxel-based morphometry (P < 0.05 corrected for multiple comparisons). All clinical groups exhibited lexical impairments relative to controls, with bvFTD presenting the most severe and widespread deficits across fluency, naming and comprehension (partial eta-squared, ηp ², ranging from 0.18 to 0.49). AD and PPD showed milder lexical inefficiencies (ηp ² = 0.11-0.39 and ηp ² = 0.07-0.29, respectively). Syntactic processing was also more impaired in bvFTD (ηp ² = 0.03-0.27) than in AD and PPD (ηp ² = 0.02-0.07 and ηp ² = 0.00-0.15, respectively). At the discourse-level, bvFTD displayed key deficits (ηp ² = 0.05-0.29), with pervasive pragmatic breakdowns whereas AD and PPD showed milder integrative deficits with preserved global coherence (ηp ² = 0.00-0.17 and ηp ² = 0.02-0.13). Transcoding and transposing tasks revealed minor deficits, mainly in bvFTD (ηp ² = 0.01-0.25). A logistic regression identified that a subset of 12/23 tasks accurately classified 85.9% of bvFTD cases (sensitivity: 57.6%; specificity: 95.6%). The analysis of the types of responses (including errors) allowed to provide a more comprehensive group profiling. In bvFTD, the decrease of language performance related to widespread frontotemporal and posterior (including cerebellar) atrophy, whereas AD showed more restricted frontal and temporal involvement. PPD displayed smaller fronto-temporal, insular and precuneal associations. In conclusion, these findings delineate a graded, multi-level linguistic profile across neurodegenerative and psychiatric conditions. bvFTD is mainly characterized by pervasive lexical and discursive-pragmatic impairments, alongside syntactic difficulties, while AD and PPD primarily show lexical inefficiencies with preserved syntax. Convergent neural evidence supports a distributed network model of language integrating frontal-insular control and temporal semantic systems. Embedding such multi-level assessments into clinical practice could enhance diagnostic precision and provide valid cognitive endpoints for future trials.