Neural signatures of cognitive heterogeneity in primary progressive aphasia: a data‐driven transdiagnostic approach
Authors: Ramanan Siddharth , Halai Ajay D , Garcia‐Penton Lorna , Perry Alistair , Patel Nikil , Peterson Katie A , Ingram Ruth , Storey Ian , Cappa Stefano F , Catricala Eleonora , Patterson Karalyn , Rowe James B. , Garrard Peter , Ralph Matthew A Lambon 
Published: December 2023

AbstractBackgroundClinical variants of primary progressive aphasia (PPA) are diagnosed on unique patterns of language dysfunction and corresponding brain changes. Mounting evidence indicates (i) within‐/between‐category clinical heterogeneity; (ii) overlapping language profiles between variants; and (iii) the presence of co‐occurring non‐linguistic cognitive deficits in some patients that may be independent of aphasia magnitude and disease severity. The neurobiological bases of such cognitive‐linguistic heterogeneity further remain unclear. An understanding of the relationship between these variables is important for improved PPA characterisation. Here, we bridge these knowledge gaps using a data‐driven transdiagnostic approach to capture language, cognitive changes and their associations with grey and white matter degeneration across PPA variants, irrespective of diagnostic labels.MethodForty‐seven PPA patients (13 semantic, 15 non‐fluent and 19 logopenic variant) underwent assessments of general cognition (Addenbrooke’s Cognitive Examination – III), errors on language performance (Mini Linguistic Status Examination), and structural and diffusion magnetic resonance imaging to capture whole‐brain grey and white matter changes, respectively. Behavioural data for all patients were entered into varimax‐rotated principal component analyses to derive statistically independent dimensions explaining the majority of performance variation. To uncover neural correlates of cognitive heterogeneity in PPA, emergent components were used as covariates in neuroimaging analyses of grey matter (voxel‐based morphometry) and white matter (network‐based statistics of structural connectomes).ResultFour behavioural principal components emerged: general cognition, semantics, working memory, and motor‐speech/phonology (Figure 1). Performance patterns on the latter three principal components were in keeping with each variant’s characteristic profile (Figure 2). General cognitive changes were most marked in logopenic PPA. Regardless of clinical diagnosis, general cognitive performance was associated with inferior/posterior parietal grey and white matter involvement, semantic dysfunction with bilateral temporal grey and white matter, working memory deficits with temporoparietal and frontostriatal involvement, and motor‐speech/phonology impairment with inferior/middle frontal regions (Figure 3).ConclusionPervasive cognitive and linguistic heterogeneity in PPA closely relates to individual‐level variations on multiple dimensions of behavioural changes and grey and white matter degeneration of regions within and beyond the language network. The employment of such transdiagnostic approaches may help expand clinical boundaries by showing symptom clusters shared across distinct variants.