Mapping behavioural, cognitive and affective transdiagnostic dimensions in frontotemporal dementia
Authors: Ramanan Siddharth , El-Omar Hashim , Roquet Daniel , Ahmed Rebekah M. , Hodges John R. , Piguet Olivier , Lambon Ralph Matthew A. , Irish Muireann 
Published: October 2021

Two common clinical variants of frontotemporal dementia (FTD) are the behavioural variant (bvFTD) presenting with behavioural and personality changes attributable to prefrontal atrophy, and semantic dementia (SD) displaying early semantic dysfunction primarily due to anterior temporal degeneration. Despite representing independent diagnostic entities, mounting evidence indicates overlapping cognitive-behavioural profiles in these syndromes, particularly with disease progression. Why such overlap occurs remains unclear. Understanding the nature of this overlap, however, is essential to improve early diagnosis, characterisation, and management of those affected. Here, we explored common cognitive-behavioural and neural mechanisms contributing to heterogeneous FTD presentations, irrespective of clinical diagnosis. This transdiagnostic approach allowed us to ascertain whether symptoms not currently considered core to these two syndromes are present in a significant proportion of cases and explore the neural basis of clinical heterogeneity. Sixty-two FTD patients (31 bvFTD, 31 SD) underwent comprehensive neuropsychological, behavioural, and structural neuroimaging assessments. Orthogonally-rotated principal component analysis of neuropsychological and behavioural data uncovered eight statistically independent factors explaining the majority of cognitive-behavioural performance variation in bvFTD and SD. These factors included Behavioural changes, Semantic dysfunction, General Cognition, Executive function, Initiation, Disinhibition, Visuospatial function, and Affective changes. Marked individual-level overlap between bvFTD and SD was evident on the Behavioural changes, General Cognition, Initiation, Disinhibition, and Affective changes factors. Compared to bvFTD, SD patients displayed disproportionate impairment on the Semantic dysfunction factor, whereas greater impairment on Executive and Visuospatial function factors was noted in bvFTD. Both patient groups showed comparable magnitude of atrophy to frontal regions, whereas severe temporal lobe atrophy was characteristic of SD. Whole-brain voxel-based morphometry correlations with emergent factors revealed associations between fronto-insular and striatal grey matter changes with Behavioural, Executive, and Initiation factor performance, bilateral temporal atrophy with Semantic dysfunction factor scores, parietal-subcortical regions with General Cognitive performance, and ventral temporal atrophy associated with Visuospatial factor scores. Together, these findings indicate that cognitive-behavioural overlap (i) occurs systematically in FTD, (ii) varies in a graded manner between individuals, and (iii) is associated with degeneration of different neural systems. Our findings suggest that phenotypic heterogeneity in FTD syndromes can be captured along continuous, multidimensional spectra of cognitive-behavioural changes. This has implications for the diagnosis of both syndromes amidst overlapping features as well as the design of symptomatic treatments applicable to multiple syndromes.