Distinct clinical subtypes of genetic frontotemporal dementia identified using disease progression modelling

This is the authors' abstract. We don't add key points for this paper.

Understanding the order in which symptoms occur in genetic frontotemporal dementia (FTD) may provide valuable insight into disease progression. Here we use a methodology called Ordinal Subtype and Stage Inference (SuStaIn) in the GENetic FTD Initiative (GENFI) cohort to estimate a probable order in which symptoms occur, and identify different subtypes based on the pattern of symptom progression within the main genetic FTD mutation groups. 968 participants were included in the cross-sectional study: 280 C9orf72, 242 GRN and 101 MAPT mutation carriers, and 345 mutation-negative controls. 379 participants underwent longitudinal analysis: 162 C9orf72, 146 GRN and 71 MAPT mutation carriers. The standardised GENFI clinical assessment provided severity scores for all FTD-relevant symptoms ranging from 0 where symptoms are absent to 3 where symptoms are severe. Ordinal SuStaIn was run in each mutation group to generate symptom progression profiles for mutation carriers from each group. In the C9orf72 cohort, Ordinal SuStaIn identified three subtypes: subtype 1 with early behavioural and cognitive deficits, subtype 2 with impaired speech and swallowing, and subtype 3 with limb impairment. In the GRN cohort, SuStaIn identified two subtypes: subtype 1 with behavioural and cognitive deficits as well as limb motor involvement, and subtype 2 with early language impairment. The MAPT cohort was best described as a single subtype with a combination of cognitive (mainly semantic) and behavioural impairment with parkinsonism. SuStaIn stage significantly correlated with clinical severity scores for all the cohorts. The subtypes were somewhat longitudinally consistent, with a trend towards increased SuStaIn stage in each subtype over time. Identifying within-genotype data-driven subtypes of FTD is a novel approach for untangling the heterogeneity of this disorder, in turn drawing us closer to individualised care.