Temporal order of clinical, imaging, and biomarker changes in frontotemporal lobar degeneration–associated syndromes
Alberto Benussi, Valeria Bracca, Enrico Premi, Valentina Cantoni, Federica Palacino, Aurora Saccavini, Maria Sofia Cotelli, Giuliano Binetti, Rosa Manenti, Antonella Alberici, Roberto Gasparotti, Nicholas J Ashton, Henrik Zetterberg, Kaj Blennow, Roberta Ghidoni, Barbara BorroniAbstract
BACKGROUND
The temporal sequence of clinical, imaging, and biological changes in sporadic frontotemporal lobar degeneration (FTLD)–associated syndromes remains poorly characterized, and a comprehensive biomarker cascade model is lacking.
METHODS
We developed a data‐driven biomarker cascade model in 489 patients across the FTLD spectrum (211 behaviorial variant frontotemporal dementia [bvFTD], 129 primary progressive aphasia [PPA], 71 corticobasal syndrome [CBS], 66 progressive supranuclear palsy [PSP], and 12 FTD associated with amyotrophic lateral sclerosis [FTD‐ALS]; 1904 patient‐visit observations). Plasma, magnetic resonance imaging (MRI), and clinical biomarkers were modeled using sigmoid trajectories fitted to covariate‐adjusted longitudinal data.
RESULTS
Plasma glial fibrillary acidic protein departed from normality earliest, followed by Trail Making Test Part B (TMT‐B), white matter lesion volume, and neurofilament light chain. Insular atrophy showed the steepest transition among MRI measures; clinical dementia rating dementia staging instrument plus National Alzheimer's Coordinating Center behavior and language domains sum of boxes declined most steeply overall. TMT‐B inflected earliest in bvFTD, whereas insula atrophy dominated in PPA.
CONCLUSIONS
This first data‐driven temporal cascade of multimodal biomarkers in sporadic FTLD‐associated syndromes offers a framework for disease staging and stage‐specific clinical trial design.