Temporal order of clinical, imaging, and biomarker changes in frontotemporal lobar degeneration-associated syndromes.

Authors

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 Borroni

Published in

Alzheimer's & dementia : the journal of the Alzheimer's Association. Volume 22. Issue 8. Pages e71722.

Abstract

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.
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.
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.
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.

PMID:
42554285
Bibliographic data and abstract were imported from PubMed on 05 Aug 2026.

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