Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia
Author(s)
Type
Journal Article
Abstract
OBJECTIVE: Progranulin-related frontotemporal dementia (FTD-GRN) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation carriers. In this cross-sectional study, we estimated the temporal cascade of biomarker changes for FTD-GRN, in a data-driven way. METHODS: We included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non-carriers. Selected biomarkers were neurofilament light chain (NfL), grey matter volume, white matter microstructure and cognitive domains. We used discriminative event-based modelling to infer the cascade of biomarker changes in FTD-GRN and estimated individual disease severity through cross-validation. We derived the biomarker cascades in non-fluent variant primary progressive aphasia (nfvPPA) and behavioural variant FTD (bvFTD) to understand the differences between these phenotypes. RESULTS: Language functioning and NfL were the earliest abnormal biomarkers in FTD-GRN. White matter tracts were affected before grey matter volume, and the left hemisphere degenerated before the right. Based on individual disease severities, presymptomatic carriers could be delineated from symptomatic carriers with a sensitivity of 100% and specificity of 96.1%. The estimated disease severity strongly correlated with functional severity in nfvPPA, but not in bvFTD. In addition, the biomarker cascade in bvFTD showed more uncertainty than nfvPPA. CONCLUSION: Degeneration of axons and language deficits are indicated to be the earliest biomarkers in FTD-GRN, with bvFTD being more heterogeneous in disease progression than nfvPPA. Our data-driven model could help identify presymptomatic GRN mutation carriers at risk of conversion to the clinical stage.
Date Issued
2021-04-15
Date Acceptance
2020-11-24
Citation
Journal of Neurology, Neurosurgery and Psychiatry, 2021, 92 (5), pp.494-501
ISSN
0022-3050
Publisher
BMJ Publishing Group
Start Page
494
End Page
501
Journal / Book Title
Journal of Neurology, Neurosurgery and Psychiatry
Volume
92
Issue
5
Copyright Statement
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
License URL
Sponsor
Medical Research Council
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33452053
PII: jnnp-2020-323541
Grant Number
MR/M023664/1
Subjects
Aged
Biomarkers
Brain
Cognition
Disease Progression
Female
Frontotemporal Dementia
Gray Matter
Humans
Language
Magnetic Resonance Imaging
Male
Middle Aged
Mutation
Neurofilament Proteins
Neuropsychological Tests
Phenotype
Progranulins
White Matter
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2021-01-15