Imperial College London
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DrChristopherButler

Faculty of Medicine, School of Public Health

Reader in Chronic and Complex Diseases
 
 
 
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Contact

 

christopher.butler Website

 
 
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Location

 

Department of Brain SciencesSir Michael Uren HubWhite City Campus

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Summary

 

Publications

Citation

BibTex format

@article{Panman:2021:10.1136/jnnp-2020-323541,
author = {Panman, JL and Venkatraghavan, V and van, der Ende EL and Steketee, RME and Jiskoot, LC and Poos, JM and Dopper, EGP and Meeter, LHH and Donker, Kaat L and Rombouts, SARB and Vernooij, MW and Kievit, AJA and Premi, E and Cosseddu, M and Bonomi, E and Olives, J and Rohrer, JD and Sánchez-Valle, R and Borroni, B and Bron, EE and Van, Swieten JC and Papma, JM and Klein, S and GENFI, consortium investigators},
doi = {10.1136/jnnp-2020-323541},
journal = {Journal of Neurology, Neurosurgery and Psychiatry},
pages = {494--501},
title = {Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia},
url = {http://dx.doi.org/10.1136/jnnp-2020-323541},
volume = {92},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Panman,JL
AU  - Venkatraghavan,V
AU  - van,der Ende EL
AU  - Steketee,RME
AU  - Jiskoot,LC
AU  - Poos,JM
AU  - Dopper,EGP
AU  - Meeter,LHH
AU  - Donker,Kaat L
AU  - Rombouts,SARB
AU  - Vernooij,MW
AU  - Kievit,AJA
AU  - Premi,E
AU  - Cosseddu,M
AU  - Bonomi,E
AU  - Olives,J
AU  - Rohrer,JD
AU  - Sánchez-Valle,R
AU  - Borroni,B
AU  - Bron,EE
AU  - Van,Swieten JC
AU  - Papma,JM
AU  - Klein,S
AU  - GENFI,consortium investigators
DO  - 10.1136/jnnp-2020-323541
EP  - 501
PY  - 2021///
SN  - 0022-3050
SP  - 494
TI  - Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia
T2  - Journal of Neurology, Neurosurgery and Psychiatry
UR  - http://dx.doi.org/10.1136/jnnp-2020-323541
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33452053
UR  - http://hdl.handle.net/10044/1/96322
VL  - 92
ER  -
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