Cargando…
Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia
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 estimate...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053353/ https://www.ncbi.nlm.nih.gov/pubmed/33452053 http://dx.doi.org/10.1136/jnnp-2020-323541 |
_version_ | 1783680104541454336 |
---|---|
author | Panman, Jessica L Venkatraghavan, Vikram van der Ende, Emma L Steketee, Rebecca M E Jiskoot, Lize C Poos, Jackie M Dopper, Elise G P Meeter, Lieke H H Donker Kaat, Laura Rombouts, Serge A R B Vernooij, Meike W Kievit, Anneke J A Premi, Enrico Cosseddu, Maura Bonomi, Elisa Olives, Jaume Rohrer, Jonathan D Sánchez-Valle, Raquel Borroni, Barbara Bron, Esther E Van Swieten, John C Papma, Janne M Klein, Stefan |
author_facet | Panman, Jessica L Venkatraghavan, Vikram van der Ende, Emma L Steketee, Rebecca M E Jiskoot, Lize C Poos, Jackie M Dopper, Elise G P Meeter, Lieke H H Donker Kaat, Laura Rombouts, Serge A R B Vernooij, Meike W Kievit, Anneke J A Premi, Enrico Cosseddu, Maura Bonomi, Elisa Olives, Jaume Rohrer, Jonathan D Sánchez-Valle, Raquel Borroni, Barbara Bron, Esther E Van Swieten, John C Papma, Janne M Klein, Stefan |
author_sort | Panman, Jessica L |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8053353 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-80533532021-05-05 Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia Panman, Jessica L Venkatraghavan, Vikram van der Ende, Emma L Steketee, Rebecca M E Jiskoot, Lize C Poos, Jackie M Dopper, Elise G P Meeter, Lieke H H Donker Kaat, Laura Rombouts, Serge A R B Vernooij, Meike W Kievit, Anneke J A Premi, Enrico Cosseddu, Maura Bonomi, Elisa Olives, Jaume Rohrer, Jonathan D Sánchez-Valle, Raquel Borroni, Barbara Bron, Esther E Van Swieten, John C Papma, Janne M Klein, Stefan J Neurol Neurosurg Psychiatry Neurodegeneration 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. BMJ Publishing Group 2021-05 2021-01-15 /pmc/articles/PMC8053353/ /pubmed/33452053 http://dx.doi.org/10.1136/jnnp-2020-323541 Text en © 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/. |
spellingShingle | Neurodegeneration Panman, Jessica L Venkatraghavan, Vikram van der Ende, Emma L Steketee, Rebecca M E Jiskoot, Lize C Poos, Jackie M Dopper, Elise G P Meeter, Lieke H H Donker Kaat, Laura Rombouts, Serge A R B Vernooij, Meike W Kievit, Anneke J A Premi, Enrico Cosseddu, Maura Bonomi, Elisa Olives, Jaume Rohrer, Jonathan D Sánchez-Valle, Raquel Borroni, Barbara Bron, Esther E Van Swieten, John C Papma, Janne M Klein, Stefan Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia |
title | Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia |
title_full | Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia |
title_fullStr | Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia |
title_full_unstemmed | Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia |
title_short | Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia |
title_sort | modelling the cascade of biomarker changes in grn-related frontotemporal dementia |
topic | Neurodegeneration |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053353/ https://www.ncbi.nlm.nih.gov/pubmed/33452053 http://dx.doi.org/10.1136/jnnp-2020-323541 |
work_keys_str_mv | AT panmanjessical modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT venkatraghavanvikram modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT vanderendeemmal modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT steketeerebeccame modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT jiskootlizec modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT poosjackiem modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT dopperelisegp modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT meeterliekehh modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT donkerkaatlaura modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT romboutssergearb modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT vernooijmeikew modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT kievitannekeja modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT premienrico modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT cosseddumaura modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT bonomielisa modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT olivesjaume modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT rohrerjonathand modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT sanchezvalleraquel modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT borronibarbara modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT bronesthere modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT vanswietenjohnc modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT papmajannem modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT kleinstefan modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia AT modellingthecascadeofbiomarkerchangesingrnrelatedfrontotemporaldementia |