{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T16:34:21Z","timestamp":1793982861178,"version":"4.8.0"},"reference-count":42,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T00:00:00Z","timestamp":1610668800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Reference Network For Rare Neurological Diseases","award":["739510"],"award-info":[{"award-number":["739510"]}]},{"name":"NIHR Rare Disease Translational Research Collaboration","award":["BRC149\/NS\/MH"],"award-info":[{"award-number":["BRC149\/NS\/MH"]}]},{"DOI":"10.13039\/501100010573","name":"Stichting Dioraphte","doi-asserted-by":"publisher","award":["09-02-00"],"award-info":[{"award-number":["09-02-00"]}],"id":[{"id":"10.13039\/501100010573","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Bluefield Project","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]},{"DOI":"10.13039\/100003607","name":"Association for Frontotemporal Degeneration","doi-asserted-by":"publisher","award":["2009"],"award-info":[{"award-number":["2009"]}],"id":[{"id":"10.13039\/100003607","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MRC UK GENFI","award":["MR\/M023664\/1"],"award-info":[{"award-number":["MR\/M023664\/1"]}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["733050103"],"award-info":[{"award-number":["733050103"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["733050813"],"award-info":[{"award-number":["733050813"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fundaci\u00f3 Marat\u00f3 de TV3","award":["20143810"],"award-info":[{"award-number":["20143810"]}]},{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","award":["2018B011"],"award-info":[{"award-number":["2018B011"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["666992"],"award-info":[{"award-number":["666992"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MRC Clinical Scientist Fellowship","award":["MR\/M008525\/1"],"award-info":[{"award-number":["MR\/M008525\/1"]}]},{"DOI":"10.13039\/501100010969","name":"Alzheimer Nederland","doi-asserted-by":"publisher","award":["WE.09-2014-4"],"award-info":[{"award-number":["WE.09-2014-4"]}],"id":[{"id":"10.13039\/501100010969","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["016-130-677"],"award-info":[{"award-number":["016-130-677"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["HCMI 056-13-018"],"award-info":[{"award-number":["HCMI 056-13-018"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"name":"EU Joint Programme - Neurodegenerative Disease Research","award":["733051042"],"award-info":[{"award-number":["733051042"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Neurol Neurosurg Psychiatry"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Progranulin-related frontotemporal dementia (FTD-<jats:italic>GRN<\/jats:italic>) 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-<jats:italic>GRN<\/jats:italic>, in a data-driven way.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We included 56 presymptomatic and 35 symptomatic <jats:italic>GRN<\/jats:italic> 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-<jats:italic>GRN<\/jats:italic> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Language functioning and NfL were the earliest abnormal biomarkers in FTD-<jats:italic>GRN<\/jats:italic>. 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Degeneration of axons and language deficits are indicated to be the earliest biomarkers in FTD-<jats:italic>GRN<\/jats:italic>, with bvFTD being more heterogeneous in disease progression than nfvPPA. Our data-driven model could help identify presymptomatic <jats:italic>GRN<\/jats:italic> mutation carriers at risk of conversion to the clinical stage.<\/jats:p><\/jats:sec>","DOI":"10.1136\/jnnp-2020-323541","type":"journal-article","created":{"date-parts":[[2021,1,15]],"date-time":"2021-01-15T18:27:04Z","timestamp":1610735224000},"page":"494-501","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":39,"title":["Modelling the cascade of biomarker changes in <i>GRN<\/i>-related frontotemporal dementia"],"prefix":"10.1136","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1126-6555","authenticated-orcid":false,"given":"Jessica L","family":"Panman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikram","family":"Venkatraghavan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2570-8796","authenticated-orcid":false,"given":"Emma L","family":"van der Ende","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca M E","family":"Steketee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1120-1858","authenticated-orcid":false,"given":"Lize C","family":"Jiskoot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8843-7247","authenticated-orcid":false,"given":"Jackie M","family":"Poos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise G P","family":"Dopper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lieke H H","family":"Meeter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Donker Kaat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge A R B","family":"Rombouts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4658-2176","authenticated-orcid":false,"given":"Meike W","family":"Vernooij","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneke J A","family":"Kievit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Premi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura","family":"Cosseddu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Bonomi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaume","family":"Olives","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6155-8417","authenticated-orcid":false,"given":"Jonathan D","family":"Rohrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"S\u00e1nchez-Valle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9340-9814","authenticated-orcid":false,"given":"Barbara","family":"Borroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther E","family":"Bron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6278-6844","authenticated-orcid":false,"given":"John C","family":"Van Swieten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janne M","family":"Papma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,1,15]]},"reference":[{"key":"2022011608400600000_92.5.494.1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2010.212225"},{"key":"2022011608400600000_92.5.494.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(08)70194-7"},{"key":"2022011608400600000_92.5.494.3","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1111\/bpa.12486","article-title":"Frontotemporal lobar degeneration: pathogenesis, pathology and pathways to phenotype","volume":"27","author":"Mann","year":"2017","journal-title":"Brain Pathol"},{"key":"2022011608400600000_92.5.494.4","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/jnc.13654","article-title":"The clinical spectrum of sporadic and familial forms of frontotemporal dementia","volume":"138 Suppl 1","author":"Woollacott","year":"2016","journal-title":"J Neurochem"},{"key":"2022011608400600000_92.5.494.5","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx198"},{"key":"2022011608400600000_92.5.494.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05892-0"},{"key":"2022011608400600000_92.5.494.7","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy288"},{"key":"2022011608400600000_92.5.494.8","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-018-8850-7"},{"key":"2022011608400600000_92.5.494.9","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1002\/acn3.325","article-title":"Neurofilament light chain: a biomarker for genetic frontotemporal dementia","volume":"3","author":"Meeter","year":"2016","journal-title":"Ann Clin Transl Neurol"},{"key":"2022011608400600000_92.5.494.10","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/S1474-4422(19)30354-0","article-title":"Serum neurofilament light chain in genetic frontotemporal dementia: a longitudinal, multicentre cohort study","volume":"18","author":"van der Ende","year":"2019","journal-title":"Lancet Neurol"},{"key":"2022011608400600000_92.5.494.11","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(14)70324-2"},{"key":"2022011608400600000_92.5.494.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2013.10.003"},{"key":"2022011608400600000_92.5.494.13","doi-asserted-by":"crossref","unstructured":"Venkatraghavan V , Bron EE , Niessen WJ . A discriminative event based model for Alzheimer\u2019s disease progression modelling. Information Processing in Medical Imaging 2017:121\u201333.","DOI":"10.1007\/978-3-319-59050-9_10"},{"key":"2022011608400600000_92.5.494.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2012.01.062"},{"key":"2022011608400600000_92.5.494.15","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.neuroimage.2018.11.024","article-title":"Disease progression timeline estimation for Alzheimer's disease using discriminative event based modeling","volume":"186","author":"Venkatraghavan","year":"2019","journal-title":"Neuroimage"},{"key":"2022011608400600000_92.5.494.16","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr179"},{"key":"2022011608400600000_92.5.494.17","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31821103e6"},{"key":"2022011608400600000_92.5.494.18","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1590\/s1980-5764-2016dn1004003","article-title":"Corticobasal syndrome: a diagnostic conundrum","volume":"10","author":"Parmera","year":"2016","journal-title":"Dement Neuropsychol"},{"key":"2022011608400600000_92.5.494.19","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.neurobiolaging.2018.12.017","article-title":"Gray and white matter changes in presymptomatic genetic frontotemporal dementia: a longitudinal MRI study","volume":"76","author":"Panman","year":"2019","journal-title":"Neurobiol Aging"},{"key":"2022011608400600000_92.5.494.20","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awn234"},{"key":"2022011608400600000_92.5.494.21","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.44.12.2308"},{"key":"2022011608400600000_92.5.494.22","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181e04070"},{"key":"2022011608400600000_92.5.494.23","doi-asserted-by":"publisher","DOI":"10.1017\/S1355617718000735"},{"key":"2022011608400600000_92.5.494.24","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.601"},{"key":"2022011608400600000_92.5.494.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2011.09.015"},{"key":"2022011608400600000_92.5.494.26","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.460030304"},{"key":"2022011608400600000_92.5.494.27","unstructured":"Mori S , Wakana S , van Zijl PCM . MRI atlas of Human White Matter. Amsterdam, the Netherlands: Elsevier, 2005."},{"key":"2022011608400600000_92.5.494.28","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1002\/acn3.212","article-title":"Csf neurofilament light chain reflects corticospinal tract degeneration in ALS","volume":"2","author":"Menke","year":"2015","journal-title":"Ann Clin Transl Neurol"},{"key":"2022011608400600000_92.5.494.29","doi-asserted-by":"publisher","DOI":"10.1111\/ggi.12661"},{"key":"2022011608400600000_92.5.494.30","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1111\/jnc.14271","article-title":"White matter degeneration in vascular and other ageing-related dementias","volume":"144","author":"Hase","year":"2018","journal-title":"J Neurochem"},{"key":"2022011608400600000_92.5.494.31","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-150806"},{"key":"2022011608400600000_92.5.494.32","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.bandl.2019.04.006","article-title":"A longitudinal study of speech production in primary progressive aphasia and behavioral variant frontotemporal dementia","volume":"194","author":"Ash","year":"2019","journal-title":"Brain Lang"},{"key":"2022011608400600000_92.5.494.33","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000004236"},{"key":"2022011608400600000_92.5.494.34","doi-asserted-by":"crossref","first-page":"93","DOI":"10.12779\/dnd.2016.15.4.93","article-title":"Primary progressive aphasia and the left hemisphere language network","volume":"15","author":"Mesulam","year":"2016","journal-title":"Dement Neurocogn Disord"},{"key":"2022011608400600000_92.5.494.35","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1093\/brain\/awy319","article-title":"Longitudinal multimodal imaging and clinical endpoints for frontotemporal dementia clinical trials","volume":"142","author":"Staffaroni","year":"2019","journal-title":"Brain"},{"key":"2022011608400600000_92.5.494.36","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70099-6"},{"key":"2022011608400600000_92.5.494.37","doi-asserted-by":"publisher","DOI":"10.3109\/09540261.2013.778822"},{"key":"2022011608400600000_92.5.494.38","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.nicl.2017.04.015","article-title":"White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort","volume":"15","author":"Sudre","year":"2017","journal-title":"Neuroimage Clin"},{"key":"2022011608400600000_92.5.494.39","doi-asserted-by":"crossref","DOI":"10.1016\/j.nicl.2019.101751","article-title":"Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers","volume":"22","author":"Lee","year":"2019","journal-title":"Neuroimage Clin"},{"key":"2022011608400600000_92.5.494.40","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.neurobiolaging.2018.12.018","article-title":"Clinical and biomarker changes in presymptomatic genetic frontotemporal dementia","volume":"76","author":"Benussi","year":"2019","journal-title":"Neurobiol Aging"},{"key":"2022011608400600000_92.5.494.41","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1016\/j.neurobiolaging.2013.10.097","article-title":"Understanding phenotype variability in frontotemporal lobar degeneration due to granulin mutation","volume":"35","author":"Bonvicini","year":"2014","journal-title":"Neurobiol Aging"},{"key":"2022011608400600000_92.5.494.42","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/alz.12004","article-title":"Tracking disease progression in familial and sporadic frontotemporal lobar degeneration: recent findings from ARTFL and LEFFTDS","volume":"16","author":"Rosen","year":"2020","journal-title":"Alzheimers Dement"}],"container-title":["Journal of Neurology, Neurosurgery &amp; Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jnnp-2020-323541","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,16]],"date-time":"2022-01-16T16:43:36Z","timestamp":1642351416000},"score":1,"resource":{"primary":{"URL":"https:\/\/jnnp.bmj.com\/lookup\/doi\/10.1136\/jnnp-2020-323541"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,15]]},"references-count":42,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,4,15]]},"published-print":{"date-parts":[[2021,5]]}},"alternative-id":["10.1136\/jnnp-2020-323541"],"URL":"https:\/\/doi.org\/10.1136\/jnnp-2020-323541","relation":{},"ISSN":["0022-3050","1468-330X"],"issn-type":[{"value":"0022-3050","type":"print"},{"value":"1468-330X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,15]]}}}