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dc.contributor.authorScotton, WJ
dc.contributor.authorBocchetta, M
dc.contributor.authorTodd, E
dc.contributor.authorCash, DM
dc.contributor.authorOxtoby, N
dc.contributor.authorVandeVrede, L
dc.contributor.authorHeuer, H
dc.contributor.authorPROSPECT Consortium, 4RTNI Consortium
dc.contributor.authorAlexander, DC
dc.contributor.authorRowe, JB
dc.contributor.authorMorris, HR
dc.contributor.authorBoxer, A
dc.contributor.authorRohrer, JD
dc.contributor.authorWijeratne, PA
dc.date.accessioned2022-06-29T19:49:25Z
dc.date.available2022-06-29T19:49:25Z
dc.date.issued2022
dc.identifier.issn2632-1297
dc.identifier.other35602649
dc.identifier.otherPMC9118104
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338586
dc.description.abstractThe most common clinical phenotype of progressive supranuclear palsy is Richardson syndrome, characterized by levodopa unresponsive symmetric parkinsonism, with a vertical supranuclear gaze palsy, early falls and cognitive impairment. There is currently no detailed understanding of the full sequence of disease pathophysiology in progressive supranuclear palsy. Determining the sequence of brain atrophy in progressive supranuclear palsy could provide important insights into the mechanisms of disease progression, as well as guide patient stratification and monitoring for clinical trials. We used a probabilistic event-based model applied to cross-sectional structural MRI scans in a large international cohort, to determine the sequence of brain atrophy in clinically diagnosed progressive supranuclear palsy Richardson syndrome. A total of 341 people with Richardson syndrome (of whom 255 had 12-month follow-up imaging) and 260 controls were included in the study. We used a combination of 12-month follow-up MRI scans, and a validated clinical rating score (progressive supranuclear palsy rating scale) to demonstrate the longitudinal consistency and utility of the event-based model's staging system. The event-based model estimated that the earliest atrophy occurs in the brainstem and subcortical regions followed by progression caudally into the superior cerebellar peduncle and deep cerebellar nuclei, and rostrally to the cortex. The sequence of cortical atrophy progresses in an anterior to posterior direction, beginning in the insula and then the frontal lobe before spreading to the temporal, parietal and finally the occipital lobe. This in vivo ordering accords with the post-mortem neuropathological staging of progressive supranuclear palsy and was robust under cross-validation. Using longitudinal information from 12-month follow-up scans, we demonstrate that subjects consistently move to later stages over this time interval, supporting the validity of the model. In addition, both clinical severity (progressive supranuclear palsy rating scale) and disease duration were significantly correlated with the predicted subject event-based model stage (P < 0.01). Our results provide new insights into the sequence of atrophy progression in progressive supranuclear palsy and offer potential utility to stratify people with this disease on entry into clinical trials based on disease stage, as well as track disease progression.
dc.languageeng
dc.publisherOxford University Press (OUP)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 2632-1297
dc.sourcenlmid: 101755125
dc.subjectBiomarkers
dc.subjectMachine Learning
dc.subjectDisease Progression
dc.subjectProgressive Supranuclear Palsy
dc.subjectEvent-based Model
dc.titleA data-driven model of brain volume changes in progressive supranuclear palsy.
dc.typeArticle
dc.date.updated2022-06-29T19:49:25Z
prism.issueIdentifier3
prism.publicationNameBrain Commun
prism.volume4
dc.identifier.doi10.17863/CAM.85999
dcterms.dateAccepted2022-04-11
rioxxterms.versionofrecord10.1093/braincomms/fcac098
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidScotton, WJ [0000-0003-0607-3190]
dc.contributor.orcidBocchetta, M [0000-0003-1814-5024]
dc.contributor.orcidTodd, E [0000-0003-1551-5691]
dc.contributor.orcidCash, DM [0000-0001-7833-616X]
dc.contributor.orcidOxtoby, N [0000-0003-0203-3909]
dc.contributor.orcidMorris, HR [0000-0002-5473-3774]
dc.contributor.orcidWijeratne, PA [0000-0002-4885-6241]
dc.identifier.eissn2632-1297
pubs.funder-project-idNational Institute for Health Research (IS-BRC-1215-20014)
pubs.funder-project-idWellcome Trust (220258/Z/20/Z)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idMedical Research Council (MC_UU_00005/12)
pubs.funder-project-idEvelyn Trust (17/09)
cam.issuedOnline2022-04-14


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International