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dc.contributor.authorPoos, Jackie M
dc.contributor.authorMoore, Katrina M
dc.contributor.authorNicholas, Jennifer
dc.contributor.authorRussell, Lucy L
dc.contributor.authorPeakman, Georgia
dc.contributor.authorConvery, Rhian S
dc.contributor.authorJiskoot, Lize C
dc.contributor.authorvan der Ende, Emma
dc.contributor.authorvan den Berg, Esther
dc.contributor.authorPapma, Janne M
dc.contributor.authorSeelaar, Harro
dc.contributor.authorPijnenburg, Yolande AL
dc.contributor.authorMoreno, Fermin
dc.contributor.authorSanchez-Valle, Raquel
dc.contributor.authorBorroni, Barbara
dc.contributor.authorLaforce, Robert
dc.contributor.authorMasellis, Mario
dc.contributor.authorTartaglia, Carmela
dc.contributor.authorGraff, Caroline
dc.contributor.authorGalimberti, Daniela
dc.contributor.authorRowe, James
dc.contributor.authorFinger, Elizabeth
dc.contributor.authorSynofzik, Matthis
dc.contributor.authorVandenberghe, Rik
dc.contributor.authorde Mendonça, Alexandre
dc.contributor.authorTiraboschi, Pietro
dc.contributor.authorSantana, Isabel
dc.contributor.authorDucharme, Simon
dc.contributor.authorButler, Chris
dc.contributor.authorGerhard, Alexander
dc.contributor.authorLevin, Johannes
dc.contributor.authorDanek, Adrian
dc.contributor.authorOtto, Markus
dc.contributor.authorLe Ber, Isabel
dc.contributor.authorPasquier, Florence
dc.contributor.authorvan Swieten, John C
dc.contributor.authorRohrer, Jonathan D
dc.contributor.authorGenetic FTD Initiative (GENFI)
dc.date.accessioned2022-01-28T16:36:12Z
dc.date.available2022-01-28T16:36:12Z
dc.date.issued2022-01-19
dc.date.submitted2021-09-07
dc.identifier.issn1758-9193
dc.identifier.others13195-022-00958-0
dc.identifier.other958
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/333170
dc.descriptionFunder: Alzheimer's Research UK
dc.descriptionFunder: Alzheimer's Society
dc.descriptionFunder: Brain Research UK
dc.descriptionFunder: the Wolfson Foundation
dc.descriptionFunder: NIHR UCL/H Biomedical Research Centre
dc.descriptionFunder: Leonard Wolfson Experimental Neurology Centre Clinical Research Facility
dc.descriptionFunder: UK Dementia Research Institute
dc.descriptionFunder: UK Medical Research Council
dc.descriptionFunder: Bluefield project
dc.descriptionFunder: the Association for Frontotemporal Dementias Research Grant 2009
dc.description.abstractBACKGROUND: Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design. METHODS: A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72, 41 GRN, and 28 MAPT mutation carriers with CDR® plus NACC-FTLD ≥ 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR® plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR® plus NACC-FTLD ≥ 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR® plus NACC-FTLD = 0.5 to ≥ 1 (and therefore how long a trial would need to be). RESULTS: The results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72, GRN, and MAPT). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR® plus NACC-FTLD 0.5 to ≥ 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR® plus NACC FTLD 0.5 to ≥ 1 without treatment over that time period. DISCUSSION: We created gene-specific cognitive composite scores for C9orf72, GRN, and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.subjectResearch
dc.subjectFrontotemporal dementia
dc.subjectCognition
dc.subjectNeuropsychology
dc.subjectComposite score
dc.subjectLanguage
dc.subjectAttention
dc.subjectExecutive function
dc.subjectMemory
dc.subjectSocial cognition
dc.titleCognitive composites for genetic frontotemporal dementia: GENFI-Cog.
dc.typeArticle
dc.date.updated2022-01-28T16:36:11Z
prism.issueIdentifier1
prism.publicationNameAlzheimers Res Ther
prism.volume14
dc.identifier.doi10.17863/CAM.80593
dcterms.dateAccepted2021-12-28
rioxxterms.versionofrecord10.1186/s13195-022-00958-0
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidRowe, James [0000-0001-7216-8679]
dc.contributor.orcidRohrer, Jonathan D [0000-0002-6155-8417]
dc.identifier.eissn1758-9193
pubs.funder-project-idMRC (via University of Oxford) (Unknown)
pubs.funder-project-idMRC (via University College London (UCL)) (523989)
cam.issuedOnline2022-01-19


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