{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T06:55:34Z","timestamp":1747205734396,"version":"3.40.5"},"posted":{"date-parts":[[2021,9,20]]},"group-title":"In Review","reference-count":0,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2021,9,7]]},"abstract":"<title>Abstract<\/title>\n        <p>Background: 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) and recommend on recruitment and duration in clinical trial design.Methods: A standardized neuropsychological test battery covering six cognitive domains was completed by 69 <italic>C9orf72<\/italic>, 41 <italic>GRN<\/italic>, and 28 <italic>MAPT<\/italic> mutation carriers with CDR\u00ae plus NACC-FTLD\u22650.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier groups 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\u00ae plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR\u00ae plus NACC-FTLD \u22651). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR\u00ae plus NACC-FTLD=0.5 to \u22651 (and therefore how long a trial would need to be). Results: Results from the logistic regression analyses resulted in different composite scores for each mutation carrier group. 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 three years ~50% of individuals had converted from CDR\u00ae plus NACC-FTLD 0.5 to \u22651.DISCUSSION: We created gene-specific cognitive composite scores for <italic>C9orf72, GRN<\/italic> and <italic>MAPT<\/italic> 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.<\/p>","DOI":"10.21203\/rs.3.rs-882691\/v1","type":"posted-content","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T15:57:58Z","timestamp":1632153478000},"source":"Crossref","is-referenced-by-count":0,"title":["Cognitive Composites for Genetic Frontotemporal Dementia: GENFI-Cog"],"prefix":"10.21203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8843-7247","authenticated-orcid":false,"given":"Jackie M.","family":"Poos","sequence":"first","affiliation":[{"name":"Erasmus Medical Center: Erasmus MC"}]},{"given":"Katrina M.","family":"Moore","sequence":"additional","affiliation":[{"name":"UCL Institute of Neurology: UCL Queen Square Institute of Neurology"}]},{"given":"Jennifer","family":"Nicholas","sequence":"additional","affiliation":[{"name":"London School of Hygiene & Tropical Medicine"}]},{"given":"Lucy L.","family":"Russell","sequence":"additional","affiliation":[{"name":"UCL Institute of Neurology: UCL Queen Square Institute of Neurology"}]},{"given":"Georgia","family":"Peakman","sequence":"additional","affiliation":[{"name":"UCL Institute of Neurology: UCL Queen Square Institute of Neurology"}]},{"given":"Rhian S.","family":"Convery","sequence":"additional","affiliation":[{"name":"UCL Institute of Neurology: UCL Queen Square Institute of Neurology"}]},{"given":"Lize C.","family":"Jiskoot","sequence":"additional","affiliation":[{"name":"Erasmus Medical Center: Erasmus MC"}]},{"given":"Emma L. van der","family":"Ende","sequence":"additional","affiliation":[{"name":"Erasmus Medical Center: Erasmus MC"}]},{"given":"Esther van den","family":"Berg","sequence":"additional","affiliation":[{"name":"Erasmus Medical Center: Erasmus MC"}]},{"given":"Janne M.","family":"Papma","sequence":"additional","affiliation":[{"name":"Erasmus Medical Center: Erasmus MC"}]},{"given":"Harro","family":"Seelaar","sequence":"additional","affiliation":[{"name":"Erasmus Medical Center: Erasmus MC"}]},{"given":"Yolande A.L.","family":"Pijnenburg","sequence":"additional","affiliation":[{"name":"Amsterdam University Medical Centres: Amsterdam Universitair Medische Centra"}]},{"given":"Fermin","family":"Moreno","sequence":"additional","affiliation":[{"name":"Donostia Ospitalea: Hospital Universitario de Donostia"}]},{"given":"Raquel","family":"Sanchez-Valle","sequence":"additional","affiliation":[{"name":"University of Barcelona: Universitat de Barcelona"}]},{"given":"Barbara","family":"Borroni","sequence":"additional","affiliation":[{"name":"University of Brescia: Universita degli Studi di Brescia"}]},{"given":"Robert","family":"Laforce","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Laval: Universite Laval"}]},{"given":"Mario","family":"Masellis","sequence":"additional","affiliation":[{"name":"University of Toronto"}]},{"given":"Carmela","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"University of Toronto"}]},{"given":"Caroline","family":"Graff","sequence":"additional","affiliation":[{"name":"Karolinska University Hospital: Karolinska Universitetssjukhuset"}]},{"given":"Daniela","family":"Galimberti","sequence":"additional","affiliation":[{"name":"University of Milan\u2013Bicocca: Universita degli Studi di Milano-Bicocca"}]},{"given":"James","family":"Rowe","sequence":"additional","affiliation":[{"name":"University of Cambridge"}]},{"given":"Elizabeth","family":"Finger","sequence":"additional","affiliation":[{"name":"University of Western Ontario: Western University"}]},{"given":"Matthis","family":"Synofzik","sequence":"additional","affiliation":[{"name":"University Hospital T\u00fcbingen Center of Neurology: Universitatsklinikum Zentrum fur Neurologie"}]},{"given":"Rik","family":"Vandenberghe","sequence":"additional","affiliation":[{"name":"KU Leuven: Katholieke Universiteit Leuven"}]},{"given":"Alexandre","family":"Mendon\u00e7a","sequence":"additional","affiliation":[{"name":"University of Lisbon: Universidade de Lisboa"}]},{"given":"Pietro","family":"Tiraboschi","sequence":"additional","affiliation":[{"name":"Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologico Carlo Besta: Fondazione IRCCS Istituto Neurologico Carlo Besta"}]},{"given":"Isabel","family":"Santana","sequence":"additional","affiliation":[{"name":"University of Coimbra: Universidade de Coimbra"}]},{"given":"Simon","family":"Ducharme","sequence":"additional","affiliation":[{"name":"McGill University"}]},{"given":"Chris","family":"Butler","sequence":"additional","affiliation":[{"name":"University of Oxford"}]},{"given":"Alexander","family":"Gerhard","sequence":"additional","affiliation":[{"name":"University of Manchester Institute of Brain"}]},{"given":"Johannes","family":"Levin","sequence":"additional","affiliation":[{"name":"Ludwig-Maximilians-Universitat Munchen"}]},{"given":"Adrian","family":"Danek","sequence":"additional","affiliation":[{"name":"Ludwig-Maximilians-Universitat Munchen"}]},{"given":"Markus","family":"Otto","sequence":"additional","affiliation":[{"name":"University of Ulm: Universitat Ulm"}]},{"given":"Isabel Le","family":"Ber","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9: Sorbonne Universite"}]},{"given":"Florence","family":"Pasquier","sequence":"additional","affiliation":[{"name":"University of Lille: Universite de Lille"}]},{"given":"John C. van","family":"Swieten","sequence":"additional","affiliation":[{"name":"Erasmus Medical Center: Erasmus MC"}]},{"given":"Jonathan D.","family":"Rohrer","sequence":"additional","affiliation":[{"name":"UCL Institute of Neurology: UCL Queen Square Institute of Neurology"}]}],"member":"297","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-882691\/v1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-882691\/v1.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T03:05:02Z","timestamp":1659063902000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-882691\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,20]]},"references-count":0,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-882691\/v1","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1002\/alz.055117","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2021,9,20]]},"subtype":"preprint"}}