Abstract
| Original language | English |
|---|---|
| Article number | 10 |
| Journal | Alzheimer's Research and Therapy |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Dec 2022 |
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Cognitive composites for genetic frontotemporal dementia : GENFI-Cog. / Poos, Jackie M.; Moore, Katrina M.; Nicholas, Jennifer et al.
In: Alzheimer's Research and Therapy, Vol. 14, No. 1, 10, 01.12.2022.Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Cognitive composites for genetic frontotemporal dementia
T2 - GENFI-Cog
AU - Poos, Jackie M.
AU - Moore, Katrina M.
AU - Nicholas, Jennifer
AU - Russell, Lucy L.
AU - Peakman, Georgia
AU - Convery, Rhian S.
AU - Jiskoot, Lize C.
AU - van der Ende, Emma
AU - van den Berg, Esther
AU - Papma, Janne M.
AU - Seelaar, Harro
AU - Pijnenburg, Yolande A. L.
AU - Moreno, Fermin
AU - Sanchez-Valle, Raquel
AU - Borroni, Barbara
AU - Laforce, Robert
AU - Masellis, Mario
AU - Tartaglia, Carmela
AU - Graff, Caroline
AU - Galimberti, Daniela
AU - Rowe, James B.
AU - Finger, Elizabeth
AU - Synofzik, Matthis
AU - Vandenberghe, Rik
AU - de Mendonça, Alexandre
AU - Tiraboschi, Pietro
AU - Santana, Isabel
AU - Ducharme, Simon
AU - Butler, Chris
AU - Gerhard, Alexander
AU - Levin, Johannes
AU - Danek, Adrian
AU - Otto, Markus
AU - le Ber, Isabel
AU - Pasquier, Florence
AU - van Swieten, John C.
AU - Rohrer, Jonathan D.
AU - on behalf of the Genetic FTD Initiative (GENFI)
AU - Bouzigues, Arabella
AU - Rossor, Martin N.
AU - Fox, Nick C.
AU - Warren, Jason D.
AU - Bocchetta, Martina
AU - Swift, Imogen J.
AU - Shafei, Rachelle
AU - Heller, Carolin
AU - Todd, Emily
AU - Cash, David
AU - Woollacott, Ione
AU - Zetterberg, Henrik
AU - Nelson, Annabel
AU - Guerreiro, Rita
AU - Bras, Jose
AU - Thomas, David L.
AU - Mead, Simon
AU - Meeter, Lieke
AU - Panman, Jessica
AU - van Minkelen, Rick
AU - Barandiaran, Myriam
AU - Indakoetxea, Begoña
AU - Gabilondo, Alazne
AU - Tainta, Mikel
AU - Gorostidi, Ana
AU - Zulaica, Miren
AU - Díez, Alina
AU - Villanua, Jorge
AU - Borrego-Ecija, Sergi
AU - Olives, Jaume
AU - Lladó, Albert
AU - Balasa, Mircea
AU - Antonell, Anna
AU - Bargallo, Nuria
AU - Premi, Enrico
AU - Gazzina, Stefano
AU - Gasparotti, Roberto
AU - Archetti, Silvana
AU - Black, Sandra
AU - Mitchell, Sara
AU - Rogaeva, Ekaterina
AU - Freedman, Morris
AU - Keren, Ron
AU - Tang-Wai, David
AU - Thonberg, Hakan
AU - Öijerstedt, Linn
AU - Andersson, Christin
AU - Jelic, Vesna
AU - Arighi, Andrea
AU - Fenoglio, Chiara
AU - Scarpini, Elio
AU - Fumagalli, Giorgio
AU - Cope, Thomas
AU - Timberlake, Carolyn
AU - Rittman, Timothy
AU - Shoesmith, Christen
AU - Bartha, Robart
AU - Rademakers, Rosa
AU - Wilke, Carlo
AU - Karnarth, Hans-Otto
AU - Bender, Benjamin
AU - Bruffaerts, Rose
AU - Vandamme, Philip
AU - Vandenbulcke, Mathieu
AU - Ferreira, Catarina B.
AU - Miltenberger, Gabriel
AU - Maruta, Carolina
AU - Verdelho, Ana
AU - Afonso, S. nia
AU - Taipa, Ricardo
AU - Caroppo, Paola
AU - di Fede, Giuseppe
AU - Giaccone, Giorgio
AU - Prioni, Sara
AU - Redaelli, Veronica
AU - Rossi, Giacomina
AU - Duro, Diana
AU - Almeida, Maria Rosario
AU - Castelo-Branco, Miguel
AU - Leitão, Maria João
AU - Tabuas-Pereira, Miguel
AU - Santiago, Beatriz
AU - Gauthier, Serge
AU - Rosa-Neto, Pedro
AU - Veldsman, Michele
AU - Thompson, Paul
AU - Langheinrich, Tobias
AU - Prix, Catharina
AU - Hoegen, Tobias
AU - Wlasich, Elisabeth
AU - Loosli, Sandra
AU - Schonecker, Sonja
AU - Anderl-Straub, Sarah
AU - Lombardi, Jolina
AU - Bargalló, Nuria
AU - Benussi, Alberto
AU - Cantoni, Valentina
AU - Bertoux, Maxime
AU - Bertrand, Anne
AU - Brice, Alexis
AU - Camuzat, Agnès
AU - Colliot, Olivier
AU - Sayah, Sabrina
AU - Funkiewiez, Aurélie
AU - Rinaldi, Daisy
AU - Lombardi, Gemma
AU - Nacmias, Benedetta
AU - Saracino, Dario
AU - Bessi, Valentina
AU - Ferrari, Camilla
AU - Cañada, Marta
AU - Deramecourt, Vincent
AU - Kuchcinski, Gregory
AU - Lebouvier, Thibaud
AU - Ourselin, Sebastien
AU - Polito, Cristina
AU - Rollin, Adeline
N1 - Funding Information: The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the NIHR UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019-02248), the Dioraphte Foundation [grant numbers 09-02-00], the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018), ZonMw Memorabel (Deltaplan Dementie, (project numbers 733 050 103 and 733 050 813), and JPND PreFrontAls Consortium (project number 733051042). JM Poos is supported by a fellowship award from Alzheimer Nederland (WE.15-2019.02). This work was conducted using the MRC Dementias Platform UK (MR/L023784/1 and MR/009076/1). Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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) 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.
AB - 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) 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.
KW - Attention
KW - Cognition
KW - Composite score
KW - Executive function
KW - Frontotemporal dementia
KW - Language
KW - Memory
KW - Neuropsychology
KW - Social cognition
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85123079789&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/35045872
U2 - 10.1186/s13195-022-00958-0
DO - 10.1186/s13195-022-00958-0
M3 - Article
C2 - 35045872
SN - 1758-9193
VL - 14
JO - Alzheimer's Research & Therapy
JF - Alzheimer's Research & Therapy
IS - 1
M1 - 10
ER -