Cognitive composites for genetic frontotemporal dementia: GENFI-Cog
Authors: Poos Jackie M. , Moore Katrina M. , Nicholas Jennifer , Russell Lucy L. , Peakman Georgia , Convery Rhian S. , Jiskoot Lize C. , van der Ende Emma , van den Berg Esther , Papma Janne M. , Seelaar Harro , Pijnenburg Yolande A. L. , Moreno Fermin , Sanchez-Valle Raquel , Borroni Barbara , Laforce Robert , Masellis Mario , Tartaglia Carmela , Graff Caroline , Galimberti Daniela , Rowe James B. , Finger Elizabeth , Synofzik Matthis , Vandenberghe Rik , de Mendonça Alexandre , Tiraboschi Pietro , Santana Isabel , Ducharme Simon , Butler Chris , Gerhard Alexander , Levin Johannes , Danek Adrian , Otto Markus , Le Ber Isabel , Pasquier Florence , van Swieten John C. , Rohrer Jonathan D. ,   on behalf of the Genetic FTD Initiative (GENFI), Bouzigues Arabella , Rossor Martin N. , Fox Nick C. , Warren Jason D. , Bocchetta Martina , Swift Imogen J. , Shafei Rachelle , Heller Carolin , Todd Emily , Cash David , Woollacott Ione , Zetterberg Henrik , Nelson Annabel , Guerreiro Rita , Bras Jose , Thomas David L. , Mead Simon , Meeter Lieke , Panman Jessica , van Minkelen Rick , Barandiaran Myriam , Indakoetxea Begoña , Gabilondo Alazne , Tainta Mikel , Gorostidi Ana , Zulaica Miren , Díez Alina , Villanua Jorge , Borrego-Ecija Sergi , Olives Jaume , Lladó Albert , Balasa Mircea , Antonell Anna , Bargallo Nuria , Premi Enrico , Gazzina Stefano , Gasparotti Roberto , Archetti Silvana , Black Sandra , Mitchell Sara , Rogaeva Ekaterina , Freedman Morris , Keren Ron , Tang-Wai David , Thonberg Hakan , Öijerstedt Linn , Andersson Christin , Jelic Vesna , Arighi Andrea , Fenoglio Chiara , Scarpini Elio , Fumagalli Giorgio , Cope Thomas , Timberlake Carolyn , Rittman Timothy , Shoesmith Christen , Bartha Robart , Rademakers Rosa , Wilke Carlo , Karnarth Hans-Otto , Bender Benjamin , Bruffaerts Rose , Vandamme Philip , Vandenbulcke Mathieu , Ferreira Catarina B. , Miltenberger Gabriel , Maruta Carolina , Verdelho Ana , Afonso Sónia , Taipa Ricardo , Caroppo Paola , Di Fede Giuseppe , Giaccone Giorgio , Prioni Sara , Redaelli Veronica , Rossi Giacomina , Duro Diana , Almeida Maria Rosario , Castelo-Branco Miguel , Leitão Maria João , Tabuas-Pereira Miguel , Santiago Beatriz , Gauthier Serge , Rosa-Neto Pedro , Veldsman Michele , Thompson Paul , Langheinrich Tobias , Prix Catharina , Hoegen Tobias , Wlasich Elisabeth , Loosli Sandra , Schonecker Sonja , Anderl-Straub Sarah , Lombardi Jolina , Bargalló Nuria , Benussi Alberto , Cantoni Valentina , Bertoux Maxime , Bertrand Anne , Brice Alexis , Camuzat Agnès , Colliot Olivier , Sayah Sabrina , Funkiewiez Aurélie , Rinaldi Daisy , Lombardi Gemma , Nacmias Benedetta , Saracino Dario , Bessi Valentina , Ferrari Camilla , Cañada Marta , Deramecourt Vincent , Kuchcinski Gregory , Lebouvier Thibaud , Ourselin Sebastien , Polito Cristina , Rollin Adeline 
Published: January 2022

Abstract
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.