Portal de Periódicos da CAPES

Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort

2022; Lippincott Williams & Wilkins; Volume: 99; Issue: 3 Linguagem: Inglês

10.1212/wnl.0000000000200384

1526-632X

Jackie M. Poos, Amy MacDougall, Esther van den Berg, Lize C. Jiskoot, Janne M. Papma, Emma L. van der Ende, Harro Seelaar, Lucy L. Russell, Georgia Peakman, Rhian S. Convery, Yolande A.L. Pijnenburg, Fermín Moreno, Raquel Sánchez‐Valle, Barbara Borroni, Robert Laforce, Marie-Claire Doré, Mario Masellis, Maria Carmela Tartaglia, Caroline Graff, Daniela Galimberti, James B. Rowe, Elizabeth Finger, Matthis Synofzik, Rik Vandenberghe, Alexandre de Mendonça, Pietro Tiraboschi, Isabel Santana, Simon Ducharme, Christopher Butler, Alexander Gerhard, Johannes Levin, Adrian Danek, Markus Otto, Isabelle Le Ber, Florence Pasquier, John C. van Swieten, Jonathan D. Rohrer, Martin N. Rossor, Nick C. Fox, Jason D. Warren, Ione Woollacott, Rachelle Shafei, Carolin Heller, Imogen J. Swift, Katrina Moore, Aitana Sogorb‐Esteve, Annabel Nelson, Arabella Bouzigues, Caroline Greaves, David L. Cash, Hanya Benotmane, Emily Todd, Henrik Zetterberg, Kiran Samra, Martina Bocchetta, Rita Guerreiro, José Brás, David L. Thomas, Jennifer Nicholas, Simon Mead, Lieke Meeter, Jessica Panman, Lucia Giannini, Rick van Minkelen, Myriam Barandiarán, Begoña Indakoetxea, Alazne Gabilondo, Mikel Tainta, María de Arriba, Ana Gorostidi, Miren Zulaica, Jorge Villanúa, Zigor Díaz, Ana Gorostidi, Marta Cañada, Patricia Alves, Sergi Borrego‐Écija, Jaume Olives, Albert Lladó, Mircea Balasa, Anna Antonell, Núria Bargalló, Enrico Premi, Maura Cosseddu, Stefano Gazzina, Alessandro Padovani, Alberto Benussi, Valentina Cantoni, Roberto Gasparotti, Silvana Archetti, Sandra E. Black, Sara Mitchell, Ekaterina Rogaeva, Morris Freedman, Ron Keren, David F. Tang‐Wai, Linn Öijerstedt, Christin Andersson, Vesna Jelić, Håkan Thonberg, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Thomas Cope, Carolyn Timberlake, Timothy Rittman, Christen Shoesmith, Robert Bartha, Rosa Rademakers, Carlo Wilke, Lisa Graf, H.‐O. Karnath, Benjamin Bender, Rose Bruffaerts, Philip Van Damme, Mathieu Vandenbulcke, Annick Vogels, Koen Poesen, Catarina B. Ferreira, Gabriel Miltenberger, Frederico Simões do Couto, Carolina Maruta, Ana Verdelho, Sónia Afonso, Ricardo Taipa, Paola Caroppo, Giuseppe Di Fede, Giorgio Giaccone, Sara Prioni, Veronica Redaelli, Giacomina Rossi, Diana Duro, Maria Rosário Almeida, Miguel Castelo‐Branco, Maria João Leitão, Miguel Tábuas‐Pereira, Beatriz Santiago, Serge Gauthier, Pedro Rosa‐Neto, Michele Veldsman, Paul Thompson, Tobias Langheinrich, Catharina Prix, Tobias Hoegen, Elisabeth Wlasich, Sandra Loosli, Sonja Schönecker, Elisa Semler, Sarah Anderl‐Straub, Jolina Lombardi, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Agnès Camuzat, Alexis Brice, Anne Bertrand, Aurélie Funkiewiez, Daisy Rinaldi, Dario Saracino, Olivier Colliot, Sabrina Sayah, Adeline Rollin, Grégory Kuchcinski, Maxime Bertoux, Thibaud Lebouvier, Vincent Deramecourt,

Alzheimer's disease research and treatments

Disease-modifying therapeutic trials for genetic frontotemporal dementia (FTD) are underway, but sensitive cognitive outcome measures are lacking. The aim of this study was to identify such cognitive tests in early stage FTD by investigating cognitive decline in a large cohort of genetic FTD pathogenic variant carriers and by investigating whether gene-specific differences are moderated by disease stage (asymptomatic, prodromal, and symptomatic).C9orf72, GRN, and MAPT pathogenic variant carriers as well as controls underwent a yearly neuropsychological assessment covering 8 cognitive domains as part of the Genetic FTD Initiative, a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center (NACC) FTLD score (0, 0.5, or ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages as well as the 3-way interaction between time, genetic group, and disease stage.A total of 207 C9orf72, 206 GRN, and 86 MAPT pathogenic variant carriers and 255 controls were included. C9orf72 pathogenic variant carriers performed lower on attention, executive function, and verbal fluency from CDR plus NACC FTLD 0 onwards, with relatively minimal decline over time regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in MAPT pathogenic variant carriers was characterized by lower memory performance at CDR plus NACC FTLD 0.5, with decline over time in language from the CDR plus NACC FTLD 0.5 stage onwards, and executive dysfunction rapidly developing at CDR plus NACC FTLD ≥1. GRN pathogenic variant carriers declined on verbal fluency and visuoconstruction in the CDR plus NACC FTLD 0.5 stage, with progressive decline in other cognitive domains starting at CDR plus NACC FTLD ≥1.We confirmed cognitive decline in the asymptomatic and prodromal stage of genetic FTD. Specifically, tests for attention, executive function, language, and memory showed clear differences between genetic groups and controls at baseline, but the speed of change over time differed depending on genetic group and disease stage. This confirms the value of neuropsychological assessment in tracking clinical onset and progression and could inform clinical trials in selecting sensitive end points for measuring treatment effects as well as characterizing the best time window for starting treatment.