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Background and Objectives 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). Methods 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. Results 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. Discussion 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.
Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort
Poos, Jackie M;MacDougall, Amy;van den Berg, Esther;Jiskoot, Lize C;Papma, Janne M;van der Ende, Emma L;Seelaar, Harro;Russell, Lucy L;Peakman, Georgia;Convery, Rhian;Pijnenburg, Yolande A L;Moreno, Fermin;Sanchez-Valle, Raquel;Borroni, Barbara;Laforce, Robert;Doré, Marie-Claire;Masellis, Mario;Tartaglia, Maria Carmela;Graff, Caroline;Galimberti, Daniela;Rowe, James B;Finger, Elizabeth;Synofzik, Matthis;Vandenberghe, Rik;Mendonça, Alexandre;Tiraboschi, Pietro;Santana, Isabel;Ducharme, Simon;Butler, Christopher;Gerhard, Alexander;Levin, Johannes;Danek, Adrian;Otto, Markus;Le Ber, Isabelle;Pasquier, Florence;van Swieten, John;Rohrer, Jonathan D;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 V Greaves;David L Cash;Hanya Benotmane;Emily Todd;Henrik Zetterberg;Kiran Samra;Martina Bocchetta;Rita Guerreiro;Jose Bras;David L Thomas;Jennifer Nicholas;Simon Mead;Lieke Meeter;Jessica Panman;Lucia Giannini;Rick van Minkelen;Myriam Barandiaran;Begoña Indakoetxea;Alazne Gabilondo;Mikel Tainta;María de Arriba;Ana Gorostidi;Miren Zulaica;Jorge Villanua;Zigor Díaz;Ana Gorostidi;Marta Cañada;Patricia Alves;Sergi Borrego-Ecija;Jaume Olives;Albert Lladó;Mircea Balasa;Anna Antonell;Nuria Bargalló;Enrico Premi;Maura Cosseddu;Stefano Gazzina;Alessandro Padovani;Alberto Benussi;Valentina Cantoni;Roberto Gasparotti;Silvana Archetti;Sandra Black;Sara Mitchell;Ekaterina Rogaeva;Morris Freedman;Ron Keren;David Tang-Wai;Linn Öijerstedt;Christin Andersson;Vesna Jelic;Hakan Thonberg;Andrea Arighi;Chiara Fenoglio;Elio Scarpini;Giorgio Fumagalli;Thomas Cope;Carolyn Timberlake;Timothy Rittman;Christen Shoesmith;Robart Bartha;Rosa Rademakers;Carlo Wilke;Lisa Graf;Hans Otto 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 Rosario 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;Gregory Kuchcinski;Maxime Bertoux;Thibaud Lebouvier;Vincent Deramecourt
2022-01-01
Abstract
Background and Objectives 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). Methods 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. Results 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. Discussion 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/400443
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Il report seguente simula gli indicatori relativi alla propria produzione scientifica in relazione alle soglie ASN 2023-2025 del proprio SC/SSD. Si ricorda che il superamento dei valori soglia (almeno 2 su 3) è requisito necessario ma non sufficiente al conseguimento dell'abilitazione. La simulazione si basa sui dati IRIS e sugli indicatori bibliometrici alla data indicata e non tiene conto di eventuali periodi di congedo obbligatorio, che in sede di domanda ASN danno diritto a incrementi percentuali dei valori. La simulazione può differire dall'esito di un’eventuale domanda ASN sia per errori di catalogazione e/o dati mancanti in IRIS, sia per la variabilità dei dati bibliometrici nel tempo. Si consideri che Anvur calcola i valori degli indicatori all'ultima data utile per la presentazione delle domande.
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