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Journal Articles JAMA Network Open Year : 2021

Progression of Behavioral Disturbances and Neuropsychiatric Symptoms in Patients With Genetic Frontotemporal Dementia

Alberto Benussi , Enrico Premi , Stefano Gazzina , Chiara Brattini , Elisa Bonomi , Antonella Alberici , Lize Jiskoot , John C van Swieten , Raquel Sanchez-Valle , Fermin Moreno , Robert Laforce , Caroline Graff , Matthis Synofzik , Daniela Galimberti , Mario Masellis , Carmela Tartaglia , James B Rowe , Elizabeth Finger , Rik Vandenberghe , Alexandre de Mendonça , Fabrizio Tagliavini , Isabel Santana , Simon Ducharme , Chris R Butler , Alexander Gerhard , Johannes Levin , Adrian Danek , Markus Otto , Giovanni Frisoni , Roberta Ghidoni , Sandro Sorbi , Isabelle Le Ber (1) , Florence Pasquier (2) , Georgia Peakman , Emily Todd , Martina Bocchetta , Jonathan D Rohrer , Barbara Borroni , Sònia Afonso , Maria Rosario Almeida , Sarah Anderl-Straub , Christin Andersson , Anna Antonell , Silvana Archetti , Andrea Arighi , Mircea Balasa , Myriam Barandiaran , Nuria Bargallò , Robart Bartha , Benjamin Bender , Luisa Benussi , Maxime Bertoux , Anne Bertrand , Valentina Bessi , Giuliano Binetti , Sandra Black , Sergi Borrego-Ecija , Jose Bras , Alexis Brice , Rose Bruffaerts , Agnès Camuzat , Marta Cañada , Paola Caroppo , David Cash , Miguel Castelo-Branco , Olivier Colliot , Rhian Convery , Thomas Cope , Maura Cosseddu , Vincent Deramecourt , Marìa de Arriba , Giuseppe Di Fede , Alina Dìez , Diana Duro , Chiara Fenoglio , Camilla Ferrari , Catarina B Ferreira , Nick Fox , Morris Freedman , Giorgio Fumagalli , Aurélie Funkiewiez , Alazne Gabilondo , Roberto Gasparotti , Serge Gauthier , Stefano Gazzina , Giorgio Giaccone , Ana Gorostidi , Caroline Greaves , Rita Guerreiro , Carolin Heller , Tobias Hoegen , Begoña Indakoetxea , Vesna Jelic , Hans-Otto Karnath , Ron Keren , Gregory Kuchcinski , Tobias Langheinrich , Thibaud Lebouvier , Maria João Leitão , Albert Lladò , Gemma Lombardi , Sandra Loosli , Carolina Maruta , Simon Mead , Lieke Meeter , Gabriel Miltenberger , Rick van Minkelen , Sara Mitchell , Katrina Moore , Benedetta Nacmias , Jennifer Nicholas , Linn Öijerstedt , Jaume Olives , Sebastien Ourselin , Alessandro Padovani , Jessica Panman , Janne M Papma , Michela Pievani , Yolande Pijnenburg , Cristina Polito , Sara Prioni , Catharina Prix , Rosa Rademakers , Veronica Redaelli , Daisy Rinaldi , Tim Rittman , Ekaterina Rogaeva , Adeline Rollin , Pedro Rosa-Neto , Giacomina Rossi , Martin Rossor , Beatriz Santiago , Dario Saracino , Sabrina Sayah , Elio Scarpini , Sonja Schönecker , Harro Seelaar , Elisa Semler , Rachelle Shafei , Christen Shoesmith , Miguel Tábuas-Pereira , Mikel Tainta , Ricardo Taipa , David Tang-Wai , David L Thomas , Paul Thompson , Hakan Thonberg , Carolyn Timberlake , Pietro Tiraboschi , Emily Todd , Philip van Damme , Mathieu Vandenbulcke , Michele Veldsman , Ana Verdelho , Jorge Villanua , Jason Warren , Carlo Wilke , Ione Woollacott , Elisabeth Wlasich , Henrik Zetterberg , Miren Zulaica
Alberto Benussi
  • Function : Author
Enrico Premi
  • Function : Author
Stefano Gazzina
  • Function : Author
Chiara Brattini
  • Function : Author
Elisa Bonomi
  • Function : Author
Antonella Alberici
  • Function : Author
Lize Jiskoot
  • Function : Author
John C van Swieten
  • Function : Author
Raquel Sanchez-Valle
  • Function : Author
Fermin Moreno
  • Function : Author
Robert Laforce
  • Function : Author
Caroline Graff
  • Function : Author
Matthis Synofzik
  • Function : Author
Daniela Galimberti
  • Function : Author
Mario Masellis
  • Function : Author
Carmela Tartaglia
  • Function : Author
James B Rowe
  • Function : Author
Elizabeth Finger
  • Function : Author
Rik Vandenberghe
  • Function : Author
Alexandre de Mendonça
  • Function : Author
Fabrizio Tagliavini
  • Function : Author
Isabel Santana
  • Function : Author
Simon Ducharme
  • Function : Author
Chris R Butler
  • Function : Author
Alexander Gerhard
  • Function : Author
Johannes Levin
  • Function : Author
Adrian Danek
  • Function : Author
Markus Otto
  • Function : Author
Giovanni Frisoni
  • Function : Author
Roberta Ghidoni
  • Function : Author
Sandro Sorbi
  • Function : Author
Georgia Peakman
  • Function : Author
Emily Todd
  • Function : Author
Martina Bocchetta
  • Function : Author
Jonathan D Rohrer
  • Function : Author
Barbara Borroni
  • Function : Author
  • PersonId : 885172
Sònia Afonso
  • Function : Author
Maria Rosario Almeida
  • Function : Author
Sarah Anderl-Straub
  • Function : Author
Christin Andersson
  • Function : Author
Anna Antonell
  • Function : Author
Silvana Archetti
  • Function : Author
Andrea Arighi
  • Function : Author
Mircea Balasa
  • Function : Author
Myriam Barandiaran
  • Function : Author
Nuria Bargallò
  • Function : Author
Robart Bartha
  • Function : Author
Benjamin Bender
  • Function : Author
Luisa Benussi
  • Function : Author
Maxime Bertoux
  • Function : Author
Anne Bertrand
  • Function : Author
Valentina Bessi
  • Function : Author
Giuliano Binetti
  • Function : Author
Sandra Black
  • Function : Author
Sergi Borrego-Ecija
  • Function : Author
Jose Bras
  • Function : Author
Alexis Brice
  • Function : Author
Rose Bruffaerts
  • Function : Author
Agnès Camuzat
  • Function : Author
Marta Cañada
  • Function : Author
Paola Caroppo
  • Function : Author
David Cash
  • Function : Author
Miguel Castelo-Branco
  • Function : Author
Olivier Colliot
  • Function : Author
Rhian Convery
  • Function : Author
Thomas Cope
  • Function : Author
Maura Cosseddu
  • Function : Author
Vincent Deramecourt
  • Function : Author
Marìa de Arriba
  • Function : Author
Giuseppe Di Fede
  • Function : Author
Alina Dìez
  • Function : Author
Diana Duro
  • Function : Author
Chiara Fenoglio
  • Function : Author
Camilla Ferrari
  • Function : Author
Catarina B Ferreira
  • Function : Author
Nick Fox
  • Function : Author
Morris Freedman
  • Function : Author
Giorgio Fumagalli
  • Function : Author
Aurélie Funkiewiez
  • Function : Author
Alazne Gabilondo
  • Function : Author
Roberto Gasparotti
  • Function : Author
Serge Gauthier
  • Function : Author
Stefano Gazzina
  • Function : Author
Giorgio Giaccone
  • Function : Author
Ana Gorostidi
  • Function : Author
Caroline Greaves
  • Function : Author
Rita Guerreiro
  • Function : Author
Carolin Heller
  • Function : Author
Tobias Hoegen
  • Function : Author
Begoña Indakoetxea
  • Function : Author
Vesna Jelic
  • Function : Author
Hans-Otto Karnath
  • Function : Author
Ron Keren
  • Function : Author
Gregory Kuchcinski
  • Function : Author
Tobias Langheinrich
  • Function : Author
Thibaud Lebouvier
  • Function : Author
Maria João Leitão
  • Function : Author
Albert Lladò
  • Function : Author
Gemma Lombardi
  • Function : Author
Sandra Loosli
  • Function : Author
Carolina Maruta
  • Function : Author
Simon Mead
  • Function : Author
Lieke Meeter
  • Function : Author
Gabriel Miltenberger
  • Function : Author
Rick van Minkelen
  • Function : Author
Sara Mitchell
  • Function : Author
Katrina Moore
  • Function : Author
Benedetta Nacmias
  • Function : Author
Jennifer Nicholas
  • Function : Author
Linn Öijerstedt
  • Function : Author
Jaume Olives
  • Function : Author
Sebastien Ourselin
  • Function : Author
Alessandro Padovani
  • Function : Author
Jessica Panman
  • Function : Author
Janne M Papma
  • Function : Author
Michela Pievani
  • Function : Author
Yolande Pijnenburg
  • Function : Author
Cristina Polito
  • Function : Author
Sara Prioni
  • Function : Author
Catharina Prix
  • Function : Author
Rosa Rademakers
  • Function : Author
Veronica Redaelli
  • Function : Author
Daisy Rinaldi
  • Function : Author
Tim Rittman
  • Function : Author
Ekaterina Rogaeva
  • Function : Author
Adeline Rollin
  • Function : Author
Pedro Rosa-Neto
  • Function : Author
Giacomina Rossi
  • Function : Author
Martin Rossor
  • Function : Author
Beatriz Santiago
  • Function : Author
Dario Saracino
  • Function : Author
Sabrina Sayah
  • Function : Author
Elio Scarpini
  • Function : Author
Sonja Schönecker
  • Function : Author
Harro Seelaar
  • Function : Author
Elisa Semler
  • Function : Author
Rachelle Shafei
  • Function : Author
Christen Shoesmith
  • Function : Author
Miguel Tábuas-Pereira
  • Function : Author
Mikel Tainta
  • Function : Author
Ricardo Taipa
  • Function : Author
David Tang-Wai
  • Function : Author
David L Thomas
  • Function : Author
Paul Thompson
  • Function : Author
Hakan Thonberg
  • Function : Author
Carolyn Timberlake
  • Function : Author
Pietro Tiraboschi
  • Function : Author
Emily Todd
  • Function : Author
Philip van Damme
  • Function : Author
Mathieu Vandenbulcke
  • Function : Author
Michele Veldsman
  • Function : Author
Ana Verdelho
  • Function : Author
Jorge Villanua
  • Function : Author
Jason Warren
  • Function : Author
Carlo Wilke
  • Function : Author
Ione Woollacott
  • Function : Author
Elisabeth Wlasich
  • Function : Author
Henrik Zetterberg
  • Function : Author
Miren Zulaica
  • Function : Author

Abstract

Importance: Behavioral disturbances are core features of frontotemporal dementia (FTD); however, symptom progression across the course of disease is not well characterized in genetic FTD. Objective: To investigate behavioral symptom frequency and severity and their evolution and progression in different forms of genetic FTD. Design, setting, and participants: This longitudinal cohort study, the international Genetic FTD Initiative (GENFI), was conducted from January 30, 2012, to May 31, 2019, at 23 multicenter specialist tertiary FTD research clinics in the United Kingdom, the Netherlands, Belgium, France, Spain, Portugal, Italy, Germany, Sweden, Finland, and Canada. Participants included a consecutive sample of 232 symptomatic FTD gene variation carriers comprising 115 with variations in C9orf72, 78 in GRN, and 39 in MAPT. A total of 101 carriers had at least 1 follow-up evaluation (for a total of 400 assessments). Gene variations were included only if considered pathogenetic. Main outcomes and measures: Behavioral and neuropsychiatric symptoms were assessed across disease duration and evaluated from symptom onset. Hierarchical generalized linear mixed models were used to model behavioral and neuropsychiatric measures as a function of disease duration and variation. Results: Of 232 patients with FTD, 115 (49.6%) had a C9orf72 expansion (median [interquartile range (IQR)] age at evaluation, 64.3 [57.5-69.7] years; 72 men [62.6%]; 115 White patients [100%]), 78 (33.6%) had a GRN variant (median [IQR] age, 63.4 [58.3-68.8] years; 40 women [51.3%]; 77 White patients [98.7%]), and 39 (16.8%) had a MAPT variant (median [IQR] age, 56.3 [49.9-62.4] years; 25 men [64.1%]; 37 White patients [94.9%]). All core behavioral symptoms, including disinhibition, apathy, loss of empathy, perseverative behavior, and hyperorality, were highly expressed in all gene variant carriers (>50% patients), with apathy being one of the most common and severe symptoms throughout the disease course (51.7%-100% of patients). Patients with MAPT variants showed the highest frequency and severity of most behavioral symptoms, particularly disinhibition (79.3%-100% of patients) and compulsive behavior (64.3%-100% of patients), compared with C9orf72 carriers (51.7%-95.8% of patients with disinhibition and 34.5%-75.0% with compulsive behavior) and GRN carriers (38.2%-100% with disinhibition and 20.6%-100% with compulsive behavior). Alongside behavioral symptoms, neuropsychiatric symptoms were very frequently reported in patients with genetic FTD: anxiety and depression were most common in GRN carriers (23.8%-100% of patients) and MAPT carriers (26.1%-77.8% of patients); hallucinations, particularly auditory and visual, were most common in C9orf72 carriers (10.3%-54.5% of patients). Most behavioral and neuropsychiatric symptoms increased in the early-intermediate phases and plateaued in the late stages of disease, except for depression, which steadily declined in C9orf72 carriers, and depression and anxiety, which surged only in the late stages in GRN carriers. Conclusions and relevance: This cohort study suggests that behavioral and neuropsychiatric disturbances differ between the common FTD gene variants and have different trajectories throughout the course of disease. These findings have crucial implications for counseling patients and caregivers and for the design of disease-modifying treatment trials in genetic FTD.
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hal-04504706 , version 1 (14-03-2024)

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Alberto Benussi, Enrico Premi, Stefano Gazzina, Chiara Brattini, Elisa Bonomi, et al.. Progression of Behavioral Disturbances and Neuropsychiatric Symptoms in Patients With Genetic Frontotemporal Dementia. JAMA Network Open, 2021, 4 (1), pp.e2030194. ⟨10.1001/jamanetworkopen.2020.30194⟩. ⟨hal-04504706⟩
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