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; Florence Pasquier; 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

doi:10.1001/jamanetworkopen.2020.30194

Journal Articles JAMA Network Open Year : 2021

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

, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , (1) , (2) , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

1
2

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

Isabelle Le Ber

Function : Author

Institut du Cerveau = Paris Brain Institute

Florence Pasquier

Function : Author

Lille Neurosciences & Cognition - U 1172

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
PersonId : 1104774
ORCID : 0000-0002-0941-3990
IdRef : 050512935

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
PersonId : 754049
IdHAL : thibaud-lebouvier
ORCID : 0000-0002-6630-394X
IdRef : 177112190

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.

Domains

Human health and pathology

Fichier principal

benussi_2021_oi_200951_1616688093.95797.pdf (1.13 Mo)

Origin	Publication funded by an institution
Licence	Attribution

Gestionnaire HAL 2 Sorbonne Université : Connect in order to contact the contributor

https://hal.sorbonne-universite.fr/hal-04504706

Submitted on : Thursday, March 14, 2024-1:59:59 PM

Last modification on : Thursday, November 7, 2024-2:21:16 PM

Long-term archiving on : Saturday, June 15, 2024-6:52:00 PM

Dates and versions

hal-04504706 , version 1 (14-03-2024)

Licence

Attribution

Identifiers

HAL Id : hal-04504706 , version 1
DOI : 10.1001/jamanetworkopen.2020.30194
PUBMED : 33404617
PUBMEDCENTRAL : PMC7788468

Cite

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⟩

Export

BibTeX XML-TEI Dublin Core DC Terms EndNote DataCite

Collections

CNRS ICM UNIV-LILLE SORBONNE-UNIVERSITE SU-MEDECINE ANR

29 View

13 Download

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

Abstract

Domains

Dates and versions

Licence

Identifiers

Cite

Export

Collections

Altmetric

Share