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Progression of behavioral disturbances and neuropsychiatric symptoms in patients with genetic frontotemporal dementia

2021-01-04Journal article Open access
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dc.contributor.authorBenussi, Alberto
dc.contributor.authorPremi, Enrico
dc.contributor.authorGazzina, Stefano
dc.contributor.authorBrattini, Chiara
dc.contributor.authorBonomi, Elisa
dc.contributor.authorAlberici, Antonella
dc.contributor.authorJiskoot, Lize
dc.contributor.authorvan Swieten, John C
dc.contributor.authorSanchez-Valle, Raquel
dc.contributor.authorMoreno, Fermin
dc.contributor.authorLaforce, Robert
dc.contributor.authorGraff, Caroline
dc.contributor.authorSynofzik, Matthis
dc.contributor.authorGalimberti, Daniela
dc.contributor.authorMasellis, Mario
dc.contributor.authorTartaglia, Carmela
dc.contributor.authorRowe, James B
dc.contributor.authorFinger, Elizabeth
dc.contributor.authorVandenberghe, Rik
dc.contributor.authorDe Mendonça, Alexandre
dc.contributor.authorTagliavini, Fabrizio
dc.contributor.authorSantana, Isabel
dc.contributor.authorDucharme, Simon
dc.contributor.authorButler, Chris R
dc.contributor.authorGerhard, Alexander
dc.contributor.authorLevin, Johannes
dc.contributor.authorDanek, Adrian
dc.contributor.authorOtto, Markus
dc.contributor.authorFrisoni, Giovanni
dc.contributor.authorGhidoni, Roberta
dc.contributor.authorSorbi, Sandro
dc.contributor.authorLe Ber, Isabelle
dc.contributor.authorPasquier, Florence
dc.contributor.authorPeakman, Georgia
dc.contributor.authorTodd, Emily
dc.contributor.authorBocchetta, Martina
dc.contributor.authorRohrer, Jonathan D
dc.contributor.authorBorroni, Barbara
dc.date.accessioned2021-01-07T11:39:17Z
dc.date.available2021-01-07T11:39:17Z
dc.date.issued2021-01-04
dc.description© 2021 Benussi A et al. JAMA Network Open. This is an open access article distributed under the terms of the CC-BY License.pt_PT
dc.description.abstractImportance: 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.pt_PT
dc.description.sponsorshipThis work is supported by the Joint Programme–Neurodegenerative Disease Research grant no. JPND2019-466-090 “GENFI-prox” (Drs Synofzik, van Swieten, Otto, Graff, Rohrer, and Borroni), the Centre d’Investigation Clinique grant no. ANR/DGOS PRTS 2015-2019 PREV-DEMALS (Dr Le Ber), the Centre pour l’Acquisition et le Traitement des Images platform grant no. ANR-10-IAIHU-06 (Dr Le Ber), the UK Medical Research Council grant no. MR/M023664/1 (Dr Rohrer), the Italian Ministry of Health grant no. 733051042 (Dr Galimberti), and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant no. MOP 327387 (Dr Masellis), a Canadian Institutes of Health Research operating grant.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationJAMA Netw Open. 2021;4(1):e2030194.pt_PT
dc.identifier.doi10.1001/jamanetworkopen.2020.30194pt_PT
dc.identifier.eissn2574-3805
dc.identifier.urihttp://hdl.handle.net/10451/45687
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Medical Associationpt_PT
dc.relationJPND2019-466-090pt_PT
dc.relationANR/DGOS PRTS 2015-2019pt_PT
dc.relationANR-10-IAIHU-06pt_PT
dc.relationMR/M023664/1pt_PT
dc.relation733051042pt_PT
dc.relationMOP 327387pt_PT
dc.relation.publisherversionhttps://jamanetwork.com/journals/jamanetworkopenpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleProgression of behavioral disturbances and neuropsychiatric symptoms in patients with genetic frontotemporal dementiapt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue1pt_PT
oaire.citation.startPagee2030194pt_PT
oaire.citation.titleJAMA Network Openpt_PT
oaire.citation.volume4pt_PT
person.familyNamede Mendonça
person.givenNameAlexandre
person.identifier.ciencia-id1615-41B4-0848
person.identifier.orcid0000-0002-0488-1453
person.identifier.scopus-author-id7003320823
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication53ca3547-99ce-4b68-9330-7879a54c47b7
relation.isAuthorOfPublication.latestForDiscovery53ca3547-99ce-4b68-9330-7879a54c47b7

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