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. 2021 Jan 4;4(1):e2030194.
doi: 10.1001/jamanetworkopen.2020.30194.

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

Alberto Benussi  1 , Enrico Premi  2 , Stefano Gazzina  3 , Chiara Brattini  1 , Elisa Bonomi  1 , Antonella Alberici  4 , Lize Jiskoot  5 , John C van Swieten  5 , Raquel Sanchez-Valle  6 , Fermin Moreno  7   8 , Robert Laforce  9 , Caroline Graff  10   11 , Matthis Synofzik  12   13 , Daniela Galimberti  14   15 , Mario Masellis  16 , Carmela Tartaglia  17 , James B Rowe  18 , Elizabeth Finger  19 , Rik Vandenberghe  20   21   22 , Alexandre de Mendonça  23 , Fabrizio Tagliavini  24 , Isabel Santana  25   26 , Simon Ducharme  27   28 , Chris R Butler  29   30 , Alexander Gerhard  31   32 , Johannes Levin  33   34   35 , Adrian Danek  33 , Markus Otto  36 , Giovanni Frisoni  37 , Roberta Ghidoni  38 , Sandro Sorbi  39   40 , Isabelle Le Ber  41   42   43   44 , Florence Pasquier  45   46   47 , Georgia Peakman  47 , Emily Todd  47 , Martina Bocchetta  47 , Jonathan D Rohrer  47 , Barbara Borroni  1 ; Genetic FTD Initiative (GENFI)
Collaborators, Affiliations

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

Alberto Benussi et al. JAMA Netw Open. .

Erratum in

  • Error in Article Information.
    [No authors listed] [No authors listed] JAMA Netw Open. 2021 Mar 1;4(3):e217664. doi: 10.1001/jamanetworkopen.2021.7664. JAMA Netw Open. 2021. PMID: 33787918 Free PMC article. No abstract available.

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Graff reported receiving grants from the Swedish Research Council Joint Programme–Neurodegenerative Disease Research GENFI-prox domain registration no. 2019-02248, the Swedish Research Council Joint Programme–Neurodegenerative Disease Research Prefrontals domain registration no. 2015-02926, the Swedish Research Council Dnr 208-02754, the Schörling Foundation Swedish FTD Initiative, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, the Region Stockholm ALF-project, the Karolinska Instututet Doctoral and StratNeuro, and from the Swedish Dementia Foundation during the conduct of the study. Dr Masellis reported receiving grants from the Canadian Institutes of Health, the Cambridge Trust, the Ontario Brain Institute, the Weston Brain Institute, the Roche Clinical Trial, the Washington University Clinical Trial, and the Alector Clinical Trial; and personal fees from Arkuda Therapeutics Advisory Board, the Ionis Advisory Board, Henry Stewart Talks Royalties, Alector Advisory Board, and Wave Life Sciences Advisory Board outside the submitted work. Dr Rowe reported receiving grants from the National Institute for Health Research, Wellcome Trust, Janssen, AZ Medimmune, Lilly, and Medical Research Council; and personal fees from Biogen, Asceneuron, UCB, Althira, Astex, and SVHealth outside the submitted work. Dr Rowe also reported serving as Trustee for the Progressive Supranuclear Palsy Association, Darwin College, and Guarantor of Brain; and reported serving as an editor of Brain. Dr Le Ber reported receiving funding from the program “Investissements d’avenir” and from Agence Nationale de la Recherche/Direction Générale de l'Offre de Soins; serving as a member of the advisory board for Prevail Therapeutic; and receiving research grants from Agence Nationale de la Recherche, Direction Générale de l'Offre de Soins, Programme Hospitalier de Recherche Clinique, Vaincre Alzheimer Association, ARSla Association, Fondation Plan Alzheimer, and PRTS PrevDemALS; personal fees from Prevail Therapeutics; and grants from Programme Hospitalier de Recherche Clinique FTLD exome, Programme Hospitalier de Recherche Clinique Predict PGRN, and ANR-10-IAIHU-06 outside the submitted work. Dr Sanchez-Valle reported receiving grants from Fundació Marató de TV3 and personal fees from Wave Pharmaceuticals for participation in advisory board meetings and Ionis for participation in advisory board meetings outside the submitted work. Dr Moreno reported receiving grants from Tau Consortium outside the submitted work. Dr Synofzik reported receiving personal fees from Actelion Pharmaceuticals and Orphazyme outside the submitted work. Dr Santana reported receiving grants from GENFI and personal fees and travel funds from commercial sponsors outside the submitted work. Dr Levin reported receiving grants from Munich Cluster of Systems Neurology (SyNergy) and personal fees from Modag GmbH, Bayer Vital, Roche, Axon Neuroscience, Thieme medical publishers, and W. Kohlhammer GmbH medical publishers; and nonfinancial support from Abbvie outside the submitted work. Dr Otto reported receiving grants from BMBF during the conduct of the study. Dr Ghidoni reported receiving grants from the Italian Ministry of Health during the conduct of the study. Dr Rohrer reported performing medical advisory board work for Alector, Wave Life Sciences, and Prevail Therapeutics outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Frequency of Behavioral and Neuropsychiatric Symptoms in A, C9orf72 Expansion; B, GRN; and C, MAPT Carriers
C9orf72 indicates chromosome 9 open reading frame 72; GRN, granulin; MAPT, microtubule-associated protein tau. aP < .05 vs GRN. bP < .05 vs C9orf72. cP < .05 vs MAPT pairwise comparisons after significant interaction at the Fisher exact test, after adjustment for multiple comparisons.
Figure 2.
Figure 2.. Predicted Behavioral (A, C9orf72 carriers; B, GRN carriers; C, MAPT carriers) and Neuropsychiatric Symptom (D, C9orf72 carriers; E, GRN carriers; F, MAPT carriers) Severity According to Disease Duration
C9orf72 indicates chromosome 9 open reading frame 72; GRN, granulin; MAPT, microtubule-associated protein tau.
See this image and copyright information in PMC

References

    1. Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet. 2015;386(10004):1672-1682. doi:10.1016/S0140-6736(15)00461-4 - DOI - PMC - PubMed
    1. Rohrer JD, Guerreiro R, Vandrovcova J, et al. . The heritability and genetics of frontotemporal lobar degeneration. Neurology. 2009;73(18):1451-1456. doi:10.1212/WNL.0b013e3181bf997a - DOI - PMC - PubMed
    1. Borroni B, Padovani A. Dementia: a new algorithm for molecular diagnostics in FTLD. Nat Rev Neurol. 2013;9(5):241-242. doi:10.1038/nrneurol.2013.72 - DOI - PubMed
    1. Benussi A, Padovani A, Borroni B. Phenotypic heterogeneity of monogenic frontotemporal dementia. Front Aging Neurosci. 2015;7(SEP):171. doi:10.3389/fnagi.2015.00171 - DOI - PMC - PubMed
    1. Rascovsky K, Hodges JR, Knopman D, et al. . Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(Pt 9):2456-2477. doi:10.1093/brain/awr179 - DOI - PMC - PubMed

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