@article {Tavares975, author = {Tamara Paulo Tavares and Derek G V Mitchell and Kristy KL Coleman and Brenda L Coleman and Christen L Shoesmith and Christopher R Butler and Isabel Santana and Adrian Danek and Alexander Gerhard and Alexandre de Mendonca and Barbara Borroni and Maria Carmela Tartaglia and Caroline Graff and Daniela Galimberti and Fabrizio Tagliavini and Fermin Moreno and Giovanni B Frisoni and James Benedict Rowe and Johannes Levin and John Cornelis Van Swieten and Markus Otto and Matthis Synofzik and Raquel Sanchez-Valle and Rik Vandenberghe and Robert Jr Laforce and Roberta Ghidoni and Sandro Sorbi and Simon Ducharme and Mario Masellis and Jonathan D Rohrer and Elizabeth Finger}, editor = {, and , and Gabilondo, Alazne and Llad{\'o}, Albert and Padovani, Alessandro and Gorostidi, Ana and Arighi, Ana Verdelho and Antonell, Anna and Santiago, Beatriz and Indakoetxea, Bego{\~n}a and Bender, Benedetta Nacmias and Ferrari, Camilla and Wilke, Carlo and Heller, Carolin and Maruta, Carolina and Greaves, Caroline and Timberlake, Carolyn and Ferreira, Catarina B and Prix, Catharina and Fenoglio, Chiara and Andersson, Christin and Polito, Cristina and Cash, David and Thomas, David L and Tang-Wai, David and Duro, Diana and Rogaeva, Ekaterina and Scarpini, Elio and Semler, Elisa and Wlasich, Elisabeth and Todd, Emily and Premi, Enrico and Miltenberger, Gabriel and Lombardi, Gemma and Peakman, Georgia and Rossi, Giacomina and Fumagalli, Giorgio and Giaccone, Giorgio and Binetti, Giuliano and Fede, Giuseppe Di and Thonberg, Hakan and Karnath, Hans-Otto and Zetterberg, Henrik and Woollacott, Ione and Papma, Janne and Warren, Jason and Olives, Jaume and Nicholas, Jennifer and Panman, Jessica and Villanua, Jorge and Bras, Jose and Moore, Katrina and Meeter, Lieke and {\"O}ijerstedt, Linn and Jiskoot, Lize and Benussi, Luisa and Arriba, Mar{\'\i}a de and Leit{\~a}o, Maria Jo{\~a}o and Almeida, Maria Rosario and Rosser, Martin and Bocchetta, Martina and Vandenbulcke, Mathieu and Cosseddu, Maura and Pievani, Michela and Veldsman, Michele and Castelo-Branco, Miguel and T{\'a}buas-Pereira, Miguel and Tainta, Mikel and Balasa, Mircea and Zulaica, Miren and Freedman, Morris and Barandiaran, Myriam and Fox, Nick and Bargall{\'o}, Nuria and Caroppo, Paola and Rosa-Neto, Pedro and Vandamme, Philip and Tiraboschi, Pietro and Shafei, Rachelle and Convery, Rhian and Taipa, Ricardo and Minkelen, Rick van and Guerreiro, Rita and Gasparotti, Roberto and Keren, Ron and Rademakers, Rosa and Bruffaerts, Rose and Black, Sandra and Loosli, Sandra and Mitchell, Sara and Prioni, Sara and Anderl-Straub, Sarah and Ourselin, Sebastien and Gauthier, Serge and Borrego-Ecija, Sergi and Archetti, Silvana and Mead, Simon and Afonso, S{\'o}nia and Sch{\"o}necker, Sonja and Gazzina, Stefano and Cope, Thomas and Rittman, Tim and Hoegen, Tobias and Flanagan, Toby and Bessi, Valentina and Redaelli, Veronica and Jelic, Vesna and Pijnenburg, Yolande and D{\'\i}az, Zigor}, title = {Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration}, volume = {91}, number = {9}, pages = {975--984}, year = {2020}, doi = {10.1136/jnnp-2020-322987}, publisher = {BMJ Publishing Group Ltd}, abstract = {Objectives The clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD. The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers.Methods The current study used data from the Genetic Frontotemporal Dementia Initiative multicentre cohort study collected between 2012 and 2018. Participants included symptomatic carriers (n=185) of a pathogenic mutation in chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) and their first-degree biological family members (n=588). Symptom endorsement was documented using informant and clinician-rated scales.Results The most frequently endorsed initial symptoms among symptomatic patients were apathy (23\%), disinhibition (18\%), memory impairments (12\%), decreased fluency (8\%) and impaired articulation (5\%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills.Conclusion Preclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group.Data may be obtained from a third party and are not publicly available. The data for this study were obtained from the GENFI data freeze 4. Further details on the GENFI protocol, cohorts and data policies can be found at http://genfi.org.uk/samples.html.}, issn = {0022-3050}, URL = {https://jnnp.bmj.com/content/91/9/975}, eprint = {https://jnnp.bmj.com/content/91/9/975.full.pdf}, journal = {Journal of Neurology, Neurosurgery \& Psychiatry} }