Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers
Elizabeth Finger, Rubina Malik, Martina Bocchetta, Kristy Coleman, Caroline Graff, Barbara Borroni, Mario Masellis, Robert Laforce, Caroline Greaves, Lucy L. Russell, Rhian S. Convery, Arabella Bouzigues, David M. Cash, Markus Otto, Matthis Synofzik, James B. Rowe, Daniela Galimberti, Pietro Tiraboschi, Robert Bartha, Christen Shoesmith, Maria Carmela Tartaglia, John C. van Swieten, Harro Seelaar, Lize C Jiskoot, Sandro Sorbi, Christopher Butler, Alexander Gerhard, Raquel Sánchez‐Valle, Alexandre de Mendonça, Fermín Moreno, Rik Vandenberghe, Isabelle Le Ber, Johannes Levin, Florence Pasquier, Isabel Santana, Jonathan D. Rohrer, Simon Ducharme, the Genetic FTD Initiative, GENFI, Aitana Sogorb‐Esteve, Carolin Heller, David L. Thomas, Emily Todd, Jennifer Nicholas, Hanya Benotmane, Henrik Zetterberg, Imogen J. Swift, Kiran Samra, Rachelle Shafei, Carolyn Timberlake, Thomas Cope, Timothy Rittman, Alberto Benussi, Enrico Premi, Roberto Gasparotti, Silvana Archetti, Stefano Gazzina, Valentina Cantoni, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Vittoria Borracci, Giacomina Rossi, Giorgio Giaccone, Giuseppe Di Fede, Paola Caroppo, Pietro Tiraboschi, Sara Prioni, Veronica Redaelli, David F. Tang‐Wai, Ekaterina Rogaeva, Miguel Castelo‐Branco, Morris Freedman, Ron Keren, Sandra E. Black, Sara Mitchell, Rosa Rademakers, Jackie M. Poos, Janne M. Papma, Lucia Giannini, Rick van Minkelen, Yolande A.L. Pijnenburg, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Michele Veldsman, Christin Andersson, Håkan Thonberg, Linn Öijerstedt, Vesna Jelić, Paul Thompson, Tobias Langheinrich, Albert Lladó, Anna Antonell, Jaume Olives, Mircea Balasa, Núria Bargalló, Sergi Borrego‐Écija
Abstract
While frontotemporal dementia has been considered a neurodegenerative disease that starts in mid-life or later, it is now clearly established that cortical and subcortical volume loss is observed more than a decade prior to symptom onset and progresses with ageing. To test the hypothesis that genetic mutations causing frontotemporal dementia have neurodevelopmental consequences, we examined the youngest adults in the GENFI cohort of pre-symptomatic frontotemporal dementia mutation carriers who are between 19 and 30 years of age. Structural brain differences and improved performance on some cognitive tests were found for MAPT and GRN mutation carriers relative to familial non-carriers, while smaller volumes were observed in C9orf72 repeat expansion carriers at a mean age of 26 years. The detection of such early differences supports potential advantageous neurodevelopmental consequences of some frontotemporal dementia-causing genetic mutations. These results have implications for the design of therapeutic interventions for frontotemporal dementia. Future studies at younger ages are needed to identify specific early pathophysiologic or compensatory processes that occur during the neurodevelopmental period.