Characterizing the Clinical Features and Atrophy Patterns of <i>MAPT</i> -Related Frontotemporal Dementia With Disease Progression Modeling
Alexandra L. Young, Martina Bocchetta, Lucy L. Russell, Rhian S. Convery, Georgia Peakman, Emily Todd, David M. Cash, Caroline Greaves, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Fermín Moreno, Raquel Sánchez‐Valle, Barbara Borroni, Robert Laforce, Mario Masellis, Maria Carmela Tartaglia, Caroline Graff, Daniela Galimberti, James B. Rowe, Elizabeth Finger, Matthis Synofzik, Rik Vandenberghe, Alexandre de Mendonça, Fabrizio Tagliavini, Isabel Santana, Simon Ducharme, Christopher Butler, Alexander Gerhard, Johannes Levin, Adrian Danek, Markus Otto, Sandro Sorbi, Steven Williams, Daniel C. Alexander, Jonathan D. Rohrer, on behalf of the Genetic FTD Initiative (GENFI), Martin N. Rossor, Nick C. Fox, Jason D. Warren, Ione Woollacott, Rachelle Shafei, Carolin Heller, Imogen J. Swift, Katrina Moore, Rita Guerreiro, José Brás, David L. Thomas, Jennifer Nicholas, Simon Mead, Lieke Meeter, Jessica Panman, Janne M. Papma, Jackie M. Poos, Rick van Minkelen, Yolande A.L. Pijnenburg, Myriam Barandiarán, Begoña Indakoetxea, Alazne Gabilondo, Mikel Tainta, María de Arriba, Ana Gorostidi, Miren Zulaica, Jorge Villanúa, Zigor Díaz, Sergi Borrego‐Écija, Jaume Olives, Albert Lladó, Mircea Balasa, Anna Antonell, Núria Bargalló, Enrico Premi, Maura Cosseddu, Stefano Gazzina, Alessandro Padovani, Roberto Gasparotti, Silvana Archetti, Sandra E. Black, Sara Mitchell, Ekaterina Rogaeva, Morris Freedman, Ron Keren, David F. Tang‐Wai, Linn Öijerstedt, Christin Andersson, Vesna Jelić, Håkan Thonberg, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Thomas Cope, Carolyn Timberlake, Timothy Rittman, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Carlo Wilke, H.‐O. Karnath, Benjamin Bender
Abstract
<h3>Background and Objective</h3> Mutations in the <i>MAPT</i> gene cause frontotemporal dementia (FTD). Most previous studies investigating the neuroanatomical signature of <i>MAPT</i> mutations have grouped all different mutations together and shown an association with focal atrophy of the temporal lobe. The variability in atrophy patterns between each particular <i>MAPT</i> mutation is less well-characterized. We aimed to investigate whether there were distinct groups of <i>MAPT</i> mutation carriers based on their neuroanatomical signature. <h3>Methods</h3> We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning technique that identifies groups of individuals with distinct progression patterns, to characterize patterns of regional atrophy in <i>MAPT-</i>associated FTD within the Genetic FTD Initiative (GENFI) cohort study. <h3>Results</h3> Eighty-two <i>MAPT</i> mutation carriers were analyzed, the majority of whom had P301L, IVS10+16, or R406W mutations, along with 48 healthy noncarriers. SuStaIn identified 2 groups of <i>MAPT</i> mutation carriers with distinct atrophy patterns: a temporal subtype, in which atrophy was most prominent in the hippocampus, amygdala, temporal cortex, and insula; and a frontotemporal subtype, in which atrophy was more localized to the lateral temporal lobe and anterior insula, as well as the orbitofrontal and ventromedial prefrontal cortex and anterior cingulate. There was one-to-one mapping between IVS10+16 and R406W mutations and the temporal subtype and near one-to-one mapping between P301L mutations and the frontotemporal subtype. There were differences in clinical symptoms and neuropsychological test scores between subtypes: the temporal subtype was associated with amnestic symptoms, whereas the frontotemporal subtype was associated with executive dysfunction. <h3>Conclusion</h3> Our results demonstrate that different <i>MAPT</i> mutations give rise to distinct atrophy patterns and clinical phenotype, providing insights into the underlying disease biology and potential utility for patient stratification in therapeutic trials.