Primary Progressive Aphasia Associated With <i>GRN</i> Mutations
Dario Saracino, Sophie Ferrieux, Marie Noguès-Lassiaille, Marion Houot, Aurélie Funkiewiez, Leila Sellami, Vincent Deramecourt, Florence Pasquier, Philippe Couratier, Jérémie Pariente, Amandine Géraudie, Stéphane Epelbaum, David Wallon, Didier Hannequin, Olivier Martinaud, Fabienne Clot, Agnès Camuzat, Simona Bottani, Daisy Rinaldi, Sophie Auriacombe, Marie Sarazin, Mira Didic, Claire Boutoleau‐Bretonnière, Christel Thauvin-Robinet, Julien Lagarde, Carole Roué-Jagot, François Sellal, Audrey Gabelle, Frédérique Etcharry‐Bouyx, Alexandre Morin, Cinzia Coppola, Richard Lévy, Bruno Dubois, Alexis Brice, Olivier Colliot, Maria Luisa Gorno‐Tempini, Marc Teichmann, Raffaella Migliaccio, Isabelle Le Ber, Ftd Ftd-Als French Research Network On, Fr´ed´eric Blanc, Mathieu Ceccaldi, Charles Duyckaerts, Ma¨ıt´e Formaglio, V´eronique Golfier, Lucette Lacomblez, Bernard- François Michel, Catherine Thomas- Anterion, Martine Vercelletto
Abstract
<h3>Objective</h3> To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with <i>GRN</i> (progranulin) mutations and to study their neuroanatomic correlates. <h3>Methods</h3> Patients with PPA carrying <i>GRN</i> mutations (PPA-<i>GRN</i>) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA. <h3>Results</h3> Among the 235 patients with PPA, 45 (19%) carried <i>GRN</i> mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%). <h3>Conclusions</h3> This study shows that the most frequent PPA variant associated with <i>GRN</i> mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. <i>GRN</i> testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming <i>GRN</i> gene–specific therapies.