Primary Progressive Aphasia Associated With <i>GRN</i> Mutations

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.