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Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant
Dario Saracino1, Sophie Ferrieux1, Marie Noguès-Lassiaille1
1From Sorbonne Université (D.S., M.H., L.S., S.E., A.C., S.B., D.R., A.M., R.L., B.D., A.B., O.C., M.T., R.M., I.L.B.), Paris Brain Institute-Institut du Cerveau (ICM), Inserm U1127, CNRS UMR 7225, AP-HP-Hôpital Pitié-Salpêtrière; Reference Centre for Rare or Early Dementias (D.S., S.F., M.N.-L., M.H., A.F., L.S., S.E., D.R., A.M., R.L., B.D., M.T., R.M., I.L.B.), IM2A, Département de Neurologie, AP-HP-Hôpital Pitié-Salpêtrière; Aramis Project Team (D.S., S.E., S.B., A.M., O.C.), Inria Research Center of Paris; Centre of Excellence of Neurodegenerative Disease (CoEN) (M.H.), ICM, CIC Neurosciences, Département de Neurologie, AP-HP-Hôpital Pitié-Salpêtrière, Sorbonne Université; FrontLab (A.F., R.L., B.D., M.T., R.M., I.L.B.), Paris Brain Institute-Institut du Cerveau (ICM); Université Lille (V.D., F.P.), Inserm U1171, CHU Lille, DistAlz, LiCEND, CNR-MAJ; CMRR Service de Neurologie (P.C.), CHU de Limoges; Department of Neurology (J.P., A.G.), Toulouse University Hospital; ToNIC (J.P., A.G.), Toulouse NeuroImaging Centre, Inserm, UPS, University of Toulouse; Normandie Université (D.W., D.H.), UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine; Rouen University Hospital (O.M.), Department of Neurology; Normandie Université (O.M.), UNICAEN, PSL Research University, EPHE, INSERM, U1077, CHU de Caen Normandie, Neuropsychologie et Imagerie de la Mémoire Humaine, Caen; UF de Neurogénétique Moléculaire et Cellulaire (F.C.), Département de Génétique, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix; EPHE (A.C.), PSL Research University, Paris; CMRR Nouvelle Aquitaine/Institut des Maladies Neurodégénératives clinique (IMNc) (S.A.), CHU de Bordeaux Hôpital Pellegrin; Unit of Neurology of Memory and Language (M.S., J.L., C.R.-J.), GHU Paris Psychiatry and Neurosciences, University of Paris, Hôpital Sainte Anne; Université Paris-Saclay (M.S., J.L., C.R.-J.), CEA, CNRS, Inserm, BioMaps, Orsay; Aix Marseille Université (M.D.), INSERM, Institut de Neurosciences des Systèmes, Marseille; APHM (M.D.), Timone, Service de Neurologie et Neuropsychologie, APHM Hôpital Timone Adultes, Marseille; CHU Nantes (C.B.-B.), Inserm CIC04, Department of Neurology, Centre Mémoire de Ressources et Recherche, Nantes; Centre de génétique (C.T.-R.), Hôpital d'Enfants, CHU Dijon Bourgogne; CMRR Département de Neurologie (F.S.), Hôpitaux Civils, Colmar, INSERM U1118, Université de Strasbourg, Faculté de Médecine, 67085 Strasbourg; CMRR (A.G.), Département de Neurologie, CHU de Montpellier, Inserm U1061, Université de Montpellier i-site MUSE; Department of Neurology (F.E.-B.), CMRR Angers University Hospital, Angers, France; Department of Advanced Medical and Surgical Sciences (C.C.), University of Campania Luigi Vanvitelli, Naples, Italy; and Department of Neurology (M.L.G.-T.), Memory and Aging Center, University of California, San Francisco.
Objective:
To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic correlates.
Methods:
Patients with PPA carrying GRN mutations (PPA-GRN) 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.
Results:
Among the 235 patients with PPA, 45 (19%) carried GRN 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%).
Conclusions:
This study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene-specific therapies.
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