Genetic forms of primary progressive aphasia within the GENetic Frontotemporal dementia Initiative (GENFI) cohort: comparison with sporadic primary progressive aphasia
Authors: Samra Kiran , MacDougall Amy M , Bouzigues Arabella , Bocchetta Martina , Cash David M , Greaves Caroline V , Convery Rhian S , Hardy Chris , van Swieten John C , Seelaar Harro , Jiskoot Lize C , Moreno Fermin , Sanchez-Valle Raquel , Laforce Robert , Graff Caroline , Masellis Mario , Tartaglia Maria Carmela , Rowe James B , Borroni Barbara , Finger Elizabeth , Synofzik Matthis , Galimberti Daniela , Vandenberghe Rik , de Mendonça Alexandre , Butler Chris R , Gerhard Alexander , Ducharme Simon , Le Ber Isabelle , Santana Isabel , Pasquier Florence , Levin Johannes , Otto Markus , Sorbi Sandro , Warren Jason D , Rohrer Jonathan D , Russell Lucy L ,   GENetic Frontotemporal dementia Initiative (GENFI), Afonso Sónia , Almeida Maria Rosario , Anderl-Straub Sarah , Andersson Christin , Antonell Anna , Archetti Silvana , Arighi Andrea , Balasa Mircea , Barandiaran Myriam , Bargalló Nuria , Bartha Robart , Bender Benjamin , Benussi Alberto , Bertoux Maxime , Bertrand Anne , Bessi Valentina , Black Sandra , Borrego-Ecija Sergi , Bras Jose , Brice Alexis , Bruffaerts Rose , Camuzat Agnès , Cañada Marta , Cantoni Valentina , Caroppo Paola , Castelo-Branco Miguel , Colliot Olivier , Cope Thomas , Deramecourt Vincent , Arriba María de , Fede Giuseppe Di , Díez Alina , Duro Diana , Fenoglio Chiara , Ferrari Camilla , Ferreira Catarina B , Fox Nick , Freedman Morris , Fumagalli Giorgio , Funkiewiez Aurélie , Cerveau Institut du , Gabilondo Alazne , Gasparotti Roberto , Gauthier Serge , Gazzina Stefano , Giaccone Giorgio , Gorostidi Ana , Guerreiro Rita , Heller Carolin , Hoegen Tobias , Indakoetxea Begoña , Jelic Vesna , Karnath Hans-Otto , Keren Ron , Kuchcinski Gregory , Langheinrich Tobias , Lebouvier Thibaud , João Leitão Maria , Lladó Albert , Lombardi Gemma , Loosli Sandra , Maruta Carolina , Mead Simon , Meeter Lieke , Miltenberger Gabriel , Minkelen Rick van , Mitchell Sara , Moore Katrina , Nacmias Benedetta , Nelson Annabel , Öijerstedt Linn , Olives Jaume , Ourselin Sebastien , Padovani Alessandro , Panman Jessica , Papma Janne M , Pijnenburg Yolande , Polito Cristina , Premi Enrico , Prioni Sara , Prix Catharina , Rademakers Rosa , Redaelli Veronica , Rinaldi Daisy , Cerveau Institut du , Rittman Tim , Rogaeva Ekaterina , Rollin Adeline , Rosa-Neto Pedro , Rossi Giacomina , Rossor Martin , Santiago Beatriz , Saracino Dario , Sayah Sabrina , Scarpini Elio , Schönecker Sonja , Semler Elisa , Shafei Rachelle , Shoesmith Christen , Swift Imogen , Tábuas-Pereira Miguel , Tainta Mikel , Taipa Ricardo , Tang-Wai David , Thomas David L , Thompson Paul , Thonberg Hakan , Timberlake Carolyn , Tiraboschi Pietro , Todd Emily , Damme Philip Van , Vandenbulcke Mathieu , Veldsman Michele , Verdelho Ana , Villanua Jorge , Wilke Carlo , Woollacott Ione , Wlasich Elisabeth , Zetterberg Henrik , Zulaica Miren 
Published: February 2023

Primary progressive aphasia is most commonly a sporadic disorder, but in some cases, it can be genetic. This study aimed to understand the clinical, cognitive and imaging phenotype of the genetic forms of primary progressive aphasia in comparison to the canonical nonfluent, semantic and logopenic subtypes seen in sporadic disease. Participants with genetic primary progressive aphasia were recruited from the international multicentre GENetic Frontotemporal dementia Initiative study and compared with healthy controls as well as a cohort of people with sporadic primary progressive aphasia. Symptoms were assessed using the GENetic Frontotemporal dementia Initiative language, behavioural, neuropsychiatric and motor scales. Participants also underwent a cognitive assessment and 3 T volumetric T1-weighted MRI. One C9orf72 (2%), 1 MAPT (6%) and 17 GRN (44%) symptomatic mutation carriers had a diagnosis of primary progressive aphasia. In the GRN cohort, 47% had a diagnosis of nonfluent variant primary progressive aphasia, and 53% had a primary progressive aphasia syndrome that did not fit diagnostic criteria for any of the three subtypes, called primary progressive aphasia-not otherwise specified here. The phenotype of the genetic nonfluent variant primary progressive aphasia group largely overlapped with that of sporadic nonfluent variant primary progressive aphasia, although the presence of an associated atypical parkinsonian syndrome was characteristic of sporadic and not genetic disease. The primary progressive aphasia -not otherwise specified group however was distinct from the sporadic subtypes with impaired grammar/syntax in the presence of relatively intact articulation, alongside other linguistic deficits. The pattern of atrophy seen on MRI in the genetic nonfluent variant primary progressive aphasia group overlapped with that of the sporadic nonfluent variant primary progressive aphasia cohort, although with more posterior cortical involvement, whilst the primary progressive aphasia-not otherwise specified group was strikingly asymmetrical with involvement particularly of the insula and dorsolateral prefrontal cortex but also atrophy of the orbitofrontal cortex and the medial temporal lobes. Whilst there are overlapping symptoms between genetic and sporadic primary progressive aphasia syndromes, there are also distinct features. Future iterations of the primary progressive aphasia consensus criteria should encompass such information with further research needed to understand the earliest features of these disorders, particularly during the prodromal period of genetic disease.