Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/114639
Title: 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
Sánchez-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.
Keywords: primary progressive aphasia; GRN; c9orf72; MAPT
Issue Date: 2023
Publisher: Oxford University Press
Project: The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK and The Wolfson Foundation. This work was supported by the National Institute for Health Research University College London/Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility and the UK Dementia Research Institute, which receives its funding from UK Dementia Research Institute Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. This work was also supported by the EU Joint Programme— Neurodegenerative Disease Research GENFI-PROX grant [2019-02248; to J.D.R., MO, BB, CG, JvS and MS. (latter via DLR/DFG 01ED2008B)]. J.D.R. is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from Medical Research Council Clinician Scientist Fellowship (MR/M008525/1) and the National Institute for Health Research Rare Disease Translational Research Collaboration (BRC149/NS/MH). This work was also supported by the Medical Research Council UK GENFI grant (MR/M023664/1), the Bluefield Project and the EU Joint Programme—Neurodegenerative Disease Research GENFI-PROX grant (2019-02248). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. R.C./C.G. are supported by a Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). M.B. is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). M.B.’s work is also supported by the UK Dementia Research Institute which receives its funding from Dementia Research Institute Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. C.H. was supported by Royal National Institute for Deaf People Dunhill Medical Trust Pauline Ashley Fellowship (PA23_Hardy) and Wellcome Institutional Strategic Support Fund (204841/Z/16/Z). J.C.V.S. was supported by the Dioraphte Foundation grant 09-02-03-00, Association for Frontotemporal Dementias Research Grant 2009, Netherlands Organization for Scientific Research grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. F.M. received funding from the Tau Consortium and the Center for Networked Biomedical Research on Neurodegenerative Disease. R.S-V. is supported by Alzheimer’s Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2) and has received funding from Fundació Marató de TV3, Spain (grant no. 20143810). C.G. received funding from EU Joint Programme—Neurodegenerative Disease Research -Prefrontals VR Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, the Swedish FTD Inititative-Schörling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. M.M. has received funding from a Canadian Institute of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. J.B.R. has received funding from the Welcome Trust (103838) and is supported by the Cambridge University Centre for Frontotemporal Dementia, the Medical Research Council (SUAG/051 G101400) and the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014). E.F. has received funding from a Canadian Institute of Health Research grant #327387. D.G. received support from the EU Joint Programme— Neurodegenerative Disease Research and the Italian Ministry of Health (PreFrontALS) grant 733051042. R.V. has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. M.O. has received funding from Germany’s Federal Ministry of Education and Research (BMBF), @@@FTLDc. J.L. received funding for this work by the Deutsche Forschungsgemeinschaft German Research Foundation under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) 
Serial title, monograph or event: Brain Communications
Volume: 5
Issue: 2
Abstract: 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.
URI: https://hdl.handle.net/10316/114639
ISSN: 2632-1297
DOI: 10.1093/braincomms/fcad036
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
FMUC Medicina - Artigos em Revistas Internacionais

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