Abstract
Objective: To investigate the optimal method of adding motor features to a clinical rating scale for frontotemporal dementia (FTD). Methods: Eight hundred and thirty-two participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 522 mutation carriers (with C9orf72, GRN and MAPT mutations) and 310 mutation-negative controls. A standardised clinical questionnaire was used to assess eight motor symptoms (dysarthria, dysphagia, tremor, slowness, weakness, gait disorder, falls and functional difficulties using hands). Frequency and severity of each motor symptom was assessed, and a principal component analysis (PCA) was performed to identify how the different motor symptoms loaded together. Finally, addition of a motor component to the CDR® plus NACC FTLD was investigated (CDR® plus NACC FTLD-M). Results: 24.3% of mutation carriers had motor symptoms (31.7% C9orf72, 18.8% GRN, 19.3% MAPT) compared to 6.8% of controls. Slowness and gait disorder were the commonest in all genetic groups while tremor and falls were the least frequent. Symptom severity scores were similar to equivalent physical motor examination scores. PCA revealed that all motor symptoms loaded together so a single additional motor component was added to the CDR® plus NACC FTLD to form the CDR® plus NACC FTLD-M. Individual global scores were more severe with the CDR® plus NACC FTLD-M, and no patients with a clinically diagnosed motor disorder (ALS/FTD-ALS or parkinsonism) were classified anymore as asymptomatic (unlike the CDR® plus NACC FTLD alone). Conclusions: Motor features are present in mutation carriers at all disease stages across all three genetic groups. Inclusion of motor symptoms in a rating scale that can be used in future clinical trials will not only ensure a more accurate severity measure is recorded but that a wider spectrum of FTD phenotypes can be included in the same trial.
Original language | English |
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Pages (from-to) | 1466-1477 |
Number of pages | 12 |
Journal | Journal of Neurology |
Volume | 270 |
Issue number | 3 |
DOIs | |
Publication status | Published - Mar 2023 |
Bibliographical note
Funding Information:We thank the research participants and their families for their contribution to the study. 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 (NIHR) Queen Square Dementia Biomedical Research Unit and the University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Italian Ministry of Health (CoEN015 and Ricerca Corrente), the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, a Canadian Institutes of Health Research operating grant, the Alzheimer's Society grant (AS-PG-16-007), the Bluefield Project and the JPND GENFI-PROX grant (2019-02248). MB is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). MB’s work was also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. JDR is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). JBR is funded by the Wellcome Trust (103838) and the National Institute for Health Research Cambridge Biomedical Research Centre. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198). RV’s work is supported by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie. Several authors of this publication (JCvS, MS, RSV, AD, MO, RV, JDR) are members of the European Reference Network for Rare Neurological Diseases (ERN-RND)—Project ID No 739510. List of GENFI consortium authors: Annabel Nelson (Department of Neurodegenerative Disease, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK), Martina Bocchetta (Department of Neurodegenerative Disease, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK), David Cash (Department of Neurodegenerative Disease, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK), David L. Thomas (Neuroimaging Analysis Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, UK), Emily Todd (Department of Neurodegenerative Disease, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK), Hanya Benotmane (UK Dementia Research Institute at University College London, UCL Queen Square Institute of Neurology, London, UK), Jennifer Nicholas (Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK), Kiran Samra (Department of Neurodegenerative Disease, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK), Rachelle Shafei (Department of Neurodegenerative Disease, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, UK), Carolyn Timberlake (Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK), Thomas Cope (Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK), Timothy Rittman (Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK), Alberto Benussi (Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy), Enrico Premi (Stroke Unit, ASST Brescia Hospital, Brescia, Italy), Roberto Gasparotti (Neuroradiology Unit, University of Brescia, Brescia, Italy), Silvana Archetti (Biotechnology Laboratory, Department of Diagnostics, ASST Brescia Hospital, Brescia, Italy), Stefano Gazzina (Neurology, ASST Brescia Hospital, Brescia, Italy), Valentina Cantoni (Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy), Andrea Arighi (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy), Chiara Fenoglio (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy), Elio Scarpini (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy), Giorgio Fumagalli (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy), Vittoria Borracci (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy), Giacomina Rossi (Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy), Giorgio Giaccone (Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy), Giuseppe Di Fede (Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy), Paola Caroppo (Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy), Pietro Tiraboschi (Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy), Sara Prioni (Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy), Veronica Redaelli (Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy), David Tang-Wai (The University Health Network, Krembil Research Institute, Toronto, Canada), Ekaterina Rogaeva (Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada, Miguel Castelo-Branco (Faculty of Medicine, University of Coimbra, Coimbra, Portugal), Morris Freedman (Baycrest Health Sciences, Rotman Research Institute, University of Toronto, Toronto, Canada), Ron Keren (The University Health Network, Toronto Rehabilitation Institute, Toronto, Canada), Sandra Black (Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada) (Sara Mitchell (Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada) (Christen Shoesmith (Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada) (Robart Bartha (Department of Medical Biophysics, The University of Western Ontario, London, Ontario, Canada; Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada) (Rosa Rademakers (Center for Molecular Neurology, University of Antwerp) (Jackie Poos (Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands (Janne M. Papma (Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands) (Lucia Giannini (Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands) (Rick van Minkelen (Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands) (Yolande Pijnenburg (Amsterdam University Medical Centre, Amsterdam VUmc, Amsterdam, Netherlands) (Benedetta Nacmias (Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy) (Camilla Ferrari (Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy) (Cristina Polito (Department of Biomedical, Experimental and Clinical Sciences ‘Mario Serio’, Nuclear Medicine Unit, University of Florence, Florence, Italy) (Gemma Lombardi (Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy) (Valentina Bessi (Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy) (Michele Veldsman (Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK) (Christin Andersson (Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden) (Hakan Thonberg (Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden) (Linn Öijerstedt (Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet, Solna, Sweden; Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden) (Vesna Jelic (Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden) (Paul Thompson (Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK) (Tobias Langheinrich (Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK; Manchester Centre for Clinical Neurosciences, Department of Neurology, Salford Royal NHS Foundation Trust, Manchester, UK) (Albert Lladó (Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain) (Anna Antonell (Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain) (Jaume Olives (Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain) (Mircea Balasa (Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain) (Nuria Bargalló (Imaging Diagnostic Center, Hospital Clínic, Barcelona, Spain) (Sergi Borrego-Ecija (Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain) (Ana Verdelho (Department of Neurosciences and Mental Health, Centro Hospitalar Lisboa.
Funding Information:
We thank the research participants and their families for their contribution to the study. 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 (NIHR) Queen Square Dementia Biomedical Research Unit and the University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Italian Ministry of Health (CoEN015 and Ricerca Corrente), the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, a Canadian Institutes of Health Research operating grant, the Alzheimer's Society grant (AS-PG-16-007), the Bluefield Project and the JPND GENFI-PROX grant (2019-02248). MB is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). MB’s work was also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. JDR is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). JBR is funded by the Wellcome Trust (103838) and the National Institute for Health Research Cambridge Biomedical Research Centre. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198). RV’s work is supported by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie. Several authors of this publication (JCvS, MS, RSV, AD, MO, RV, JDR) are members of the European Reference Network for Rare Neurological Diseases (ERN-RND)—Project ID No 739510.
Publisher Copyright:
© 2022, Crown.