10.1002/(ISSN)2352-8729 DAD2 Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring Alzheimer's Dement. 2352-8729 2352-8729 10.1002/dad2.12571 DAD212571 RESEARCH ARTICLE RESEARCH ARTICLES Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia SAMRA et al. Samra Kiran https://orcid.org/0000-0002-3105-7099 1 Peakman Georgia 1 MacDougall Amy M. 2 Bouzigues Arabella 1 Greaves Caroline V. 1 Convery Rhian S. 1 van Swieten John C. 3 Jiskoot Lize 3 Seelaar Harro 3 Moreno Fermin 4 5 Sanchez‐Valle Raquel 6 Laforce Robert 7 Graff Caroline 8 9 Masellis Mario 10 Tartaglia Maria Carmela 11 Rowe James B. 12 Borroni Barbara 13 Finger Elizabeth 14 Synofzik Matthis 15 16 Galimberti Daniela 17 18 Vandenberghe Rik 19 20 21 de Mendonça Alexandre 22 Butler Chris R. 23 24 Gerhard Alexander 25 26 Ducharme Simon 27 28 Ber Isabelle Le 29 30 31 32 Tiraboschi Pietro 33 Santana Isabel 34 35 Pasquier Florence 36 37 38 Levin Johannes 39 40 41 Otto Markus 42 Sorbi Sandro 43 44 Rohrer Jonathan D. https://orcid.org/0000-0002-6155-8417 1 Russell Lucy L. l.russell@ucl.ac.uk * 1  Genetic FTD Initiative (GENFI) Bocchetta Martina 45 Cash David 45 Thomas David L 46 Cope Thomas 47 Rittman Timothy 47 Benussi Alberto 48 Premi Enrico 49 Gasparotti Roberto 50 Archetti Silvana 51 Gazzina Stefano 52 Cantoni Valentina 48 Arighi Andrea 53 Fenoglio Chiara 53 Scarpini Elio 53 Fumagalli Giorgio 53 Borracci Vittoria 53 Rossi Giacomina 54 Giaccone Giorgio 54 Fede Giuseppe Di 54 Caroppo Paola 54 Tiraboschi Pietro 54 Prioni Sara 54 Redaelli Veronica 54 Tang‐Wai David 55 Rogaeva Ekaterina 56 Castelo‐Branco Miguel 57 Freedman Morris 58 Keren Ron 59 Black Sandra 60 Mitchell Sara 60 Shoesmith Christen 14 Bartha Robart 61 Rademakers Rosa 62 Poos Jackie 63 Papma Janne M. 63 Giannini Lucia 63 van Minkelen Rick 64 Pijnenburg Yolande 65 Nacmias Benedetta 66 Ferrari Camilla 66 Polito Cristina 67 Lombardi Gemma 66 Bessi Valentina 66 Veldsman Michele 68 Andersson Christin 69 Thonberg Hakan 70 Öijerstedt Linn 71 Jelic Vesna 72 Thompson Paul 73 Langheinrich Tobias 74 Lladó Albert 75 Antonell Anna 75 Olives Jaume 75 Balasa Mircea 75 Bargalló Nuria 76 Borrego‐Ecija Sergi 75 Verdelho Ana 77 Maruta Carolina 78 Ferreira Catarina B. 79 Miltenberger Gabriel 80 do Couto Frederico Simões 81 Gabilondo Alazne 82 Gorostidi Ana 83 Villanua Jorge 84 Cañada Marta 85 Tainta Mikel 83 Zulaica Miren 83 Barandiaran Myriam 82 Alves Patricia 86 Bender Benjamin 87 Wilke Carlo 88 Graf Lisa 89 Vogels Annick 90 Vandenbulcke Mathieu 91 Van Damme Philip 92 Bruffaerts Rose 93 Poesen Koen 94 Rosa‐Neto Pedro 95 Gauthier Serge 96 Camuzat Agnès 97 Brice Alexis 97 Bertrand Anne 98 Funkiewiez Aurélie 99 Rinaldi Daisy 100 Saracino Dario 101 Colliot Olivier 98 Sayah Sabrina 97 Prix Catharina 102 Wlasich Elisabeth 102 Wagemann Olivia 102 Loosli Sandra 102 Schönecker Sonja 102 Hoegen Tobias 102 Lombardi Jolina 42 Anderl‐Straub Sarah 42 Rollin Adeline 38 Kuchcinski Gregory 103 Bertoux Maxime 104 Lebouvier Thibaud 103 Deramecourt Vincent 103 Santiago Beatriz 105 Duro Diana 57 Leitão Maria João 106 Almeida Maria Rosario 57 Tábuas‐Pereira Miguel 105 Afonso Sónia 107 Dementia Research Centre Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology London UK Department of Medical Statistics London School of Hygiene and Tropical Medicine London UK Department of Neurology Erasmus Medical Centre Rotterdam the Netherlands Cognitive Disorders Unit Department of Neurology Donostia Universitary Hospital Donostia Spain Neuroscience Area Biodonostia Health Research Institute San Sebastián Spain Alzheimer's Disease and Other Cognitive Disorders Unit Neurology Service Hospital Clínic Institut d'Investigacións Biomèdiques August Pi I Sunyer University of Barcelona Barcelona Spain Clinique Interdisciplinaire de Mémoire Département des Sciences Neurologiques CHU de Québec, and Faculté de Médecine Université Laval, Québec City Québec Canada Center for Alzheimer Research Division of Neurogeriatrics Department of Neurobiology Care Sciences and Society, Bioclinicum, Karolinska Institutet, Solnavägen Solna Sweden Unit for Hereditary Dementias Theme Aging Karolinska University Hospital Hälsovägen Stockholm Sweden Sunnybrook Health Sciences Centre Sunnybrook Research Institute University of Toronto Toronto Ontario Canada Tanz Centre for Research in Neurodegenerative Diseases University of Toronto Toronto Ontario Canada Department of Clinical Neurosciences University of Cambridge Cambridge UK Neurology Unit Department of Clinical and Experimental Sciences University of Brescia Piazza del Mercato Brescia Italy Department of Clinical Neurological Sciences University of Western Ontario London Ontario Canada Department of Neurodegenerative Diseases Hertie‐Institute for Clinical Brain Research and Center of Neurology University of Tübingen Tübingen Germany Center for Neurodegenerative Diseases (DZNE) Tübingen Germany Fondazione Ca’ Granda IRCCS Ospedale Policlinico Milan Italy University of Milan Centro Dino Ferrari Milan Italy Laboratory for Cognitive Neurology Department of Neurosciences KU Leuven Leuven Belgium Neurology Service University Hospitals Leuven Leuven Belgium Leuven Brain Institute KU Leuven Leuven Belgium Faculty of Medicine University of Lisbon Lisbon Portugal Nuffield Department of Clinical Neurosciences Medical Sciences Division University of Oxford Oxford UK Department of Brain Sciences Imperial College London London UK Division of Neuroscience and Experimental Psychology Wolfson Molecular Imaging Centre University of Manchester Manchester UK Departments of Geriatric Medicine and Nuclear Medicine University of Duisburg‐Essen Duisburg Germany Department of Psychiatry McGill University Health Centre McGill University Montreal Québec Canada McConnell Brain Imaging Centre Montreal Neurological Institute McGill University Montreal Québec Canada Sorbonne Université Paris Brain Institute – Institut du Cerveau – ICM Inserm U1127, CNRS UMR 7225 AP‐HP ‐ Hôpital Pitié‐Salpêtrière Paris France Centre de référence des démences rares ou précoces IM2A, Département de Neurologie AP‐HP ‐ Hôpital Pitié‐Salpêtrière Paris France Département de Neurologie AP‐HP ‐ Hôpital Pitié‐Salpêtrière Paris France Reference Network for Rare Neurological Diseases (ERN‐RND) University Hospital Tübingen Tübingen Germany Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy University Hospital of Coimbra (HUC) Neurology Service, Faculty of Medicine University of Coimbra Coimbra Portugal Center for Neuroscience and Cell Biology Faculty of Medicine University of Coimbra Coimbra Portugal Univ Lille Lille France Inserm 1172 Lille France CHU, CNR‐MAJ, Labex Distalz, LiCEND Lille Lille France Department of Neurology Ludwig‐Maximilians Universität München Munich Germany German Center for Neurodegenerative Diseases (DZNE) Munich Germany Munich Cluster of Systems Neurology (SyNergy) Munich Germany Department of Neurology University of Ulm Ulm Germany Department of Neurofarba University of Florence Firenze Florence Italy IRCCS Fondazione Don Carlo Gnocchi Firenze Florence Italy Department of Neurodegenerative Disease, Dementia Research Centre UCL Queen Square Institute of Neurology London UK Neuroimaging Analysis Centre Department of Brain Repair and Rehabilitation UCL Institute of Neurology Queen Square London UK Department of Clinical Neuroscience University of Cambridge Cambridge UK Centre for Neurodegenerative Disorders Department of Clinical and Experimental Sciences University of Brescia Brescia Italy Stroke Unit ASST Brescia Hospital Brescia Italy Neuroradiology Unit University of Brescia Brescia Italy Biotechnology Laboratory Department of Diagnostics ASST Brescia Hospital Brescia Italy Neurology, ASST Brescia Hospital Brescia Italy Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari Milan Italy Fondazione IRCCS Istituto Neurologico Carlo Besta Milano Italy The University Health Network Krembil Research Institute Toronto Canada Tanz Centre for Research in Neurodegenerative Diseases University of Toronto Toronto Canada Faculty of Medicine University of Coimbra Coimbra Portugal Baycrest Health Sciences Rotman Research Institute University of Toronto Toronto Canada The University Health Network Toronto Rehabilitation Institute Toronto Canada Sunnybrook Health Sciences Centre Sunnybrook Research Institute University of Toronto Toronto Canada 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 Center for Molecular Neurology, University of Antwerp Department of Neurology Erasmus Medical Center Rotterdam Netherlands Department of Clinical Genetics Erasmus Medical Center Rotterdam Netherlands Amsterdam University Medical Centre Amsterdam VUmc Amsterdam Netherlands Department of Neuroscience Psychology, Drug Research and Child Health, University of Florence Florence Italy Department of Biomedical Experimental and Clinical Sciences "Mario Serio", Nuclear Medicine Unit, University of Florence Florence Italy Nuffield Department of Clinical Neurosciences Medical Sciences Division, University of Oxford Oxford UK Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden Center for Alzheimer Research Division of Neurogeriatrics, Karolinska Institutet Stockholm Sweden 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 Division of Clinical Geriatrics Karolinska Institutet Stockholm Sweden Division of Neuroscience and Experimental Psychology Wolfson Molecular Imaging Centre, University of Manchester Manchester UK 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 Alzheimer's disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic Barcelona Spain Imaging Diagnostic Center, Hospital Clínic Barcelona Spain Department of Neurosciences and Mental Health Centro Hospitalar Lisboa Norte ‐ Hospital de Santa Maria & Faculty of Medicine, University of Lisbon Lisbon Portugal Laboratory of Language Research Centro de Estudos Egas Moniz, Faculty of Medicine, University of Lisbon Lisbon Portugal Laboratory of Neurosciences Faculty of Medicine, University of Lisbon Lisbon Portugal Faculty of Medicine, University of Lisbon Lisbon Portugal Faculdade de Medicina, Universidade Católica Portuguesa Cognitive Disorders Unit, Department of Neurology Donostia University Hospital, San Sebastian, Gipuzkoa, Spain; Neuroscience Area, Biodonostia Health Research Insitute San Sebastian Gipuzkoa Spain Neuroscience Area, Biodonostia Health Research Insitute San Sebastian Gipuzkoa Spain OSATEK University of Donostia San Sebastian Gipuzkoa Spain CITA Alzheimer San Sebastian Gipuzkoa Spain Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Department of Educational Psychology and Psychobiology, Faculty of Education, International University of La Rioja Logroño Spain Department of Diagnostic and Interventional Neuroradiology University of Tübingen Tübingen Germany Department of Neurodegenerative Diseases Hertie‐Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; Center for Neurodegenerative Diseases DZNE Tübingen Germany Department of Neurodegenerative Diseases Hertie‐Institute for Clinical Brain Research and Center of Neurology, University of Tübingen Tübingen Germany Department of Human Genetics KU Leuven Leuven Belgium Geriatric Psychiatry Service, University Hospitals Leuven, Belgium; Neuropsychiatry, Department of Neurosciences KU Leuven Leuven Belgium Neurology Service, University Hospitals Leuven, Belgium; Laboratory for Neurobiology VIB‐KU Leuven Centre for Brain Research Leuven Belgium Department of Biomedical Sciences University of Antwerp, Antwerp, Belgium; Biomedical Research Institute, Hasselt University 3500 Hasselt Belgium Laboratory for Molecular Neurobiomarker Research KU Leuven Leuven Belgium Translational Neuroimaging Laboratory McGill Centre for Studies in Aging, McGill University Montreal Québec Canada Alzheimer Disease Research Unit, McGill Centre for Studies in Aging, Department of Neurology & Neurosurgery McGill University Montreal Québec Canada Sorbonne Université Paris Brain Institute ‐ Institut du Cerveau ‐ ICM, Inserm U1127, CNRS UMR 7225, AP‐HP ‐ Hôpital Pitié‐Salpêtrière, Reference Network for Rare Neurological Diseases ERN‐RND Paris France Sorbonne Université Paris Brain Institute ‐ Institut du Cerveau ‐ ICM, Inserm U1127, CNRS UMR 7225, AP‐HP ‐ Hôpital Pitié‐Salpêtrière, Paris, France; Inria, Aramis project‐team, F‐75013, Paris, France; Centre pour l'Acquisition et le Traitement des Images, Institut du Cerveau et la Moelle Paris France Centre de référence des démences rares ou précoces, IM2A, Département de Neurologie AP‐HP ‐ Hôpital Pitié‐Salpêtrière, Paris, France; Sorbonne Université, Paris Brain Institute ‐ Institut du Cerveau ‐ ICM, Inserm U1127, CNRS UMR 7225, AP‐HP ‐ Hôpital Pitié‐Salpêtrière Paris France Centre de référence des démences rares ou précoces, IM2A, Département de Neurologie AP‐HP ‐ Hôpital Pitié‐Salpêtrière, Paris, France; Sorbonne Université, Paris Brain Institute ‐ Institut du Cerveau ‐ ICM, Inserm U1127, CNRS UMR 7225, AP‐HP ‐ Hôpital Pitié‐Salpêtrière, Paris, France; Département de Neurologie, AP‐HP ‐ Hôpital Pitié‐Salpêtrière Paris France Sorbonne Université, Paris Brain Institute ‐ Institut du Cerveau ‐ ICM, Inserm U1127, CNRS UMR 7225, AP‐HP ‐ Hôpital Pitié‐Salpêtrière, Paris, France; Inria, Aramis project‐team, F‐75013, Paris, France; Centre de référence des démences rares ou précoces, IM2A, Département de Neurologie, AP‐HP ‐ Hôpital Pitié‐Salpêtrière Paris France Neurologische Klinik, Ludwig‐Maximilians‐Universität München Munich Germany Univ Lille, France; Inserm 1172, Lille, France; CHU, CNR‐MAJ, Labex Distalz, LiCEND Lille Lille France Inserm 1172, Lille, France; CHU, CNR‐MAJ, Labex Distalz, LiCEND Lille Lille France Neurology Department Centro Hospitalar e Universitario de Coimbra Coimbra Portugal Centre of Neurosciences and Cell Biology, Universidade de Coimbra Coimbra Portugal Instituto Ciencias Nucleares Aplicadas a Saude, Universidade de Coimbra Coimbra Portugal CorrespondenceLucy L. Russell, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. Email: l.russell@ucl.ac.uk 14 04 2024 0406 2024 16 2 10.1002/dad2.v16.2 e12571 15 02 2024 03 02 2023 17 02 2024 © 2024 the Alzheimer's Association. © 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association. 2024 © 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association. http://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Abstract INTRODUCTION

We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD).

 METHODS

Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD‐NM scale. This was assessed in 522 mutation carriers and 310 mutation‐negative controls from the Genetic Frontotemporal dementia Initiative (GENFI).

 RESULTS

The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales.

 DISCUSSION

Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely.

 Highlights

The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD‐NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS).

No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD‐NM rating scale.

Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains.

A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.

C9orf72 frontotemporal dementia genetics progranulin tau JPND GENFI‐PROX 2019‐02248 DLR/DFG 01ED2008B Alzheimer's Research UK ARUK‐CRF2017B‐2 Association for Frontotemporal Dementias Research 2009 Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659 EXC 2145 SyNergy – ID 390857198 DFG, German Research Foundation 01ED2008B European Reference Network for Rare Neurological Diseases (ERN‐RND) 739510 GENFI MR/M023664/1 Germany's Excellence Strategy 390857198 EXC 2145 Government of Canada, Canadian Institutes of Health Research 327387 MOP‐ 371851 PJT‐175242 Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 PI20/00448 Fundació Marató TV3  20143810 Italian Ministry of Health JPND Prefrontals 2015‐029262018‐02754 Karolinska Institutet, Doctoral Funding MRC UK GENFI MR/M023664/1 National Brain Appeal http://dx.doi.org/10.13039/100015873 RCN 290173 National Institute for Health Research (NIHR) BRC‐1215‐20014 National Institute for Health Research Queen Square Dementia, Biomedical Research Unit; NIHR Rare Disease Translational Research Collaboration BRC149/NS/MH The Wolfson Foundation UK Dementia Research Institute http://dx.doi.org/10.13039/501100017510 SM‐UCLO‐MA‐0519 UK Medical Research Council SUAG/051 G101400 University College London Hospitals Biomedical Research Centre http://dx.doi.org/10.13039/501100012317 Wellcome Trust http://dx.doi.org/10.13039/100010269 103838 National Institute for Health Research Cambridge Biomedical Research Centre Mady Browaeys Fund for Research into Frontotemporal Dementia Miriam Marks Brain Research UK Senior