Article Text

Original research
Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort
  1. Georgia Peakman1,
  2. Lucy L Russell1,
  3. Rhian S Convery1,
  4. Jennifer M Nicholas2,
  5. John C Van Swieten3,
  6. Lize C Jiskoot3,
  7. Fermin Moreno4,5,
  8. Raquel Sanchez-Valle6,
  9. Robert Laforce7,
  10. Caroline Graff8,9,
  11. Mario Masellis10,
  12. Maria Carmela Tartaglia11,
  13. James B Rowe12,
  14. Barbara Borroni13,
  15. Elizabeth Finger14,
  16. Matthis Synofzik15,16,
  17. Daniela Galimberti17,18,
  18. Rik Vandenberghe19,20,21,
  19. Alexandre de Mendonça22,
  20. Chris R Butler23,24,
  21. Alex Gerhard25,26,
  22. Simon Ducharme27,28,
  23. Isabelle Le Ber29,30,31,
  24. Fabrizio Tagliavini32,
  25. Isabel Santana33,34,
  26. Florence Pasquier35,36,37,
  27. Johannes Levin38,39,40,
  28. Adrian Danek38,
  29. Markus Otto41,
  30. Sandro Sorbi42,43,
  31. Jonathan D Rohrer1
  32. Genetic FTD Initiative (GENFI)
    1. 1Department of Neurodegenerative Disease, University College London Dementia Research Centre, London, UK
    2. 2Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK
    3. 3Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands
    4. 4Cognitive Disorders Unit, Department of Neurology, Hospital Universitario de Donostia, San Sebastian, Spain
    5. 5Neuroscience Area, Biodonostia Health Research Institute, Donostia-san Sebastian, Spain
    6. 6Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Institut d’Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain
    7. 7Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Laval University, Quebec, Quebec, Canada
    8. 8Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet, Stockholm, Sweden
    9. 9Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Stockholm, Sweden
    10. 10Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada
    11. 11Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
    12. 12Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
    13. 13Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
    14. 14Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada
    15. 15Dept. of Neurodegenerative Diseases, Eberhard Karls University Tubingen Hertie Institute for Clinical Brain Research, Tubingen, Germany
    16. 16Center for Neurodegenerative Diseases, DZNE, Tübingen, Germany
    17. 17Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
    18. 18Centro Dino Ferrari, University of Milan, Milan, Italy
    19. 19Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium
    20. 20Neurology Service, KU Leuven University Hospitals Leuven, Leuven, Belgium
    21. 21Leuven Brain Institute, KU Leuven, Leuven, Belgium
    22. 22Faculty of Medicine, University of Lisbon, Lisbon, Portugal
    23. 23Nuffield Department of Clinical Neurosciences, University of Oxford Medical Sciences Division, Oxford, UK
    24. 24Department of Brain Sciences, Imperial College London, London, UK
    25. 25Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, The University of Manchester, Manchester, UK
    26. 26Departments of Geriatric Medicine and Nuclear Medicine, University of Duisburg-Essen, Duisburg, Germany
    27. 27Department of Psychiatry, McGill University Health Centre, Montreal, Québec, Canada
    28. 28McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, Montreal, Québec, Canada
    29. 29Sorbonne Université, Paris Brain Institute – Institut du Cerveau – ICM, Inserm U1127, CNRS UMR 7225, Hôpital Universitaire Pitié Salpêtrière, Paris, France
    30. 30Centre de référence des démences rares ou précoces, IM2A, Département de Neurologie, Hôpital Universitaire Pitié Salpêtrière, Paris, France
    31. 31Départment de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France
    32. 32Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
    33. 33University Hospital of Coimbra (HUC), Neurology Service, University of Coimbra Faculty of Medicine, Coimbra, Portugal
    34. 34Center for Neuroscience and Cell Biology, University of Coimbra Faculty of Medicine, Coimbra, Portugal
    35. 35University of Lille, Lille, France
    36. 36CNR-MAJ, Labex Distalz, LiCEND Lille, CHU Lille, Lille, France
    37. 37Inserm 1172, Lille, France
    38. 38Department of Neurology, Ludwig-Maximilians-Universität München, Munchen, Germany
    39. 39German Center for Neurodegenerative Diseases, DZNE, Munich, Germany
    40. 40Munich Cluster of Systems Neurology (SyNergy), Munich, Germany
    41. 41Department of Neurology, University of Ulm, Ulm, Germany
    42. 42Department of Neurofarba, University of Florence, Firenze, Italy
    43. 43IRCCS Fondazione Don Carlo Gnocchi, Firenze, Italy
    1. Correspondence to Dr Jonathan D Rohrer, Department of Neurodegenerative Disease, University College London Dementia Research Centre, London, London, UK; j.rohrer{at}ucl.ac.uk

    Abstract

    Background Therapeutic trials are now underway in genetic forms of frontotemporal dementia (FTD) but clinical outcome measures are limited. The two most commonly used measures, the Clinical Dementia Rating (CDR)+National Alzheimer’s Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) and the FTD Rating Scale (FRS), have yet to be compared in detail in the genetic forms of FTD.

    Methods The CDR+NACC FTLD and FRS were assessed cross-sectionally in 725 consecutively recruited participants from the Genetic FTD Initiative: 457 mutation carriers (77 microtubule-associated protein tau (MAPT), 187 GRN, 193 C9orf72) and 268 family members without mutations (non-carrier control group). 231 mutation carriers (51 MAPT, 92 GRN, 88 C9orf72) and 145 non-carriers had available longitudinal data at a follow-up time point.

    Results Cross-sectionally, the mean FRS score was lower in all genetic groups compared with controls: GRN mutation carriers mean 83.4 (SD 27.0), MAPT mutation carriers 78.2 (28.8), C9orf72 mutation carriers 71.0 (34.0), controls 96.2 (7.7), p<0.001 for all comparisons, while the mean CDR+NACC FTLD Sum of Boxes was significantly higher in all genetic groups: GRN mutation carriers mean 2.6 (5.2), MAPT mutation carriers 3.2 (5.6), C9orf72 mutation carriers 4.2 (6.2), controls 0.2 (0.6), p<0.001 for all comparisons. Mean FRS score decreased and CDR+NACC FTLD Sum of Boxes increased with increasing disease severity within each individual genetic group. FRS and CDR+NACC FTLD Sum of Boxes scores were strongly negatively correlated across all mutation carriers (rs=−0.77, p<0.001) and within each genetic group (rs=−0.67 to −0.81, p<0.001 in each group). Nonetheless, discrepancies in disease staging were seen between the scales, and with each scale and clinician-judged symptomatic status. Longitudinally, annualised change in both FRS and CDR+NACC FTLD Sum of Boxes scores initially increased with disease severity level before decreasing in those with the most severe disease: controls −0.1 (6.0) for FRS, −0.1 (0.4) for CDR+NACC FTLD Sum of Boxes, asymptomatic mutation carriers −0.5 (8.2), 0.2 (0.9), prodromal disease −2.3 (9.9), 0.6 (2.7), mild disease −10.2 (18.6), 3.0 (4.1), moderate disease −9.6 (16.6), 4.4 (4.0), severe disease −2.7 (8.3), 1.7 (3.3). Sample sizes were calculated for a trial of prodromal mutation carriers: over 180 participants per arm would be needed to detect a moderate sized effect (30%) for both outcome measures, with sample sizes lower for the FRS.

    Conclusions Both the FRS and CDR+NACC FTLD measure disease severity in genetic FTD mutation carriers throughout the timeline of their disease, although the FRS may be preferable as an outcome measure. However, neither address a number of key symptoms in the FTD spectrum, for example, motor and neuropsychiatric deficits, which future scales will need to incorporate.

    • frontotemporal dementia

    Data availability statement

    Data are available on reasonable request. Anonymised participant data are held by GENFI and available upon reasonable request from JDR, j.rohrer@ucl.ac.uk.

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    Introduction

    Frontotemporal dementia (FTD) is a spectrum of heterogenous disorders characterised by neurodegeneration of the frontal and temporal lobes. A total of 20%–30% of FTD cases are genetic,1 2 with the majority caused by autosomal dominant mutations in three genes3: chromosome 9 open reading frame 72 (C9orf72),4 progranulin (GRN)5 and microtubule-associated protein tau (MAPT).6 Clinical syndromes span changes in behaviour (behavioural variant FTD, bvFTD),7 language (primary progressive aphasia, PPA)8 and motor function (progressive supranuclear palsy, PSP, corticobasal syndrome, CBS and FTD with amyotrophic lateral sclerosis, FTD-ALS).9–11 Age of symptom onset, and disease progression and duration vary between and within genetic groups.12

    The ability to accurately evaluate disease stage and track clinical change in FTD across the spectrum of phenotypes is critical for the design of future trials of disease-modifying therapies. Two candidate global severity measures specific to FTD are the Clinical Dementia Rating (CDR) Dementia Staging Instrument and the FTD Rating Scale (FRS). The CDR is a widely used scale that was developed to stage the severity of dementia in the Alzheimer’s Disease spectrum.13 14 Impairment in six cognitive and functional domains are assessed by a neurologist through semistructured interview with both the patient and caregiver. The CDR was extended for FTD by introducing a behaviour and a language domain, taken from the National Alzheimer’s Disease Coordinating Centre (NACC) Frontotemporal Lobar Degeneration (FTLD) module (CDR+NACC FTLD).15 16 A version of the global CDR scoring system17 (without the emphasis on the memory domain) has been developed to apply to the CDR+NACC FTLD, which classifies cases into five severity levels based on the number and severity of the ratings given for the eight domains.18 The CDR+NACC FTLD has shown ability to detect mild to severe symptoms in sporadic and genetic FTD cohorts15 16 18 19 and capture disease progression over 1–2 years.15 20 The FRS is a 30-item caregiver questionnaire developed with the aim of staging FTD severity based on behavioural changes and functional decline.21 The scale captures six levels of impairment from very mild to profound. Disease severity according to the FRS has been found to correlate with the CDR21 22 and CDR+NACC-FTLD,23 but a detailed evaluation of the measure across the range of presymptomatic and symptomatic FTD has not been reported.

    Few studies have directly compared the FRS and CDR+NACC FTLD staging tools, particularly in relation to the increasingly used CDR+NACC FTLD global scoring system. The objectives of this study were to: (1) evaluate and compare how the FRS and CDR+NACC FTLD scales characterise disease stage and severity in the spectrum of presymptomatic and symptomatic genetic FTD, using cross-sectional data from the Genetic FTD Initiative (GENFI) cohort; (2) examine and compare longitudinal change in the scales using data at 1-year follow-up and (3) estimate the sample sizes required to detect a small or moderate size effect on disease progression based on the two candidate outcome measures.

    Methods

    Cohort

    From the fifth data freeze of the GENFI study, 725 participants with both FRS and CDR+NACC FTLD data available for at least one time point were included in the study: 457 mutation carriers (77 MAPT, 187 GRN, 193 C9orf72) and 268 family members without mutations (non-carrier control group).

    Measures

    All participants underwent a standardised history and examination including the Mini-Mental State Examination (MMSE), with symptomatic status judged by the assessing clinician according to consensus diagnostic criteria.

    Frontotemporal dementia Rating Scale (FRS)

    The FRS is a 30-item questionnaire covering seven areas: behaviour, outing and shopping, household chores and telephone, finances, medications, meal preparation and eating, and self care and mobility. The FRS was completed by an informant (family member or caregiver) by rating the frequency of difficulties in these areas (‘all the time’, ‘sometimes’, ‘never’). Raw scores are converted to a percentage (total number of ‘never’ responses/total number of applicable questions) to exclude any items that were not applicable to the patient. Lower percentage scores therefore denote greater impairment of everyday abilities and behavioural change. In the original development of the scale, six severity stages were identified and operationalised in 75 patients with FTD (very mild, 100%–97%; mild, 96%–80%; moderate, 79%–41%; severe, 40%–13%; very severe, 12%–3%; profound, 2%–0%).21 One modification was made to these classifications for use in the GENFI cohort because the FRS is also collected on non-carrier family members: a score of 100% was considered ‘asymptomatic’ rather than ‘very mild’. The ‘very mild’ category in this study therefore encompasses scores of 97%–99% instead of 97%–100%.

    CDR+NACC-FTLD

    The eight domains of the CDR+NACC FTLD assess memory, orientation, judgement and problem solving, community affairs, home and hobbies, personal care, overall behaviour and overall language. Based on a semistructured interview with the patient and an informant, the presence of impairment in each of these domains is rated by a clinician using scores of 0 (absent), 0.5 (questionable/very mild), 1 (mild), 2 (moderate) and 3 (severe).15–17 The sum of boxes score (CDR+NACC-FTLD-SB) is calculated by summing the ratings given for the eight domains. Thus, a higher sum of boxes value denotes greater symptomatology. The CDR+NACC FTLD global rating was determined using the published scoring rules,18 whereby a rating on a five-point scale is given (0, 0.5, 1, 2, 3) based on the severity of the ratings given for the eight domains. All eight domains are given equal weighting when calculating the global score, so it does not relate to a specific FTD variant, and if any domain has a rating above 0 then the global score is at least 0.5. Therefore, cases with no impairment in any domain are given a global rating of 0, those with mild cognitive, behavioural or language impairment are rated 0.5, those with mild but definite symptomology are intended to receive a rating of 1, those with moderate dementia 2 and severe dementia 3. Global ratings can be reduced into three broader disease severity levels: normal or asymptomatic (0), very mild or prodromal cognitive, behavioural or language impairment (0.5) and fully symptomatic (≥1).18

    Statistical analysis

    Descriptive statistics and group comparisons

    Data were analysed using SPSS V.26 or STATA V.16. Demographic variables were compared between groups using independent sample t-tests or Mann-Whitney U tests when n<30. Sex was compared between groups using χ2 tests. A linear regression model was used to compare both FRS and CDR+NACC-FTLD-SB scores between groups; bootstrapping with 1000 repetitions was used for data that were not normally distributed. Correlations between FRS percentage score and CDR+NACC FTLD Sum of Boxes scores were generated using Spearman rank correlation coefficients (two-tailed), as were correlations of both scales with disease duration (years since clinician-judged symptom onset – analysis restricted to symptomatic participants) and MMSE score.

    Longitudinal analyses

    Of the baseline sample, 231 mutation carriers (51 MAPT, 92 GRN, 88 C9orf72) and 145 non-carriers had FRS and CDR+NACC FTLD data available at a follow-up time point. Mean time between baseline and follow-up was 1.3 years (SD=0.5). For both scales, annualised change was calculated as: [follow-up score] - [baseline score]/time between baseline and follow-up. Annualised change was compared between the mutation carrier group and controls using a linear regression model; bootstrapping with 1000 repetitions was used for data that were not normally distributed.

    Sample size calculation

    To explore the use of the FRS and CDR+NACC-FTLD-SB scores as potential outcome measures in treatment trials, sample sizes per arm of a two-arm trial of a disease modifying therapy (with 1:1 randomisation to placebo vs active treatment) were calculated using an analysis of covariance method. The analysis focused on mutation carriers with a baseline CDR+NACC FTLD global rating of 0.5 (ie, a prodromal trial), with the desired treatment effect hypothesised as a reduction in progression from the mean score of the outcome measure in the global 0.5 CDR+NACC FTLD group to the mean score of the outcome measure in the global 1 CDR+NACC FTLD group, that is, slowing of progression from prodromal to fully symptomatic. The following formula was used:

    ρ is the correlation between baseline and follow-up scores of the outcome measure in mutation carriers, σ is the SD of scores at follow-up, δ is the treatment effect (difference in mean score between the prodromal (0.5) group and mild symptomatic (1) group), α is the significance level, set at 0.05. and 1- β is the power to detect a treatment effect, set at β=0.2 ie,that is, power 80%.

    Results

    Demographics

    The demographic and clinical characteristics of the participants in each genetic group at their baseline time point are summarised in table 1. The groups shared similar demographic profiles, except that the MAPT mutation carriers and the controls were younger than the C9orf72 mutation carriers (MAPT t=−3.207, p=0.002; controls t=−4.030, p<0.001) and GRN mutation carriers (MAPT t=−2.875, p=0.004; controls t=−3.501, p=0.001).

    Table 1

    Baseline demographic and clinical characteristics of study cohort by genetic group

    Defining disease severity in the mutation carriers by CDR+NACC FTLD global rating, 54.3% were asymptomatic (CDR+NACC FTLD global=0), 15.3% had a prodromal phenotype (0.5) and 30.4% had a symptomatic phenotype (≥1).

    Cross-sectional change in the FRS and CDR+NACC-FTLD

    Comparison of both FRS and CDR+NACC-FTLD-SB between groups

    The mean FRS% score in all genetic groups was lower than controls (p<0.001 for all comparisons): GRN mutation carriers mean 83.4 (SD 27.0), MAPT mutation carriers 78.2 (28.8), C9orf72 mutation carriers 71.0 (34.0), controls 96.2 (7.7) (table 1 and online supplemental table 1). There was also a significant difference between the C9orf72 group and both the GRN group (p<0.001) and the MAPT group (p=0.032).

    Supplemental material

    The mean CDR+NACC-FTLD-SB score was higher in all genetic groups compared with controls (all p<0.001): GRN mutation carriers mean 2.6 (5.2), MAPT mutation carriers 3.2 (5.6), C9orf72 mutation carriers 4.2 (6.2), controls 0.2 (0.6) (table 1, online supplemental table 2). A significant difference was seen between the C9orf72 and GRN groups (p=0.001).

    Comparison of both FRS and CDR+NACC-FTLD-SB within genetic groups by disease severity

    Mean scores on the FRS according to CDR+NACC FTLD severity level (0, 0.5, ≥1) for each genetic group are reported in table 2, and according to individual CDR+NACC FTLD global rating (0–3) are presented in figure 1. GRN, MAPT and C9orf72 mutation carriers with a global rating of 0 had comparable FRS scores to controls (online supplemental table 3). Within both the GRN and C9orf72 mutation carriers, the mean FRS score was significantly lower in cases with a global rating of 0.5 compared with those with 0. Within every genetic group, the cases with a global rating of ≥1 had significantly lower FRS scores than those with 0 or 0.5.

    Figure 1

    Mean FRS percentage score according to CDR+NACC FTLD global rating in mutation carriers at baseline. Error bars represent SE of the mean. CDR+NACC FTLD global ratings: GRN 0, N=114; 0.5, N=25; 1, N=19; 2, N=15; 3, N=14; MAPT 0, N=42; 0.5, N=13; 1, N=7; 2, N=8; 3, N=7; C9orf72 0, N=92; 0.5, N=32; 1, N=18; 2, N=26; 3, N=25. CDR, Clinical Dementia Rating; FRS, Frontotemporal dementia Rating Scale; NACC, National Alzheimer’s Disease Coordinating Center.

    Table 2

    Baseline FRS scores according to CDR+NACC FTLD severity level, by genetic group

    For comparison, mean CDR+NACC-FTLD-SB scores according to severity level for each genetic group are also reported in table 2. The mean CDR+NACC-FTLD-SB scores were higher in those with a global rating of 0.5 and ≥1 than either controls or those with a global rating of 0 in all three genetic groups (online supplemental table 4).

    Correlation of FRS and CDR+NACC-FTLD-SB

    In the mutation carriers as a whole, FRS and CDR+NACC-FTLD-SB scores were strongly negatively correlated (rs=−0.77, p<0.001) (figure 2). Similar associations were found in the individual genetic groups: GRN mutation carriers (rs=−0.75, p<0.001); MAPT mutation carriers (rs=−0.67, p<0.001); C9orf72 mutation carriers (rs=−0.81, p<0.001) (online supplemental figure 1).

    Figure 2

    Scatter plot of FRS percentage scores and CDR+NACC FTLD sum of boxes scores in all mutation carriers at baseline. CDR, Clinical Dementia Rating; FRS, Frontotemporal dementia Rating Scale; NACC, National Alzheimer’s Disease Coordinating Center.

    Comparison of FRS and CDR+NACC-FTLD-SB by severity categories

    The percentage of mutation carriers in each FRS severity category according to their CDR+NACC FTLD global rating, and vice versa, are shown in figure 3 (and individually for GRN, MAPT and C9orf72 mutation carriers in online supplemental figure 2). Mutation carriers who had an FRS score in the ‘asymptomatic’ range most frequently had a global rating of 0 (84.0%); cases in the ‘very mild’ FRS category also predominantly had a global rating of 0 (78.8%); the ‘mild’ category encompassed cases with mostly global ratings of 0 (62.4%) or 0.5 (26.7%); the ‘moderate’ category covered cases with global ratings of 0 (20.0%), 0.5 (15.0%), 1 (40.0%) and 2 (23.3%); the ‘severe’ category mostly included ratings of 2 (41.3%) or 3 (44.4%); the ‘very severe’ category encompassed ratings of largely 3 (69.6%) as well as 2 (26.1%); and of the two participants who had an FRS score in the ‘profound’ range, one had a global rating of 2 (50%) and the other 3 (50%).

    Figure 3

    Bar graph and Sankey diagram presenting proportions of participants in each FRS severity category according to CDR+NACC FTLD global rating, in all mutation carriers at baseline. CDR+NACC FTLD global rating 0, N=248; 0.5, N=70; 1, N=44; 2, N=49; 3, N=46. CDR, Clinical Dementia Rating; FRS, Frontotemporal dementia Rating Scale; NACC, National Alzheimer’s Disease Coordinating Center.

    Frequency and severity of individual CDR+NACC-FTLD domains within each FRS severity category

    The frequency of abnormal ratings (≥0.5) on the individual domains of the CDR+NACC FTLD within each FRS severity level are shown in figure 4A for mutation carriers and controls, and for the individual genetic groups in online supplemental figure 3A. Memory was the most commonly affected domain in the asymptomatic, very mild and mild FRS severity levels in both non-carriers and carriers.

    Figure 4

    (A) Frequencies of CDR+NACC FTLD domains affected (rating ≥0.5) within each FRS severity category, in mutation carriers and non-carrier controls at baseline. FRS severity categories: controls: asymptomatic, N=165; very mild, N=29; mild, N=63; moderate, N=11; severe, N=0; very severe, N=0; profound, N=0; mutation carriers: asymptomatic, N=175; very mild, N=33; mild, N=101; moderate, N=60; severe, N=63; very severe, N=23; profound, N=2. Note that very severe and profound groups were combined for the mutation carriers due to limited cases in the profound group. (B) Mean scores on CDR+NACC FTLD domains within each FRS severity category, in mutation carriers and in non-carrier controls at baseline. Error bars represent SE of the mean. domains are rated using scores of 0 (absent), 0.5 (questionable/very mild), 1 (mild), 2 (moderate) and 3 (severe). CDR, Clinical Dementia Rating; FRS, Frontotemporal dementia Rating Scale; NACC, National Alzheimer’s Disease Coordinating Center.

    The mean ratings for the CDR+NACC FTLD domains (ie, the severity) in each of the FRS levels are shown in figure 4B for mutation carriers and controls, and for the individual genetic groups in online supplemental figure 3B. Comparing the mean domain score of mutation carriers at each FRS stage against the mean score in controls for that domain: in the asymptomatic and very mild FRS stages, none of the domains were different from controls; in the mild stage, the memory (p=0.009), community affairs (p=0.040) and behaviour (p=0.002) domains had higher ratings than controls; and in the moderate, severe and very severe/profound FRS stages, all of the CDR+NACC FTLD domains had more severe ratings than controls.

    Correlation of both FRS and CDR+NACC-FTLD-SB with other measures of disease severity

    The FRS score was moderately negatively correlated with disease duration in symptomatic participants except in C9orf72 mutation carriers (all symptomatic participants rs=−0.383, p<0.001; GRN rs=−0.541, p<0.001; MAPT rs=−0.525, p=0.008; C9orf72 rs=−0.201, p=0.078), and positively correlated with MMSE score (all mutation carriers rs=0.614, p<0.001; GRN rs=0.654, p<0.001; MAPT rs=0.623, p<0.001; C9orf72 rs=0.558, p<0.001).

    The CDR+NACC-FTLD-SB score was also moderately positively correlated with increased disease duration in symptomatic participants (all symptomatic participants rs=0.426, p<0.001; GRN rs=0.518, p<0.001; MAPT rs=0.529, p=0.008; C9orf72 rs=0.330, p=0.003), and negatively correlated with MMSE score (all mutation carriers rs=−0.646, p<0.001; GRN rs=−0.638, p<0.001; MAPT rs=−0.685, p<0.001; C9orf72 rs=−0.618, p<0.001).

    Comparison of both FRS and CDR+NACC-FTLD-SB with clinician judgment of diagnosis

    The number of participants judged to be symptomatic by clinicians was 152: 103 bvFTD7 (27 GRN, 21 MAPT, 55 C9orf72), 24 PPA8 (20 GRN, 1 MAPT, 3 C9orf72), 16 ALS or FTD-ALS24 (all C9orf72), 4 with parkinsonian disorders10 11 (2 GRN, 1 MAPT, 1 C9orf72), and five diagnosed with a dementia not otherwise specified (1 GRN, 1 MAPT, 3 C9orf72).

    The distributions of these diagnoses across the FRS severity categories and CDR+NACC FTLD global rating groups are shown in online supplemental table 5. Both rating scales classified four participants who had been judged as symptomatic within the lowest severity category (asymptomatic for FRS: 2 bvFTD, 1 PPA, 1 ALS/FTD-ALS; 0 for CDR+NACC-FTLD: 1 bvFTD, 2 ALS/FTD-ALS, 1 with a parkinsonian disorder). With increasing FRS severity and CDR+NACC FTLD global rating, an increasingly larger number of participants were judged to be symptomatic: by FRS severity – very mild 6.5%, mild 9.8%, moderate 60.6%, severe 95.2%, very severe/profound 100.0%; by CDR+NACC FTLD global rating – 0.5 16.2%, 1 70.0%, 2 98.0%, 3 100.0%.

    Longitudinal change in the FRS and CDR+NACC-FTLD

    Annualised change on the FRS and CDR+NACC-FTLD-SB in controls and according to baseline CDR+NACC FTLD severity level in mutation carriers are reported in table 3 and online supplemental table 6 and shown in figure 5. Annualised change in FRS and CDR+NACC-FTLD-SB scores initially increased with global severity level and was greatest in carriers with symptomatic baseline global ratings of 1 or 2 before decreasing in cases with a global rating of 3. Mutation carriers with global ratings of 1 or 2 were the only groups to show change on the FRS over 1 year that significantly exceeded controls (p=0.011 and 0.005, respectively). On the CDR+NACC FTLD, annualised change in the Sum of Boxes score exceeded controls in each of the global severity levels except in the 0.5 group (0 group vs controls, p=0.001, 0.5 group vs controls, p=0.202, 1 group vs controls, p=0.001, 2 group vs controls (p<0.001, 3 group vs controls, p=0.033).

    Table 3

    Annualised change in FRS percentage and CDR+NACC FTLD sum of boxes scores in mutation carriers according to baseline CDR+NACC FTLD global rating, and non-carrier controls

    Figure 5

    Annualised change in FRS percentage score and CDR+NACC FTLD sum of boxes score in mutation carriers according to baseline CDR+NACC FTLD global rating and controls. Baseline values=mean score, follow-up values=(baseline mean score)+(mean annualised change in score). Controls N=145; carriers N=232 (baseline CDR+NACC FTLD global 0, N=140; 0.5, N=30; 1, N=22; 2, N=23; 3, N=16). CDR, Clinical Dementia Rating; FRS, Frontotemporal dementia Rating Scale; NACC, National Alzheimer’s Disease Coordinating Center.

    Sample size calculations

    Table 4 shows the number of participants required to demonstrate efficacy on change in FRS percentage score and CDR+NACC FTLD Sum of Boxes score as potential outcome measures when assuming small (10%) to moderate (30%) effect sizes. For a trial entering prodromal mutation carriers (with a global rating of 0.5), over 180 participants per arm would be needed to detect a moderate sized effect (30%) for both outcome measures. Power calculations using the FRS yielded projected sample sizes that were more favourable than the CDR+NACC FTLD Sum of Boxes.

    Table 4

    Sample sizes for small to moderate effect sizes on progression in mean FRS percentage score and mean CDR+NACC FTLD Sum of Boxes score, in mutation carriers with a global rating of 0.5

    As the treatment effect is based on preventing progression from global CDR+NACC FTLD 0.5–1, the length of the trial depends on the natural history of this progression. A survival analysis in the GENFI cohort previously showed that ~50% of mutation carriers progress from a global rating of 0.5–1 in 3 years (Poos et al in submission). Against this background, a 6-year trial of prodromal mutation carriers would therefore be required to detect the proposed treatment effect (eg, for a 30% effect on FRS, N=181), or a 3-year trial of the same treatment would require the sample size equivalent to assuming half the percentage change in the target value (eg, if there was a 30% effect on FRS, as only 50% of people will have progressed, the sample size would be equivalent to a 15% effect on FRS that is, N=725).

    Discussion

    This study has systematically evaluated and compared disease staging and progression defined by the FRS against the widely used CDR+NACC FTLD scale in a large cohort covering the spectrum of genetic FTD. Scores on both scales are strongly related to disease severity in FTD, and in GRN, C9orf72 and MAPT mutation carriers, FRS scores decreased with progression while CDR+NACC-FTLD-SB increased. In direct comparison, both scores were strongly correlated with each other in all three genetic groups.

    However, disease staging and severity were not entirely consistent between the two scales. Analysis indicated that the FRS might capture more subtle changes associated with disease progression. A notable proportion of cases were asymptomatic according to the CDR+NACC FTLD (zero cognitive, behavioural or language impairments recorded) despite a mild or moderate degree of functional and/or behavioural change being reported via the FRS questionnaire. Vice versa, a number of cases with a global rating of 0.5, or in a small number a rating of 1, scored 100% on the FRS (indicating zero behavioural or functional changes). In line with previous studies,22 23 our data suggest that the CDR+NACC FTLD may be more likely to underestimate disease severity when compared with FRS scores: 41% of cases with an asymptomatic CDR+NACC FTLD global rating had a degree of disability or behavioural change according to the FRS, vs 16% of cases with an asymptomatic FRS score having some symptomatology according to the CDR+NACC FTLD. Although the scales both broadly centre around everyday functioning and behaviour, there are differences between them e.g. the CDR+NACC FTLD evaluates language impairment, which the FRS lacks, but conversely, the CDR+NACC FTLD may not as comprehensively capture other changes apparent to the caregiver, for example, behaviour is captured as a single domain in the CDR+NACC FTLD which may underestimate social and personality impairments that rely on subjective report and are difficult to operationalise. Another consideration is that several of the activities of daily living probed by the FRS have the potential to be affected by apathy or depression (four items begin with ‘Lacks interest in… (activity)’), which are symptoms less relevant to the domains of the CDR+NACC FTLD. Whether depressive symptoms are directly related to evolving FTD pathology or are distinct and related to the impact of living at-risk of FTD is challenging to disentangle. Responses to the individual items of the FRS questionnaire were not available in the GENFI cohort to enable exploring trends among the cases with discrepant FRS and CDR+NACC FTLD scores, but this is a consideration for future studies of the scales.

    There were also discrepancies seen between both scales and symptomatic status, with a small number of participants being judged to be symptomatic by clinicians despite an asymptomatic or very mild score on the two scales. This may relate at least in part to a further issue with both scales, which is the lack of an assessment for motor or neuropsychiatric symptoms. Parkinsonian symptoms are seen across all of the genetic forms of FTD,25 while ALS is seen mainly in those with C9orf72 mutations. Such motor deficits are associated with disease progression,26 and impact on function in genetic FTD but are poorly captured by the FRS27 and not measured at all in the CDR+NACC FTLD. In this cohort, half of the participants diagnosed with ALS/FTD-ALS were in the asymptomatic, very mild or mild FRS severity categories or had asymptomatic (0) or very mild (0.5) CDR+NACC FTLD global ratings. Similarly, neuropsychiatric symptoms are also prevalent across the different forms of genetic FTD,28 29 particularly in carriers of the C9orf72 expansion where they can be a defining feature.30 31 Neither of the scales directly measure these features (ie, hallucinations, delusions, etc) and therefore are likely to be underestimating any effect of such symptoms on function and disease progression. Overall, given the heterogeneity in clinical presentation and disease course within people that share the same underlying genetic cause,12 the inclusion of assessments of motor and neuropsychiatric symptomatology into clinical rating scales will be important for achieving accurate evaluation of disease stage. In turn, this will allow the full spectrum of FTD phenotypes to be included within the same clinical trial.

    To evaluate the scale’s abilities to track progression, annualised change was analysed in the cases with a follow-up time point, stratified by global impairment at baseline according to the CDR+NACC FTLD. On both scales, change over 1 year is small in the prodromal stages and then accelerates in carriers with a global rating considered to be symptomatic. Previous studies have reported significant changes in CDR+NACC FTLD scores over 115 and 2 years20 in patients with FTD. We found that annualised change also accelerated moving from an asymptomatic global rating to a very mild 0.5 rating, and moving from 0.5 to 1. Our data align with previous findings that the FRS is able to detect deterioration over 1 year in symptomatic patients,21 and show that this is the case particularly in those with ‘mild’ and ‘moderate’ FTD defined by the CDR+NACC FTLD global score.

    Lastly, we estimated the sample sizes required to achieve at least 80% power to detect small to moderate sized effects of a disease-modifying therapy on change in the two scales as outcome measures. The sample sizes generated for both scales, even with a moderate (30%) treatment effect, suggest that a trial entering mutation carriers at a prodromal starting point (of CDR+NACC FTLD global rating 0.5) in an unselective way (ie, that does not further distinguish cases that are likely to soon progress) will require large numbers (with even greater numbers being required if randomisation was unequal rather than 1:1) and several years. The period in close proximity to phenoconversion is a useful target period for disease-modifying therapies, but for such a trial to require achievable sample sizes, this study suggests that better stratification will be needed, potentially combining clinical stage with neuroanatomical and/or fluid biomarkers to accurately identify likely converters. For example, a study involving GENFI and another genetic FTD cohort has recently shown that mutation carriers whose score worsens on the CDR+NACC FTLD over the next 1–2 years have high plasma neurofilament light chain concentrations at baseline compared with non-converters.32

    Limitations

    By including a large number of mutation carriers at varied proximities to symptom onset, this study was able to evaluate the utility of disease staging tools across the spectrum of genetic FTD. However, the study cohort at baseline contains a larger proportion of asymptomatic than symptomatic carriers, and once stratified, individual group numbers were smaller. We took a transdiagnostic approach to the study, incorporating all phenotypes in the analysis. We, therefore, did not establish whether the scales were better at evaluating one phenotype over the other, although this is difficult as our study contained mainly people with a bvFTD phenotype (as is the case for genetic FTD), and few with PPA or FTD-ALS.27 We were also not able to directly assess the ability of the scales to specifically measure the presence of prodromal symptoms as we did not have another marker of this stage, for example, clinician judgment. As discussed above, it may be that both scales (but particularly the CDR+NACC FTLD) are not sensitive enough to adequately capture this stage, and further studies should try to address this point.

    Conclusions

    Global rating scales such as the CDR+NACC FTLD and FRS serve a helpful purpose in clinical trials in providing a single score that can condense clinical judgement about disease severity. Although the CDR+NACC FTLD has become the most prominent clinical rating scale in FTD, there are potential issues with its use in clinical trials. In this study we show that there are similarities to the FRS as well as differences, and highlight the potential benefits for using the FRS both in clinical stratification and as an outcome measure in prevention trials of genetic FTD mutation carriers. However, both measures do not fully capture the entire spectrum of FTD symptomatology, and future improvements to the scales should consider the inclusion of motor and neuropsychiatric deficits.

    Data availability statement

    Data are available on reasonable request. Anonymised participant data are held by GENFI and available upon reasonable request from JDR, j.rohrer@ucl.ac.uk.

    Ethics statements

    Ethics approval

    The study procedures were approved by local ethics committees at each of the participating sites and participants provided informed written consent.

    Acknowledgments

    We thank the GENFI research participants for their contribution to the study.

    References

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Twitter @georgia_peakman, @sducharme66

    • Collaborators Genetic FTD Initiative (GENFI): Sónia Afonso, Instituto Ciencias Nucleares Aplicadas a Saude, Universidade de Coimbra, Coimbra, Portugal; Maria Rosario Almeida, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Sarah Anderl-Straub, Department of Neurology, University of Ulm, Ulm, Germany; Christin Andersson, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Anna Antonell, Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; Silvana Archetti, Biotechnology Laboratory, Department of Diagnostics, ASST Brescia Hospital, Brescia, Italy; Andrea Arighi, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; Mircea Balasa, Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; Myriam Barandiaran, Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain; Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Nuria Bargalló, Imaging Diagnostic Center, Hospital Clínic, Barcelona, Spain; 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; Benjamin Bender, Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany; Alberto Benussi, Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Italy; Maxime Bertoux, Inserm 1172, Lille, France; CHU, CNR-MAJ, Labex Distalz, LiCEND Lille, France; Anne Bertrand, 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 Valentina Bessi, Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy; Sandra Black, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada; Martina Bocchetta, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Sergi Borrego-Ecija, Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; Jose Bras, Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan, MI 49503, USA; Alexis Brice, Sorbonne Université, Paris Brain Institute, Institut du Cerveau, ICM, Inserm U1127, CNRS UMR 7225, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France; Reference Network for Rare Neurological Diseases (ERN-RND); Rose Bruffaerts, Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium; Agnès Camuzat, Sorbonne Université, Paris Brain Institute, Institut du Cerveau, ICM, Inserm U1127, CNRS UMR 7225, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France; Marta Cañada, CITA Alzheimer, San Sebastian, Gipuzkoa, Spain Valentina Cantoni, Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy; Paola Caroppo, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; David Cash, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Miguel Castelo-Branco, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Olivier Colliot, 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; Thomas Cope, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK; Vincent Deramecourt, Univ Lille, France; Inserm 1172, Lille, France; CHU, CNR-MAJ, Labex Distalz, LiCEND Lille, France; María de Arriba, Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Giuseppe Di Fede, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Alina Díez, Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Diana Duro, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Chiara Fenoglio, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; Camilla Ferrari, Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy; Catarina B. Ferreira -Laboratory of Neurosciences, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Nick Fox, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Morris Freedman, Baycrest Health Sciences, Rotman Research Institute, University of Toronto, Toronto, Canada; Giorgio Fumagalli, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; Aurélie Funkiewiez, 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; Alazne Gabilondo -Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Roberto Gasparotti, Neuroradiology Unit, University of Brescia, Brescia, Italy; Serge Gauthier, Alzheimer Disease Research Unit, McGill Centre for Studies in Aging, Department of Neurology & Neurosurgery, McGill University, Montreal, Québec, Canada; Stefano Gazzina, Neurology, ASST Brescia Hospital, Brescia, Italy Giorgio Giaccone, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Ana Gorostidi, Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Caroline Greaves, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Rita Guerreiro, Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan, MI 49503, USA; Carolin Heller, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Tobias Hoegen, Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; Begoña Indakoetxea, Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain; Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Vesna Jelic, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden; Hans-Otto Karnath, Division of Neuropsychology, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; Ron Keren -The University Health Network, Toronto Rehabilitation Institute, Toronto, Canada; Gregory Kuchcinski, Univ Lille, France; Inserm 1172, Lille, France; CHU, CNR-MAJ, Labex Distalz, LiCEND Lille, France; 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; Thibaud Lebouvier, Univ Lille, France; Inserm 1172, Lille, France; CHU, CNR-MAJ, Labex Distalz, LiCEND Lille, France; Maria João Leitão, Centre of Neurosciences and Cell Biology, Universidade de Coimbra, Coimbra, Portugal; Albert Lladó, Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; Gemma Lombardi, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; Sandra Loosli -Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; Carolina Maruta, Laboratory of Language Research, Centro de Estudos Egas Moniz, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Simon Mead, MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Lieke Meeter, Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands; Gabriel Miltenberger, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Rick van Minkelen, Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands; Sara Mitchell, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada; Katrina Moore, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London UK; Benedetta Nacmias, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; Annabel Nelson, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; 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; Jaume Olives, Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; Sebastien Ourselin, School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK; Alessandro Padovani, Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Italy Jessica Panman, Department of Neurology, Erasmus Medical Center, Rotterdam, Netherlands; Janne M. Papma, Department of Neurology, Erasmus Medical Center, Rotterdam; Yolande Pijnenburg, Amsterdam University Medical Centre, Amsterdam VUmc, Amsterdam, Netherlands; Cristina Polito, Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, Nuclear Medicine Unit, University of Florence, Florence, Italy Enrico Premi, Stroke Unit, ASST Brescia Hospital, Brescia, Italy Sara Prioni, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Catharina Prix -Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; Rosa Rademakers [as London Ontario geneticist], Department of Neurosciences, Mayo Clinic, Jacksonville, Florida, USA; Veronica Redaelli -Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Daisy Rinaldi, 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; Reference Network for Rare Neurological Diseases (ERN-RND); Tim Rittman, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Ekaterina Rogaeva -Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; Adeline Rollin, CHU, CNR-MAJ, Labex Distalz, LiCEND Lille, France; Pedro Rosa-Neto -Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, McGill University, Montreal, Québec, Canada; Giacomina Rossi, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Martin Rossor, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Beatriz Santiago, Neurology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; Dario Saracino, 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; Sabrina Sayah, Sorbonne Université, Paris Brain Institute, Institut du Cerveau, ICM, Inserm U1127, CNRS UMR 7225, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France; Elio Scarpini, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; Sonja Schönecker, Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; Harro Seelaar, Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands; Elisa Semler -Department of Neurology, University of Ulm, Ulm; Rachelle Shafei, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Christen Shoesmith, Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada; Imogen Swift, Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Miguel Tábuas-Pereira, Neurology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; Mikel Tainta, Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Ricardo Taipa, Neuropathology Unit and Department of Neurology, Centro Hospitalar do Porto, Hospital de Santo António, Oporto, Portugal; David Tang-Wai -The University Health Network, Krembil Research Institute, Toronto, Canada; David L Thomas, Neuroimaging Analysis Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, UK; Paul Thompson, Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK; Hakan Thonberg, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden; Carolyn Timberlake, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Pietro Tiraboschi, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Emily Todd, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, UK; Philip Van Damme, Neurology Service, University Hospitals Leuven, Belgium; Laboratory for Neurobiology, VIB-KU Leuven Centre for Brain Research, Leuven, Belgium; Mathieu Vandenbulcke, Geriatric Psychiatry Service, University Hospitals Leuven, Belgium; Neuropsychiatry, Department of Neurosciences, KU Leuven, Leuven, Belgium; Michele Veldsman, Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK; Ana Verdelho, Department of Neurosciences and Mental Health, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria & Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Jorge Villanua, OSATEK, University of Donostia, San Sebastian, Gipuzkoa, Spain; Jason Warren, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Carlo Wilke, 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; Ione Woollacott, Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Elisabeth Wlasich, Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; Henrik Zetterberg, Dementia Research Institute, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Miren Zulaica, Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain.

    • Contributors GP and JDR contributed to the study design, acquisition, analysis and interpretation of the data as well as drafting and revising the manuscript. All other authors (LLR, RC, JMN, JCVS, LCJ, FM, RS-V, RJL, CG, MM, MCT, JBR, BB, EF, MS, DG, RV, AdM, CRB, AG, SD, ILB, FT, IS, FP, JL, AD, MO and SS) contributed to the acquisition of data and study coordination as well as helping to critically review and revise the manuscript.

    • Funding 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 NIHR UCL/H 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, 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). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project and the JPND 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.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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