# Neuropsychiatric symptoms in genetic frontotemporal dementia: developing a new module for Clinical Rating Scales

Kiran Samra, Amy Macdougall, Georgia Peakman, Arabella Bouzigues, Martina Bocchetta, David M Cash, Caroline V Greaves, Rhian S Convery, John C van Swieten, Lize C Jiskoot, et al.

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## ► To cite this version:

Kiran Samra, Amy Macdougall, Georgia Peakman, Arabella Bouzigues, Martina Bocchetta, et al. Neuropsychiatric symptoms in genetic frontotemporal dementia: developing a new module for Clinical Rating Scales. Journal of Neurology, Neurosurgery and Psychiatry, 2023, 94 (5), pp.357-368. 10.1136/jnnp-2022-330152. [https://doi.org/10.1136/jnnp-2022-330152](https://doi.org/10.1136/jnnp-2022-330152)

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OPEN ACCESS

Original research

# Neuropsychiatric symptoms in genetic frontotemporal dementia: developing a new module for Clinical Rating Scales

Kiran Samra,¹ Amy Macdougall,² Georgia Peakman,¹ Arabella Bouziges,¹ Martina Bocchetta,¹ David M Cash,¹,³ Caroline V Greaves,¹ Rhian S Convery,¹ John C van Swieten,⁴ Lize C Jiskoot,⁴ Harro Seelaar,⁵ Fermin Moreno,⁶ Raquel Sánchez-Valle,⁷ Robert Laforce,⁸ Caroline Graff,⁹,¹⁰ Mario Masellis,¹¹ Maria Carmela Tartaglia,¹² James B Rowe,¹³ Barbara Borroni,¹⁴ Elizabeth Finger,¹⁵ Matthis Synofzik,¹⁶ Daniela Galimberti,¹⁷ Rik Vandenberghe,¹⁸,¹⁹ Alexandre de Mendonca,²⁰ Christopher R Butler,²¹,²² Alexander Gerhard,²³,²⁴ Simon Ducharme,²⁵,²⁶ Isabelle Le Ber,²⁷,²⁸ Pietro Tiraboschi,²⁹ Isabel Santana,³⁰,³¹ Florence Pasquier,³²,³³ Johannes Levin,³⁴,³⁵ Markus Otto,³⁶ Sandro Sorbi,³⁷,³⁸ Jonathan D Rohrer,¹ Lucy L Russell,¹ On behalf of the Genetic FTD Initiative (GENFI)

► Additional supplemental material is published online only. To view, please visit the journal online (http://dx.doi.org/10.1136/jnnp-2022-330152).

For numbered affiliations see end of article.

**Correspondence to**
Ms Lucy L Russell, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; l.russell@ucl.ac.uk

Received 12 August 2022
Accepted 5 December 2022
Published Online First 10
January 2023

<figure><img src="image_2.png" /></figure>

Check for updates

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.

**To cite:** Samra K, Macdougall A, Peakman G, et al. J Neurol Neurosurg Psychiatry 2023;94:357–368.

## ABSTRACT

**Background** Current clinical rating scales in frontotemporal dementia (FTD) often do not incorporate neuropsychiatric features and may therefore inadequately measure disease stage.

**Methods** 832 participants from the Genetic FTD Initiative (GENFI) were recruited: 522 mutation carriers and 310 mutation-negative controls. The standardised GENFI clinical questionnaire assessed the frequency and severity of 14 neuropsychiatric symptoms: visual, auditory, and tactile hallucinations, delusions, depression, anxiety, irritability/lability, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality, hyperreligiosity, impaired sleep, and altered sense of humour. A principal component analysis (PCA) was performed to identify key groupings of neuropsychiatric and behavioural items in order to create a new neuropsychiatric module that could be used as an addition to the Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center Behaviour and Language Domains (NACC FTLD) rating scale.

**Results** Overall, 46.4% of mutation carriers had neuropsychiatric symptoms (51.6% C9orf72, 40.8% GRN, 46.6% MAPT) compared with 24.5% of controls. Anxiety and depression were the most common in all genetic groups but fluctuated longitudinally and loaded separately in the PCA. Hallucinations and delusions loaded together, with the remaining neuropsychiatric symptoms loading with the core behavioural features of FTD. These results suggest using a single 'psychosis' neuropsychiatric module consisting of hallucinations and delusions. Adding this to the CDR plus NACC FTLD, called the CDR plus NACC FTLD-N, leads to a number of participants being scored more severely, including those who were previously considered asymptomatic now being scored as prodromal.

## WHAT IS ALREADY KNOWN ON THIS TOPIC

⇒ Neuropsychiatric features are common in sporadic and genetic forms of frontotemporal dementia (FTD), particularly the behavioural variant.

## WHAT THIS STUDY ADDS

⇒ Neuropsychiatric symptoms occur early on in FTD, before individuals become symptomatic. There are three main groups: affective symptoms (anxiety and depression), 'psychosis' symptoms (hallucinations and delusions) and other neuropsychiatric symptoms that formed a group with the core behavioural criteria of FTD. The affective symptoms were common in controls as well as mutation carriers and fluctuated longitudinally, so were excluded from the scale. The psychosis symptoms therefore formed the neuropsychiatric component that was added to the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Behaviour and Language Domains, resulting in individuals being scored more severely.

## HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

⇒ Future revisions of FTD clinical rating scales should include neuropsychiatric symptoms to capture the entire spectrum of disease. This will in turn optimise selection of individuals into therapeutic trials.

**Conclusions** Neuropsychiatric symptoms occur in mutation carriers at all disease stages across all three genetic groups. However, only psychosis features provided additional staging benefit to the CDR plus
<figure><img src="image_3.png" /></figure>

OPEN ACCESS

Original research

# Neuropsychiatric symptoms in genetic frontotemporal dementia: developing a new module for Clinical Rating Scales

Kiran Samra,¹ Amy Macdougall,² Georgia Peakman,¹ Arabella Bouziges,¹
Martina Bocchetta,¹ David M Cash,¹,³ Caroline V Greaves,¹ Rhian S Convery,¹
John C van Swieten,⁴ Lize C Jiskoot,⁴ Harro Seelaar,⁵ Fermin Moreno,⁶
Raquel Sánchez-Valle,⁷ Robert Laforce,⁸ Caroline Graff,⁹,¹⁰ Mario Masellis,¹¹
Maria Carmela Tartaglia,¹² James B Rowe,¹³ Barbara Borroni,¹⁴
Elizabeth Finger,¹⁵ Matthis Synofzik,¹⁶ Daniela Galimberti,¹⁷
Rik Vandenberghe,¹⁸,¹⁹ Alexandre de Mendonca,²⁰ Christopher R Butler,²¹,²²
Alexander Gerhard,²³,²⁴ Simon Ducharme,²⁵,²⁶ Isabelle Le Ber,²⁷,²⁸
Pietro Tiraboschi,²⁹ Isabel Santana,³⁰,³¹ Florence Pasquier,³²,³³ Johannes Levin,³⁴,³⁵
Markus Otto,³⁶ Sandro Sorbi,³⁷,³⁸ Jonathan D Rohrer,¹ Lucy L Russell,¹ On
behalf of the Genetic FTD Initiative (GENFI)

► Additional supplemental material is published online only. To view, please visit the journal online (http://dx.doi.org/10.1136/jnnp-2022-330152).

For numbered affiliations see end of article.

**Correspondence to**
Ms Lucy L Russell, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; l.russell@ucl.ac.uk

Received 12 August 2022
Accepted 5 December 2022
Published Online First 10
January 2023

<figure><img src="image_4.png" /></figure>

Check for updates

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.

**To cite:** Samra K, Macdougall A, Peakman G, et al. J Neurol Neurosurg Psychiatry 2023;94:357–368.

## ABSTRACT

**Background** Current clinical rating scales in frontotemporal dementia (FTD) often do not incorporate neuropsychiatric features and may therefore inadequately measure disease stage.

**Methods** 832 participants from the Genetic FTD Initiative (GENFI) were recruited: 522 mutation carriers and 310 mutation-negative controls. The standardised GENFI clinical questionnaire assessed the frequency and severity of 14 neuropsychiatric symptoms: visual, auditory, and tactile hallucinations, delusions, depression, anxiety, irritability/lability, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality, hyperreligiosity, impaired sleep, and altered sense of humour. A principal component analysis (PCA) was performed to identify key groupings of neuropsychiatric and behavioural items in order to create a new neuropsychiatric module that could be used as an addition to the Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center Behaviour and Language Domains (NACC FTLD) rating scale.

**Results** Overall, 46.4% of mutation carriers had neuropsychiatric symptoms (51.6% C9orf72, 40.8% GRN, 46.6% MAPT) compared with 24.5% of controls. Anxiety and depression were the most common in all genetic groups but fluctuated longitudinally and loaded separately in the PCA. Hallucinations and delusions loaded together, with the remaining neuropsychiatric symptoms loading with the core behavioural features of FTD. These results suggest using a single 'psychosis' neuropsychiatric module consisting of hallucinations and delusions. Adding this to the CDR plus NACC FTLD, called the CDR plus NACC FTLD-N, leads to a number of participants being scored more severely, including those who were previously considered asymptomatic now being scored as prodromal.

## WHAT IS ALREADY KNOWN ON THIS TOPIC

⇒ Neuropsychiatric features are common in sporadic and genetic forms of frontotemporal dementia (FTD), particularly the behavioural variant.

## WHAT THIS STUDY ADDS

⇒ Neuropsychiatric symptoms occur early on in FTD, before individuals become symptomatic. There are three main groups: affective symptoms (anxiety and depression), 'psychosis' symptoms (hallucinations and delusions) and other neuropsychiatric symptoms that formed a group with the core behavioural criteria of FTD. The affective symptoms were common in controls as well as mutation carriers and fluctuated longitudinally, so were excluded from the scale. The psychosis symptoms therefore formed the neuropsychiatric component that was added to the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Behaviour and Language Domains, resulting in individuals being scored more severely.

## HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

⇒ Future revisions of FTD clinical rating scales should include neuropsychiatric symptoms to capture the entire spectrum of disease. This will in turn optimise selection of individuals into therapeutic trials.

**Conclusions** Neuropsychiatric symptoms occur in mutation carriers at all disease stages across all three genetic groups. However, only psychosis features provided additional staging benefit to the CDR plus
NACC FTLD. Inclusion of these features brings us closer to optimising the rating scale for use in trials.

## INTRODUCTION

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder that commonly presents with either personality change (behavioural variant FTD, bvFTD) or speech and language difficulties (primary progressive aphasia, PPA). The core behavioural symptoms recognised in the diagnostic criteria of bvFTD are disinhibition, apathy, loss of sympathy or empathy, ritualistic-compulsive behaviour and appetite change.¹ However, a number of changes in personality and behaviour that are seen in people with FTD do not fit into these core criteria, and it has become increasingly recognised that there is a wider set of neuropsychiatric symptoms that occur in bvFTD,² and to a lesser extent in PPA,³ many of which overlap with those seen in primary psychiatric disorders like major depressive disorder, bipolar disorder and schizophrenia.

While studies have highlighted the presence of neuropsychiatric symptoms in sporadic forms of FTD,²,³ they seem to be particularly prevalent in genetic FTD⁴⁻⁸ caused by mutations in progranulin (GRN), chromosome 9 open reading frame 72 (C9orf72) and microtubule-associated protein tau (MAPT).⁹ However, such symptoms are not included in either of the main clinical rating scales for FTD, the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behaviour and Language Domains (CDR plus NACC FTLD),¹⁰⁻¹² or the FTD Rating Scale.¹³ ¹⁴ Inclusion of a neuropsychiatric domain in rating scales is particularly relevant to people with FTD and their caregivers, as such symptoms are highly associated with morbidity and caregiver burden.¹⁵ ¹⁶ Furthermore, exclusion of a neuropsychiatric domain risks inappropriately rating people at an earlier, less severe stage of the disease than they actually are.

This study, therefore, aims to understand how best to include neuropsychiatric symptoms as an additional module to the CDR plus NACC FTLD, a scale commonly used in current clinical trials of FTD. In particular, the study aims to investigate whether neuropsychiatric symptoms are best assessed as part of, or separately to, the core behavioural symptoms that are currently included in the behaviour module of the CDR plus NACC FTLD. Better understanding of an individual's disease stage and their progression by incorporating neuropsychiatric symptoms into the scale will enhance therapeutic trial design and improve identification of treatment response.

## METHODS

### Participants

Participants were recruited from the fifth data freeze of the Genetic FTD Initiative (GENFI) study between 20 January 2012 and 30 May 2019, including sites in the UK, Canada, Belgium, France, Germany, Italy, the Netherlands, Portugal, Spain and Sweden.

The standardised GENFI clinical assessment included a clinical history and neurological examination, neuropsychometric assessment and the CDR plus NACC FTLD.¹⁰ Mutation carriers were classified into asymptomatic, prodromal or symptomatic if they scored 0, 0.5 or ≥1, respectively, using the CDR plus NACC FTLD global score. To investigate neuropsychiatric features, we reviewed all mutation carriers recruited in the study at baseline visit, including 221 C9orf72, 213 GRN and 88 MAPT mutation carriers. Of these 522 mutation carriers, the CDR plus

NACC FTLD global score was 0 in 55.7%, 0.5 in 15.7% and ≥1 in 28.5%. Participants were also separately judged by a clinician whether they were felt to be symptomatic. In this group, 109 had bvFTD (20.9% of the mutation carriers studied),¹ and 26 had PPA (5.0%).¹⁷ Additionally, 17 had amyotrophic lateral sclerosis (ALS) or FTD-ALS (3.3%),¹⁸ ¹⁹ and 5 had a parkinsonian disorder (1.0%).²⁰ ²¹ The control group consisted of healthy non-mutation carriers from the GENFI cohort with a CDR plus NACC FTLD global score of 0 or 0.5 (310 in total). Demographics are shown in table 1.

### Neuropsychiatric symptoms

Neuropsychiatric symptoms were assessed using the GENFI neuropsychiatric symptom scale (online supplemental table 1).⁴ This contains 14 symptoms scored as per the CDR scale, that is, 0=asymptomatic, 0.5=questionable/very mild, 1=mild, 2=moderate and 3=severe: visual, auditory and tactile hallucinations, delusions, depression, anxiety, irritability/lability, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality, hyperreligiosity, impaired sleep and altered sense of humour.

We also wanted to explore the overlap of these neuropsychiatric symptoms with the core behavioural symptoms described in the international consensus criteria for bvFTD.¹ In the GENFI behavioural symptom scale, seven symptoms are measured: disinhibition, apathy, loss of sympathy/empathy, ritualistic/compulsive behaviour and hyperorality and appetite changes, as well as poor response to social/emotional cues and inappropriate trusting behaviour.

### Statistical analysis

All statistical analyses were performed using Stata/MP V.16.1 unless otherwise specified. All graphs were produced using GraphPad Prism V.9 except for the Sankey diagrams which were made using SankeyMATIC. Demographics were compared between groups using either linear regression (age and education) or a $\chi^2$ test (sex), and age- and sex-adjusted linear regressions to compare the Mini-Mental State Examination (MMSE) and CDR plus NACC FTLD. Frequency and severity of individual neuropsychiatric symptoms were compared between groups using ordinal logistic regressions adjusting for age and sex, except for the comparisons of disease group versus controls for severity (as there was minimal variation from zero for the control group) and frequency (when the controls scored zero) where linear regressions adjusting for age and sex were used, with 95% bias-corrected bootstrapped confidence intervals with 2000 repetitions.

Principal component analysis (PCA) was performed in R V.4.1.2²² in order to see whether it was possible to combine the multiple items in the neuropsychiatric symptom list into a smaller number of variables with minimal loss of information that could then form one or more modules to incorporate into a rating scale. Components with an eigenvalue greater than one were selected and the varimax rotation was used. An initial PCA was performed looking only at neuropsychiatric symptoms in all mutation carriers and in each of the genetic mutation subgroups (C9orf72, GRN, MAPT). A further PCA included behavioural as well as neuropsychiatric symptoms in the analyses was also performed. Items within a component with loadings closest to +1.00 or -1.00 were interpreted as loading strongly onto that factor, while those nearest to zero were considered as loading weakly.
NACC FTLD. Inclusion of these features brings us closer to optimising the rating scale for use in trials.

## INTRODUCTION

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder that commonly presents with either personality change (behavioural variant FTD, bvFTD) or speech and language difficulties (primary progressive aphasia, PPA). The core behavioural symptoms recognised in the diagnostic criteria of bvFTD are disinhibition, apathy, loss of sympathy or empathy, ritualistic-compulsive behaviour and appetite change.¹ However, a number of changes in personality and behaviour that are seen in people with FTD do not fit into these core criteria, and it has become increasingly recognised that there is a wider set of neuropsychiatric symptoms that occur in bvFTD,² and to a lesser extent in PPA,³ many of which overlap with those seen in primary psychiatric disorders like major depressive disorder, bipolar disorder and schizophrenia.

While studies have highlighted the presence of neuropsychiatric symptoms in sporadic forms of FTD,²,³ they seem to be particularly prevalent in genetic FTD⁴⁻⁸ caused by mutations in progranulin (GRN), chromosome 9 open reading frame 72 (C9orf72) and microtubule-associated protein tau (MAPT).⁹ However, such symptoms are not included in either of the main clinical rating scales for FTD, the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behaviour and Language Domains (CDR plus NACC FTLD),¹⁰⁻¹² or the FTD Rating Scale.¹³ ¹⁴ Inclusion of a neuropsychiatric domain in rating scales is particularly relevant to people with FTD and their caregivers, as such symptoms are highly associated with morbidity and caregiver burden.¹⁵ ¹⁶ Furthermore, exclusion of a neuropsychiatric domain risks inappropriately rating people at an earlier, less severe stage of the disease than they actually are.

This study, therefore, aims to understand how best to include neuropsychiatric symptoms as an additional module to the CDR plus NACC FTLD, a scale commonly used in current clinical trials of FTD. In particular, the study aims to investigate whether neuropsychiatric symptoms are best assessed as part of, or separately to, the core behavioural symptoms that are currently included in the behaviour module of the CDR plus NACC FTLD. Better understanding of an individual's disease stage and their progression by incorporating neuropsychiatric symptoms into the scale will enhance therapeutic trial design and improve identification of treatment response.

## METHODS

### Participants

Participants were recruited from the fifth data freeze of the Genetic FTD Initiative (GENFI) study between 20 January 2012 and 30 May 2019, including sites in the UK, Canada, Belgium, France, Germany, Italy, the Netherlands, Portugal, Spain and Sweden.

The standardised GENFI clinical assessment included a clinical history and neurological examination, neuropsychometric assessment and the CDR plus NACC FTLD.¹⁰ Mutation carriers were classified into asymptomatic, prodromal or symptomatic if they scored 0, 0.5 or ≥1, respectively, using the CDR plus NACC FTLD global score. To investigate neuropsychiatric features, we reviewed all mutation carriers recruited in the study at baseline visit, including 221 C9orf72, 213 GRN and 88 MAPT mutation carriers. Of these 522 mutation carriers, the CDR plus

NACC FTLD global score was 0 in 55.7%, 0.5 in 15.7% and ≥1 in 28.5%. Participants were also separately judged by a clinician whether they were felt to be symptomatic. In this group, 109 had bvFTD (20.9% of the mutation carriers studied),¹ and 26 had PPA (5.0%).¹⁷ Additionally, 17 had amyotrophic lateral sclerosis (ALS) or FTD-ALS (3.3%),¹⁸ ¹⁹ and 5 had a parkinsonian disorder (1.0%).²⁰ ²¹ The control group consisted of healthy non-mutation carriers from the GENFI cohort with a CDR plus NACC FTLD global score of 0 or 0.5 (310 in total). Demographics are shown in table 1.

### Neuropsychiatric symptoms

Neuropsychiatric symptoms were assessed using the GENFI neuropsychiatric symptom scale (online supplemental table 1).⁴ This contains 14 symptoms scored as per the CDR scale, that is, 0=asymptomatic, 0.5=questionable/very mild, 1=mild, 2=moderate and 3=severe: visual, auditory and tactile hallucinations, delusions, depression, anxiety, irritability/lability, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality, hyperreligiosity, impaired sleep and altered sense of humour.

We also wanted to explore the overlap of these neuropsychiatric symptoms with the core behavioural symptoms described in the international consensus criteria for bvFTD.¹ In the GENFI behavioural symptom scale, seven symptoms are measured: disinhibition, apathy, loss of sympathy/empathy, ritualistic/compulsive behaviour and hyperorality and appetite changes, as well as poor response to social/emotional cues and inappropriate trusting behaviour.

### Statistical analysis

All statistical analyses were performed using Stata/MP V.16.1 unless otherwise specified. All graphs were produced using GraphPad Prism V.9 except for the Sankey diagrams which were made using SankeyMATIC. Demographics were compared between groups using either linear regression (age and education) or a $\chi^2$ test (sex), and age- and sex-adjusted linear regressions to compare the Mini-Mental State Examination (MMSE) and CDR plus NACC FTLD. Frequency and severity of individual neuropsychiatric symptoms were compared between groups using ordinal logistic regressions adjusting for age and sex, except for the comparisons of disease group versus controls for severity (as there was minimal variation from zero for the control group) and frequency (when the controls scored zero) where linear regressions adjusting for age and sex were used, with 95% bias-corrected bootstrapped confidence intervals with 2000 repetitions.

Principal component analysis (PCA) was performed in R V.4.1.2²² in order to see whether it was possible to combine the multiple items in the neuropsychiatric symptom list into a smaller number of variables with minimal loss of information that could then form one or more modules to incorporate into a rating scale. Components with an eigenvalue greater than one were selected and the varimax rotation was used. An initial PCA was performed looking only at neuropsychiatric symptoms in all mutation carriers and in each of the genetic mutation subgroups (C9orf72, GRN, MAPT). A further PCA included behavioural as well as neuropsychiatric symptoms in the analyses was also performed. Items within a component with loadings closest to +1.00 or -1.00 were interpreted as loading strongly onto that factor, while those nearest to zero were considered as loading weakly.
<table><caption>**Table 1** Demographics, clinical scores and frequency of neuropsychiatric symptoms for all mutation carriers (C9orf72, GRN, MAPT) and healthy controls</caption><thead><tr><th rowspan="2">CDR plus NACC FTLD global score</th><th rowspan="2">Controls</th><th colspan="3">All mutation carriers</th><th colspan="3">C9orf72</th><th colspan="3">GRN</th><th colspan="3">MAPT</th></tr><tr><th>All</th><th>0</th><th>0.5</th><th>≥1</th><th>All</th><th>0</th><th>0.5</th><th>≥1</th><th>All</th><th>0</th><th>0.5</th><th>≥1</th></tr></thead><tbody><tr><td>No of participants</td><td>310</td><td>522</td><td>291</td><td>82</td><td>149</td><td>221</td><td>112</td><td>37</td><td>72</td><td>213</td><td>130</td><td>31</td><td>52</td><td>88</td><td>49</td><td>14</td><td>25</td></tr><tr><td>% male</td><td>44</td><td>44</td><td>38</td><td>41</td><td>58</td><td>49</td><td>41</td><td>41</td><td>65</td><td>39</td><td>35</td><td>48</td><td>46</td><td>45</td><td>41</td><td>29</td><td>64</td></tr><tr><td>Age (years)</td><td>46.0 (12.7)</td><td>50.1 (13.7)</td><td>44.2 (11.9)</td><td>49.7 (12.3)</td><td>62.0 (9.2)</td><td>51.2 (13.6)</td><td>44.5 (11.7)</td><td>49.4 (11.2)</td><td>62.7 (9.3)</td><td>51.0 (13.6)</td><td>45.8 (12.2)</td><td>51.8 (13.2)</td><td>63.5 (7.7)</td><td>45.3 (13.1)</td><td>39.2 (10.4)</td><td>45.7 (12.6)</td><td>57.0 (10.1)</td></tr><tr><td>Education (years)</td><td>14.5 (3.3)</td><td>13.9 (3.4)</td><td>14.5 (3.2)</td><td>13.9 (3.1)</td><td>12.8 (3.7)</td><td>13.9 (3.2)</td><td>14.4 (3.0)</td><td>14.1 (2.6)</td><td>13.1 (3.7)</td><td>13.9 (3.7)</td><td>14.7 (3.4)</td><td>14.0 (4.0)</td><td>11.9 (3.5)</td><td>14.1 (3.3)</td><td>14.4 (3.3)</td><td>13.5 (2.4)</td><td>13.6 (3.8)</td></tr><tr><td>MMSE</td><td>29.3 (1.0)</td><td>27.1 (5.3)</td><td>29.3 (1.0)</td><td>28.5 (2.2)</td><td>21.9 (7.6)</td><td>27.2 (4.7)</td><td>29.1 (1.2)</td><td>28.5 (2.1)</td><td>23.4 (6.6)</td><td>26.9 (6.0)</td><td>29.4 (0.9)</td><td>28.5 (2.4)</td><td>19.3 (8.4)</td><td>27.4 (5.1)</td><td>29.5 (0.8)</td><td>28.2 (2.3)</td><td>22.8 (7.7)</td></tr><tr><td>CDR plus NACC FTLD Global score</td><td>0.1 (0.2)</td><td>0.6 (1.0)</td><td>0.0 (0.0)</td><td>0.5 (0.0)</td><td>2.0 (0.8)</td><td>0.8 (1.0)</td><td>0.0 (0.0)</td><td>0.5 (0.0)</td><td>2.1 (0.8)</td><td>0.5 (0.9)</td><td>0.0 (0.0)</td><td>0.5 (0.0)</td><td>1.9 (0.8)</td><td>0.6 (0.9)</td><td>0.0 (0.0)</td><td>0.5 (0.0)</td><td>1.9 (0.8)</td></tr><tr><td>CDR plus NACC FTLD Sum of Boxes</td><td>0.2 (0.4)</td><td>3.1 (5.5)</td><td>0.0 (0.0)</td><td>1.1 (0.8)</td><td>10.3 (5.8)</td><td>3.8 (6.0)</td><td>0.0 (0.0)</td><td>1.1 (0.8)</td><td>10.9 (5.7)</td><td>2.5 (5.1)</td><td>0.0 (0.0)</td><td>1.0 (0.8)</td><td>9.8 (6.0)</td><td>2.9 (5.3)</td><td>0.0 (0.0)</td><td>1.1 (0.8)</td><td>9.7 (5.8)</td></tr><tr><td>Neuropsychiatric symptoms (%)</td><td>24.5</td><td>46.4</td><td>18.0</td><td>70.7</td><td>89.3</td><td>51.6</td><td>19.6</td><td>70.3</td><td>91.7</td><td>40.8</td><td>16.9</td><td>71.0</td><td>82.7</td><td>46.6</td><td>14.3</td><td>71.4</td><td>96.0</td></tr></tbody><tfoot><tr><td colspan="18">Age, education, MMSE and Clinical Rating Scale scores are shown as mean (SD). CDR, Clinical Dementia Rating; MMSE, Mini-Mental State Examination; NACC FTLD, National Alzheimer's Coordinating Center Behaviour and Language Domains.</td></tr></tfoot></table>

As mood symptoms are common in the general population and can fluctuate with time, both with and without treatment (whether pharmacological or talking therapies), we decided to additionally perform a subanalysis of depression and anxiety and how these features change in frequency and severity over time. Descriptive differences were reported for each time point over three visits.

## Rating scale analysis

Finally, we investigated the addition of a neuropsychiatric module to the CDR plus NACC FTLD rating scale. We compared this new scale (termed CDR plus NACC FTLD-N) with the original CDR plus NACC FTLD. We also developed a new version of the behavioural module based on the PCA findings and compared this (termed CDR plus NACC FTLD-N-B+) with the original CDR plus NACC FTLD.

## RESULTS

### Demographics

No significant differences were seen between the mutation groups in years of education, but the overall mutation carrier group and C9orf72 mutation carriers had, on average, significantly fewer years of education than controls (p=0.024 and p=0.048, respectively). C9orf72 and GRN mutation carriers were significantly older than controls (both p<0.001) and MAPT mutation carriers (p<0.001 and p=0.001 respectively), while the C9orf72 group contained more males than the GRN group (χ²=3.91, p=0.048) (table 1).

### Disease severity

The MMSE and CDR plus NACC FTLD Sum of Boxes scores were significantly different to controls in each genetic group overall (table 1). There were no significant differences between the genetic groups (all mutation carriers combined) apart from for the CDR plus NACC FTLD which was higher in C9orf72 compared with the GRN group (both global and sum of boxes scores, p<0.05).

### Frequency and severity of neuropsychiatric symptoms in the GENFI cohort

Neuropsychiatric symptoms were reported in 46.4% of all mutation carriers: 51.6% of the C9orf72 group, 40.8% of the GRN group and 46.6% of the MAPT group. In comparison, 24.5% of controls were reported as showing symptoms. Stratifying by CDR plus NACC FTLD, neuropsychiatric symptoms occurred in 18.0% of mutation carriers with a global score of 0 (19.6% C9orf72, 16.9% GRN, 14.3% MAPT), 70.7% of mutation carriers with a global score of 0.5 (70.3% C9orf72, 71.0% GRN, 71.4% MAPT) and 89.3% of mutation carriers with a global score≥1 (91.7% C9orf72, 82.7% GRN, 96.0% MAPT) (table 1).

When looking at the individual symptoms in the combined mutation carrier group, anxiety was the most frequent and severe neuropsychiatric symptom, followed by depression, impaired sleep and irritability/lability. Stratifying this group by CDR plus NACC FTLD, all of the neuropsychiatric symptoms were significantly more impaired (ie, more frequent and more severe) than controls when the global score was ≥1 (figure 1, table 2, online supplemental table 2): lability/irritability (frequency 51.7%, mean (SD) severity 0.60 (0.79)), anxiety (49.7%, 0.57 (0.73)), altered sense of humour (46.3%, 0.60 (0.84)), impaired sleep (44.3%, 0.55 (0.76)) and depression (40.3%, 0.48 (0.73)), were the most frequent and severe. At the prodromal stage (CDR plus NACC FTLD global score of 0.5), anxiety (40.2%, 0.33
<table><caption>**Table 1** Demographics, clinical scores and frequency of neuropsychiatric symptoms for all mutation carriers (C9orf72, GRN, MAPT) and healthy controls</caption><thead><tr><th rowspan="2">CDR plus NACC FTLD global score</th><th rowspan="2">Controls</th><th colspan="3">All mutation carriers</th><th colspan="3">C9orf72</th><th colspan="3">GRN</th><th colspan="3">MAPT</th></tr><tr><th>All</th><th>0</th><th>0.5</th><th>≥1</th><th>All</th><th>0</th><th>0.5</th><th>≥1</th><th>All</th><th>0</th><th>0.5</th><th>≥1</th></tr></thead><tbody><tr><td>No of participants</td><td>310</td><td>522</td><td>291</td><td>82</td><td>149</td><td>221</td><td>112</td><td>37</td><td>72</td><td>213</td><td>130</td><td>31</td><td>52</td><td>88</td><td>49</td><td>14</td><td>25</td></tr><tr><td>% male</td><td>44</td><td>44</td><td>38</td><td>41</td><td>58</td><td>49</td><td>41</td><td>41</td><td>65</td><td>39</td><td>35</td><td>48</td><td>46</td><td>45</td><td>41</td><td>29</td><td>64</td></tr><tr><td>Age (years)</td><td>46.0 (12.7)</td><td>50.1 (13.7)</td><td>44.2 (11.9)</td><td>49.7 (12.3)</td><td>62.0 (9.2)</td><td>51.2 (13.6)</td><td>44.5 (11.7)</td><td>49.4 (11.2)</td><td>62.7 (9.3)</td><td>51.0 (13.6)</td><td>45.8 (12.2)</td><td>51.8 (13.2)</td><td>63.5 (7.7)</td><td>45.3 (13.1)</td><td>39.2 (10.4)</td><td>45.7 (12.6)</td><td>57.0 (10.1)</td></tr><tr><td>Education (years)</td><td>14.5 (3.3)</td><td>13.9 (3.4)</td><td>14.5 (3.2)</td><td>13.9 (3.1)</td><td>12.8 (3.7)</td><td>13.9 (3.2)</td><td>14.4 (3.0)</td><td>14.1 (2.6)</td><td>13.1 (3.7)</td><td>13.9 (3.7)</td><td>14.7 (3.4)</td><td>14.0 (4.0)</td><td>11.9 (3.5)</td><td>14.1 (3.3)</td><td>14.4 (3.3)</td><td>13.5 (2.4)</td><td>13.6 (3.8)</td></tr><tr><td>MMSE</td><td>29.3 (1.0)</td><td>27.1 (5.3)</td><td>29.3 (1.0)</td><td>28.5 (2.2)</td><td>21.9 (7.6)</td><td>27.2 (4.7)</td><td>29.1 (1.2)</td><td>28.5 (2.1)</td><td>23.4 (6.6)</td><td>26.9 (6.0)</td><td>29.4 (0.9)</td><td>28.5 (2.4)</td><td>19.3 (8.4)</td><td>27.4 (5.1)</td><td>29.5 (0.8)</td><td>28.2 (2.3)</td><td>22.8 (7.7)</td></tr><tr><td>CDR plus NACC FTLD Global score</td><td>0.1 (0.2)</td><td>0.6 (1.0)</td><td>0.0 (0.0)</td><td>0.5 (0.0)</td><td>2.0 (0.8)</td><td>0.8 (1.0)</td><td>0.0 (0.0)</td><td>0.5 (0.0)</td><td>2.1 (0.8)</td><td>0.5 (0.9)</td><td>0.0 (0.0)</td><td>0.5 (0.0)</td><td>1.9 (0.8)</td><td>0.6 (0.9)</td><td>0.0 (0.0)</td><td>0.5 (0.0)</td><td>1.9 (0.8)</td></tr><tr><td>CDR plus NACC FTLD Sum of Boxes</td><td>0.2 (0.4)</td><td>3.1 (5.5)</td><td>0.0 (0.0)</td><td>1.1 (0.8)</td><td>10.3 (5.8)</td><td>3.8 (6.0)</td><td>0.0 (0.0)</td><td>1.1 (0.8)</td><td>10.9 (5.7)</td><td>2.5 (5.1)</td><td>0.0 (0.0)</td><td>1.0 (0.8)</td><td>9.8 (6.0)</td><td>2.9 (5.3)</td><td>0.0 (0.0)</td><td>1.1 (0.8)</td><td>9.7 (5.8)</td></tr><tr><td>Neuropsychiatric symptoms (%)</td><td>24.5</td><td>46.4</td><td>18.0</td><td>70.7</td><td>89.3</td><td>51.6</td><td>19.6</td><td>70.3</td><td>91.7</td><td>40.8</td><td>16.9</td><td>71.0</td><td>82.7</td><td>46.6</td><td>14.3</td><td>71.4</td><td>96.0</td></tr></tbody><tfoot><tr><td colspan="18">Age, education, MMSE and Clinical Rating Scale scores are shown as mean (SD). CDR, Clinical Dementia Rating; MMSE, Mini-Mental State Examination; NACC FTLD, National Alzheimer's Coordinating Center Behaviour and Language Domains.</td></tr></tfoot></table>

As mood symptoms are common in the general population and can fluctuate with time, both with and without treatment (whether pharmacological or talking therapies), we decided to additionally perform a subanalysis of depression and anxiety and how these features change in frequency and severity over time. Descriptive differences were reported for each time point over three visits.

### Rating scale analysis

Finally, we investigated the addition of a neuropsychiatric module to the CDR plus NACC FTLD rating scale. We compared this new scale (termed CDR plus NACC FTLD-N) with the original CDR plus NACC FTLD. We also developed a new version of the behavioural module based on the PCA findings and compared this (termed CDR plus NACC FTLD-N-B+) with the original CDR plus NACC FTLD.

## RESULTS

### Demographics

No significant differences were seen between the mutation groups in years of education, but the overall mutation carrier group and C9orf72 mutation carriers had, on average, significantly fewer years of education than controls (p=0.024 and p=0.048, respectively). C9orf72 and GRN mutation carriers were significantly older than controls (both p<0.001) and MAPT mutation carriers (p<0.001 and p=0.001 respectively), while the C9orf72 group contained more males than the GRN group ($\chi^2=3.91$, p=0.048) (table 1).

### Disease severity

The MMSE and CDR plus NACC FTLD Sum of Boxes scores were significantly different to controls in each genetic group overall (table 1). There were no significant differences between the genetic groups (all mutation carriers combined) apart from for the CDR plus NACC FTLD which was higher in C9orf72 compared with the GRN group (both global and sum of boxes scores, p<0.05).

### Frequency and severity of neuropsychiatric symptoms in the GENFI cohort

Neuropsychiatric symptoms were reported in 46.4% of all mutation carriers: 51.6% of the C9orf72 group, 40.8% of the GRN group and 46.6% of the MAPT group. In comparison, 24.5% of controls were reported as showing symptoms. Stratifying by CDR plus NACC FTLD, neuropsychiatric symptoms occurred in 18.0% of mutation carriers with a global score of 0 (19.6% C9orf72, 16.9% GRN, 14.3% MAPT), 70.7% of mutation carriers with a global score of 0.5 (70.3% C9orf72, 71.0% GRN, 71.4% MAPT) and 89.3% of mutation carriers with a global score $\ge 1$ (91.7% C9orf72, 82.7% GRN, 96.0% MAPT) (table 1).

When looking at the individual symptoms in the combined mutation carrier group, anxiety was the most frequent and severe neuropsychiatric symptom, followed by depression, impaired sleep and irritability/lability. Stratifying this group by CDR plus NACC FTLD, all of the neuropsychiatric symptoms were significantly more impaired (ie, more frequent and more severe) than controls when the global score was $\ge 1$ (figure 1, table 2, online supplemental table 2): lability/irritability (frequency 51.7%, mean (SD) severity 0.60 (0.79)), anxiety (49.7%, 0.57 (0.73)), altered sense of humour (46.3%, 0.60 (0.84)), impaired sleep (44.3%, 0.55 (0.76)) and depression (40.3%, 0.48 (0.73)), were the most frequent and severe. At the prodromal stage (CDR plus NACC FTLD global score of 0.5), anxiety (40.2%, 0.33
<figure><img src="image_3.png" /><figcaption>**Figure 1** Frequency (top panel) and severity (bottom panel) of symptoms in the GENFI neuropsychiatric symptom scale in all mutation carriers when asymptomatic (CDR plus NACC FTLD global score of 0), prodromal (score of 0.5) and symptomatic (score of 1+). Frequency and severity of symptoms in the individual genetic groups (*C9orf72*, *GRN* and *MAPT*) are shown similarly to the right of the combined mutation carrier group. CDR, Clinical Dementia Rating; GENFI, Genetic FTD Initiative; NACC FTLD, National Alzheimer's Coordinating Center Behaviour and Language Domains.</figcaption></figure>

(0.47)), depression (32.9%, 0.30 (0.52)), irritability/lability (26.8%, 0.21 (0.42)) and impaired sleep (26.8%, 0.25 (0.49)) remained the most frequent and severe symptoms, but visual hallucinations, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality and altered sense of humour all occurred significantly more frequently than controls (table 2).

a CDR plus NACC FTLD global score of 0 none of the symptoms were significantly more frequent or severe than controls, but anxiety, irritability/lability and impaired sleep occurred less frequently.

Stratifying by genetic group, all symptoms were significantly more frequent and severe in the symptomatic (CDR plus NACC

<table><caption>**Table 2** Percentage frequency of individual neuropsychiatric symptoms in controls and mutation carriers</caption><thead><tr><th rowspan="2"></th><th rowspan="2">Controls</th><th colspan="3">All mutation carriers</th><th colspan="3">C9orf72</th><th colspan="3">GRN</th><th colspan="3">MAPT</th></tr><tr><th>CDR 0</th><th>CDR 0.5</th><th>CDR ≥1</th><th>CDR 0</th><th>CDR 0.5</th><th>CDR ≥1</th><th>CDR 0</th><th>CDR 0.5</th><th>CDR ≥1</th><th>CDR 0</th><th>CDR 0.5</th><th>CDR ≥1</th></tr></thead><tbody><tr><td>Visual hallucinations</td><td>0.3</td><td>0.3</td><td><strong>6.1</strong></td><td><strong>15.4</strong></td><td>0.9</td><td><strong>5.4</strong></td><td><strong>23.6</strong></td><td>0.0</td><td><strong>6.5</strong></td><td><strong>7.7</strong></td><td>0.0</td><td><strong>7.1</strong></td><td><strong>8.0</strong></td></tr><tr><td>Auditory hallucinations</td><td>1.3</td><td>0.3</td><td>0.0</td><td><strong>13.4</strong></td><td>0.9</td><td>0.0</td><td><strong>22.2</strong></td><td>0.0</td><td>0.0</td><td><strong>7.7</strong></td><td>0.0</td><td>0.0</td><td>0.0</td></tr><tr><td>Tactile hallucinations</td><td>0.0</td><td>0.3</td><td>2.4</td><td><strong>5.4</strong></td><td>0.9</td><td>5.4</td><td><strong>9.7</strong></td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>4.0</td></tr><tr><td>Delusions</td><td>1.0</td><td>0.7</td><td>1.2</td><td><strong>25.5</strong></td><td>0.9</td><td>0.0</td><td><strong>36.1</strong></td><td>0.0</td><td>0.0</td><td><strong>17.3</strong></td><td>2.0</td><td>7.1</td><td><strong>12.0</strong></td></tr><tr><td>Depression</td><td>12.9</td><td>8.9</td><td><strong>32.9</strong></td><td><strong>40.3</strong></td><td>8.9</td><td>21.6</td><td><strong>40.3</strong></td><td>7.7</td><td><strong>41.9</strong></td><td><strong>42.3</strong></td><td>12.2</td><td><strong>42.9</strong></td><td><strong>36.0</strong></td></tr><tr><td>Anxiety</td><td>15.5</td><td><strong>10.0</strong></td><td><strong>40.2</strong></td><td><strong>49.7</strong></td><td>8.9</td><td><strong>35.1</strong></td><td><strong>51.4</strong></td><td>10.8</td><td><strong>41.9</strong></td><td><strong>48.1</strong></td><td>10.2</td><td><strong>50.0</strong></td><td><strong>48.0</strong></td></tr><tr><td>Irritability/lability</td><td>11.9</td><td><strong>4.8</strong></td><td><strong>26.8</strong></td><td><strong>51.7</strong></td><td>5.4</td><td><strong>32.4</strong></td><td><strong>56.9</strong></td><td>3.8</td><td>22.6</td><td><strong>42.3</strong></td><td>6.1</td><td>21.4</td><td><strong>56.0</strong></td></tr><tr><td>Agitation/aggression</td><td>2.6</td><td>1.4</td><td><strong>11.0</strong></td><td><strong>33.6</strong></td><td>1.8</td><td><strong>10.8</strong></td><td><strong>37.5</strong></td><td>0.8</td><td><strong>16.1</strong></td><td><strong>25.0</strong></td><td>2.0</td><td><strong>0.0</strong></td><td><strong>40.0</strong></td></tr><tr><td>Euphoria/elation</td><td>0.3</td><td>1.0</td><td><strong>6.1</strong></td><td><strong>29.5</strong></td><td>2.7</td><td><strong>5.4</strong></td><td><strong>34.7</strong></td><td>0.0</td><td>3.2</td><td><strong>21.2</strong></td><td>0.0</td><td><strong>14.3</strong></td><td><strong>32.0</strong></td></tr><tr><td>Aberrant motor behaviour</td><td>1.3</td><td>0.3</td><td><strong>6.1</strong></td><td><strong>24.2</strong></td><td><strong>0.0</strong></td><td>5.4</td><td><strong>40.3</strong></td><td><strong>0.0</strong></td><td><strong>9.7</strong></td><td><strong>32.7</strong></td><td>2.0</td><td>0.0</td><td><strong>40.0</strong></td></tr><tr><td>Hypersexuality</td><td>0.3</td><td>0.0</td><td><strong>3.7</strong></td><td><strong>14.8</strong></td><td>0.0</td><td><strong>8.1</strong></td><td><strong>16.7</strong></td><td>0.0</td><td>0.0</td><td><strong>11.5</strong></td><td>0.0</td><td>0.0</td><td><strong>16.0</strong></td></tr><tr><td>Hyperreligiosity</td><td>0.0</td><td>0.3</td><td>2.4</td><td><strong>10.7</strong></td><td>0.0</td><td>0.0</td><td><strong>12.5</strong></td><td>0.8</td><td>6.5</td><td><strong>5.8</strong></td><td>0.0</td><td>0.0</td><td><strong>16.0</strong></td></tr><tr><td>Impaired sleep</td><td>13.2</td><td>7.2</td><td><strong>26.8</strong></td><td><strong>44.3</strong></td><td><strong>3.6</strong></td><td><strong>27.0</strong></td><td><strong>48.6</strong></td><td>9.2</td><td><strong>29.0</strong></td><td><strong>40.4</strong></td><td>10.2</td><td>21.4</td><td><strong>40.0</strong></td></tr><tr><td>Altered sense of humour</td><td>0.6</td><td>0.3</td><td><strong>4.9</strong></td><td><strong>46.3</strong></td><td>0.0</td><td><strong>8.1</strong></td><td><strong>40.3</strong></td><td>0.8</td><td>3.2</td><td><strong>42.3</strong></td><td>0.0</td><td>0.0</td><td><strong>72.0</strong></td></tr></tbody><tfoot><tr><td colspan="14">Number of cases is as per table 1. Bold items are significantly more frequent than controls and italicised items are significantly less frequent than controls (p&lt;0.05). Other differences are shown as *significantly more frequent compared with GRN, †significantly more frequent compared with MAPT and ‡significantly more frequent compared with C9orf72 (p&lt;0.05). See online supplemental file 1 for similar analysis of severity.</td></tr></tfoot></table>
<figure><img src="image_5.png" /><figcaption>**Figure 1** Frequency (top panel) and severity (bottom panel) of symptoms in the GENFI neuropsychiatric symptom scale in all mutation carriers when asymptomatic (CDR plus NACC FTLD global score of 0), prodromal (score of 0.5) and symptomatic (score of 1+). Frequency and severity of symptoms in the individual genetic groups (*C9orf72*, *GRN* and *MAPT*) are shown similarly to the right of the combined mutation carrier group. CDR, Clinical Dementia Rating; GENFI, Genetic FTD Initiative; NACC FTLD, National Alzheimer's Coordinating Center Behaviour and Language Domains.</figcaption></figure>

(0.47)), depression (32.9%, 0.30 (0.52)), irritability/lability (26.8%, 0.21 (0.42)) and impaired sleep (26.8%, 0.25 (0.49)) remained the most frequent and severe symptoms, but visual hallucinations, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality and altered sense of humour all occurred significantly more frequently than controls (table 2). At

a CDR plus NACC FTLD global score of 0 none of the symptoms were significantly more frequent or severe than controls, but anxiety, irritability/lability and impaired sleep occurred less frequently.

Stratifying by genetic group, all symptoms were significantly more frequent and severe in the symptomatic (CDR plus NACC

<table><caption>**Table 2** Percentage frequency of individual neuropsychiatric symptoms in controls and mutation carriers</caption><thead><tr><th rowspan="2"></th><th rowspan="2">Controls</th><th colspan="3">All mutation carriers</th><th colspan="3">C9orf72</th><th colspan="3">GRN</th><th colspan="3">MAPT</th></tr><tr><th>CDR 0</th><th>CDR 0.5</th><th>CDR ≥1</th><th>CDR 0</th><th>CDR 0.5</th><th>CDR ≥1</th><th>CDR 0</th><th>CDR 0.5</th><th>CDR ≥1</th><th>CDR 0</th><th>CDR 0.5</th><th>CDR ≥1</th></tr></thead><tbody><tr><td>Visual hallucinations</td><td>0.3</td><td>0.3</td><td><strong>6.1</strong></td><td><strong>15.4</strong></td><td>0.9</td><td><strong>5.4</strong></td><td><strong>23.6</strong></td><td>0.0</td><td><strong>6.5</strong></td><td><strong>7.7</strong></td><td>0.0</td><td><strong>7.1</strong></td><td><strong>8.0</strong></td></tr><tr><td>Auditory hallucinations</td><td>1.3</td><td>0.3</td><td>0.0</td><td><strong>13.4</strong></td><td>0.9</td><td>0.0</td><td><strong>22.2</strong></td><td>0.0</td><td>0.0</td><td><strong>7.7</strong></td><td>0.0</td><td>0.0</td><td>0.0</td></tr><tr><td>Tactile hallucinations</td><td>0.0</td><td>0.3</td><td>2.4</td><td><strong>5.4</strong></td><td>0.9</td><td>5.4</td><td><strong>9.7</strong></td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>0.0</td><td>4.0</td></tr><tr><td>Delusions</td><td>1.0</td><td>0.7</td><td>1.2</td><td><strong>25.5</strong></td><td>0.9</td><td>0.0</td><td><strong>36.1</strong></td><td>0.0</td><td>0.0</td><td><strong>17.3</strong></td><td>2.0</td><td>7.1</td><td><strong>12.0</strong></td></tr><tr><td>Depression</td><td>12.9</td><td>8.9</td><td><strong>32.9</strong></td><td><strong>40.3</strong></td><td>8.9</td><td>21.6</td><td><strong>40.3</strong></td><td>7.7</td><td><strong>41.9</strong></td><td><strong>42.3</strong></td><td>12.2</td><td><strong>42.9</strong></td><td><strong>36.0</strong></td></tr><tr><td>Anxiety</td><td>15.5</td><td><strong>10.0</strong></td><td><strong>40.2</strong></td><td><strong>49.7</strong></td><td>8.9</td><td><strong>35.1</strong></td><td><strong>51.4</strong></td><td>10.8</td><td><strong>41.9</strong></td><td><strong>48.1</strong></td><td>10.2</td><td><strong>50.0</strong></td><td><strong>48.0</strong></td></tr><tr><td>Irritability/lability</td><td>11.9</td><td><strong>4.8</strong></td><td><strong>26.8</strong></td><td><strong>51.7</strong></td><td>5.4</td><td><strong>32.4</strong></td><td><strong>56.9</strong></td><td>3.8</td><td>22.6</td><td><strong>42.3</strong></td><td>6.1</td><td>21.4</td><td><strong>56.0</strong></td></tr><tr><td>Agitation/aggression</td><td>2.6</td><td>1.4</td><td><strong>11.0</strong></td><td><strong>33.6</strong></td><td>1.8</td><td><strong>10.8</strong></td><td><strong>37.5</strong></td><td>0.8</td><td><strong>16.1</strong></td><td><strong>25.0</strong></td><td>2.0</td><td><strong>0.0</strong></td><td><strong>40.0</strong></td></tr><tr><td>Euphoria/elation</td><td>0.3</td><td>1.0</td><td><strong>6.1</strong></td><td><strong>29.5</strong></td><td>2.7</td><td><strong>5.4</strong></td><td><strong>34.7</strong></td><td>0.0</td><td>3.2</td><td><strong>21.2</strong></td><td>0.0</td><td><strong>14.3</strong></td><td><strong>32.0</strong></td></tr><tr><td>Aberrant motor behaviour</td><td>1.3</td><td>0.3</td><td><strong>6.1</strong></td><td><strong>24.2</strong></td><td><strong>0.0</strong></td><td>5.4</td><td><strong>40.3</strong></td><td><strong>0.0</strong></td><td><strong>9.7</strong></td><td><strong>32.7</strong></td><td>2.0</td><td>0.0</td><td><strong>40.0</strong></td></tr><tr><td>Hypersexuality</td><td>0.3</td><td>0.0</td><td><strong>3.7</strong></td><td><strong>14.8</strong></td><td>0.0</td><td><strong>8.1</strong></td><td><strong>16.7</strong></td><td>0.0</td><td>0.0</td><td><strong>11.5</strong></td><td>0.0</td><td>0.0</td><td><strong>16.0</strong></td></tr><tr><td>Hyperreligiosity</td><td>0.0</td><td>0.3</td><td>2.4</td><td><strong>10.7</strong></td><td>0.0</td><td>0.0</td><td><strong>12.5</strong></td><td>0.8</td><td>6.5</td><td><strong>5.8</strong></td><td>0.0</td><td>0.0</td><td><strong>16.0</strong></td></tr><tr><td>Impaired sleep</td><td>13.2</td><td>7.2</td><td><strong>26.8</strong></td><td><strong>44.3</strong></td><td><strong>3.6</strong></td><td><strong>27.0</strong></td><td><strong>48.6</strong></td><td>9.2</td><td><strong>29.0</strong></td><td><strong>40.4</strong></td><td>10.2</td><td>21.4</td><td><strong>40.0</strong></td></tr><tr><td>Altered sense of humour</td><td>0.6</td><td>0.3</td><td><strong>4.9</strong></td><td><strong>46.3</strong></td><td>0.0</td><td><strong>8.1</strong></td><td><strong>40.3</strong></td><td>0.8</td><td>3.2</td><td><strong>42.3</strong></td><td>0.0</td><td>0.0</td><td><strong>72.0</strong></td></tr></tbody><tfoot><tr><td colspan="14">Number of cases is as per table 1. Bold items are significantly more frequent than controls and italicised items are significantly less frequent than controls (p&lt;0.05). Other differences are shown as *significantly more frequent compared with GRN, †significantly more frequent compared with MAPT and ‡significantly more frequent compared with C9orf72 (p&lt;0.05). See online supplemental file 1 for similar analysis of severity.</td></tr></tfoot></table>
<table><caption>**Table 3** Principal component analysis of neuropsychiatric symptoms in all mutation carriers</caption><thead><tr><th>Component</th><th>1</th><th>2</th><th>3</th><th>4</th></tr></thead><tbody><tr><td>Visual hallucinations</td><td>0.19</td><td>0.88</td><td>0.22</td><td>0.00</td></tr><tr><td>Auditory hallucinations</td><td>0.25</td><td>0.88</td><td>0.27</td><td>0.00</td></tr><tr><td>Tactile hallucinations</td><td>0.38</td><td>0.24</td><td>0.32</td><td>-0.85</td></tr><tr><td>Delusions</td><td>0.41</td><td>0.73</td><td>0.28</td><td>0.00</td></tr><tr><td>Depression</td><td>0.00</td><td>0.19</td><td>0.85</td><td>0.00</td></tr><tr><td>Anxiety</td><td>0.25</td><td>0.22</td><td>0.80</td><td>0.00</td></tr><tr><td>Irritability/lability</td><td>0.68</td><td>0.11</td><td>0.58</td><td>0.00</td></tr><tr><td>Agitation/aggression</td><td>0.75</td><td>0.10</td><td>0.40</td><td>0.00</td></tr><tr><td>Euphoria/elation</td><td>0.84</td><td>0.26</td><td>0.13</td><td>0.00</td></tr><tr><td>Aberrant motor behaviour</td><td>0.66</td><td>0.49</td><td>0.16</td><td>0.11</td></tr><tr><td>Hypersexuality</td><td>0.77</td><td>0.22</td><td>0.20</td><td>-0.14</td></tr><tr><td>Hyperreligiosity</td><td>0.32</td><td>0.36</td><td>0.22</td><td>0.83</td></tr><tr><td>Impaired sleep</td><td>0.28</td><td>0.31</td><td>0.72</td><td>0.00</td></tr><tr><td>Altered sense of humour</td><td>0.74</td><td>0.39</td><td>0.00</td><td>0.34</td></tr><tr><td>Cumulative variance</td><td>0.28</td><td>0.49</td><td>0.69</td><td>0.81</td></tr></tbody></table>

FTLD≥1) C9orf72 mutation carriers with the majority of symptoms also significantly more frequent (and in most cases more severe) in the symptomatic GRN and MAPT groups (table 2, online supplemental table 2). Comparing groups, hallucinations and delusions were more frequent and severe in the C9orf72 group: visual hallucinations frequency 23.6%, severity 0.26 (0.58) vs 7.7%, 0.10 (0.36) in GRN mutation carriers and 8.0%, 0.06 (0.22) in MAPT mutation carriers; auditory hallucinations 22.2%, 0.31 (0.71) vs 7.7%, 0.06 (0.21) and 0.0%, 0.00 (0.00); tactile hallucinations 9.7%, 0.14 (0.53) vs 0.0%, 0.00 (0.00)

and 4.0%, 0.02 (0.10); delusions 36.1%, 0.51 (0.81) vs 17.3%, 0.13 (0.36) and 12.0%, 0.16 (0.47). In contrast, altered sense of humour was more frequent and severe in symptomatic MAPT mutation carriers compared with the other two groups (72.0%, 1.12 (1.07) vs 40.3%, 0.52 (0.79) in C9orf72 and 42.3%, 0.47 (0.70) in GRN). When the CDR plus NACC FTLD was 0.5 anxiety (C9orf72 35.1%, GRN 41.9%, MAPT 50.0%), depression (C9orf72 21.6%, GRN 41.9%, MAPT 42.9%), impaired sleep (C9orf72 27.0%, GRN 29.0%, MAPT 21.4%) and irritability/lability (C9orf72 32.4%, GRN 22.6%, MAPT 21.4%) were the most frequent symptoms. However, visual hallucinations were more common in all three groups (C9orf72 5.4%, GRN 6.5%, MAPT 7.1%) and agitation/aggression (in C9orf72 and GRN), euphoria/elation (in C9orf72 and MAPT), aberrant motor behaviour (in GRN), hypersexuality (in C9orf72) and altered sense of humour (in C9orf72) all occurred more frequently than in controls. Only euphoria/elation was more frequent (in the C9orf72 group) at a CDR plus NACC FTLD of 0 with no other symptoms more frequent or severe than controls (figure 1, table 2, online supplemental table 2).

## Principal component analysis

PCA of the neuropsychiatric symptoms loaded on to four main components, which cumulatively explained 28%, 49%, 69% and 81% of the variation in the data respectively. Component one showed loading mainly of the non-psychosis and non-affective ('behavioural') symptoms, component two strongly loaded visual and auditory hallucinations and delusions (ie, features of 'psychosis'), component three loaded depression, anxiety and impaired sleep (ie, 'mood' symptoms), and component four loaded hyperreligiosity (table 3, figure 2). PCA of the

<figure><img src="image_4.png" /><figcaption>**Figure 2** Visual representation of the principal component analysis (PCA) results. The PCA of the neuropsychiatric symptom scale revealed four components, named for the items which loaded most strongly: 'psychosis', 'mood' and 'behavioural', with a fourth component of hyperreligiosity. The dotted boxes represent the finding that in a further PCA which included the core behavioural symptoms of FTD these items loaded alongside the 'behavioural' features of the neuropsychiatric symptom scale. FTD, frontotemporal dementia.</figcaption></figure>
<table><caption>**Table 3** Principal component analysis of neuropsychiatric symptoms in all mutation carriers</caption><thead><tr><th>Component</th><th>1</th><th>2</th><th>3</th><th>4</th></tr></thead><tbody><tr><td>Visual hallucinations</td><td>0.19</td><td>0.88</td><td>0.22</td><td>0.00</td></tr><tr><td>Auditory hallucinations</td><td>0.25</td><td>0.88</td><td>0.27</td><td>0.00</td></tr><tr><td>Tactile hallucinations</td><td>0.38</td><td>0.24</td><td>0.32</td><td>-0.85</td></tr><tr><td>Delusions</td><td>0.41</td><td>0.73</td><td>0.28</td><td>0.00</td></tr><tr><td>Depression</td><td>0.00</td><td>0.19</td><td>0.85</td><td>0.00</td></tr><tr><td>Anxiety</td><td>0.25</td><td>0.22</td><td>0.80</td><td>0.00</td></tr><tr><td>Irritability/lability</td><td>0.68</td><td>0.11</td><td>0.58</td><td>0.00</td></tr><tr><td>Agitation/aggression</td><td>0.75</td><td>0.10</td><td>0.40</td><td>0.00</td></tr><tr><td>Euphoria/elation</td><td>0.84</td><td>0.26</td><td>0.13</td><td>0.00</td></tr><tr><td>Aberrant motor behaviour</td><td>0.66</td><td>0.49</td><td>0.16</td><td>0.11</td></tr><tr><td>Hypersexuality</td><td>0.77</td><td>0.22</td><td>0.20</td><td>-0.14</td></tr><tr><td>Hyperreligiosity</td><td>0.32</td><td>0.36</td><td>0.22</td><td>0.83</td></tr><tr><td>Impaired sleep</td><td>0.28</td><td>0.31</td><td>0.72</td><td>0.00</td></tr><tr><td>Altered sense of humour</td><td>0.74</td><td>0.39</td><td>0.00</td><td>0.34</td></tr><tr><td>Cumulative variance</td><td>0.28</td><td>0.49</td><td>0.69</td><td>0.81</td></tr></tbody></table>

FTLD≥1) C9orf72 mutation carriers with the majority of symptoms also significantly more frequent (and in most cases more severe) in the symptomatic GRN and MAPT groups (table 2, online supplemental table 2). Comparing groups, hallucinations and delusions were more frequent and severe in the C9orf72 group: visual hallucinations frequency 23.6%, severity 0.26 (0.58) vs 7.7%, 0.10 (0.36) in GRN mutation carriers and 8.0%, 0.06 (0.22) in MAPT mutation carriers; auditory hallucinations 22.2%, 0.31 (0.71) vs 7.7%, 0.06 (0.21) and 0.0%, 0.00 (0.00); tactile hallucinations 9.7%, 0.14 (0.53) vs 0.0%, 0.00 (0.00)

and 4.0%, 0.02 (0.10); delusions 36.1%, 0.51 (0.81) vs 17.3%, 0.13 (0.36) and 12.0%, 0.16 (0.47). In contrast, altered sense of humour was more frequent and severe in symptomatic MAPT mutation carriers compared with the other two groups (72.0%, 1.12 (1.07) vs 40.3%, 0.52 (0.79) in C9orf72 and 42.3%, 0.47 (0.70) in GRN). When the CDR plus NACC FTLD was 0.5 anxiety (C9orf72 35.1%, GRN 41.9%, MAPT 50.0%), depression (C9orf72 21.6%, GRN 41.9%, MAPT 42.9%), impaired sleep (C9orf72 27.0%, GRN 29.0%, MAPT 21.4%) and irritability/lability (C9orf72 32.4%, GRN 22.6%, MAPT 21.4%) were the most frequent symptoms. However, visual hallucinations were more common in all three groups (C9orf72 5.4%, GRN 6.5%, MAPT 7.1%) and agitation/aggression (in C9orf72 and GRN), euphoria/elation (in C9orf72 and MAPT), aberrant motor behaviour (in GRN), hypersexuality (in C9orf72) and altered sense of humour (in C9orf72) all occurred more frequently than in controls. Only euphoria/elation was more frequent (in the C9orf72 group) at a CDR plus NACC FTLD of 0 with no other symptoms more frequent or severe than controls (figure 1, table 2, online supplemental table 2).

## Principal component analysis

PCA of the neuropsychiatric symptoms loaded on to four main components, which cumulatively explained 28%, 49%, 69% and 81% of the variation in the data respectively. Component one showed loading mainly of the non-psychosis and non-affective ('behavioural') symptoms, component two strongly loaded visual and auditory hallucinations and delusions (ie, features of 'psychosis'), component three loaded depression, anxiety and impaired sleep (ie, 'mood' symptoms), and component four loaded hyperreligiosity (table 3, figure 2). PCA of the

<figure><img src="image_6.png" /><figcaption>**Figure 2** Visual representation of the principal component analysis (PCA) results. The PCA of the neuropsychiatric symptom scale revealed four components, named for the items which loaded most strongly: 'psychosis', 'mood' and 'behavioural', with a fourth component of hyperreligiosity. The dotted boxes represent the finding that in a further PCA which included the core behavioural symptoms of FTD these items loaded alongside the 'behavioural' features of the neuropsychiatric symptom scale. FTD, frontotemporal dementia.</figcaption></figure>
<table><caption>**Table 4** Principal component analysis of combined neuropsychiatric and behavioural symptoms in all mutation carriers</caption><thead><tr><th>Component</th><th>1</th><th>2</th><th>3</th><th>4</th></tr></thead><tbody><tr><td>Visual hallucinations</td><td>0.13</td><td>0.89</td><td>0.21</td><td>-0.21</td></tr><tr><td>Auditory hallucinations</td><td>0.32</td><td>0.90</td><td>0.11</td><td>0.00</td></tr><tr><td>Tactile hallucinations</td><td>0.00</td><td>0.00</td><td>-0.89</td><td>0.26</td></tr><tr><td>Delusions</td><td>0.43</td><td>0.74</td><td>-0.15</td><td>0.20</td></tr><tr><td>Depression</td><td>-0.76</td><td>-0.11</td><td>0.00</td><td>0.35</td></tr><tr><td>Anxiety</td><td>-0.68</td><td>-0.20</td><td>0.00</td><td>0.47</td></tr><tr><td>Irritability/lability</td><td>0.31</td><td>-0.61</td><td>-0.19</td><td>0.58</td></tr><tr><td>Agitation/aggression</td><td>0.59</td><td>-0.56</td><td>-0.22</td><td>0.26</td></tr><tr><td>Euphoria/elation</td><td>0.78</td><td>-0.33</td><td>-0.14</td><td>-0.39</td></tr><tr><td>Aberrant motor behaviour</td><td>0.85</td><td>0.14</td><td>0.18</td><td>0.00</td></tr><tr><td>Hypersexuality</td><td>0.60</td><td>-0.35</td><td>-0.43</td><td>-0.25</td></tr><tr><td>Hyperreligiosity</td><td>0.38</td><td>0.19</td><td>0.83</td><td>0.00</td></tr><tr><td>Impaired sleep</td><td>-0.37</td><td>0.00</td><td>-0.18</td><td>0.78</td></tr><tr><td>Altered sense of humour</td><td>0.85</td><td>0.00</td><td>0.40</td><td>-0.16</td></tr><tr><td>Disinhibition</td><td>0.94</td><td>0.00</td><td>-0.21</td><td>0.00</td></tr><tr><td>Apathy</td><td>0.88</td><td>0.23</td><td>0.16</td><td>0.00</td></tr><tr><td>Loss of sympathy/empathy</td><td>0.93</td><td>0.20</td><td>0.17</td><td>0.00</td></tr><tr><td>Ritualistic/compulsive behaviour</td><td>0.93</td><td>0.00</td><td>0.00</td><td>0.00</td></tr><tr><td>Hyperorality and appetite changes</td><td>0.92</td><td>0.19</td><td>0.27</td><td>0.00</td></tr><tr><td>Poor response to social/emotional cues</td><td>0.96</td><td>0.12</td><td>0.00</td><td>0.00</td></tr><tr><td>Inappropriate trusting behaviour</td><td>0.95</td><td>0.00</td><td>0.00</td><td>-0.13</td></tr><tr><td>Cumulative variance</td><td>0.50</td><td>0.66</td><td>0.77</td><td>0.85</td></tr></tbody></table>

neuropsychiatric symptoms in the individual genetic groups produced similar results (online supplemental table 3a).

When adding the core behavioural symptoms to the PCA, a similar result was found with four components, but in this analysis all the core behavioural symptoms loaded with the other 'behavioural' (ie, non-psychosis, non-affective) symptoms from the neuropsychiatric symptom scale (apart from hyperreligiosity, which as previously, loaded separately) (table 4, online supplemental table 3b, figure 2).

## Subanalysis of longitudinal change in depression and anxiety

In the PCA, depression and anxiety consistently loaded together, often with symptoms likely to be secondary to these affective disorders such as impaired sleep and irritability/lability. In order to further consider whether affective symptoms should be included or excluded from any rating scale the longitudinal change was assessed. Within the combined mutation carrier group, and stratifying by CDR plus NACC FTLD, 55.6% had depression (mean severity 0.7 (0.8)) and 51.9% had anxiety (0.7 (0.9)) at visit one in the symptomatic (≥1) group, while at visit two 37.0% had depression (mean severity 0.4 (0.7)) and 44.4% had anxiety (0.6 (0.8)) and at visit three 40.7% had depression (mean severity 0.5 (0.7)) and 40.7% had anxiety (0.8 (0.8)). For the prodromal (0.5) group, 25.0% had depression (mean severity 0.2 (0.4)) and 25.0% had anxiety (0.2 (0.4)) at visit one, while at visit two 12.5% had depression (mean severity 0.3 (0.7)) and 31.3% had anxiety (0.3 (0.6)), and at visit three 25.0% had depression (mean severity 0.3 (0.5)) and 25.0% had anxiety (0.3 (0.6)). Finally, for the asymptomatic (0) group 7.8% had depression (mean severity 0.1 (0.3)) and 10.3% had anxiety (0.1 (0.4)) at visit one, while at visit two 12.9% had depression (mean severity 0.1 (0.4)) and 15.5% had anxiety (0.1 (0.4)), and at visit three 12.1% had depression (mean severity 0.1 (0.3)) and 12.1% had anxiety (0.1 (0.3)). Figure 3A highlights the change in mean severity of anxiety and depression within each group

over time (with online supplemental figure 1 showing the same data for each of the genetic groups), while figure 3B,C shows the individual fluctuation in depression (3b) and anxiety (3c) symptoms over time.

## Rating scale analysis

In light of the above results, we first investigated adding a neuropsychiatric module to the CDR plus NACC FTLD rating scale consisting only of the psychosis symptoms (hallucinations and delusions), excluding both affective symptoms and the other symptoms which loaded with the core behavioural features. We termed this the CDR plus NACC FTLD-N. This scale was positively correlated with the original CDR plus NACC FTLD (r=0.992, p<0.001). The new scale led to a number of participants (0.6%) now being considered prodromal who had previously been asymptomatic on the CDR plus NACC FTLD, as well as symptomatic participants with a bvFTD diagnosis now being considered more severely affected (figure 4).

Second, we investigated a change to the behavioural module of the CDR plus NACC FTLD by (1) incorporating the non-psychosis and non-affective symptoms included in the GENFI neuropsychiatric symptoms scale and (2) generating an Algorithm-based Behaviour score from each of the individual behavioural symptoms (rather than using a Global Behaviour Score; see online supplemental table 4 for how this was generated). We termed this the CDR plus NACC FTLD-N-B+. In general, the Algorithm-based Behaviour Score led to fewer people being scored as 0 (68.4%, compared with 77.9% using the Global Behaviour Score), and more people being scored as 0.5 (very mild symptoms; 14.3%, compared with 6.4% using the Global Behaviour Score) (online supplemental figure 2). Including this within the CDR plus NACC FTLD alongside the new neuropsychiatric module also leads to more participants being considered prodromal (6% of people were asymptomatic on the CDR plus NACC FTLD but prodromal on the CDR plus NACC FTLD-N-B+) (figure 5) as well as clinically judged symptomatic participants being considered as more severe on the new scale, particularly those with a diagnosis of bvFTD (figure 4). Analysis of individual genetic mutation groups shows most of this change is in C9orf72 mutation carriers (online supplemental figure 3).

## DISCUSSION

This study has shown that neuropsychiatric features are common in genetic FTD and can occur early on in the disease process many years before people receive a clinical diagnosis. As such, they should be incorporated into any comprehensive clinical rating scale of FTD. However, the results here show that some of the neuropsychiatric symptoms can be variable, and careful thought is required in terms of which features are included in any scale. A PCA suggested that there are three main groups of neuropsychiatric symptoms: affective symptoms of anxiety and depression, 'psychotic' symptoms of hallucinations and delusions, and a set of 'other' symptoms including agitation, irritability and hypersexuality that loaded with the core behavioural features of bvFTD. While anxiety and depression are prominent symptoms in mutation carriers, they are also common in controls and fluctuate longitudinally over time suggesting they should be excluded from any scale. Furthermore, the association of the 'other' symptoms with the behavioural features of FTD suggest they should be considered as part of the 'behavioural' component of the scale rather than as a separate module. However, the third component including visual and auditory hallucinations and
<table><caption>**Table 4** Principal component analysis of combined neuropsychiatric and behavioural symptoms in all mutation carriers</caption><thead><tr><th>Component</th><th>1</th><th>2</th><th>3</th><th>4</th></tr></thead><tbody><tr><td>Visual hallucinations</td><td>0.13</td><td>0.89</td><td>0.21</td><td>-0.21</td></tr><tr><td>Auditory hallucinations</td><td>0.32</td><td>0.90</td><td>0.11</td><td>0.00</td></tr><tr><td>Tactile hallucinations</td><td>0.00</td><td>0.00</td><td>-0.89</td><td>0.26</td></tr><tr><td>Delusions</td><td>0.43</td><td>0.74</td><td>-0.15</td><td>0.20</td></tr><tr><td>Depression</td><td>-0.76</td><td>-0.11</td><td>0.00</td><td>0.35</td></tr><tr><td>Anxiety</td><td>-0.68</td><td>-0.20</td><td>0.00</td><td>0.47</td></tr><tr><td>Irritability/lability</td><td>0.31</td><td>-0.61</td><td>-0.19</td><td>0.58</td></tr><tr><td>Agitation/aggression</td><td>0.59</td><td>-0.56</td><td>-0.22</td><td>0.26</td></tr><tr><td>Euphoria/elation</td><td>0.78</td><td>-0.33</td><td>-0.14</td><td>-0.39</td></tr><tr><td>Aberrant motor behaviour</td><td>0.85</td><td>0.14</td><td>0.18</td><td>0.00</td></tr><tr><td>Hypersexuality</td><td>0.60</td><td>-0.35</td><td>-0.43</td><td>-0.25</td></tr><tr><td>Hyperreligiosity</td><td>0.38</td><td>0.19</td><td>0.83</td><td>0.00</td></tr><tr><td>Impaired sleep</td><td>-0.37</td><td>0.00</td><td>-0.18</td><td>0.78</td></tr><tr><td>Altered sense of humour</td><td>0.85</td><td>0.00</td><td>0.40</td><td>-0.16</td></tr><tr><td>Disinhibition</td><td>0.94</td><td>0.00</td><td>-0.21</td><td>0.00</td></tr><tr><td>Apathy</td><td>0.88</td><td>0.23</td><td>0.16</td><td>0.00</td></tr><tr><td>Loss of sympathy/empathy</td><td>0.93</td><td>0.20</td><td>0.17</td><td>0.00</td></tr><tr><td>Ritualistic/compulsive behaviour</td><td>0.93</td><td>0.00</td><td>0.00</td><td>0.00</td></tr><tr><td>Hyperorality and appetite changes</td><td>0.92</td><td>0.19</td><td>0.27</td><td>0.00</td></tr><tr><td>Poor response to social/emotional cues</td><td>0.96</td><td>0.12</td><td>0.00</td><td>0.00</td></tr><tr><td>Inappropriate trusting behaviour</td><td>0.95</td><td>0.00</td><td>0.00</td><td>-0.13</td></tr><tr><td>Cumulative variance</td><td>0.50</td><td>0.66</td><td>0.77</td><td>0.85</td></tr></tbody></table>

neuropsychiatric symptoms in the individual genetic groups produced similar results (online supplemental table 3a).

When adding the core behavioural symptoms to the PCA, a similar result was found with four components, but in this analysis all the core behavioural symptoms loaded with the other 'behavioural' (ie, non-psychosis, non-affective) symptoms from the neuropsychiatric symptom scale (apart from hyperreligiosity, which as previously, loaded separately) (table 4, online supplemental table 3b, figure 2).

## Subanalysis of longitudinal change in depression and anxiety

In the PCA, depression and anxiety consistently loaded together, often with symptoms likely to be secondary to these affective disorders such as impaired sleep and irritability/lability. In order to further consider whether affective symptoms should be included or excluded from any rating scale the longitudinal change was assessed. Within the combined mutation carrier group, and stratifying by CDR plus NACC FTLD, 55.6% had depression (mean severity 0.7 (0.8)) and 51.9% had anxiety (0.7 (0.9)) at visit one in the symptomatic (≥1) group, while at visit two 37.0% had depression (mean severity 0.4 (0.7)) and 44.4% had anxiety (0.6 (0.8)) and at visit three 40.7% had depression (mean severity 0.5 (0.7)) and 40.7% had anxiety (0.8 (0.8)). For the prodromal (0.5) group, 25.0% had depression (mean severity 0.2 (0.4)) and 25.0% had anxiety (0.2 (0.4)) at visit one, while at visit two 12.5% had depression (mean severity 0.3 (0.7)) and 31.3% had anxiety (0.3 (0.6)), and at visit three 25.0% had depression (mean severity 0.3 (0.5)) and 25.0% had anxiety (0.3 (0.6)). Finally, for the asymptomatic (0) group 7.8% had depression (mean severity 0.1 (0.3)) and 10.3% had anxiety (0.1 (0.4)) at visit one, while at visit two 12.9% had depression (mean severity 0.1 (0.4)) and 15.5% had anxiety (0.1 (0.4)), and at visit three 12.1% had depression (mean severity 0.1 (0.3)) and 12.1% had anxiety (0.1 (0.3)). Figure 3A highlights the change in mean severity of anxiety and depression within each group

over time (with online supplemental figure 1 showing the same data for each of the genetic groups), while figure 3B,C shows the individual fluctuation in depression (3b) and anxiety (3c) symptoms over time.

## Rating scale analysis

In light of the above results, we first investigated adding a neuropsychiatric module to the CDR plus NACC FTLD rating scale consisting only of the psychosis symptoms (hallucinations and delusions), excluding both affective symptoms and the other symptoms which loaded with the core behavioural features. We termed this the CDR plus NACC FTLD-N. This scale was positively correlated with the original CDR plus NACC FTLD (r=0.992, p<0.001). The new scale led to a number of participants (0.6%) now being considered prodromal who had previously been asymptomatic on the CDR plus NACC FTLD, as well as symptomatic participants with a bvFTD diagnosis now being considered more severely affected (figure 4).

Second, we investigated a change to the behavioural module of the CDR plus NACC FTLD by (1) incorporating the non-psychosis and non-affective symptoms included in the GENFI neuropsychiatric symptoms scale and (2) generating an Algorithm-based Behaviour score from each of the individual behavioural symptoms (rather than using a Global Behaviour Score; see online supplemental table 4 for how this was generated). We termed this the CDR plus NACC FTLD-N-B+. In general, the Algorithm-based Behaviour Score led to fewer people being scored as 0 (68.4%, compared with 77.9% using the Global Behaviour Score), and more people being scored as 0.5 (very mild symptoms; 14.3%, compared with 6.4% using the Global Behaviour Score) (online supplemental figure 2). Including this within the CDR plus NACC FTLD alongside the new neuropsychiatric module also leads to more participants being considered prodromal (6% of people were asymptomatic on the CDR plus NACC FTLD but prodromal on the CDR plus NACC FTLD-N-B+) (figure 5) as well as clinically judged symptomatic participants being considered as more severe on the new scale, particularly those with a diagnosis of bvFTD (figure 4). Analysis of individual genetic mutation groups shows most of this change is in C9orf72 mutation carriers (online supplemental figure 3).

## DISCUSSION

This study has shown that neuropsychiatric features are common in genetic FTD and can occur early on in the disease process many years before people receive a clinical diagnosis. As such, they should be incorporated into any comprehensive clinical rating scale of FTD. However, the results here show that some of the neuropsychiatric symptoms can be variable, and careful thought is required in terms of which features are included in any scale. A PCA suggested that there are three main groups of neuropsychiatric symptoms: affective symptoms of anxiety and depression, 'psychotic' symptoms of hallucinations and delusions, and a set of 'other' symptoms including agitation, irritability and hypersexuality that loaded with the core behavioural features of bvFTD. While anxiety and depression are prominent symptoms in mutation carriers, they are also common in controls and fluctuate longitudinally over time suggesting they should be excluded from any scale. Furthermore, the association of the 'other' symptoms with the behavioural features of FTD suggest they should be considered as part of the 'behavioural' component of the scale rather than as a separate module. However, the third component including visual and auditory hallucinations and
<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /><figcaption>**Figure 3** Longitudinal change in depression and anxiety in asymptomatic (CDR plus NACC FTLD global score of 0), prodromal (0.5) and symptomatic (≥1) mutation carriers: (A) mean severity of depression (solid line) and anxiety (dotted line) within all carriers; (B, C) Sankey diagrams showing individual change in depression (B) and anxiety (C) scores. CDR, Clinical Dementia Rating; NACC FTLD, National Alzheimer's Coordinating Center Behaviour and Language Domains.</figcaption></figure>

delusions separated out from the other features and was distinct to any current module in clinical FTD scales, particularly within the CDR plus NACC FTLD, suggesting this component should form a new neuropsychiatric module to specifically capture this element of the FTD phenotype. Adding this module to the CDR plus NACC FTLD (called here the CDR plus NACC FTLD-N) resulted in people previously being considered as asymptomatic now being considered prodromal, and in general people being rated as more severe, highlighting the importance of including psychotic symptoms in clinical rating scales of FTD.

## Frequency and severity of symptoms

Neuropsychiatric features were present in almost half the cohort studied, more commonly in those who were judged as symptomatic, but also occurring to a lesser extent prodromally (CDR

plus NACC FTLD global score 0.5) and in some people at an asymptomatic stage (CDR plus NACC FTLD global score 0). Anxiety, depression and impaired sleep were the most common symptoms in mutation carriers. The presence of affective symptoms has been previously reported in symptomatic FTD, for example, a systematic review suggested a prevalence of 7%–69% of depression in FTD in general, and of 19%–63% of anxiety in bvFTD; the frequency in our study of 40.3% (depression) and 49.7% (anxiety) fits well within this range. However, such symptoms were also common in our controls with 12.9%, 15.5% and 13.2% reporting symptoms of depression, anxiety and impaired sleep, respectively. The prevalence of these conditions is around 5% for depression, 7% for anxiety and up to 30% for sleep problems in European countries, suggesting potentially higher rates in our cohort of controls compared with the general population
<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /><figcaption>**Figure 3** Longitudinal change in depression and anxiety in asymptomatic (CDR plus NACC FTLD global score of 0), prodromal (0.5) and symptomatic (≥1) mutation carriers: (A) mean severity of depression (solid line) and anxiety (dotted line) within all carriers; (B, C) Sankey diagrams showing individual change in depression (B) and anxiety (C) scores. CDR, Clinical Dementia Rating; NACC FTLD, National Alzheimer's Coordinating Center Behaviour and Language Domains.</figcaption></figure>

delusions separated out from the other features and was distinct to any current module in clinical FTD scales, particularly within the CDR plus NACC FTLD, suggesting this component should form a new neuropsychiatric module to specifically capture this element of the FTD phenotype. Adding this module to the CDR plus NACC FTLD (called here the CDR plus NACC FTLD-N) resulted in people previously being considered as asymptomatic now being considered prodromal, and in general people being rated as more severe, highlighting the importance of including psychotic symptoms in clinical rating scales of FTD.

## Frequency and severity of symptoms

Neuropsychiatric features were present in almost half the cohort studied, more commonly in those who were judged as symptomatic, but also occurring to a lesser extent prodromally (CDR

plus NACC FTLD global score 0.5) and in some people at an asymptomatic stage (CDR plus NACC FTLD global score 0). Anxiety, depression and impaired sleep were the most common symptoms in mutation carriers. The presence of affective symptoms has been previously reported in symptomatic FTD, for example, a systematic review suggested a prevalence of 7%–69% of depression in FTD in general, and of 19%–63% of anxiety in bvFTD; the frequency in our study of 40.3% (depression) and 49.7% (anxiety) fits well within this range. However, such symptoms were also common in our controls with 12.9%, 15.5% and 13.2% reporting symptoms of depression, anxiety and impaired sleep, respectively. The prevalence of these conditions is around 5% for depression, 7% for anxiety and up to 30% for sleep problems in European countries, suggesting potentially higher rates in our cohort of controls compared with the general population
<figure><img src="image_7.png" /><figcaption>**Figure 4** Comparison of the standard CDR plus NACC FTLD with a new CDR plus NACC FTLD plus Neuropsychiatric Score (CDR plus NACC FTLD-N). The top figure shows the change in global score in individual participants (five participants moved from 0 to 0.5 and 1 participant from 1 to 2). The bottom figure shows the percentage of symptomatic participants with a particular CDR score (left shows standard CDR plus NACC FTLD, right shows the change with the new CDR plus NACC FTLD-N). bvFTD, behavioural variant frontotemporal dementia; CDR, Clinical Dementia Rating; NACC FTLD, National Alzheimer's Coordinating Center Behaviour and Language Domains; PPA, Primary Progressive Aphasia.</figcaption></figure>

(with the caveat that in GENFI we are measuring symptoms rather than making specific mental health diagnoses).²³ ²⁴ The increased prevalence of affective disorders in mutation-negative family members has been poorly studied in genetic FTD but is a well-known phenomenon in neurogenetic disorders and can relate to multiple issues including survivor guilt in those who test negative within the family.

Of the mutation groups studied, *C9orf72* expansion carriers had the highest frequency of neuropsychiatric symptoms, followed by *MAPT* then *GRN* mutation carriers. Many studies have shown a close link between *C9orf72* expansion carriers and the presence of neuropsychiatric symptoms, both early on as a presenting feature and during the course of the disease.²⁵⁻²⁸ Moreover, *C9orf72* mutations are the most common genetic cause of ALS,²⁹ ³⁰ with previous studies showing an association

of ALS with early neuropsychiatric disturbances independent of other behavioural symptoms.³¹

Although less common than affective symptoms, 'psychosis' features, that is, hallucinations and delusions occur in up to a quarter of symptomatic patients, and more frequently in *C9orf72* than *GRN* and *MAPT* mutation carriers. This is consistent with prior studies showing they occur commonly in *C9orf72* mutation carriers,⁶ although not uniquely and can be present in the other genetic groups.⁷ ³² In the current study, hallucinations and delusions were present only infrequently in *C9orf72* mutation carriers in the presymptomatic period, increasing in frequency when entering the symptomatic phase.³³ Psychosis-type symptoms were least frequent and mildest in *MAPT* mutation carriers, although were still present, suggesting that these symptoms are not pathognomonic of a particular genetic subtype.
A

<figure><img src="image_9.png" /></figure>

B

<figure><img src="image_10.png" /><figcaption>**Figure 4** Comparison of the standard CDR plus NACC FTLD with a new CDR plus NACC FTLD plus Neuropsychiatric Score (CDR plus NACC FTLD-N). The top figure shows the change in global score in individual participants (five participants moved from 0 to 0.5 and 1 participant from 1 to 2). The bottom figure shows the percentage of symptomatic participants with a particular CDR score (left shows standard CDR plus NACC FTLD, right shows the change with the new CDR plus NACC FTLD-N). bvFTD, behavioural variant frontotemporal dementia; CDR, Clinical Dementia Rating; NACC FTLD, National Alzheimer's Coordinating Center Behaviour and Language Domains; PPA, Primary Progressive Aphasia.</figcaption></figure>

(with the caveat that in GENFI we are measuring symptoms rather than making specific mental health diagnoses).²³ ²⁴ The increased prevalence of affective disorders in mutation-negative family members has been poorly studied in genetic FTD but is a well-known phenomenon in neurogenetic disorders and can relate to multiple issues including survivor guilt in those who test negative within the family.

Of the mutation groups studied, *C9orf72* expansion carriers had the highest frequency of neuropsychiatric symptoms, followed by *MAPT* then *GRN* mutation carriers. Many studies have shown a close link between *C9orf72* expansion carriers and the presence of neuropsychiatric symptoms, both early on as a presenting feature and during the course of the disease.²⁵⁻²⁸ Moreover, *C9orf72* mutations are the most common genetic cause of ALS,²⁹ ³⁰ with previous studies showing an association

of ALS with early neuropsychiatric disturbances independent of other behavioural symptoms.³¹

Although less common than affective symptoms, 'psychosis' features, that is, hallucinations and delusions occur in up to a quarter of symptomatic patients, and more frequently in *C9orf72* than *GRN* and *MAPT* mutation carriers. This is consistent with prior studies showing they occur commonly in *C9orf72* mutation carriers,⁶ although not uniquely and can be present in the other genetic groups.⁷ ³² In the current study, hallucinations and delusions were present only infrequently in *C9orf72* mutation carriers in the presymptomatic period, increasing in frequency when entering the symptomatic phase.³³ Psychosis-type symptoms were least frequent and mildest in *MAPT* mutation carriers, although were still present, suggesting that these symptoms are not pathognomonic of a particular genetic subtype.
<figure><img src="image_8.png" /><figcaption>**Figure 5** Comparison of the standard CDR plus NACC FTLD with the CDR plus NACC FTLD-N-B+. The top figure shows the change in global score in individual participants (50 participants moved from 0 to 0.5, 1 participant from 0 to 1, 4 participants from 0.5 to 1, 2 participants from 1 to 0.5 and 4 participants from 1 to 2). The bottom figure shows the percentage of symptomatic participants with a particular CDR score (left shows standard CDR plus NACC FTLD, right shows the change with the new CDR plus NACC FTLD-N-B+). CDR, Clinical Dementia Rating; FTD, behavioural variant frontotemporal dementia; NACC FTLD, National Alzheimer's Coordinating Center Behaviour and Language Domains.</figcaption></figure>

The only symptom that was more frequent in *MAPT* mutation carriers compared with the other groups was altered sense of humour. This has been poorly studied but has been associated with temporal lobe atrophy and *MAPT*-related FTD in one prior study.³⁴

Principal component analysis

PCA identified three main groups of symptoms as hypothesised. Importantly, this suggests that one cannot use a single neuropsychiatric score within a rating scale that incorporates all of the psychotic, affective and other neuropsychiatric symptoms. Combined with the depression/anxiety subanalysis, the results from this study suggest that a single neuropsychiatric score consisting of features of psychosis (ie, hallucinations and delusions) will be necessary in any future clinical rating scale.

Depression and anxiety not only formed a separate group to other neuropsychiatric symptoms, but also fluctuated longitudinally. These two factors combined with the relatively common occurrence in non-carriers support the argument for excluding depression and anxiety from global CDR scoring. There are multiple potential reasons for this fluctuation: the presence of depression and/or anxiety may coincide with life events including recovery with therapy or medication, a change in insight as the disease progresses, biological processes associated with the disease process, heightened anxiety/depression as individuals approach the age at onset of their relatives and subsequent fall in these symptoms if they pass this age, and a disease-related increase in anxiety as mutation carriers get older and more symptomatic from other affected domains.
A

<figure><img src="image_11.png" /></figure>

B

<figure><img src="image_12.png" /><figcaption>**Figure 5** Comparison of the standard CDR plus NACC FTLD with the CDR plus NACC FTLD-N-B+. The top figure shows the change in global score in individual participants (50 participants moved from 0 to 0.5, 1 participant from 0 to 1, 4 participants from 0.5 to 1, 2 participants from 1 to 0.5 and 4 participants from 1 to 2). The bottom figure shows the percentage of symptomatic participants with a particular CDR score (left shows standard CDR plus NACC FTLD, right shows the change with the new CDR plus NACC FTLD-N-B+). CDR, Clinical Dementia Rating; FTD, behavioural variant frontotemporal dementia; NACC FTLD, National Alzheimer's Coordinating Center Behaviour and Language Domains.</figcaption></figure>

The only symptom that was more frequent in *MAPT* mutation carriers compared with the other groups was altered sense of humour. This has been poorly studied but has been associated with temporal lobe atrophy and *MAPT*-related FTD in one prior study.³⁴

## Principal component analysis

PCA identified three main groups of symptoms as hypothesised. Importantly, this suggests that one cannot use a single neuropsychiatric score within a rating scale that incorporates all of the psychotic, affective and other neuropsychiatric symptoms. Combined with the depression/anxiety subanalysis, the results from this study suggest that a single neuropsychiatric score consisting of features of psychosis (ie, hallucinations and delusions) will be necessary in any future clinical rating scale.

Depression and anxiety not only formed a separate group to other neuropsychiatric symptoms, but also fluctuated longitudinally. These two factors combined with the relatively common occurrence in non-carriers support the argument for excluding depression and anxiety from global CDR scoring. There are multiple potential reasons for this fluctuation: the presence of depression and/or anxiety may coincide with life events including recovery with therapy or medication, a change in insight as the disease progresses, biological processes associated with the disease process, heightened anxiety/depression as individuals approach the age at onset of their relatives and subsequent fall in these symptoms if they pass this age, and a disease-related increase in anxiety as mutation carriers get older and more symptomatic from other affected domains.
Behavioural symptoms within the consensus diagnostic criteria for bvFTD<fnref n="1" /> are currently included in the CDR plus NACC FTLD and have often been viewed as separate from neuropsychiatric features. Nonetheless, multiple studies have highlighted the presence of both behavioural and neuropsychiatric symptoms in FTD and interestingly up to half of individuals with bvFTD may initially be given a psychiatric diagnosis.<fnref n="2" /> The loading of some of the neuropsychiatric symptoms (aberrant motor behaviour, euphoria/elation, altered sense of humour, irritability/lability, agitation/aggression and hypersexuality) with the core behavioural features of bvFTD suggests these should be considered when thinking about the behavioural component of any clinical rating scale rather than being included in a separate neuropsychiatric module.

Interestingly, the symptom of hyperreligiosity was distinct from the other three groups. This symptom has been described in association with temporal lobe deficits, particularly of the right hemisphere, and can be seen in right temporal lobe epilepsy³⁵ as well as in people with right temporal lobe variant FTD.³⁶ It is unclear why this does not associate with the other symptoms in the PCA, but in people with right temporal lobe variant FTD, the majority of the other symptoms are cognitive, for example, topographical memory loss and prosopagnosia, rather than behavioural, and it may be that the unique neuroanatomical association separates it from the other neuropsychiatric features. A further important point to note is that in the main analyses, tactile hallucinations (which are rare in FTD) had a negative loading with hyperreligiosity, the reason for which is unclear.

Overall, the PCAs and depression/anxiety subanalyses within the individual genetic mutation groups mirrored the findings when all mutation carriers were studied together, supporting the use of the same approach for all FTD individuals regardless of the genetic mutation, that is, a neuropsychiatric module consisting of 'psychotic' features, consideration of the 'other' neuropsychiatric features when scoring the behavioural domain, and exclusion of affective symptoms from the scale.

## A new neuropsychiatric module to add to the CDR plus NACC FTLD

Inclusion of the neuropsychiatric score into the CDR plus NACC FTLD (CDR plus NACC FTLD-N) led to more people being considered at higher disease stages than the original CDR, including some people being considered prodromal who were previously considered asymptomatic. In people clinically judged to be symptomatic the change in stage was mainly seen in those with bvFTD and minimal change in those with other clinical phenotypes, consistent with prior studies showing that while neuropsychiatric symptoms are seen in PPA and parkinsonian syndromes they are less common.

We also investigated a second addition to the CDR plus NACC FTLD, incorporating a version of the behavioural score that required consideration of multiple different symptoms including not only the core bvFTD symptoms but also the 'other' symptoms from the neuropsychiatric feature list. This also led to a general increase in disease stage severity, suggesting that perhaps clinicians are not considering the whole spectrum of behavioural features in FTD when scoring the behavioural module in the CDR plus NACC FTLD.

It is likely that these two additions to the CDR plus NACC FTLD lead to improved accuracy of rating disease stage in FTD and bring us closer to optimising the rating scale for use in therapeutic trials where precise scoring of an individual's disease

severity is important so that treatment responses can be more representative of their real-life experience with FTD.

## Limitations

Although this study represents one of the largest familial FTD cohorts, numbers become smaller in each group as they are stratified, particularly in longitudinal analyses, such as performed for depression and anxiety.

We had included symptoms in the GENFI neuropsychiatric symptom scale that had been previously reported in patients with FTD. However, reports of other symptoms such as anhedonia³⁷ that have been more recently recognised as part of the FTD spectrum were not included.

When considering depression and anxiety we did not record the effect of therapeutic interventions on symptom severity such as antidepressants or psychological therapies. This did not allow us to measure their effect on the longer-term fluctuation in symptoms, and future studies should address this limitation.

All of the neuropsychiatric symptoms were recorded as being present or absent through the use of the GENFI symptom scale. While this is helpful for our current focus on improving clinical rating scales, it is important to note that this is distinct from making formal clinical diagnoses according to standard criteria of depression, anxiety, psychosis, etc, and therefore, may not be a true representation of the prevalence. Nonetheless, there are also potential reasons why neuropsychiatric symptoms may be underrepresented in GENFI as participants with active affective or psychotic disorders may not be able to (or want to) take part in an ongoing observational research study.

Lastly, although each rater received training in use of the neuropsychiatric symptom scales, now that its use is established it will be important in future studies to formally assess both intra- and inter-rater reliability.

In summary, neuropsychiatric symptoms commonly occur in individuals with FTD in all the main genetic mutation groups, including in those classed as 'asymptomatic'. The failure of the current CDR plus NACC FTLD scale to account for psychotic symptoms runs the risk of adopting inaccurate tools to identify the disease staging and treatment response in individuals enrolled in therapeutic studies. This study suggests an initial step to rectifying this issue.

## Author affiliations

<footnote n="1">¹Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK</footnote>

<footnote n="2">²London School of Hygiene & Tropical Medicine, London, UK</footnote>

<footnote n="3">³Centre for Medical Image Computing, University College London, London, UK</footnote>

<footnote n="4">⁴Neurology, Erasmus MC, Rotterdam, The Netherlands</footnote>

<footnote n="5">⁵Neurology, Erasmus MC Alzheimer Centre, Rotterdam, The Netherlands</footnote>

<footnote n="6">⁶Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital Gipuzkoa Building, San Sebastian, Spain</footnote>

<footnote n="7">⁷Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain</footnote>

<footnote n="8">⁸Interdisciplinary Memory Clinic, Department of Neurological Sciences, Laval University, Quebec, Quebec, Canada</footnote>

<footnote n="9">⁹Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden</footnote>

<footnote n="10">¹⁰Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden</footnote>

<footnote n="11">¹¹Neurology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada</footnote>

<footnote n="12">¹²Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada</footnote>

<footnote n="13">¹³Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK</footnote>

<footnote n="14">¹⁴Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy</footnote>

<footnote n="15">¹⁵Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada</footnote>
Behavioural symptoms within the consensus diagnostic criteria for bvFTD<fnref n="1" /> are currently included in the CDR plus NACC FTLD and have often been viewed as separate from neuropsychiatric features. Nonetheless, multiple studies have highlighted the presence of both behavioural and neuropsychiatric symptoms in FTD and interestingly up to half of individuals with bvFTD may initially be given a psychiatric diagnosis.<fnref n="2" /> The loading of some of the neuropsychiatric symptoms (aberrant motor behaviour, euphoria/elation, altered sense of humour, irritability/lability, agitation/aggression and hypersexuality) with the core behavioural features of bvFTD suggests these should be considered when thinking about the behavioural component of any clinical rating scale rather than being included in a separate neuropsychiatric module.

Interestingly, the symptom of hyperreligiosity was distinct from the other three groups. This symptom has been described in association with temporal lobe deficits, particularly of the right hemisphere, and can be seen in right temporal lobe epilepsy³⁵ as well as in people with right temporal lobe variant FTD.³⁶ It is unclear why this does not associate with the other symptoms in the PCA, but in people with right temporal lobe variant FTD, the majority of the other symptoms are cognitive, for example, topographical memory loss and prosopagnosia, rather than behavioural, and it may be that the unique neuroanatomical association separates it from the other neuropsychiatric features. A further important point to note is that in the main analyses, tactile hallucinations (which are rare in FTD) had a negative loading with hyperreligiosity, the reason for which is unclear.

Overall, the PCAs and depression/anxiety subanalyses within the individual genetic mutation groups mirrored the findings when all mutation carriers were studied together, supporting the use of the same approach for all FTD individuals regardless of the genetic mutation, that is, a neuropsychiatric module consisting of ‘psychotic’ features, consideration of the ‘other’ neuropsychiatric features when scoring the behavioural domain, and exclusion of affective symptoms from the scale.

## A new neuropsychiatric module to add to the CDR plus NACC FTLD

Inclusion of the neuropsychiatric score into the CDR plus NACC FTLD (CDR plus NACC FTLD-N) led to more people being considered at higher disease stages than the original CDR, including some people being considered prodromal who were previously considered asymptomatic. In people clinically judged to be symptomatic the change in stage was mainly seen in those with bvFTD and minimal change in those with other clinical phenotypes, consistent with prior studies showing that while neuropsychiatric symptoms are seen in PPA and parkinsonian syndromes they are less common.

We also investigated a second addition to the CDR plus NACC FTLD, incorporating a version of the behavioural score that required consideration of multiple different symptoms including not only the core bvFTD symptoms but also the ‘other’ symptoms from the neuropsychiatric feature list. This also led to a general increase in disease stage severity, suggesting that perhaps clinicians are not considering the whole spectrum of behavioural features in FTD when scoring the behavioural module in the CDR plus NACC FTLD.

It is likely that these two additions to the CDR plus NACC FTLD lead to improved accuracy of rating disease stage in FTD and bring us closer to optimising the rating scale for use in therapeutic trials where precise scoring of an individual's disease

severity is important so that treatment responses can be more representative of their real-life experience with FTD.

## Limitations

Although this study represents one of the largest familial FTD cohorts, numbers become smaller in each group as they are stratified, particularly in longitudinal analyses, such as performed for depression and anxiety.

We had included symptoms in the GENFI neuropsychiatric symptom scale that had been previously reported in patients with FTD. However, reports of other symptoms such as anhedonia³⁷ that have been more recently recognised as part of the FTD spectrum were not included.

When considering depression and anxiety we did not record the effect of therapeutic interventions on symptom severity such as antidepressants or psychological therapies. This did not allow us to measure their effect on the longer-term fluctuation in symptoms, and future studies should address this limitation.

All of the neuropsychiatric symptoms were recorded as being present or absent through the use of the GENFI symptom scale. While this is helpful for our current focus on improving clinical rating scales, it is important to note that this is distinct from making formal clinical diagnoses according to standard criteria of depression, anxiety, psychosis, etc, and therefore, may not be a true representation of the prevalence. Nonetheless, there are also potential reasons why neuropsychiatric symptoms may be underrepresented in GENFI as participants with active affective or psychotic disorders may not be able to (or want to) take part in an ongoing observational research study.

Lastly, although each rater received training in use of the neuropsychiatric symptom scales, now that its use is established it will be important in future studies to formally assess both intra- and inter-rater reliability.

In summary, neuropsychiatric symptoms commonly occur in individuals with FTD in all the main genetic mutation groups, including in those classed as ‘asymptomatic’. The failure of the current CDR plus NACC FTLD scale to account for psychotic symptoms runs the risk of adopting inaccurate tools to identify the disease staging and treatment response in individuals enrolled in therapeutic studies. This study suggests an initial step to rectifying this issue.

## Author affiliations

<footnote n="1">¹Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK</footnote>

<footnote n="2">²London School of Hygiene & Tropical Medicine, London, UK</footnote>

<footnote n="3">³Centre for Medical Image Computing, University College London, London, UK</footnote>

<footnote n="4">⁴Neurology, Erasmus MC, Rotterdam, The Netherlands</footnote>

<footnote n="5">⁵Neurology, Erasmus MC Alzheimer Centre, Rotterdam, The Netherlands</footnote>

<footnote n="6">⁶Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital Gipuzkoa Building, San Sebastian, Spain</footnote>

<footnote n="7">⁷Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain</footnote>

<footnote n="8">⁸Interdisciplinary Memory Clinic, Department of Neurological Sciences, Laval University, Quebec, Quebec, Canada</footnote>

<footnote n="9">⁹Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden</footnote>

<footnote n="10">¹⁰Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden</footnote>

<footnote n="11">¹¹Neurology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada</footnote>

<footnote n="12">¹²Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada</footnote>

<footnote n="13">¹³Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK</footnote>

<footnote n="14">¹⁴Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy</footnote>

<footnote n="15">¹⁵Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada</footnote>
¹⁶Dept. of Neurodegenerative Diseases, Eberhard Karls University Tubingen Hertie Institute for Clinical Brain Research, Tubingen, Germany

¹⁷Department of Neurological Sciences, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

¹⁸Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium

¹⁹Neurology Service, KU Leuven University Hospitals Leuven, Leuven, Belgium

²⁰Faculty of Medicine, University of Lisbon, Lisboa, Portugal

²¹Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

²²Department of Brain Sciences, Imperial College London, London, UK

²³Division of Neuroscience and Experimental Psychology, The University of Manchester, Manchester, UK

²⁴Departments of Geriatric Medicine and Nuclear Medicine, University of Duisburg-Essen, Duisburg, Germany

²⁵McConnell Brain Imaging Centre, Department of Neurology & Neurosurgery, Montreal Neurological Institute and Hospital, Montreal, Québec, Canada

²⁶Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Québec, Canada

²⁷Inserm U1127, CNRS UMR 7225, FrontLab - Reference Centre for Rare or Early Dementias, IM2A, Département de Neurologie, Hôpital Universitaire Pitié Salpêtrière, Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Paris, France

²⁸National Reference Center On Rare Dementias, Groupe Hospitalier La Pitié Salpêtrière-Charles Foix, Paris, France

²⁹Division of Neurology V and Neuropathology, Foundation IRCCS Carlo Besta Neurological Institute, Milano, Italy

³⁰Neurology, Hospital and University Centre of Coimbra, Coimbra, Portugal

³¹Centre for Neuroscience and Cell Biology (CNC).IBILI, University of Coimbra, Coimbra, Portugal

³²Inserm U1171, University of Lille, Lille, France

³³Memory Clinic, Neurology, CHU Lille, Lille, France

³⁴German Center for Neurodegenerative Diseases (DZNE), DZNE, Bonn, Germany

³⁵Department of Neurology, Ludwig Maximilians University Munich, Munchen, Germany

³⁶Department of Neurology, University of Ulm, Ulm, Germany

³⁷Neurosciences Drugs and Child Health, University of Florence, Firenze, Italy

³⁸IRCCS Firenze, Fondazione Don Carlo Gnocchi Onlus, Firenze, Italy

**Twitter** Georgia Peakman @georgia_peakman, Harro Seelaar @HarroSeelaar and Simon Ducharme @sducharme66

**Acknowledgements** We thank the research participants and their families for their contribution to the study. Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510.

**Collaborators** Genetic FTD Initiative (GENFI) consortium: Annabel Nelson, David L Thomas, Emily Todd, Hanya Benotmane, Jennifer Nicholas, Rachelle Shafei, Carolyn Timberlake, Thomas Cope, Timothy Rittman, Alberto Benussi, Enrico Premi, Roberto Gasparotti, Silvana Archetti, Stefano Gazzina, Valentina Cantoni, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Vittoria Borracci, Giacomina Rossi, Giorgio Giaccone, Giuseppe Di Fede, Paola Caroppo, Sara Prioni, Veronica Redaelli, David Tang-Wai, Ekaterina Rogaeva, Miguel Castelo-Branco, Morris Freedman, Ron Keren, Sandra Black, Sara Mitchell, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Jackie Poos, Janne M Papma, Lucia Giannini, Rick van Minkelen, Yolande Pijnenburg, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Michele Veldsman, Christin Andersson, Hakan Thonberg, Linn Öjerstedt, Vesna Jelic, Paul Thompson, Tobias Langheinrich, Albert Lladó, Anna Antonell, Jaume Olives, Mircea Balasa, Nuria Bargalló, Sergi Borrego-Ecija, Ana Verdelho, Carolina Maruta, Catarina B Ferreira, Gabriel Miltenberger, Frederico Simões do Couto, Alazne Gabilondo, Ana Gorostidi, Jorge Villanua, Marta Cañada, Mikel Tainta, Miren Zulaica, Myriam Barandiaran, Patricia Alves, Benjamin Bender, Carlo Wilke, Lisa Graf, Annick Vogels, Mathieu Vandenbulcke, Philip Van Damme, Rose Bruffaerts, Koen Poesen, Pedro Rosa-Neto, Serge Gauthier, Agnès Camuzat, Alexis Brice, Anne Bertrand, Aurélie Funkiewiez, Daisy Rinaldi, Dario Saracino, Olivier Colliot, Sabrina Sayah, Catharina Prix, Elisabeth Wlasich, Olivia Wagemann, Sandra Loosli, Sonja Schönecker, Tobias Hoegen, Jolina Lombardi, Sarah Anderl-Straub, Adeline Rollin, Gregory Kuchcinski, Maxime Bertoux, Thibaud Lebouvier, Vincent Deramecourt, Beatriz Santiago, Diana Duro, Maria João Leitão, Maria Rosario Almeida, Miguel Tábuas-Pereira, Sónia Afonso.

**Contributors** All authors contributed to the study conception and design. Material preparation, data manipulation and analysis were performed by KS, LLR and JDR. AM contributed to the analysis of the data. The first draft of the manuscript was written by KS, LLR and JDR and all authors commented on previous versions of the manuscript. LLR is the guarantor. All authors read and approved the final 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 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. Several authors of this publication (JCVS, MS, RV, AdM, MO, RV, JDR) are members of the European Reference Network for Rare Neurological Diseases (ERN-RND) - Project ID No 739510. Other funders include: Alzheimer's Research UK (ARUK-CRF2017B-2), Alzheimer's Society (AS-JF-19a-004-517), Alzheimer's Society (AS-PG-16-007), Association for Frontotemporal Dementias Research (2009), Bluefield Project, JPND GENFI-PROX 2019-02248, Government of Canada, Canadian Institutes of Health Research (327387), Deutsche Forschungsgemeinschaft (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 operating grant (MOP- 371851 and PJT-175242), Instituto de Salud Carlos III (PI20/00448), Fundació Marató TV3 (20143810), Italian Ministry of Health (CoEN015 and Ricerca Corrente, PreFrontALS JPND - 733051042), JPND Prefrontals (2015-02926, 2018-02754), Karolinska Institutet, Doctoral Funding, London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre, (LWENC), Mady Browaeks Fund for Research into Frontotemporal Dementia, Miriam Marks Brain Research UK Senior Fellowship, MRC (MR/M008525/1), MRC UK GENFI grant (MR/M023664/1), National Brain Appeal (RCN 290173), National Institute for Health Research Square Queen Square Dementia, Biomedical Research Unit, NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH), The Wolfson Foundation, UK Dementia Research Institute (SM-UCLO-MA-0519), UK Medical Research Council (SUAG/051 G101400), University College London Hospitals Biomedical Research Centre, Wellcome Trust (103838), National Institute for Health Research Cambridge Biomedical Research Centre.

**Competing interests** None declared.

**Patient consent for publication** Not applicable.

**Ethics approval** Ethical approval granted by the London Queen Square Research Ethics Committee. Ethics numbers: 140377. Participants gave informed consent to participate in the study before taking part.

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

**Data availability statement** Data are available on reasonable request. Some data are available on reasonable request after review by the GENFI Data Access Committee. Email is genfi@ucl.ac.uk.

**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.

**Open access** This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

### ORCID iDs

Kiran Samra http://orcid.org/0000-0002-3105-7099
Georgia Peakman http://orcid.org/0000-0002-3319-138X
Martina Bocchetta http://orcid.org/0000-0003-1814-5024
Rhian S Convery http://orcid.org/0000-0002-9477-1812
John C van Swieten http://orcid.org/0000-0001-6278-6844
Lize C Jiskoot http://orcid.org/0000-0002-1120-1858
Harro Seelaar http://orcid.org/0000-0003-1989-7527
James B Rowe http://orcid.org/0000-0001-7216-8679
Barbara Borroni http://orcid.org/0000-0001-9340-9814
Elizabeth Finger http://orcid.org/0000-0003-4461-7427
Matthias Synofzik http://orcid.org/0000-0002-2280-7273
Daniela Galimberti http://orcid.org/0000-0002-9284-5953
Alexander Gerhard http://orcid.org/0000-0002-8071-6062
Simon Ducharme http://orcid.org/0000-0002-7309-1113
Isabelle Le Ber http://orcid.org/0000-0002-2508-5181
Pietro Tiraboschi http://orcid.org/0000-0002-2171-1720
Sandro Sorbi http://orcid.org/0000-0002-0380-6670
Jonathan D Rohrer http://orcid.org/0000-0002-6155-8417
¹⁶Dept. of Neurodegenerative Diseases, Eberhard Karls University Tubingen Hertie Institute for Clinical Brain Research, Tubingen, Germany

¹⁷Department of Neurological Sciences, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

¹⁸Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium

¹⁹Neurology Service, KU Leuven University Hospitals Leuven, Leuven, Belgium

²⁰Faculty of Medicine, University of Lisbon, Lisboa, Portugal

²¹Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

²²Department of Brain Sciences, Imperial College London, London, UK

²³Division of Neuroscience and Experimental Psychology, The University of Manchester, Manchester, UK

²⁴Departments of Geriatric Medicine and Nuclear Medicine, University of Duisburg-Essen, Duisburg, Germany

²⁵McConnell Brain Imaging Centre, Department of Neurology & Neurosurgery, Montreal Neurological Institute and Hospital, Montreal, Québec, Canada

²⁶Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Québec, Canada

²⁷Inserm U1127, CNRS UMR 7225, FrontLab - Reference Centre for Rare or Early Dementias, IM2A, Département de Neurologie, Hôpital Universitaire Pitié Salpêtrière, Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Paris, France

²⁸National Reference Center On Rare Dementias, Groupe Hospitalier La Pitié Salpêtrière-Charles Foix, Paris, France

²⁹Division of Neurology V and Neuropathology, Foundation IRCCS Carlo Besta Neurological Institute, Milano, Italy

³⁰Neurology, Hospital and University Centre of Coimbra, Coimbra, Portugal

³¹Centre for Neuroscience and Cell Biology (CNC).IBILI, University of Coimbra, Coimbra, Portugal

³²Inserm U1171, University of Lille, Lille, France

³³Memory Clinic, Neurology, CHU Lille, Lille, France

³⁴German Center for Neurodegenerative Diseases (DZNE), DZNE, Bonn, Germany

³⁵Department of Neurology, Ludwig Maximilians University Munich, Munchen, Germany

³⁶Department of Neurology, University of Ulm, Ulm, Germany

³⁷Neurosciences Drugs and Child Health, University of Florence, Firenze, Italy

³⁸IRCCS Firenze, Fondazione Don Carlo Gnocchi Onlus, Firenze, Italy

**Twitter** Georgia Peakman @georgia_peakman, Harro Seelaar @HarroSeelaar and Simon Ducharme @sducharme66

**Acknowledgements** We thank the research participants and their families for their contribution to the study. Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510.

**Collaborators** Genetic FTD Initiative (GENFI) consortium: Annabel Nelson, David L Thomas, Emily Todd, Hanya Benotmane, Jennifer Nicholas, Rachelle Shafei, Carolyn Timberlake, Thomas Cope, Timothy Rittman, Alberto Benussi, Enrico Premi, Roberto Gasparotti, Silvana Archetti, Stefano Gazzina, Valentina Cantoni, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Vittoria Borracci, Giacomina Rossi, Giorgio Giaccone, Giuseppe Di Fede, Paola Caroppo, Sara Prioni, Veronica Redaelli, David Tang-Wai, Ekaterina Rogaeva, Miguel Castelo-Branco, Morris Freedman, Ron Keren, Sandra Black, Sara Mitchell, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Jackie Poos, Janne M Papma, Lucia Giannini, Rick van Minkelen, Yolande Pijnenburg, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Michele Veldsman, Christin Andersson, Hakan Thonberg, Linn Öjerstedt, Vesna Jelic, Paul Thompson, Tobias Langheinrich, Albert Lladó, Anna Antonell, Jaume Olives, Mircea Balasa, Nuria Bargalló, Sergi Borrego-Ecija, Ana Verdelho, Carolina Maruta, Catarina B Ferreira, Gabriel Miltenberger, Frederico Simões do Couto, Alazne Gabilondo, Ana Gorostidi, Jorge Villanua, Marta Cañada, Mikel Tainta, Miren Zulaica, Myriam Barandiaran, Patricia Alves, Benjamin Bender, Carlo Wilke, Lisa Graf, Annick Vogels, Mathieu Vandenbulcke, Philip Van Damme, Rose Bruffaerts, Koen Poesen, Pedro Rosa-Neto, Serge Gauthier, Agnès Camuzat, Alexis Brice, Anne Bertrand, Aurélie Funkiewiez, Daisy Rinaldi, Dario Saracino, Olivier Colliot, Sabrina Sayah, Catharina Prix, Elisabeth Wlasich, Olivia Wagemann, Sandra Loosli, Sonja Schönecker, Tobias Hoegen, Jolina Lombardi, Sarah Anderl-Straub, Adeline Rollin, Gregory Kuchcinski, Maxime Bertoux, Thibaud Lebouvier, Vincent Deramecourt, Beatriz Santiago, Diana Duro, Maria João Leitão, Maria Rosario Almeida, Miguel Tábuas-Pereira, Sónia Afonso.

**Contributors** All authors contributed to the study conception and design. Material preparation, data manipulation and analysis were performed by KS, LLR and JDR. AM contributed to the analysis of the data. The first draft of the manuscript was written by KS, LLR and JDR and all authors commented on previous versions of the manuscript. LLR is the guarantor. All authors read and approved the final 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 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. Several authors of this publication (JCVS, MS, RV, AdM, MO, RV, JDR) are members of the European Reference Network for Rare Neurological Diseases (ERN-RND) - Project ID No 739510. Other funders include: Alzheimer's Research UK (ARUK-CRF2017B-2), Alzheimer's Society (AS-JF-19a-004-517), Alzheimer's Society (AS-PG-16-007), Association for Frontotemporal Dementias Research (2009), Bluefield Project, JPND GENFI-PROX 2019-02248, Government of Canada, Canadian Institutes of Health Research (327387), Deutsche Forschungsgemeinschaft (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 operating grant (MOP- 371851 and PJT-175242), Instituto de Salud Carlos III (PI20/00448), Fundació Marató TV3 (20143810), Italian Ministry of Health (CoEN015 and Ricerca Corrente, PreFrontALS JPND - 733051042), JPND Prefrontals (2015-02926, 2018-02754), Karolinska Institutet, Doctoral Funding, London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre, (LWENC), Mady Browaeks Fund for Research into Frontotemporal Dementia, Miriam Marks Brain Research UK Senior Fellowship, MRC (MR/M008525/1), MRC UK GENFI grant (MR/M023664/1), National Brain Appeal (RCN 290173), National Institute for Health Research Square Queen Square Dementia, Biomedical Research Unit, NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH), The Wolfson Foundation, UK Dementia Research Institute (SM-UCLO-MA-0519), UK Medical Research Council (SUAG/051 G101400), University College London Hospitals Biomedical Research Centre, Wellcome Trust (103838), National Institute for Health Research Cambridge Biomedical Research Centre.

**Competing interests** None declared.

**Patient consent for publication** Not applicable.

**Ethics approval** Ethical approval granted by the London Queen Square Research Ethics Committee. Ethics numbers: 140377. Participants gave informed consent to participate in the study before taking part.

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

**Data availability statement** Data are available on reasonable request. Some data are available on reasonable request after review by the GENFI Data Access Committee. Email is genfi@ucl.ac.uk.

**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.

**Open access** This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

### ORCID iDs

Kiran Samra http://orcid.org/0000-0002-3105-7099
Georgia Peakman http://orcid.org/0000-0002-3319-138X
Martina Bocchetta http://orcid.org/0000-0003-1814-5024
Rhian S Convery http://orcid.org/0000-0002-9477-1812
John C van Swieten http://orcid.org/0000-0001-6278-6844
Lize C Jiskoot http://orcid.org/0000-0002-1120-1858
Harro Seelaar http://orcid.org/0000-0003-1989-7527
James B Rowe http://orcid.org/0000-0001-7216-8679
Barbara Borroni http://orcid.org/0000-0001-9340-9814
Elizabeth Finger http://orcid.org/0000-0003-4461-7427
Matthias Synofzik http://orcid.org/0000-0002-2280-7273
Daniela Galimberti http://orcid.org/0000-0002-9284-5953
Alexander Gerhard http://orcid.org/0000-0002-8071-6062
Simon Ducharme http://orcid.org/0000-0002-7309-1113
Isabelle Le Ber http://orcid.org/0000-0002-2508-5181
Pietro Tiraboschi http://orcid.org/0000-0002-2171-1720
Sandro Sorbi http://orcid.org/0000-0002-0380-6670
Jonathan D Rohrer http://orcid.org/0000-0002-6155-8417
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22 Team, R.C. R: a language and environment for statistical computing, 2013.

23 Collins JD, Henley SMD, Suárez-González A. A systematic review of the prevalence of depression, anxiety, and apathy in frontotemporal dementia, atypical and young-onset Alzheimer's disease, and inherited dementia. *Int Psychogeriatr* 2020:1-20.

24 Chakrabarty T, Sepehry AA, Jacova C, et al. The prevalence of depressive symptoms in frontotemporal dementia: a meta-analysis. *Dement Geriatr Cogn Disord* 2015;39:257-71.

25 Boeve BF, Boylan KB, Graff-Radford NR, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9orf72. *Brain* 2012;135:765-83.

26 Mahoney CJ, Beck J, Rohrer JD, et al. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. *Brain* 2012;135:736-50.

27 Simón-Sánchez J, Dopper EGP, Cohn-Hokke PE, et al. The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. *Brain* 2012;135:723-35.

28 Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C 9ORF72 mutations. *Brain* 2012;135:693-708.

29 DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. *Neuron* 2011;72:245-56.

30 Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. *Neuron* 2011;72:257-68.

31 Sha SJ, Takada LT, Rankin KP, et al. Frontotemporal dementia due to C9ORF72 mutations. *Neurology* 2012;79:1002-11.

32 Kumfor F, Liang CT, Hazelton JL, et al. Examining the presence and nature of delusions in Alzheimer's disease and frontotemporal dementia syndromes. *Int J Geriatr Psychiatry* 2022;37. doi:10.1002/gps.5692. [Epub ahead of print: 08 Feb 2022].

33 Benussi A, Premi E, Gazzina S, et al. Progression of behavioral disturbances and neuropsychiatric symptoms in patients with genetic frontotemporal dementia. *JAMA Netw Open* 2021;4:e2030194.

34 Clark CN, Nicholas JM, Gordon E, et al. Altered sense of humor in dementia. *J Alzheimers Dis* 2016;49:111-9.

35 Ogata A, Miyakawa T. Religious experiences in epileptic patients with a focus on ictus-related episodes. *Psychiatry Clin Neurosci* 1998;52:321-5.

36 Chan D, Anderson V, Pijnenburg Y, et al. The clinical profile of right temporal lobe atrophy. *Brain* 2009;132:1287-98.

37 Shaw SR, El-Omar H, Roquet D, et al. Uncovering the prevalence and neural substrates of anhedonia in frontotemporal dementia. *Brain* 2021;144:1551-64.
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19 Strong MJ, Grace GM, Freedman M, et al. Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. *Amyotroph Lateral Scler* 2009;10:131-46.

20 Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. *Neurology* 2013;80:496-503.

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23 Collins JD, Henley SMD, Suárez-González A. A systematic review of the prevalence of depression, anxiety, and apathy in frontotemporal dementia, atypical and young-onset Alzheimer's disease, and inherited dementia. *Int Psychogeriatr* 2020;1-20.

24 Chakrabarty T, Sepehry AA, Jacova C, et al. The prevalence of depressive symptoms in frontotemporal dementia: a meta-analysis. *Dement Geriatr Cogn Disord* 2015;39:257-71.

25 Boeve BF, Boylan KB, Graff-Radford NR, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9orf72. *Brain* 2012;135:765-83.

26 Mahoney CJ, Beck J, Rohrer JD, et al. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. *Brain* 2012;135:736-50.

27 Simón-Sánchez J, Dopper EGP, Cohn-Hokke PE, et al. The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. *Brain* 2012;135:723-35.

28 Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C 9ORF72 mutations. *Brain* 2012;135:693-708.

29 DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. *Neuron* 2011;72:245-56.

30 Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. *Neuron* 2011;72:257-68.

31 Sha SJ, Takada LT, Rankin KP, et al. Frontotemporal dementia due to C9ORF72 mutations. *Neurology* 2012;79:1002-11.

32 Kumfor F, Liang CT, Hazelton JL, et al. Examining the presence and nature of delusions in Alzheimer's disease and frontotemporal dementia syndromes. *Int J Geriatr Psychiatry* 2022;37. doi:10.1002/gps.5692. [Epub ahead of print: 08 Feb 2022].

33 Benussi A, Premi E, Gazzina S, et al. Progression of behavioral disturbances and neuropsychiatric symptoms in patients with genetic frontotemporal dementia. *JAMA Netw Open* 2021;4:e2030194.

34 Clark CN, Nicholas JM, Gordon E, et al. Altered sense of humor in dementia. *J Alzheimers Dis* 2016;49:111-9.

35 Ogata A, Miyakawa T. Religious experiences in epileptic patients with a focus on ictus-related episodes. *Psychiatry Clin Neurosci* 1998;52:321-5.

36 Chan D, Anderson V, Pijnenburg Y, et al. The clinical profile of right temporal lobe atrophy. *Brain* 2009;132:1287-98.

37 Shaw SR, El-Omar H, Roquet D, et al. Uncovering the prevalence and neural substrates of anhedonia in frontotemporal dementia. *Brain* 2021;144:1551-64.
<table><caption>Supplementary Table 1. Neuropsychiatric symptoms included in the GENFI Symptom Scales in the History assessment. Scoring of each symptom is on a scale similar to the CDR i.e. 0 (absent), 0.5 (very mild/questionable), 1 (mild), 2 (moderate), and 3 (severe).</caption><thead><tr><th></th><th></th><th>Questionable/<br>Very mild</th><th>Mild</th><th>Moderate</th><th>Severe</th></tr></thead><tbody><tr><td>0</td><td><strong>Neuropsychiatric</strong></td><td>Questionable neuropsychiatric symptoms.</td><td>Mild but definite neuropsychiatric symptoms.</td><td>Moderate neuropsychiatric symptoms.</td><td>Severe neuropsychiatric symptoms.</td></tr><tr><td>1</td><td><strong>Visual hallucinations</strong><br>Sees things that are not there</td><td>Some hallucinations may have occurred but are of questionable significance</td><td>Hallucinations are present but harmless and cause little distress for the patient.</td><td>Hallucinations are distressing and are disruptive to the patient.</td><td>Hallucinations are very disruptive and a major source of behavioural disturbance. PRN medications may be required to control them.</td></tr><tr><td>2</td><td><strong>Auditory hallucinations</strong><br>Hears voices</td><td>Some hallucinations may have occurred but are of questionable significance.</td><td>Hallucinations are present but harmless and cause little distress for the patient.</td><td>Hallucinations are distressing and are disruptive to the patient.</td><td>Hallucinations are very disruptive and a major source of behavioural disturbance. PRN medications may be required to control them.</td></tr><tr><td>3</td><td><strong>Tactile hallucinations</strong><br>Feels things that are not there</td><td>Some hallucinations may have occurred but are of questionable significance.</td><td>Hallucinations are present but harmless and cause little distress for the patient.</td><td>Hallucinations are distressing and are disruptive to the patient.</td><td>Hallucinations are very disruptive and a major source of behavioural disturbance. PRN medications may be required to control them.</td></tr><tr><td>4</td><td><strong>Delusions</strong><br>Paranoia, fear of harm, fear of theft, fear of abandonment, delusional misidentification</td><td>Some delusions may have occurred but are of questionable significance.</td><td>Delusions present but seem harmless and produce little distress in the patient.</td><td>Delusions are distressing and disruptive.</td><td>Delusions are very disruptive and are a major source of behavioural disruption. If PRN medications are prescribed, their use signals marked severity.</td></tr><tr><td>5</td><td><strong>Depression</strong><br>Low mood, tearful, talks about deserving punishment, talks about dying</td><td>Some features of depression may be present but are not distressing.</td><td>Depression is distressing but usually responds to redirection or reassurance.</td><td>Depression is distressing; depressive symptoms are spontaneously voiced by the patient and difficult to alleviate.</td><td>Depression is very distressing and a major source of suffering for the patient.</td></tr><tr><td>6</td><td><strong>Anxiety</strong><br>Feels shaky or tense, worried about planned events, phobic avoidance, separation anxiety</td><td>Some features of anxiety may be present but are not distressing.</td><td>Anxiety is distressing but usually responds to redirection or reassurance.</td><td>Anxiety is distressing, anxiety symptoms are spontaneously voiced by the patient and difficult to alleviate.</td><td>Anxiety is very distressing and a major source of suffering for the patient.</td></tr></tbody></table>
<table><caption>Supplementary Table 1. Neuropsychiatric symptoms included in the GENFI Symptom Scales in the History assessment. Scoring of each symptom is on a scale similar to the CDR i.e. 0 (absent), 0.5 (very mild/questionable), 1 (mild), 2 (moderate), and 3 (severe).</caption><thead><tr><th></th><th></th><th>Questionable/<br>Very mild</th><th>Mild</th><th>Moderate</th><th>Severe</th></tr></thead><tbody><tr><td>0</td><td><strong>Neuropsychiatric</strong></td><td>Questionable neuropsychiatric symptoms.</td><td>Mild but definite neuropsychiatric symptoms.</td><td>Moderate neuropsychiatric symptoms.</td><td>Severe neuropsychiatric symptoms.</td></tr><tr><td>1</td><td><strong>Visual hallucinations</strong><br>Sees things that are not there</td><td>Some hallucinations may have occurred but are of questionable significance</td><td>Hallucinations are present but harmless and cause little distress for the patient.</td><td>Hallucinations are distressing and are disruptive to the patient.</td><td>Hallucinations are very disruptive and a major source of behavioural disturbance. PRN medications may be required to control them.</td></tr><tr><td>2</td><td><strong>Auditory hallucinations</strong><br>Hears voices</td><td>Some hallucinations may have occurred but are of questionable significance.</td><td>Hallucinations are present but harmless and cause little distress for the patient.</td><td>Hallucinations are distressing and are disruptive to the patient.</td><td>Hallucinations are very disruptive and a major source of behavioural disturbance. PRN medications may be required to control them.</td></tr><tr><td>3</td><td><strong>Tactile hallucinations</strong><br>Feels things that are not there</td><td>Some hallucinations may have occurred but are of questionable significance.</td><td>Hallucinations are present but harmless and cause little distress for the patient.</td><td>Hallucinations are distressing and are disruptive to the patient.</td><td>Hallucinations are very disruptive and a major source of behavioural disturbance. PRN medications may be required to control them.</td></tr><tr><td>4</td><td><strong>Delusions</strong><br>Paranoia, fear of harm, fear of theft, fear of abandonment, delusional misidentification</td><td>Some delusions may have occurred but are of questionable significance.</td><td>Delusions present but seem harmless and produce little distress in the patient.</td><td>Delusions are distressing and disruptive.</td><td>Delusions are very disruptive and are a major source of behavioural disruption. If PRN medications are prescribed, their use signals marked severity.</td></tr><tr><td>5</td><td><strong>Depression</strong><br>Low mood, tearful, talks about deserving punishment, talks about dying</td><td>Some features of depression may be present but are not distressing.</td><td>Depression is distressing but usually responds to redirection or reassurance.</td><td>Depression is distressing; depressive symptoms are spontaneously voiced by the patient and difficult to alleviate.</td><td>Depression is very distressing and a major source of suffering for the patient.</td></tr><tr><td>6</td><td><strong>Anxiety</strong><br>Feels shaky or tense, worried about planned events, phobic avoidance, separation anxiety</td><td>Some features of anxiety may be present but are not distressing.</td><td>Anxiety is distressing but usually responds to redirection or reassurance.</td><td>Anxiety is distressing, anxiety symptoms are spontaneously voiced by the patient and difficult to alleviate.</td><td>Anxiety is very distressing and a major source of suffering for the patient.</td></tr></tbody></table>
<table><tr><td>7</td><td><strong>Irritability/Lability</strong><br>Bad temper, rapid changes in mood, sudden flashes of anger, impatient, argumentative</td><td>Some irritable or labile behaviour may have occurred but of questionable significance.</td><td>Irritability or lability is notable but usually responds to redirection or reassurance.</td><td>Irritability and lability are very evident and difficult to overcome by the caregiver.</td><td>Irritability and lability are very evident; they usually fail to respond to any intervention by the caregiver, and they are a major source of distress.</td></tr><tr><td>8</td><td><strong>Agitation/Aggression</strong><br>Stubborn, unco-operative, hard to handle, slams doors, throws things, hits or harms others</td><td>Some agitated or aggressive behaviour may have occurred but of questionable significance.</td><td>Agitation is disruptive but can be managed by redirection or reassurance.</td><td>Agitation is disruptive and difficult to redirect or control.</td><td>Agitation is very disruptive and a major source of difficulty; there may be a threat of personal harm.</td></tr><tr><td>9</td><td><strong>Euphoria/Elation</strong><br>Feels too good or too happy, grandiose, childish behaviour</td><td>Some euphoria or elated behaviour may have occurred but of questionable significance.</td><td>Elation is notable to friends and family but is not disruptive.</td><td>Elation is notably abnormal, and disruptive.</td><td>Elation is very pronounced.</td></tr><tr><td>10</td><td><strong>Aberrant motor behaviour</strong><br>Paces without purpose, repeatedly dresses or undresses, excessively fidgety</td><td>Some aberrant motor behaviour may have occurred but of questionable significance.</td><td>Abnormal motor activity is notable but produces little interference with daily routines.</td><td>Abnormal motor activity is very evident; can be overcome by the caregiver.</td><td>Abnormal motor activity is evident, usually fails to respond to any intervention by the caregiver and is a major source of distress.</td></tr><tr><td>11</td><td><strong>Hypersexuality</strong><br>Unusual or excessive sexual behaviour</td><td>Some unusual or excessive sexual behaviour may have occurred but of questionable significance.</td><td>Sexual behaviour is disruptive but can be managed by redirection or reassurance.</td><td>Sexual behaviour is disruptive and difficult to redirect or control.</td><td>Sexual behaviour is very disruptive and a major source of difficulty.</td></tr><tr><td>12</td><td><strong>Hyperreligiosity</strong><br>Increased or unusual religious experiences or feelings</td><td>Possible increased or unusual religious experiences may have occurred but are of questionable significance.</td><td>Increased or unusual religious experiences are present but seem harmless and produce little distress in the patient.</td><td>Increased or unusual religious experiences may be distressing and disruptive.</td><td>Increased or unusual religious experiences are very disruptive and are a major source of behavioural disruption.</td></tr><tr><td>13</td><td><strong>Impaired sleep</strong><br>Difficulty sleeping at night, excessive sleep during the day</td><td>Possible impaired sleep but of questionable significance.</td><td>Sleep is notably impaired but produces little interference with daily routines (minimal daytime sleepiness).</td><td>Sleep very impaired during the night and may sleep regularly the day.</td><td>Extremely poor sleep; may be distressed during the night; partner's sleep markedly disturbed.</td></tr><tr><td>14</td><td><strong>Altered sense of humour</strong><br>Change in sense of humour, finds things funny which others don't</td><td>Sense of humour possibly altered but of questionable significance.</td><td>Mild but definite change in sense of humour. May finds things funny which others don't.</td><td>Sense of humour completely different from previously (e.g. may prefer more physical or 'slapstick' humour)</td><td>Complete loss of sense of humour.</td></tr></table>
<table><tr><td>7</td><td><strong>Irritability/Lability</strong><br>Bad temper, rapid changes in mood, sudden flashes of anger, impatient, argumentative</td><td>Some irritable or labile behaviour may have occurred but of questionable significance.</td><td>Irritability or lability is notable but usually responds to redirection or reassurance.</td><td>Irritability and lability are very evident and difficult to overcome by the caregiver.</td><td>Irritability and lability are very evident; they usually fail to respond to any intervention by the caregiver, and they are a major source of distress.</td></tr><tr><td>8</td><td><strong>Agitation/Aggression</strong><br>Stubborn, unco-operative, hard to handle, slams doors, throws things, hits or harms others</td><td>Some agitated or aggressive behaviour may have occurred but of questionable significance.</td><td>Agitation is disruptive but can be managed by redirection or reassurance.</td><td>Agitation is disruptive and difficult to redirect or control.</td><td>Agitation is very disruptive and a major source of difficulty; there may be a threat of personal harm.</td></tr><tr><td>9</td><td><strong>Euphoria/Elation</strong><br>Feels too good or too happy, grandiose, childish behaviour</td><td>Some euphoria or elated behaviour may have occurred but of questionable significance.</td><td>Elation is notable to friends and family but is not disruptive.</td><td>Elation is notably abnormal, and disruptive.</td><td>Elation is very pronounced.</td></tr><tr><td>10</td><td><strong>Aberrant motor behaviour</strong><br>Paces without purpose, repeatedly dresses or undresses, excessively fidgety</td><td>Some aberrant motor behaviour may have occurred but of questionable significance.</td><td>Abnormal motor activity is notable but produces little interference with daily routines.</td><td>Abnormal motor activity is very evident; can be overcome by the caregiver.</td><td>Abnormal motor activity is evident, usually fails to respond to any intervention by the caregiver and is a major source of distress.</td></tr><tr><td>11</td><td><strong>Hypersexuality</strong><br>Unusual or excessive sexual behaviour</td><td>Some unusual or excessive sexual behaviour may have occurred but of questionable significance.</td><td>Sexual behaviour is disruptive but can be managed by redirection or reassurance.</td><td>Sexual behaviour is disruptive and difficult to redirect or control.</td><td>Sexual behaviour is very disruptive and a major source of difficulty.</td></tr><tr><td>12</td><td><strong>Hyperreligiosity</strong><br>Increased or unusual religious experiences or feelings</td><td>Possible increased or unusual religious experiences may have occurred but are of questionable significance.</td><td>Increased or unusual religious experiences are present but seem harmless and produce little distress in the patient.</td><td>Increased or unusual religious experiences may be distressing and disruptive.</td><td>Increased or unusual religious experiences are very disruptive and are a major source of behavioural disruption.</td></tr><tr><td>13</td><td><strong>Impaired sleep</strong><br>Difficulty sleeping at night, excessive sleep during the day</td><td>Possible impaired sleep but of questionable significance.</td><td>Sleep is notably impaired but produces little interference with daily routines (minimal daytime sleepiness).</td><td>Sleep very impaired during the night and may sleep regularly the day.</td><td>Extremely poor sleep; may be distressed during the night; partner's sleep markedly disturbed.</td></tr><tr><td>14</td><td><strong>Altered sense of humour</strong><br>Change in sense of humour, finds things funny which others don't</td><td>Sense of humour possibly altered but of questionable significance.</td><td>Mild but definite change in sense of humour. May finds things funny which others don't.</td><td>Sense of humour completely different from previously (e.g. may prefer more physical or 'slapstick' humour)</td><td>Complete loss of sense of humour.</td></tr></table>
Supplementary Table 2. Severity of neuropsychiatric symptoms in controls and mutation carriers. Scores are shown as mean (standard deviation).

Bold items are significantly different to controls using linear regression (p < 0.05). Other differences are shown as <sup>a</sup>significantly impaired compared to GRN, <sup>b</sup>significantly impaired compared to MAPT and <sup>c</sup>significantly impaired compared to C9orf72 using logistic regression (p < 0.05).

<table><thead><tr><th rowspan="2"></th><th rowspan="2">Controls</th><th colspan="3">All mutation carriers</th><th colspan="3">C9orf72</th><th colspan="3">GRN</th><th colspan="3">MAPT</th></tr><tr><th>CDR 0</th><th>CDR 5</th><th>CDR 1+</th><th>CDR 0</th><th>CDR 5</th><th>CDR 1+</th><th>CDR 0</th><th>CDR 5</th><th>CDR 1+</th><th>CDR 0</th><th>CDR 5</th><th>CDR 1+</th></tr></thead><tbody><tr><td>Visual hallucinations</td><td>0.00 (0.03)</td><td>0.01 (0.12)</td><td><strong>0.04</strong> (0.15)</td><td><strong>0.17</strong> (0.47)</td><td>0.02 (0.19)</td><td>0.04 (0.18)</td><td><strong>0.26</strong> (0.58)<sup>a</sup></td><td>0.00 (0.00)</td><td>0.03 (0.12)</td><td>0.10 (0.36)</td><td>0.00 (0.00)</td><td>0.04 (0.13)</td><td>0.06 (0.22)</td></tr><tr><td>Auditory<br>hallucinations</td><td>0.01 (0.12)</td><td>0.00 (0.06)</td><td>0.00 (0.00)</td><td><strong>0.17</strong> (0.53)</td><td>0.01 (0.09)</td><td>0.00 (0.00)</td><td><strong>0.31</strong> (0.71)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.06 (0.21)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td></tr><tr><td>Tactile<br>hallucinations</td><td>0.00 (0.00)</td><td>0.00 (0.03)</td><td>0.01 (0.08)</td><td><strong>0.07</strong> (0.38)</td><td>0.00 (0.05)</td><td>0.03 (0.11)</td><td><strong>0.14</strong> (0.53)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.02 (0.10)</td></tr><tr><td>Delusions</td><td>0.01 (0.07)</td><td>0.01 (0.07)</td><td>0.01 (0.06)</td><td><strong>0.32</strong> (0.65)</td><td>0.00 (0.05)</td><td>0.00 (0.00)</td><td><strong>0.51</strong> (0.81)<sup>ab</sup></td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td><strong>0.13</strong> (0.36)</td><td>0.02 (0.14)</td><td>0.04 (0.13)</td><td>0.16 (0.47)</td></tr><tr><td>Depression</td><td>0.12 (0.39)</td><td>0.09 (0.33)</td><td><strong>0.30</strong> (0.52)</td><td><strong>0.48</strong> (0.73)</td><td>0.09 (0.33)</td><td>0.26 (0.58)</td><td><strong>0.53</strong> (0.81)</td><td>0.07 (0.27)</td><td><strong>0.29</strong> (0.38)</td><td><strong>0.45</strong> (0.64)</td><td>0.14 (0.44)</td><td>0.43 (0.62)</td><td><strong>0.40</strong> (0.68)</td></tr><tr><td>Anxiety</td><td>0.15 (0.42)</td><td>0.10 (0.35)</td><td><strong>0.33</strong> (0.47)</td><td><strong>0.57</strong> (0.73)</td><td>0.08 (0.32)</td><td>0.30 (0.48)</td><td><strong>0.62</strong> (0.78)</td><td>0.12 (0.41)</td><td><strong>0.34</strong> (0.49)</td><td><strong>0.49</strong> (0.67)</td><td>0.08 (0.26)</td><td>0.39 (0.45)</td><td><strong>0.58</strong> (0.75)</td></tr><tr><td>Irritability/lability</td><td>0.09 (0.30)</td><td>0.03 (0.13)</td><td><strong>0.21</strong> (0.42)</td><td><strong>0.60</strong> (0.79)</td><td>0.03 (0.11)</td><td>0.23 (0.42)</td><td><strong>0.71</strong> (0.84)</td><td>0.02 (0.12)</td><td>0.19 (0.44)</td><td><strong>0.42</strong> (0.68)</td><td>0.04 (0.17)</td><td>0.18 (0.37)</td><td><strong>0.68</strong> (0.83)</td></tr><tr><td>Agitation/aggression</td><td>0.02 (0.17)</td><td>0.01 (0.06)</td><td>0.07 (0.20)</td><td><strong>0.31</strong> (0.55)</td><td>0.01 (0.07)</td><td>0.08 (0.25)</td><td><strong>0.37</strong> (0.61)</td><td>0.00 (0.04)</td><td>0.08 (0.19)</td><td><strong>0.18</strong> (0.34)</td><td>0.01 (0.07)</td><td>0.00 (0.00)</td><td><strong>0.42</strong> (0.67)</td></tr><tr><td>Euphoria/elation</td><td>0.00 (0.03)</td><td>0.01 (0.05)</td><td><strong>0.04</strong> (0.18)</td><td><strong>0.34</strong> (0.66)</td><td>0.01 (0.08)</td><td>0.04 (0.18)</td><td><strong>0.42</strong> (0.76)</td><td>0.00 (0.00)</td><td>0.03 (0.18)</td><td><strong>0.17</strong> (0.39)</td><td>0.00 (0.00)</td><td>0.07 (0.18)</td><td><strong>0.44</strong> (0.75)</td></tr><tr><td>Aberrant motor<br>behaviour</td><td>0.01 (0.07)</td><td>0.00 (0.06)</td><td>0.03 (0.12)</td><td><strong>0.51</strong> (0.84)</td><td>0.00 (0.00)</td><td>0.03 (0.11)</td><td><strong>0.60</strong> (0.92)</td><td>0.00 (0.00)</td><td>0.05 (0.15)</td><td><strong>0.35</strong> (0.68)</td><td>0.02 (0.14)</td><td>0.00 (0.00)</td><td><strong>0.56</strong> (0.89)</td></tr><tr><td>Hypersexuality</td><td>0.00 (0.03)</td><td>0.00 (0.00)</td><td>0.02 (0.09)</td><td><strong>0.21</strong> (0.57)</td><td>0.00 (0.00)</td><td>0.04 (0.14)</td><td><strong>0.24</strong> (0.59)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td><strong>0.13</strong> (0.43)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.26 (0.72)</td></tr><tr><td>Hyperreligiosity</td><td>0.00 (0.00)</td><td>0.00 (0.03)</td><td>0.01 (0.08)</td><td><strong>0.14</strong> (0.52)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td><strong>0.18</strong> (0.60)</td><td>0.00 (0.04)</td><td>0.03 (0.12)</td><td>0.05 (0.20)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.24 (0.71)</td></tr><tr><td>Impaired sleep</td><td>0.13 (0.40)</td><td>0.06 (0.27)</td><td>0.25 (0.49)</td><td><strong>0.55</strong> (0.76)</td><td>0.02 (0.12)</td><td>0.24 (0.47)</td><td><strong>0.69</strong> (0.87)</td><td>0.07 (0.29)</td><td>0.31 (0.57)</td><td><strong>0.38</strong> (0.57)</td><td>0.12 (0.43)</td><td>0.14 (0.31)</td><td><strong>0.48</strong> (0.70)</td></tr><tr><td>Altered sense of<br>humour</td><td>0.00 (0.04)</td><td>0.00 (0.03)</td><td>0.03 (0.14)</td><td><strong>0.60</strong> (0.84)</td><td>0.00 (0.00)</td><td>0.05 (0.20)</td><td><strong>0.52</strong> (0.79)</td><td>0.00 (0.04)</td><td>0.02 (0.09)</td><td><strong>0.47</strong> (0.70)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td><strong>1.12</strong> (1.07)<sup>ac</sup></td></tr></tbody></table>
Supplementary Table 2. Severity of neuropsychiatric symptoms in controls and mutation carriers. Scores are shown as mean (standard deviation).

Bold items are significantly different to controls using linear regression (p < 0.05). Other differences are shown as <sup>a</sup>significantly impaired compared to GRN, <sup>b</sup>significantly impaired compared to MAPT and <sup>c</sup>significantly impaired compared to C9orf72 using logistic regression (p < 0.05).

<table><thead><tr><th rowspan="2"></th><th rowspan="2">Controls</th><th colspan="3">All mutation carriers</th><th colspan="3">C9orf72</th><th colspan="3">GRN</th><th colspan="3">MAPT</th></tr><tr><th>CDR 0</th><th>CDR 5</th><th>CDR 1+</th><th>CDR 0</th><th>CDR 5</th><th>CDR 1+</th><th>CDR 0</th><th>CDR 5</th><th>CDR 1+</th><th>CDR 0</th><th>CDR 5</th><th>CDR 1+</th></tr></thead><tbody><tr><td>Visual hallucinations</td><td>0.00 (0.03)</td><td>0.01 (0.12)</td><td><strong>0.04</strong> (0.15)</td><td><strong>0.17</strong> (0.47)</td><td>0.02 (0.19)</td><td>0.04 (0.18)</td><td><strong>0.26</strong> (0.58)<sup>a</sup></td><td>0.00 (0.00)</td><td>0.03 (0.12)</td><td>0.10 (0.36)</td><td>0.00 (0.00)</td><td>0.04 (0.13)</td><td>0.06 (0.22)</td></tr><tr><td>Auditory<br>hallucinations</td><td>0.01 (0.12)</td><td>0.00 (0.06)</td><td>0.00 (0.00)</td><td><strong>0.17</strong> (0.53)</td><td>0.01 (0.09)</td><td>0.00 (0.00)</td><td><strong>0.31</strong> (0.71)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.06 (0.21)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td></tr><tr><td>Tactile<br>hallucinations</td><td>0.00 (0.00)</td><td>0.00 (0.03)</td><td>0.01 (0.08)</td><td><strong>0.07</strong> (0.38)</td><td>0.00 (0.05)</td><td>0.03 (0.11)</td><td><strong>0.14</strong> (0.53)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.02 (0.10)</td></tr><tr><td>Delusions</td><td>0.01 (0.07)</td><td>0.01 (0.07)</td><td>0.01 (0.06)</td><td><strong>0.32</strong> (0.65)</td><td>0.00 (0.05)</td><td>0.00 (0.00)</td><td><strong>0.51</strong> (0.81)<sup>ab</sup></td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td><strong>0.13</strong> (0.36)</td><td>0.02 (0.14)</td><td>0.04 (0.13)</td><td>0.16 (0.47)</td></tr><tr><td>Depression</td><td>0.12 (0.39)</td><td>0.09 (0.33)</td><td><strong>0.30</strong> (0.52)</td><td><strong>0.48</strong> (0.73)</td><td>0.09 (0.33)</td><td>0.26 (0.58)</td><td><strong>0.53</strong> (0.81)</td><td>0.07 (0.27)</td><td><strong>0.29</strong> (0.38)</td><td><strong>0.45</strong> (0.64)</td><td>0.14 (0.44)</td><td>0.43 (0.62)</td><td><strong>0.40</strong> (0.68)</td></tr><tr><td>Anxiety</td><td>0.15 (0.42)</td><td>0.10 (0.35)</td><td><strong>0.33</strong> (0.47)</td><td><strong>0.57</strong> (0.73)</td><td>0.08 (0.32)</td><td>0.30 (0.48)</td><td><strong>0.62</strong> (0.78)</td><td>0.12 (0.41)</td><td><strong>0.34</strong> (0.49)</td><td><strong>0.49</strong> (0.67)</td><td>0.08 (0.26)</td><td>0.39 (0.45)</td><td><strong>0.58</strong> (0.75)</td></tr><tr><td>Irritability/lability</td><td>0.09 (0.30)</td><td>0.03 (0.13)</td><td><strong>0.21</strong> (0.42)</td><td><strong>0.60</strong> (0.79)</td><td>0.03 (0.11)</td><td>0.23 (0.42)</td><td><strong>0.71</strong> (0.84)</td><td>0.02 (0.12)</td><td>0.19 (0.44)</td><td><strong>0.42</strong> (0.68)</td><td>0.04 (0.17)</td><td>0.18 (0.37)</td><td><strong>0.68</strong> (0.83)</td></tr><tr><td>Agitation/aggression</td><td>0.02 (0.17)</td><td>0.01 (0.06)</td><td>0.07 (0.20)</td><td><strong>0.31</strong> (0.55)</td><td>0.01 (0.07)</td><td>0.08 (0.25)</td><td><strong>0.37</strong> (0.61)</td><td>0.00 (0.04)</td><td>0.08 (0.19)</td><td><strong>0.18</strong> (0.34)</td><td>0.01 (0.07)</td><td>0.00 (0.00)</td><td><strong>0.42</strong> (0.67)</td></tr><tr><td>Euphoria/elation</td><td>0.00 (0.03)</td><td>0.01 (0.05)</td><td><strong>0.04</strong> (0.18)</td><td><strong>0.34</strong> (0.66)</td><td>0.01 (0.08)</td><td>0.04 (0.18)</td><td><strong>0.42</strong> (0.76)</td><td>0.00 (0.00)</td><td>0.03 (0.18)</td><td><strong>0.17</strong> (0.39)</td><td>0.00 (0.00)</td><td>0.07 (0.18)</td><td><strong>0.44</strong> (0.75)</td></tr><tr><td>Aberrant motor<br>behaviour</td><td>0.01 (0.07)</td><td>0.00 (0.06)</td><td>0.03 (0.12)</td><td><strong>0.51</strong> (0.84)</td><td>0.00 (0.00)</td><td>0.03 (0.11)</td><td><strong>0.60</strong> (0.92)</td><td>0.00 (0.00)</td><td>0.05 (0.15)</td><td><strong>0.35</strong> (0.68)</td><td>0.02 (0.14)</td><td>0.00 (0.00)</td><td><strong>0.56</strong> (0.89)</td></tr><tr><td>Hypersexuality</td><td>0.00 (0.03)</td><td>0.00 (0.00)</td><td>0.02 (0.09)</td><td><strong>0.21</strong> (0.57)</td><td>0.00 (0.00)</td><td>0.04 (0.14)</td><td><strong>0.24</strong> (0.59)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td><strong>0.13</strong> (0.43)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.26 (0.72)</td></tr><tr><td>Hyperreligiosity</td><td>0.00 (0.00)</td><td>0.00 (0.03)</td><td>0.01 (0.08)</td><td><strong>0.14</strong> (0.52)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td><strong>0.18</strong> (0.60)</td><td>0.00 (0.04)</td><td>0.03 (0.12)</td><td>0.05 (0.20)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td>0.24 (0.71)</td></tr><tr><td>Impaired sleep</td><td>0.13 (0.40)</td><td>0.06 (0.27)</td><td>0.25 (0.49)</td><td><strong>0.55</strong> (0.76)</td><td>0.02 (0.12)</td><td>0.24 (0.47)</td><td><strong>0.69</strong> (0.87)</td><td>0.07 (0.29)</td><td>0.31 (0.57)</td><td><strong>0.38</strong> (0.57)</td><td>0.12 (0.43)</td><td>0.14 (0.31)</td><td><strong>0.48</strong> (0.70)</td></tr><tr><td>Altered sense of<br>humour</td><td>0.00 (0.04)</td><td>0.00 (0.03)</td><td>0.03 (0.14)</td><td><strong>0.60</strong> (0.84)</td><td>0.00 (0.00)</td><td>0.05 (0.20)</td><td><strong>0.52</strong> (0.79)</td><td>0.00 (0.04)</td><td>0.02 (0.09)</td><td><strong>0.47</strong> (0.70)</td><td>0.00 (0.00)</td><td>0.00 (0.00)</td><td><strong>1.12</strong> (1.07)<sup>ac</sup></td></tr></tbody></table>
Supplementary Table 3. Principal component analysis of (a) neuropsychiatric symptoms and (b) combined neuropsychiatric and behavioural symptoms in *C9orf72*, *GRN* and *MAPT* mutation carriers. As there were no observations for tactile hallucination in the *GRN* group, and for auditory hallucinations in the *MAPT* group these variables were excluded from the PCA in these groups.

(a)

<table><thead><tr><th rowspan="2">Component</th><th colspan="4">C9orf72</th><th colspan="3">GRN</th><th colspan="4">MAPT</th></tr><tr><th>1</th><th>2</th><th>3</th><th>4</th><th>1</th><th>2</th><th>3</th><th>1</th><th>2</th><th>3</th><th>4</th></tr></thead><tbody><tr><td>Visual hallucinations</td><td>0.00</td><td>0.89</td><td>0.27</td><td>0.00</td><td>0.49</td><td>0.71</td><td>0.00</td><td>0.76</td><td>-0.39</td><td>-0.49</td><td>-0.13</td></tr><tr><td>Auditory hallucinations</td><td>0.22</td><td>0.86</td><td>0.26</td><td>0.00</td><td>0.23</td><td>0.84</td><td>0.33</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Tactile hallucinations</td><td>0.33</td><td>0.17</td><td>0.42</td><td>-0.81</td><td>-</td><td>-</td><td>-</td><td>-0.37</td><td>0.74</td><td>-0.43</td><td>-0.36</td></tr><tr><td>Delusions</td><td>0.41</td><td>0.74</td><td>0.33</td><td>0.00</td><td>0.76</td><td>0.25</td><td>0.18</td><td>0.00</td><td>0.00</td><td>0.85</td><td>0.27</td></tr><tr><td>Depression</td><td>0.00</td><td>0.20</td><td>0.83</td><td>-0.14</td><td>0.14</td><td>0.34</td><td>0.78</td><td>0.27</td><td>0.00</td><td>0.25</td><td>0.82</td></tr><tr><td>Anxiety</td><td>0.13</td><td>0.41</td><td>0.72</td><td>0.00</td><td>0.26</td><td>0.12</td><td>0.85</td><td>0.32</td><td>0.57</td><td>0.00</td><td>0.50</td></tr><tr><td>Irritability/lability</td><td>0.62</td><td>0.00</td><td>0.65</td><td>0.15</td><td>0.74</td><td>0.21</td><td>0.49</td><td>0.00</td><td>0.84</td><td>0.20</td><td>0.31</td></tr><tr><td>Agitation/aggression</td><td>0.66</td><td>0.00</td><td>0.61</td><td>0.14</td><td>0.85</td><td>0.16</td><td>0.35</td><td>0.56</td><td>0.68</td><td>-0.10</td><td>0.00</td></tr><tr><td>Euphoria/elation</td><td>0.84</td><td>0.23</td><td>0.17</td><td>0.00</td><td>0.69</td><td>0.58</td><td>0.00</td><td>0.21</td><td>0.21</td><td>0.87</td><td>0.00</td></tr><tr><td>Aberrant motor behaviour</td><td>0.68</td><td>0.55</td><td>0.00</td><td>0.00</td><td>0.69</td><td>0.40</td><td>0.21</td><td>0.88</td><td>0.14</td><td>0.18</td><td>0.25</td></tr><tr><td>Hypersexuality</td><td>0.76</td><td>0.11</td><td>0.18</td><td>-0.26</td><td>0.59</td><td>0.68</td><td>0.34</td><td>0.00</td><td>0.80</td><td>0.46</td><td>0.00</td></tr><tr><td>Hyperreligiosity</td><td>0.20</td><td>0.46</td><td>0.17</td><td>0.83</td><td>0.00</td><td>0.66</td><td>0.50</td><td>0.76</td><td>0.00</td><td>0.52</td><td>-0.18</td></tr><tr><td>Impaired sleep</td><td>0.32</td><td>0.39</td><td>0.69</td><td>0.00</td><td>0.34</td><td>0.16</td><td>0.72</td><td>-0.22</td><td>0.00</td><td>0.11</td><td>0.88</td></tr><tr><td>Altered sense of humour</td><td>0.76</td><td>0.49</td><td>0.00</td><td>0.27</td><td>0.39</td><td>0.76</td><td>0.20</td><td>0.58</td><td>0.18</td><td>0.61</td><td>0.33</td></tr><tr><td>Cumulative variance</td><td><strong>0.26</strong></td><td><strong>0.50</strong></td><td><strong>0.71</strong></td><td><strong>0.82</strong></td><td><strong>0.29</strong></td><td><strong>0.56</strong></td><td><strong>0.77</strong></td><td><strong>0.23</strong></td><td><strong>0.45</strong></td><td><strong>0.68</strong></td><td><strong>0.85</strong></td></tr></tbody></table>
Supplementary Table 3. Principal component analysis of (a) neuropsychiatric symptoms and (b) combined neuropsychiatric and behavioural symptoms in *C9orf72*, *GRN* and *MAPT* mutation carriers. As there were no observations for tactile hallucination in the *GRN* group, and for auditory hallucinations in the *MAPT* group these variables were excluded from the PCA in these groups.

(a)

<table><thead><tr><th rowspan="2">Component</th><th colspan="4">C9orf72</th><th colspan="3">GRN</th><th colspan="4">MAPT</th></tr><tr><th>1</th><th>2</th><th>3</th><th>4</th><th>1</th><th>2</th><th>3</th><th>1</th><th>2</th><th>3</th><th>4</th></tr></thead><tbody><tr><td>Visual hallucinations</td><td>0.00</td><td>0.89</td><td>0.27</td><td>0.00</td><td>0.49</td><td>0.71</td><td>0.00</td><td>0.76</td><td>-0.39</td><td>-0.49</td><td>-0.13</td></tr><tr><td>Auditory hallucinations</td><td>0.22</td><td>0.86</td><td>0.26</td><td>0.00</td><td>0.23</td><td>0.84</td><td>0.33</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Tactile hallucinations</td><td>0.33</td><td>0.17</td><td>0.42</td><td>-0.81</td><td>-</td><td>-</td><td>-</td><td>-0.37</td><td>0.74</td><td>-0.43</td><td>-0.36</td></tr><tr><td>Delusions</td><td>0.41</td><td>0.74</td><td>0.33</td><td>0.00</td><td>0.76</td><td>0.25</td><td>0.18</td><td>0.00</td><td>0.00</td><td>0.85</td><td>0.27</td></tr><tr><td>Depression</td><td>0.00</td><td>0.20</td><td>0.83</td><td>-0.14</td><td>0.14</td><td>0.34</td><td>0.78</td><td>0.27</td><td>0.00</td><td>0.25</td><td>0.82</td></tr><tr><td>Anxiety</td><td>0.13</td><td>0.41</td><td>0.72</td><td>0.00</td><td>0.26</td><td>0.12</td><td>0.85</td><td>0.32</td><td>0.57</td><td>0.00</td><td>0.50</td></tr><tr><td>Irritability/lability</td><td>0.62</td><td>0.00</td><td>0.65</td><td>0.15</td><td>0.74</td><td>0.21</td><td>0.49</td><td>0.00</td><td>0.84</td><td>0.20</td><td>0.31</td></tr><tr><td>Agitation/aggression</td><td>0.66</td><td>0.00</td><td>0.61</td><td>0.14</td><td>0.85</td><td>0.16</td><td>0.35</td><td>0.56</td><td>0.68</td><td>-0.10</td><td>0.00</td></tr><tr><td>Euphoria/elation</td><td>0.84</td><td>0.23</td><td>0.17</td><td>0.00</td><td>0.69</td><td>0.58</td><td>0.00</td><td>0.21</td><td>0.21</td><td>0.87</td><td>0.00</td></tr><tr><td>Aberrant motor behaviour</td><td>0.68</td><td>0.55</td><td>0.00</td><td>0.00</td><td>0.69</td><td>0.40</td><td>0.21</td><td>0.88</td><td>0.14</td><td>0.18</td><td>0.25</td></tr><tr><td>Hypersexuality</td><td>0.76</td><td>0.11</td><td>0.18</td><td>-0.26</td><td>0.59</td><td>0.68</td><td>0.34</td><td>0.00</td><td>0.80</td><td>0.46</td><td>0.00</td></tr><tr><td>Hyperreligiosity</td><td>0.20</td><td>0.46</td><td>0.17</td><td>0.83</td><td>0.00</td><td>0.66</td><td>0.50</td><td>0.76</td><td>0.00</td><td>0.52</td><td>-0.18</td></tr><tr><td>Impaired sleep</td><td>0.32</td><td>0.39</td><td>0.69</td><td>0.00</td><td>0.34</td><td>0.16</td><td>0.72</td><td>-0.22</td><td>0.00</td><td>0.11</td><td>0.88</td></tr><tr><td>Altered sense of humour</td><td>0.76</td><td>0.49</td><td>0.00</td><td>0.27</td><td>0.39</td><td>0.76</td><td>0.20</td><td>0.58</td><td>0.18</td><td>0.61</td><td>0.33</td></tr><tr><td>Cumulative variance</td><td>0.26</td><td>0.50</td><td>0.71</td><td>0.82</td><td>0.29</td><td>0.56</td><td>0.77</td><td>0.23</td><td>0.45</td><td>0.68</td><td>0.85</td></tr></tbody></table>
(b)

<table><thead><tr><th rowspan="2">Component</th><th colspan="4">C9orf72</th><th colspan="4">GRN</th><th colspan="4">MAPT</th></tr><tr><th>1</th><th>2</th><th>3</th><th>4</th><th>1</th><th>2</th><th>3</th><th>4</th><th>1</th><th>2</th><th>3</th><th>4</th></tr></thead><tbody><tr><td>Visual hallucinations</td><td>0.25</td><td>0.86</td><td>0.26</td><td>0.11</td><td>0.38</td><td>0.78</td><td>0.00</td><td>0.11</td><td>0.43</td><td>-0.26</td><td>-0.13</td><td>-0.84</td></tr><tr><td>Auditory hallucinations</td><td>0.41</td><td>0.81</td><td>0.22</td><td>0.10</td><td>0.25</td><td>0.74</td><td>0.30</td><td>0.50</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Tactile hallucinations</td><td>0.32</td><td>0.15</td><td>0.42</td><td>-0.81</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-0.42</td><td>0.85</td><td>-0.27</td><td>0.00</td></tr><tr><td>Delusions</td><td>0.47</td><td>0.66</td><td>0.35</td><td>0.00</td><td>0.68</td><td>0.29</td><td>0.32</td><td>-0.13</td><td>0.43</td><td>-0.11</td><td>0.22</td><td>0.71</td></tr><tr><td>Depression</td><td>0.00</td><td>0.22</td><td>0.83</td><td>-0.11</td><td>0.00</td><td>0.33</td><td>0.75</td><td>0.35</td><td>0.25</td><td>-0.13</td><td>0.83</td><td>0.00</td></tr><tr><td>Anxiety</td><td>0.16</td><td>0.40</td><td>0.72</td><td>0.00</td><td>0.15</td><td>0.00</td><td>0.86</td><td>0.19</td><td>0.22</td><td>0.45</td><td>0.62</td><td>0.00</td></tr><tr><td>Irritability/lability</td><td>0.61</td><td>0.00</td><td>0.65</td><td>0.00</td><td>0.45</td><td>0.41</td><td>0.67</td><td>-0.14</td><td>0.17</td><td>0.74</td><td>0.41</td><td>0.28</td></tr><tr><td>Agitation/aggression</td><td>0.67</td><td>-0.13</td><td>0.61</td><td>0.00</td><td>0.55</td><td>0.39</td><td>0.57</td><td>-0.27</td><td>0.54</td><td>0.69</td><td>0.00</td><td>-0.29</td></tr><tr><td>Euphoria/elation</td><td>0.82</td><td>0.00</td><td>0.20</td><td>-0.15</td><td>0.53</td><td>0.72</td><td>0.23</td><td>0.00</td><td>0.63</td><td>0.00</td><td>0.11</td><td>0.65</td></tr><tr><td>Aberrant motor behaviour</td><td>0.73</td><td>0.42</td><td>0.12</td><td>0.00</td><td>0.75</td><td>0.26</td><td>0.29</td><td>0.00</td><td>0.83</td><td>0.00</td><td>0.27</td><td>-0.28</td></tr><tr><td>Hypersexuality</td><td>0.70</td><td>0.00</td><td>0.23</td><td>-0.30</td><td>0.53</td><td>0.61</td><td>0.41</td><td>0.25</td><td>0.33</td><td>0.67</td><td>0.00</td><td>0.47</td></tr><tr><td>Hyperreligiosity</td><td>0.33</td><td>0.39</td><td>0.17</td><td>0.83</td><td>0.31</td><td>0.14</td><td>0.35</td><td>0.72</td><td>0.79</td><td>0.00</td><td>-0.11</td><td>0.00</td></tr><tr><td>Impaired sleep</td><td>0.32</td><td>0.33</td><td>0.70</td><td>0.00</td><td>0.41</td><td>0.00</td><td>0.69</td><td>0.20</td><td>0.00</td><td>0.00</td><td>0.82</td><td>0.25</td></tr><tr><td>Altered sense of humour</td><td>0.81</td><td>0.34</td><td>0.00</td><td>0.20</td><td>0.62</td><td>0.48</td><td>0.14</td><td>0.44</td><td>0.87</td><td>0.00</td><td>0.31</td><td>0.24</td></tr><tr><td>Disinhibition</td><td>0.79</td><td>0.37</td><td>0.27</td><td>-0.14</td><td>0.70</td><td>0.52</td><td>0.20</td><td>0.00</td><td>0.73</td><td>0.62</td><td>0.00</td><td>0.13</td></tr><tr><td>Apathy</td><td>0.74</td><td>0.37</td><td>0.38</td><td>0.11</td><td>0.80</td><td>0.25</td><td>0.19</td><td>0.35</td><td>0.86</td><td>0.00</td><td>0.25</td><td>0.00</td></tr><tr><td>Loss of sympathy/empathy</td><td>0.75</td><td>0.41</td><td>0.31</td><td>0.16</td><td>0.83</td><td>0.37</td><td>0.15</td><td>0.23</td><td>0.77</td><td>0.45</td><td>0.00</td><td>0.00</td></tr><tr><td>Ritualistic/compulsive behaviour</td><td>0.79</td><td>0.30</td><td>0.22</td><td>0.00</td><td>0.72</td><td>0.28</td><td>0.31</td><td>0.30</td><td>0.68</td><td>0.56</td><td>0.14</td><td>0.14</td></tr><tr><td>Hyperorality and appetite changes</td><td>0.83</td><td>0.38</td><td>0.11</td><td>0.13</td><td>0.77</td><td>0.20</td><td>0.35</td><td>0.26</td><td>0.88</td><td>0.00</td><td>0.24</td><td>0.20</td></tr><tr><td>Poor response to social/emotional cues</td><td>0.76</td><td>0.37</td><td>0.29</td><td>0.00</td><td>0.93</td><td>0.23</td><td>0.14</td><td>0.14</td><td>0.81</td><td>0.48</td><td>0.11</td><td>0.00</td></tr><tr><td>Inappropriate trusting behaviour</td><td>0.81</td><td>0.33</td><td>0.15</td><td>0.00</td><td>0.80</td><td>0.36</td><td>0.16</td><td>0.17</td><td>0.90</td><td>0.12</td><td>0.10</td><td>0.13</td></tr><tr><td>Cumulative variance</td><td>0.39</td><td>0.56</td><td>0.73</td><td>0.81</td><td>0.37</td><td>0.55</td><td>0.73</td><td>0.82</td><td>0.40</td><td>0.59</td><td>0.71</td><td>0.82</td></tr></tbody></table>
(b)

<table><thead><tr><th rowspan="2">Component</th><th colspan="4">C9orf72</th><th colspan="4">GRN</th><th colspan="4">MAPT</th></tr><tr><th>1</th><th>2</th><th>3</th><th>4</th><th>1</th><th>2</th><th>3</th><th>4</th><th>1</th><th>2</th><th>3</th><th>4</th></tr></thead><tbody><tr><td>Visual hallucinations</td><td>0.25</td><td>0.86</td><td>0.26</td><td>0.11</td><td>0.38</td><td>0.78</td><td>0.00</td><td>0.11</td><td>0.43</td><td>-0.26</td><td>-0.13</td><td>-0.84</td></tr><tr><td>Auditory hallucinations</td><td>0.41</td><td>0.81</td><td>0.22</td><td>0.10</td><td>0.25</td><td>0.74</td><td>0.30</td><td>0.50</td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Tactile hallucinations</td><td>0.32</td><td>0.15</td><td>0.42</td><td>-0.81</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-0.42</td><td>0.85</td><td>-0.27</td><td>0.00</td></tr><tr><td>Delusions</td><td>0.47</td><td>0.66</td><td>0.35</td><td>0.00</td><td>0.68</td><td>0.29</td><td>0.32</td><td>-0.13</td><td>0.43</td><td>-0.11</td><td>0.22</td><td>0.71</td></tr><tr><td>Depression</td><td>0.00</td><td>0.22</td><td>0.83</td><td>-0.11</td><td>0.00</td><td>0.33</td><td>0.75</td><td>0.35</td><td>0.25</td><td>-0.13</td><td>0.83</td><td>0.00</td></tr><tr><td>Anxiety</td><td>0.16</td><td>0.40</td><td>0.72</td><td>0.00</td><td>0.15</td><td>0.00</td><td>0.86</td><td>0.19</td><td>0.22</td><td>0.45</td><td>0.62</td><td>0.00</td></tr><tr><td>Irritability/lability</td><td>0.61</td><td>0.00</td><td>0.65</td><td>0.00</td><td>0.45</td><td>0.41</td><td>0.67</td><td>-0.14</td><td>0.17</td><td>0.74</td><td>0.41</td><td>0.28</td></tr><tr><td>Agitation/aggression</td><td>0.67</td><td>-0.13</td><td>0.61</td><td>0.00</td><td>0.55</td><td>0.39</td><td>0.57</td><td>-0.27</td><td>0.54</td><td>0.69</td><td>0.00</td><td>-0.29</td></tr><tr><td>Euphoria/elation</td><td>0.82</td><td>0.00</td><td>0.20</td><td>-0.15</td><td>0.53</td><td>0.72</td><td>0.23</td><td>0.00</td><td>0.63</td><td>0.00</td><td>0.11</td><td>0.65</td></tr><tr><td>Aberrant motor behaviour</td><td>0.73</td><td>0.42</td><td>0.12</td><td>0.00</td><td>0.75</td><td>0.26</td><td>0.29</td><td>0.00</td><td>0.83</td><td>0.00</td><td>0.27</td><td>-0.28</td></tr><tr><td>Hypersexuality</td><td>0.70</td><td>0.00</td><td>0.23</td><td>-0.30</td><td>0.53</td><td>0.61</td><td>0.41</td><td>0.25</td><td>0.33</td><td>0.67</td><td>0.00</td><td>0.47</td></tr><tr><td>Hyperreligiosity</td><td>0.33</td><td>0.39</td><td>0.17</td><td>0.83</td><td>0.31</td><td>0.14</td><td>0.35</td><td>0.72</td><td>0.79</td><td>0.00</td><td>-0.11</td><td>0.00</td></tr><tr><td>Impaired sleep</td><td>0.32</td><td>0.33</td><td>0.70</td><td>0.00</td><td>0.41</td><td>0.00</td><td>0.69</td><td>0.20</td><td>0.00</td><td>0.00</td><td>0.82</td><td>0.25</td></tr><tr><td>Altered sense of humour</td><td>0.81</td><td>0.34</td><td>0.00</td><td>0.20</td><td>0.62</td><td>0.48</td><td>0.14</td><td>0.44</td><td>0.87</td><td>0.00</td><td>0.31</td><td>0.24</td></tr><tr><td>Disinhibition</td><td>0.79</td><td>0.37</td><td>0.27</td><td>-0.14</td><td>0.70</td><td>0.52</td><td>0.20</td><td>0.00</td><td>0.73</td><td>0.62</td><td>0.00</td><td>0.13</td></tr><tr><td>Apathy</td><td>0.74</td><td>0.37</td><td>0.38</td><td>0.11</td><td>0.80</td><td>0.25</td><td>0.19</td><td>0.35</td><td>0.86</td><td>0.00</td><td>0.25</td><td>0.00</td></tr><tr><td>Loss of sympathy/empathy</td><td>0.75</td><td>0.41</td><td>0.31</td><td>0.16</td><td>0.83</td><td>0.37</td><td>0.15</td><td>0.23</td><td>0.77</td><td>0.45</td><td>0.00</td><td>0.00</td></tr><tr><td>Ritualistic/compulsive behaviour</td><td>0.79</td><td>0.30</td><td>0.22</td><td>0.00</td><td>0.72</td><td>0.28</td><td>0.31</td><td>0.30</td><td>0.68</td><td>0.56</td><td>0.14</td><td>0.14</td></tr><tr><td>Hyperorality and appetite changes</td><td>0.83</td><td>0.38</td><td>0.11</td><td>0.13</td><td>0.77</td><td>0.20</td><td>0.35</td><td>0.26</td><td>0.88</td><td>0.00</td><td>0.24</td><td>0.20</td></tr><tr><td>Poor response to social/emotional cues</td><td>0.76</td><td>0.37</td><td>0.29</td><td>0.00</td><td>0.93</td><td>0.23</td><td>0.14</td><td>0.14</td><td>0.81</td><td>0.48</td><td>0.11</td><td>0.00</td></tr><tr><td>Inappropriate trusting behaviour</td><td>0.81</td><td>0.33</td><td>0.15</td><td>0.00</td><td>0.80</td><td>0.36</td><td>0.16</td><td>0.17</td><td>0.90</td><td>0.12</td><td>0.10</td><td>0.13</td></tr><tr><td>Cumulative variance</td><td>0.39</td><td>0.56</td><td>0.73</td><td>0.81</td><td>0.37</td><td>0.55</td><td>0.73</td><td>0.82</td><td>0.40</td><td>0.59</td><td>0.71</td><td>0.82</td></tr></tbody></table>
<table><caption>Supplementary Table 4. Methodology for calculating the Algorithm-based Behaviour Score.</caption><thead><tr><td>Individual scores</td><td>Overall score</td></tr></thead><tbody><tr><td>All 0</td><td>0</td></tr><tr><td>Maximum 0.5</td><td>0.5</td></tr><tr><td>Maximum &gt; 0.5:</td><td></td></tr><tr><td>Maximum 1, all others 0</td><td>0.5</td></tr><tr><td>Maximum 2 or 3, all others 0</td><td>1</td></tr><tr><td>Maximum occurs once, another rating &gt; 0</td><td>One level &lt; maximum</td></tr><tr><td>Maximum occurs &gt; once</td><td>Maximum score</td></tr></tbody></table>
<table><caption>Supplementary Table 4. Methodology for calculating the Algorithm-based Behaviour Score.</caption><thead><tr><td>Individual scores</td><td>Overall score</td></tr></thead><tbody><tr><td>All 0</td><td>0</td></tr><tr><td>Maximum 0.5</td><td>0.5</td></tr><tr><td>Maximum &gt; 0.5:</td><td></td></tr><tr><td>Maximum 1, all others 0</td><td>0.5</td></tr><tr><td>Maximum 2 or 3, all others 0</td><td>1</td></tr><tr><td>Maximum occurs once, another rating &gt; 0</td><td>One level &lt; maximum</td></tr><tr><td>Maximum occurs &gt; once</td><td>Maximum score</td></tr></tbody></table>
Supplementary Figure 1. Longitudinal change in severity of depression and anxiety in asymptomatic (CDR® plus NACC FTLD global score 0), prodromal (0.5) and symptomatic (≥1) C9orf72, GRN and MAPT mutation carriers. Solid lines represent depression severity scores and dotted lines represent anxiety severity scores.

<figure><img src="image_9.png" /></figure>
Supplementary Figure 1. Longitudinal change in severity of depression and anxiety in asymptomatic (CDR® plus NACC FTLD global score 0), prodromal (0.5) and symptomatic (≥1) C9orf72, GRN and MAPT mutation carriers. Solid lines represent depression severity scores and dotted lines represent anxiety severity scores.

<figure><img src="image_13.png" /></figure>
<figure><img src="image_10.png" /><figcaption>Supplementary Figure 2. Comparison of Global Behaviour Score and newly designed Algorithm-based Behaviour Score. Individual (left panel) and group (right panel) comparisons are shown.</figcaption></figure>
<figure><img src="image_14.png" /><figcaption>Supplementary Figure 2. Comparison of Global Behaviour Score and newly designed Algorithm-based Behaviour Score. Individual (left panel) and group (right panel) comparisons are shown.</figcaption></figure>
Supplementary Figure 3. Comparison of the standard CDR® plus NACC FTLD with a new CDR® plus NACC FTLD which adds in a new Neuropsychiatric Score and replaces the original NACC global Behaviour component with an algorithm-based Behaviour Score (CDR® plus NACC FTLD-N-B+) in genetic mutation carrier groups (C9orf72, GRN and MAPT) judged clinically to be symptomatic.

<figure><img src="image_11.png" /></figure>
Supplementary Figure 3. Comparison of the standard CDR® plus NACC FTLD with a new CDR® plus NACC FTLD which adds in a new Neuropsychiatric Score and replaces the original NACC global Behaviour component with an algorithm-based Behaviour Score (CDR® plus NACC FTLD-N-B+) in genetic mutation carrier groups (C9orf72, GRN and MAPT) judged clinically to be symptomatic.

<figure><img src="image_15.png" /></figure>