The Revised Self-monitoring Scale Detects Early Impairment of Social Cognition in Genetic Frontotemporal Dementia Within the GENFI Cohort

<jats:title>Abstract</jats:title>         <jats:p>BackgroundAlthough social cognitive dysfunction is a major feature of frontotemporal dementia (FTD) it has been poorly studied in familial forms. A key goal of studies is to detect early cognitive impairment using validated measures in large patient cohorts. MethodsWe used the Revised Self-Monitoring Scale (RSMS) as a measure of socioemotional sensitivity in 730 participants from the Genetic FTD initiative (GENFI) observational study: 269 mutation-negative healthy controls, 193 <jats:italic>C9orf72</jats:italic> expansion carriers, 193 <jats:italic>GRN</jats:italic> mutation carriers and 75 <jats:italic>MAPT</jats:italic> mutation carriers. All participants underwent the standardised GENFI clinical assessment including the ‘CDR® plus NACC FTLD’ scale and RSMS. The RSMS Total score and its two subscores, socioemotional expressiveness (EX score), and modification of self-presentation (SP score) were measured. Volumetric T1-weighted magnetic resonance imaging was available from 377 mutation carriers for voxel-based morphometry (VBM) analysis.  ResultsThe RSMS was decreased in symptomatic mutation carriers in all genetic groups but at a prodromal stage only in the <jats:italic>C9orf72</jats:italic> (for the total score and both subscores), and <jats:italic>GRN</jats:italic> (for the modification of self-presentation subscore) groups. RSMS score correlated with disease severity in all groups. The VBM analysis implicated an overlapping network of regions including the orbitofrontal cortex, insula, temporal pole, medial temporal lobe and striatum. ConclusionsThe RSMS indexes socioemotional impairment at an early stage of genetic FTD, and may be a suitable outcome measure in forthcoming trials.</jats:p>

section_content: Frontotemporal dementia (FTD) is a complex and heterogeneous neurodegenerative disease, manifesting itself as a diverse spectrum of clinical syndromes. 

However, despite differences in presentation, many people with FTD develop impaired social cognition [1], a set of psychological processes which includes the ability to evaluate social and emotional cues from others and then select an appropriate behavioural response, a phenomenon often referred to as 'socioemotional sensitivity' or 'self-monitoring'. In both healthy and clinical populations, the Revised Self-Monitoring Scale (RSMS) [2] has often been used to study socioemotional sensitivity and responsiveness as well as the neural networks that underlie them [3, 4]. Unlike many neurodegenerative diseases, FTD is highly heritable with approximately a third of patients having a causative autosomal dominant genetic mutation [5]. Mutations are most commonly found in one of three genes, chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) [6], with the most common clinical presentation being behavioural variant FTD (bvFTD) [7]. However, whilst social cognitive dysfunction has been studied extensively in sporadic FTD, few investigations have looked at genetic cohorts exclusively. 

The Genetic FTD Initiative (GENFI) is a multicentre natural history study aimed at investigating early biomarkers in a large genetic FTD cohort, including measures of cognition [5]. This study sought to assess whether the RSMS could detect early changes in social cognition and what the underlying neural correlates of the RSMS were in people with mutations in C9orf72, GRN and MAPT.
section_name: Background

section_name: Methods

section_content: Participants were recruited from the fth data freeze of GENFI, incorporating data from 24 sites. Of the 849 participants enrolled in the second phase of the study, cross-sectional data on the RSMS was available from 730 participants, consisting of 269 healthy controls (family members who tested negative for the mutation carried within the family), 193 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers (Table 1 ). All participants provided written informed consent.
section_name: Participants

section_content: All participants were given the standardised GENFI clinical assessment battery including a medical history, physical examination, the Mini-Mental State Examination, and the CDR ® Dementia Staging Instrument with National Alzheimer Coordinating Centre Frontotemporal Lobar Degeneration component (CDR ® plus NACC FTLD) (Table 1 ). The CDR ® plus NACC FTLD is a clinical measure of disease severity in FTD, consisting of a core six cognitive/functional domains with a further 2 domains addressing behaviour and language [8]. Each domain is rated on a ve-point scale ranging from 0 (normal), 0. 5 (questionably or minimally impaired), 1 (mildly but de nitely impaired), 2 (moderately impaired), to 3 (severely impaired). The sum of ratings across all eight domains is used to generate the CDR ® plus NACC FTLD sum of boxes (CDR ® plus NACC FTLD-SB) (Table 1 ). A second measure, a global CDR ® plus NACC FTLD score can also be generated, using a speci c algorithm [9]. We used this global score to classify each of the genetic groups cross-sectionally into those who scored 0 (i. e. were asymptomatic), 0. 5 (possibly or mildly symptomatic i. e. prodromal), and 1 or more (fully symptomatic mutation carriers).
section_name: Assessments

section_content: Demographics are shown in Table 1. There was a signi cant difference in sex between these groups: symptomatic C9orf72 carriers had a signi cantly higher percentage of males than in the mildly symptomatic and asymptomatic C9orf72 carrier groups and in the controls (X 2 (1) = 4. 08, p = 0. 044, X 2 (1) = 9. 12, p = 0. 003 and X 2 (1) = 11. 79, p = 0. 001 respectively). There was also a signi cant difference in age between groups (F(9,720)) = 27. 5, p < 0. 001): asymptomatic MAPT mutation carriers were signi cantly younger and mildly symptomatic GRN mutation carriers were signi cantly older than controls (p < 0. 001 and p = 0. 043 respectively). All symptomatic mutation carriers were signi cantly older than controls (p < 0. 001). Analysis of differences in years spent in education (F(9,720)) = 4. 09, p < 0. 001), showed that symptomatic C9orf72 and GRN mutation carriers spent signi cantly fewer years when compared to controls (p = 0. 003 and p < 0. 001 respectively). All analyses were therefore adjusted for sex, age and education.
section_name: Demographics

section_content: The RSMS is a widely used questionnaire made up of 13 items designed to measure an individual's awareness of social behaviour and sensitivity to subtle emotional expressions during face-to-face interaction [10]. Items include 'In conversations, the subject is sensitive to even the slightest change in the facial expression of the person he/she is conversing with' and 'If someone is lying to the subject, he/she usually knows it at once from that person's manner or expression'. Each item is rated by a participant's informant on a 6-point scale, ranging from 'certainly, always false' (0 points) to 'certainly, always true' (6 points). As well as a Total score, two subscores of the RSMS can also be calculated: socioemotional expressiveness i. e. the ability to understand subtle social cues in others (EX score, out of 30), and modi cation of self-presentation i. e. the ability to change one's behaviour when it is not appropriate for the current social situation (SP score, out of 35).
section_name: Revised Self-Monitoring Scale (RSMS)

section_content: Statistical analyses were performed using StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC. In the healthy control group, Spearman rank correlations were performed to assess the relationship between the RSMS Total score, age, sex and education. Cross-sectional RSMS Total, EX and SP scores were compared between groups (healthy controls, and 0, 0. 5 and 1+ in each genetic group) using a linear regression model adjusting for age, sex and education, with 95% bias-corrected bootstrapped con dence intervals with 1000 repetitions (to correct for non-normally distributed data).
section_name: Statistical Analysis

section_content: Participants underwent volumetric T1-weighted magnetic resonance imaging according to the harmonized GENFI protocol on a 3T scanner. All images underwent quality control and any scans with movement or artefacts were eliminated from analysis. In addition, any scans displaying moderate to severe vascular disease or any lesion presentation were also excluded. 377 scans were included in the analysis: 151 C9orf72 expansion carriers, 162 GRN mutation carriers and 64 MAPT mutation carriers. A Voxel-Based Morphometry (VBM) was subsequently performed using Statistical Parametric Mapping (SPM) 12 software, version 6685 (www. l. ion. ucl. ac. uk/spm), running under Matlab R2014a (Mathworks, USA). T1-weighted images were normalised and segmented into Grey Matter (GM), White Matter (WM) and Cerebrospinal Fluid (CSF) probability maps using standard procedures and a fast-diffeomorphic image registration algorithm (DARTEL) [11]. Prior to analysis, GM segmentations were then transformed into Montreal Neurological Institute (MNI) space, modulated and smoothed using a Gaussian kernel with 6mm ll-width at half maximum, before applying a mask image as reported in Ridgway et al., 2009 [12]. In order to investigate the neural correlates of socioemotional sensitivity in each genetic group, multiple regression models were performed to explore the relationship of RSMS Total score and GM density in mutation carriers in each genetic group. Age, sex, scanner type and total intracranial volume (TIV, calculated using SPM [13] ) were included as nuisance covariates. The Family-Wise Error (FWE) correction for multiple comparisons was set at 0. 05. However, if no ndings were observed at that strict level of correction, results were reviewed at an uncorrected p value of 0. 001.
section_name: Image acquisition and processing

section_name: Results

section_content: Mean (standard deviation) RSMS Total score was 47. 8 (8. 4) in controls (Tables S1 and S2 ). Overall, there was no signi cant difference between performance in females (n = 157: 48. 5 (8. 0)) and males (n = 112: 46. 8 (9. 0) (p = 0. 21). No signi cant correlations between RSMS Total score and age (rho = 0. 01, p = 0. 87) or education (rho = 0. 12, p = 0. 06) were observed.
section_name: Healthy control performance on the RSMS

section_content: Mean RSMS Total scores in all symptomatic (CDR 1+) mutation carriers were signi cantly lower than in healthy controls (Tables 1 and 2, Figure 1 ): C9orf72 23. 5 (12. 3), GRN 28. 6 (12. 1), MAPT 22. 8 (18. 9). In the CDR 0. 5 groups, the C9orf72 group also scored signi cantly lower than controls with a trend for a lower score in the GRN group and no difference in the MAPT group: C9orf72 41. 9 (11. 4), GRN 43. 8 (12. 1), MAPT 50. 1 (14. 2). No signi cant differences were observed between the asymptomatic (CDR 0) mutation carrier groups and controls. 

Within each genetic group, there was a signi cantly lower RSMS Total score in the symptomatic group compared with the CDR 0. 5 and CDR 0 groups (Tables 1 and 2, Figure 1 ). 

Stratifying by individual global CDR ® plus NACC FTLD score (0, 0. 5, 1, 2 and 3), all genetic groups show decreasing RSMS Total score with increasing CDR (Figure 2 ). RSMS EX and SP scores followed a similar pattern as for RSMS Total performance (Table 1, Tables S3 and S4, Figures S1 and S2 ): mean scores in all symptomatic (CDR 1+) mutation carriers and the C9orf72 CDR 0. 5 group were signi cantly lower than in healthy controls for both EX and SP scores. However, additionally, the GRN CDR 0. 5 group had signi cantly lower mean SP score than controls. Within each genetic group, there was a signi cantly lower RSMS EX and SP score in the symptomatic groups compared with the CDR 0. 5 and CDR 0 groups, with EX score also lower in the C9orf72 CDR 0. 5 group compared with the CDR 0 group (Tables S3 and S4, Figures S1 and S2 ).
section_name: Cross-sectional analysis of mutation carriers

section_content: A strong negative correlation between RSMS Total score and CDR ® plus NACC FTLD-SB scores was observed for all genetic groups (Figure S3 ): C9orf72 (r = -0. 67, p < 0. 001), GRN (r = -0. 59, p < 0. 001), MAPT (r = -0. 53, p < 0. 001).
section_name: Relationship between RSMS and CDR ® plus NACC FTLD-SB

section_content: The VBM analysis revealed positive associations of the RSMS total score with grey matter volume corrected for multiple comparisons in the C9orf72 and GRN groups, but only at an uncorrected p value of <0. 001 for the MAPT group. Overlapping neural correlates were seen in each of the genetic groups, with an association of decreased score with lower grey matter volume in the orbitofrontal lobe, insula, temporal pole, medial temporal lobe and both caudate and putamen (Figure 3, Table S5 ).
section_name: Neural correlates of RSMS in each genetic group

section_content: In this study, we have shown that the RSMS detects social cognitive impairment in genetic FTD, including early di culties within the CDR 0. 5 group of C9orf72 mutation carriers for the Total score, and for both C9orf72 and GRN mutation carriers for the modi cation of self-presentation (SP) subscore. RSMS Total score is highly correlated with 'CDR ® plus NACC FTLD' score and with an overlapping 'social cognitive' network of regions including orbitofrontal, anteromedial temporal, insula and striatal areas. 

The results here show that the RSMS score decreases with increasing disease severity as measured by the CDR ® plus NACC FTLD score, with a signi cant negative correlation between both scores in each genetic group i. e. RSMS decreases as CDR ® plus NACC FTLD increases. This relationship has also been described in a recent study [14], although that study did not separate mutation carriers into separate genetic groups. 

Carriers of C9orf72 repeat expansions at CDR 0. 5 (i. e. possibly or mildly symptomatic) perform signi cantly worse on the Total RSMS score and both subscores than controls, whilst GRN mutation carriers have a signi cantly lower SP subscore and a trend to lower Total and EX scores than controls. These results highlight the potential for the RSMS to detect early de cits in social cognition in these genetic cohorts of FTD, prior to phenoconversion to being fully symptomatic. 

The pro les of RSMS performance in MAPT mutation carriers seem to be somewhat unique. Symptomatic MAPT mutation carriers scored much lower at baseline than the other MAPT mutation carriers, a result that is consistent with ndings from other cross-sectional [5, [28] [29] [30] and longitudinal [31] familial FTD studies. This could imply that self-monitoring in MAPT mutation carriers is relatively stable in early disease stages until soon before or at the point of conversion when there is a rapid decline in social cognitive function, as opposed to a more gradual (and earlier) deterioration in GRN and C9orf72 mutation carriers [32] [33] [34] [35]. 

Previous studies in sporadic FTD have described links between de cits in emotional processing and empathic perspective taking and a 'social cognition network' comprising bifrontal (particularly orbitofrontal), anterior and inferior temporal and insula cortical regions [15] [16] [17]. Subcortical structures such as the amygdala and caudate have also been implicated in driving such dysfunction [17]. Results of the VBM analysis in this study highlighted frontal involvement across all mutation carrier groups, in particular the orbitofrontal cortex, a region known to be involved in decision-making and coordinating complex social and emotional behaviours [18] [19] [20] with its atrophy and circuitry disruption having been previously described in patients with behavioural variant FTD [21]. Previous studies speci cally utilising the RSMS as a tool to measure social cognition have identi ed a positive association between socioemotional sensitivity and functional connectivity within the brain's salience network, largely between the right anterior insula and both cortical and subcortical nodes [10], as well as between right supramarginal and angular gyri, and right frontal pole [22, 23]. Here we demonstrate widespread insula involvement, anteriorly in C9orf72 and GRN mutation carriers and posteriorly in MAPT mutation carriers, in addition to anterior cingulate cortex involvement in GRN mutation carriers exclusively, another crucial element of the salience network [24]. 

Other brain regions associated with such behavioural de cits in FTD include the inferior and medial temporal gyri [4], areas particularly involved in emotion perception and recognition. Grey matter volume of the temporal pole was positively correlated with RSMS score in all mutation groups, with C9orf72 carriers also exhibiting an association with superior temporal gyrus and GRN and MAPT carriers showing a correlation with inferior temporal gyri speci cally. Our results also show an association of the basal ganglia, particularly the caudate and putamen, in all genetic groups. These subcortical regions are also known to be implicated in emotion recognition [25] [26] [27], an integral factor in an individual's performance on the RSMS. 

Overall, there appears to be a network of brain regions associated with impairment of socioemotional sensitivity in FTD that includes frontal, temporal, insula and striatal areas, including signi cant crossover with areas involved in the salience network, thus supporting the established role of aberrant saliency detection in FTD-related social cognitive dysfunction.
section_name: Discussion

section_content: These data should be interpreted in light of some limitations. Despite the large nature of GENFI in comparison to other FTD studies, one limitation lies in the relatively small numbers in some of the groups once strati ed. Future studies should aim to replicate these ndings in larger cohorts, as well as investigate longitudinal changes in socioemotional sensitivity over time. 

Another limitation lies in the design of the RSMS, due to the inclusion of reverse scoring. While every effort is taken to ensure the informant understands how to answer correctly, we cannot eliminate the chance of misinterpretation. Lastly, while global CDR ® plus NACC FTLD scoring is a validated and robust tool used to measure disease severity in FTD, the assessment of motor and neuropsychiatric symptoms is not included. With FTD representing a diverse spectrum of symptomatic pro les, a limitation of this study lies in possible miscategorisation of individuals who might be at a more advanced stage of their disease but present with symptoms that are not speci cally addressed by this scale.
section_name: Limitations

section_content: In summary, this study describes the ability of the RSMS to detect early changes in socioemotional behaviour in distinct genetic cohorts of FTD and illustrates the neural correlates of self-monitoring in these populations. The earliest symptoms of FTD are a product of altered functional connectivity that precedes structural atrophy [36, 37] thus tests such as the RSMS that have been shown to correlate well with these functional changes may prove to be the most powerful diagnostically, providing scope to successfully distinguish behavioural symptoms of FTD from psychiatric disorders [38], as well as serving as a potentially useful outcome measure in clinical trials.
section_name: Conclusions

section_name: Acknowledgements

section_content: We thank all participants and their family members for taking part in the GENFI study.
section_name: Acknowledgements

section_name: References

section_content: Funding The Dementia Research Centre is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility as well as an Alzheimer's Society grant [ AS-PG-16-007 ]. This work was also supported by the MRC UK GENFI grant [ MR/M023664/1 ], the Italian Ministry of Health ( CoEN015 and Ricerca Corrente ) and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, a Canadian Institutes of Health Research operating grant, The Blue eld Project, and the JPND GENFI-PROX grant [ 2019-02248 ]. JDR is supported by an MRC Clinician Scientist Fellowship [ MR/M008525/1 ] and has received funding from the NIHR Rare Disease Translational Research Collaboration [ BRC149/NS/MH], the Blue eld Project and the Association for Frontotemporal Degeneration. MB is supported by a Fellowship award from the Alzheimer's Society, UK [ AS-JF-19a-004-517 ]. JBR is supported by the Wellcome Trust [103838], the Medical Research Council and NIHR Cambridge Biomedical Research Centre. This work was also funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation ) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology [EXC 2145 SyNergy -ID 390857198 ]. Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases -Project ID No 739510.

section_name: Availability of data and materials

section_content: Data available upon reasonable request. The raw data of this project are part of GENFI and are not publicly available in accordance with the ethical approval. Data can be accessed upon reasonable request to JDR (j. rohrer@ucl. ac. uk).
section_name: Availability of data and materials

section_name: Declarations

section_content: Ethics approval and consent to participate was collected at GENFI sites under individual ethics approval approved by the local ethics board. Written consent was obtained from all participants before entering the study.
section_name: Declarations

section_content: Consent for publication of data is included within the written consent when entering into the study.
section_name: Consent for publication

section_content: The authors declare that they have no competing interests. Authors' contributions HDF, LLR JDR designed the study, processed the data, performed analyses, and wrote the rst draft of the manuscript. All other authors have collected and helped to analyse data and contributed to the writing and critical revision of the manuscript.
section_name: Competing interests

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