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© The Author(s). 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data., Background: Although 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. Methods: We 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 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT 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. Results: The RSMS was decreased in symptomatic mutation carriers in all genetic groups but at a prodromal stage only in the C9orf72 (for the total score and both subscores) and GRN (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. Conclusions: The RSMS indexes socioemotional impairment at an early stage of genetic FTD and may be a suitable outcome measure in forthcoming trials., 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 Bluefield 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 Bluefield 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.

Additional file 1: Figure S1. RSMS EX scores in each genetic carrier group, stratified by Global CDR® plus NACC FTLD scores. Significant differences from controls and within each carrier group are starred. Differences between carrier groups are not shown. Figure S2. RSMS SP scores in each genetic carrier group, stratified by Global CDR® plus NACC FTLD scores. Significant differences from controls and within each carrier group are starred. Differences between carrier groups are not shown. Figure S3. Negative correlations between RSMS total and CDR® plus FTLD NACC SOB scores were observed across all mutation carrier groups: C9orf72 (r = -0.67, p < 0.001), GRN (r = -0.59, p < 0.001), MAPT (r = -0.53, p < 0.001). Each dot represents one mutation carrier. Table S1. RSMS total test scores (mean and SD) in healthy controls split by age group. Table S2. Cumulative frequency of RSMS total test scores in healthy controls. Table S3. Adjusted mean differences in RSMS EX scores between the genetic groups stratified by Global CDR® plus NACC FTLD scores with 95% bias-corrected confidence intervals (significant values in bold). Table S4. Adjusted mean differences in RSMS SP scores between the genetic groups stratified by Global CDR® plus NACC FTLD scores with 95% bias-corrected confidence intervals (significant values in bold). Table S5. Correlation of RSMS total test score with cognitive tests. Significant results are in bold. Table S6. Positive neuroanatomical correlates of grey matter volume with the RSMS total score in each genetic group.

Additional file 2: Figure S1. Summary of bioinformatic pipeline for single cell WGS. Figure S2. Number of cells counted and analysed in each case / category in the cingulate cortex (a,b) and SN (c,d). Figure S3. SNCA CNVs and α-synuclein nuclear inclusions in MSA pontine neurons. Figure S4. Mate-pair sequencing results of MSA SNand cerebellum. Figure S5. Visual isolation of nuclei on an inverted microscope. Figure S6. Profiles of cells with CNVs. Figure S7. Detailed visualisation of boundaries of gains with evidence of shared breakpoints suggesting clonality, and gains possibly arising at segmental duplications (SDs). Figure S8. Pathway analysis of neuronal CNVs in each SN separately.