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© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com, Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions., This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. 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); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany 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) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Supplementary Information: Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; Additional file 2 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; both files are available online at https://doi.org/10.1186/s13024-021-00499-4 Copyright © The Author(s) 2021. Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD. This study has received support from the Swedish FTD initiative funded by the Schörling Family Foundation. This work was also funded by KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, grants from Vetenskapsrådet Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Åhlén foundation, Demensfonden, Stohnes foundation, Gamla Tjänarinnor and Stockholm County Council ALF. Furthermore, support was received by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019-02248), the Dioraphte Foundation [grant numbers 09-02-00]; the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018); ZonMw Memorabel (Deltaplan Dementie), (project numbers 733 050 103 and 733 050 813); JPND PreFrontAls consortium (project number 733051042). 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). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. M.S. was supported by the JPND grant “GENFI-prox” (by DLR/BMBF to M. S, joint with JDR., J.vS., M.O., B.B. and C.G.). Open Access funding provided by Royal Institute of Technology.

© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)., A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the disease.

© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license., Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset., The authors thank all the volunteers for their participation in this study. SBE is a recipient of the Rio-Hortega post-residency grant from the Instituto de Salud Carlos III, Spain. This study was partially funded by Fundació Marató de TV3, Spain (grant no. 20143810 to RSV). The GENFI study has been supported by the Medical Research Council UK, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, as well as other individual funding to investigators. KM has received funding from an Alzheimer’s Society PhD studentship. JDR acknowledges support from 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, the UK Dementia Research Institute, Alzheimer’s Research UK, the Brain Research Trust and the Wolfson Foundation. JCvS was supported by the Dioraphte Foundation grant 09-02-03-00, the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organization for Scientific Research (NWO) grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. CG have received funding from JPND-Prefrontals VR Dnr 529-2014-7504, VR: 2015-02926, and 2018-02754, the Swedish FTD Initiative-Schörling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. DG has received support from the EU Joint Programme – Neurodegenerative Disease Research (JPND) and the Italian Ministry of Health (PreFrontALS) grant 733051042. JBR is funded by the Wellcome Trust (103838) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. MM has received funding from a Canadian Institutes of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. RV has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. EF has received funding from a CIHR grant #327387. JDR is an MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration. MS was supported by a grant 779257 “Solve-RD” from the Horizon 2020 research and innovation programme.

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial. ispartof: NEUROIMAGE-CLINICAL vol:24 ispartof: location:Netherlands status: published

BACKGROUND: Neurofilament light chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and MAPT. A better understanding of NfL dynamics is essential for upcoming therapeutic trials. We aimed to study longitudinal NfL trajectories in people with presymptomatic and symptomatic genetic frontotemporal dementia.METHODS: We recruited participants from 14 centres collaborating in the Genetic Frontotemporal Dementia Initiative (GENFI), which is a multicentre cohort study of families with genetic frontotemporal dementia done across Europe and Canada. Eligible participants (aged ≥18 years) either had frontotemporal dementia due to a pathogenic mutation in GRN, C9orf72, or MAPT (symptomatic mutation carriers) or were healthy at-risk first-degree relatives (either presymptomatic mutation carriers or non-carriers), and had at least two serum samples with a time interval of 6 months or more. Participants were excluded if they had neurological comorbidities that were likely to affect NfL, including cerebrovascular events. We measured NfL longitudinally in serum samples collected between June 8, 2012, and Dec 8, 2017, through follow-up visits annually or every 2 years, which also included MRI and neuropsychological assessments. Using mixed-effects models, we analysed NfL changes over time and correlated them with longitudinal imaging and clinical parameters, controlling for age, sex, and study site. The primary outcome was the course of NfL over time in the various stages of genetic frontotemporal dementia.FINDINGS: We included 59 symptomatic carriers and 149 presymptomatic carriers of a mutation in GRN, C9orf72, or MAPT, and 127 non-carriers. Nine presymptomatic carriers became symptomatic during follow-up (so-called converters). Baseline NfL was elevated in symptomatic carriers (median 52 pg/mL [IQR 24-69]) compared with presymptomatic carriers (9 pg/mL [6-13]; pINTERPRETATION: Our findings show the value of blood NfL as a disease progression biomarker in genetic frontotemporal dementia and suggest that longitudinal NfL measurements could identify mutation carriers approaching symptom onset and capture rates of brain atrophy. The characterisation of NfL over the course of disease provides valuable information for its use as a treatment effect marker.FUNDING: ZonMw and the Bluefield project.