Frontoparietal network integrity supports cognitive function despite atrophy and hypoperfusion in pre-symptomatic frontotemporal dementia: multimodal analysis of brain function, structure and perfusion

INTRODUCTION: Gene carriers of frontotemporal dementia can remain cognitively well despite neurodegeneration. A better understanding of brain structural, perfusion and functional patterns in pre-symptomatic stage could inform accurate staging and potential mechanisms. METHODS: We included 207 pre-symptomatic carriers and 188 relatives without mutations. The grey matter volume, cerebral perfusion, and resting-state functional network maps were co-analyzed using linked independent component analysis (LICA). Multiple regression analysis was used to investigate the relationship of LICA components to genetic status and cognition. RESULTS: Pre-symptomatic carriers showed an age-related decrease in the left frontoparietal network integrity while non-carriers did not. Executive functions of pre-symptomatic carriers dissociated from the level of atrophy and cerebrovascular dysfunction, but became dependent on the left frontoparietal network integrity in older age. DISCUSSION: The frontoparietal network integrity of pre-symptomatic carriers showed a distinctive relationship to age and cognition compared to non-carriers, despite atrophy and hypoperfusion. Functional network integrity may contribute to brain resilience in pre-symptomatic frontotemporal dementia, mitigating the effects of atrophy and hypoperfusion. ### Competing Interest Statement James B. Rowe is a non-remunerated trustee of the Guarantors of Brain, Darwin College, and the PSP Association; he provides consultancy to Alzheimer Research UK, Asceneuron, Alector, Biogen, CuraSen, CumulusNeuro, UCB, SV Health, and Wave, and has research grants from AZ-Medimmune, Janssen, Lilly as industry partners in the Dementias Platform UK. ### Funding Statement X.L. is supported by the Cambridge Commonwealth, European and International Trust. J.C.V.S., L.C.J. and H.S. are supported by the Dioraphte Foundation grant 09-02-03-00, Association for Frontotemporal Dementias Research Grant 2009, Netherlands Organization for Scientific Research grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), ZonMw Onderzoeksprogramma Dementie (YOD-INCLUDED, project number10510032120002), EU Joint Programme-Neurodegenerative Disease Research-GENFI-PROX, Alzheimer Nederland and the Bluefield Project. R.S-V. is supported by Alzheimer's Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2) and has received funding from Fundacio Marato de TV3, Spain (grant no. 20143810). C.G. received funding from EU Joint Programme-Neurodegenerative Disease Research-Prefrontals Vetenskapsradet Dnr 529-2014-7504, EU Joint Programme-Neurodegenerative Disease Research-GENFI-PROX, Vetenskapsradet 2019-0224, Vetenskapsradet 2015-02926, Vetenskapsradet 2018-02754, the Swedish FTD Inititative-Schorling Foundation, Alzheimer Foundation, Brain Foundation, Dementia Foundation and Region Stockholm ALF-project. D.G. received support from the EU Joint Programme-Neurodegenerative Disease Research and the Italian Ministry of Health (PreFrontALS) grant 733051042. R.V. has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. J.L. received funding for this work by the Deutsche Forschungsgemeinschaft German Research Foundation under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy-ID 390857198). M.O. has received funding from Germany's Federal Ministry of Education and Research (BMBF). E.F. has received funding from a Canadian Institute of Health Research grant #327387. M.M. has received funding from a Canadian Institute of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. F.M. is supported by the Tau Consortium and has received funding from the Carlos III Health Institute (PI19/01637). J.D.R. is supported by the Bluefield Project and the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and a Miriam Marks Brain Research UK Senior Fellowship. Several authors of this publication (J.C.V.S., M.S., R.V., A.d.M., M.O., R.V., J.D.R.) are members of the European Reference Network for Rare Neurological Diseases (ERN-RND) - Project ID No 739510. K.A.T. was supported by the Guarantors of Brain (G101149) and Alzheimer's Society (Grant Nr. 602). J.B.R. has received funding from the Welcome Trust (103838; 220258) and is supported by the Cambridge University Centre for Frontotemporal Dementia, the Medical Research Council (MC\_UU\_00030/14; MR/T033371/1 ) and the National Institute for Health Research Cambridge Biomedical Research Centre (NIHR203312: BRC-1215-20014) and the Holt Fellowship. This work was also supported by the EU Joint Programme-Neurodegenerative Disease Research GENFI-PROX grant [2019-02248; to J.D.R., M.O., B.B., C.G., J.C.V.S. and M.S. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was given a favourable opinion by the Cambridge 2 Research Ethics Committee REC 17/EE/0032 IRAS ID 204052 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. Data restrictions may apply in order to preserve participant confidentiality.