INTRODUCTION: Cerebrovascular reactivity (CVR) is an indicator of cerebrovascular health and its signature in hereditary frontotemporal dementia (FTD) remains unknown. We investigated CVR in genetic FTD and its relationship to cognition. METHODS: CVR differences were assessed between 284 pre-symptomatic and 124 symptomatic mutation carriers, and 265 non-carriers, using resting-state fluctuation amplitudes (RSFA) on component-based and voxel-level RSFA maps. Associations and interactions between RSFA, age, genetic status, and cognition were examined using generalised linear models. RESULTS: Compared to non-carriers, mutation carriers exhibited greater RSFA reductions, predominantly in frontal cortex. These reductions increased with age. The RSFA in these regions correlated with cognitive function in symptomatic and, to a lesser extent, pre-symptomatic individuals, independent of disease stage. DISCUSSION: CVR impairment in genetic FTD predominantly affects frontal cortical areas, and its preservation may yield cognitive benefits for at-risk individuals. Cerebrovascular health may be a potential target for biomarker identification and disease-modifying efforts.

The authors have declared no competing interest.

K.A.T. was supported by Fellowship awards from the Guarantors of Brain (G101149) and Alzheimers Society, UK (grant number 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. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. 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 Organisation for Scientific Research grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), ZonMw Onderzoeksprogramma Dementie (YOD-INCLUDED, project number 10510032120002), EU Joint Programme-Neurodegenerative Disease Research-GENFI-PROX, Alzheimer Nederland and the Bluefield Project. R.S-V. is supported by Alzheimers 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 Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy ID 390857198). M.O. has received funding from Ministry of Education and Research (BMBF) in Germany. E.F. has received funding from a Canadian Institute of Health Research grant number 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. 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. JBR 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.

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The study uses data from human patients from the Genetic Frontotemporal Dementia (GENFI) Consortium initiative. The data are available upon request from the respective consortium website. (https://www.genfi.org/)

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All data produced in the present study are available upon request to the authors.