Peripheral inflammatory markers relate to central inflammation and survival in syndromes associated with frontotemporal lobar degeneration

Neuroinflammation is an important pathogenic mechanism in many neurodegenerative diseases, including those caused by frontotemporal lobar degeneration (FTLD). There is a pressing need for scalable and mechanistically relevant blood markers of inflammation to facilitate drug development and experimental medicine. We assessed inflammatory profiles of serum cytokines from 214 patients with FTLD-associated syndromes (behavioural and language variants of frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome). We tested the association with brain microglial activation (by positron emission tomography) and survival. A pro-inflammatory profile across the FTLD spectrum (including TNF-α, TNF-R1, M-CSF, IL-17A, IL-12, IP-10 and IL-6) differentiated patients (all syndromes) from controls. A higher pro-inflammatory profile scores was associated with higher microglial activation in frontal and brainstem regions, and with lower survival. Blood-based markers of inflammation could increase the scalability and access to neuroinflammatory assessment of people with dementia, to facilitate clinical trials and experimental medicine studies. ### Competing Interest Statement The authors have no conflicts of interest to report related to this work. Unrelated to this work, JTO has received honoraria for work as DSMB chair or member for TauRx, Axon, Eisai and Novo Nordisk, and has acted as a consultant for Biogen and Roche, and has received research support from Alliance Medical and Merck. JBR is a non-remunerated trustee of the Guarantors of Brain and Darwin College. He provides consultancy unrelated to the current work to Asceneuron, Astronautx, Astex, Alector, Curasen, CumulusNeuro, Prevail, Wave, SVHealth, and has research grants from AstraZeneca, Janssen, GSK and Lilly as industry partners in the Dementias Platform UK. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). ### Funding Statement This study was co-funded by the Dementias Platform UK and Medical Research Council (MCUU00030/14; MR/T033371/1); the Wellcome trust (220258); Race Against Dementia Alzheimer's Research UK (ARUK-RADF2021A-010); the Cambridge University Centre for Parkinson-Plus (RG95450); the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (NIHR203312: the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care); the Progressive Supranuclear Palsy Association (PSPA2022/SMALL GRANTS002); the Addenbrookes Charitable Trust (ref 900380); Guarantors of Brain (G101149); Alzheimer's Society (Grant Nr. 602). This work is licensed under a Creative Commons Attribution 4.0 International License. HZ is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356; #2022-01018 and #2019-02397), the European Union's Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C), the Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen for Gamla Tjanarinnor, Hjarnfonden, Sweden (#FO2022-0270), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme - Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). ### 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: The research protocols were approved by the National Research Ethics Service's East of England Cambridge Central Committee, and the UK Administration of Radioactive Substances Advisory Committee. 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 Anonymized processed data can be shared upon request to the corresponding or senior authors. Raw data may also be requested but are likely to be subject to a data transfer agreement with restrictions required to comply with participant consent and data protection regulations.