The International Concussion and Head Injury Research Foundation Brain health in Retired athletes Study of Ageing and Impact-Related Neurodegenerative Disease (ICHIRF-BRAIN Study)

Introduction and aims Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Large registry studies have demonstrated a dose–response relationship between TBI and neurodegenerative disease ; however, disentangling the direct effects of TBI from ageing and/or a progressive neurodegenerative process is problematic. This study is a prospective long-term cohort study to examine a population of retired elite athletes at high risk of concussion and mTBI during their sporting careers compared to age- and sex-matched controls with no history of TBI. The aim is to determine the incidence and risk factors for neurodegenerative disease and/or age-related effects on brain health in this population. Methods and analysis A population of retired male and female elite athletes and controls aged 40-85 years, will be assessed at baseline and serial time points over 10 years during life using a multi-dimensional assessment including: Questionnaire; SCAT3/5; Neurological and physical examination; Instrumented balance assessment; Computerised neurocognitive screen; Neuropsychological assessment; Advanced MR brain neuroimaging; Visual saccades; Blood workup; Fluid biomarkers; Gut metabolomics; Salivary MicroRNA analysis; Genetic analysis; and where available Brain banking and neuropathology Ethics and dissemination Ethics approval was granted by St Mary’s University SMEC as well as at the various satellite trial sites. The trial is registered with ISRCTN (BioMed Central) with ID number: 11312093. In addition to the usual dissemination process, this phenotypically well-characterised dataset will reside in a publicly accessible infrastructure of integrated databases, imaging repositories, and biosample repositories and de-identified data will be made available to collaborating researchers. ### Competing Interest Statement Michael Turner is employed by ICHIRF as CEO and Medical Director. He has been reimbursed by universities, scientific bodies, and commercial organizations for travel and accommodation related to presenting research relating to concussion at meetings, scientific conferences, and symposiums. He did not receive any form of financial support related to this manuscript. Cliff Beirne no conflicts declared Antonio Belli is a founding member, consultant and shareholder of Marker Diagnostics, a spinout company of the University of Birmingham. He is a Director of ICHIRF. Kaj Blennow is supported by the Swedish Research Council (#2017.00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB.201809.2016615), the Swedish Alzheimer Foundation (#AF.742881), Hjarnfonden, Sweden (#FO2017.0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF agreement (#ALFGBG.715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019.466.236). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Bonnie Kate Dewar is employed by the International Concussion and Head Injury Research Foundation to provide screening and consultancy services. She has also received reimbursement for travel from ICHIRF Valentina di Pietro is a founding member and shareholder of Marker Diagnostics, a spinout company of the University of Birmingham. Conor Gissane is employed by the International Concussion and Head Injury Research Foundation to provide statistical analysis services. He has also received reimbursement for travel from ICHIRF Amanda Heslegrave no conflicts declared Etienne Laverse is employed by the International Concussion and Head Injury Research Foundation to provide screening and consultancy services. He has also received reimbursement for travel from ICHIRF Victoria McEneaney has had travel and accommodation reimbursed by the International Concussion and Head Injury Research Foundation Adrian McGoldrick no conflicts declared. He has received reimbursement for travel and accommodation from ICHIRF. He is a Trustee of the Concussion Foundation. James Murray is employed by the International Concussion and Head Injury Research Foundation to provide consultancy services. He has also received reimbursement for travel from ICHIRF Patrick O'Halloran has received financial support from the Drake Foundation and University of Birmingham in support of research in sport concussion and has been reimbursed by scientific organisations for travel and accommodation to present concussion related research at scientific conferences. He does not hold any shares in or receive monies from any company related to brain injury assessment or technology Ben Pearson is employed by the International Concussion and Head Injury Research Foundation to provide screening and consultancy services. He has also received reimbursement for travel from ICHIRF Yannis Pitsiladis no conflicts declared Marco Toffoli no conflicts declared Huw Williams is a Director of ICHIRF Henrik Zetterberg has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, 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). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018.02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG.720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and the UK Dementia Research Institute at UCL. Paul McCrory has been funded by the National Health & Medical Research Council of Australia. He has been reimbursed by the government, professional scientific bodies, and commercial organizations including ICHIRF for discussing or presenting research relating to MTBI and sport-related concussion at meetings, scientific conferences, and symposiums. He does not hold any individual shares in or receive monies from any company related to concussion or brain injury assessment or technology. He acknowledges unrestricted philanthropic support from CogState Inc. (2001.16). He is Scientific Consultant to ICHIRF and the Sports Surgery Clinic in Dublin. Dr. McCrory did not receive any form of financial support related to this manuscript. ### Clinical Protocols ### Funding Statement Funding: The ICHIRF project is currently funded by a combination of competitive grant funding (EU Erasmus - Galway-Mayo Institute of Technology SCAT Project); commercial funding (Marker AG); and philanthropically funding (Godolphin Racing, the Injured Jockeys Fund (UK), the Irish Injured Jockeys Fund, British Association of Sports and Exercise Medicine, the National Football League (US), the Professional Footballers Association, the Racing Foundation and private donors) as well as charitable donations. Reimbursement for travel expenses is available to participants however they are not paid for their involvement in the study. Statistical analysis was provided by Dr James Ruffle with funding provided by the Racing Foundation. ### 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: Staged ethical approval was obtained from St Mary's University, Twickenham, Waldgrave Road, London TW1 4SX, UK initially on 1st June 2015 (no reference number was provided by the University Ethics Committee). Study approved. 27th October 2015, as above, Reference SMEC.2015.16.53. Approved 12th June 2017, as above, Reference SMEC.2016.17.115. Approved 26th January 2018, as above, Reference SMEC.2017.18.051. Approved Ethical approval for the saliva collection was obtained by Professor Antonio Belli from The East of England, Essex Research Ethics Committee, The Old Chapel, Royal Standard Place, Nottingham NG1 6FS on 22nd September 2017. An investigation into Repetitive Concussion in Sport (RECOS). REC Reference 17/EE/0275. IRAS Project ID 216703. Protocol number ERN.11.0429AP28. Approved. In preparation for BREXIT, and prior to screening in Dublin, the whole study was re-submitted for ethical approval to the Beacon Hospital Research Ethics Committee (BHREC), The Beacon Hospital, Sandyford, Dublin D18 AK68, Ireland, and approved on 10th October 2019. Reference BEA0130. An International, multicentre study into the long term effects of concussion. The International Concussion and Head Injury Research Foundation (ICHIRF) Study. Fully Approved. All participants provide informed consent in writing. The trial is registered as [ISRCTN 11312093][1]. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data is under collection and will be available as outlined in the paper [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN11312093