Brain health in retired athletes
| ISRCTN | ISRCTN11312093 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11312093 |
| IRAS number | 216703 |
| Secondary identifying numbers | IRAS 216703 |
- Submission date
- 11/08/2020
- Registration date
- 12/08/2020
- Last edited
- 24/01/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Nervous System Diseases
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English Summary
Background and study aims
Mild head injury is also often referred to as concussion, minor head injury or mild traumatic brain injury (mTBI). Regardless of the terminology used, the occurrence of a head injury in these cases causes the brain to shake back and forth inside the skull, causing mild damage.
Mild head injury is commonly caused by falls, road crashes, assaults and sports accidents. While most mild head injuries result in no long-term damage to the brain, it can cause temporary disruption to brain function that can last for at least a number of weeks.
This study is a long-term study to look at retired elite men and women athletes (who had a high risk of concussion during their sporting careers) and compare them to similarly aged controls with no history of TBI. The overall aim is to see whether a history of head injury makes individuals more at risk of Alzheimer’s disease, Parkinson’s disease, motor neuron disease or other brain problems.
Who can participate?
Anyone who is a retired former elite sports man or woman aged 40-85 years and can understand and participate in the testing procedures. Controls are drawn from individuals with no previous head injuries and do not have to be former elite athletes. There is an online screening questionnaire to check eligibility.
What does the study involve?
This study involves an initial online screening questionnaire. If accepted into the study, the subject will be invited to attend one of the test centres (London, Dublin) for an initial baseline assessment. This will involve a physical examination, doing a detailed questionnaire, having a blood test, a MRI brain scan, a cognitive (memory) test with a neuropsychologist, an eye test and providing saliva, blood and urine samples. The testing will take most of a day to complete and subjects are reimbursed for their travel expenses (including the expenses fora partner or carer to attend). Results will be made available to the individual and their usual general practitioner. Subjects may be invited for retesting after a gap of no less than 5 years with the same testing process.
What are the possible benefits and risks of participating?
There are no anticipated risks with the testing and no medical interventions or treatments are given with this study. Blood testing will be performed by professional phlebotomists. All data obtained is coded and de-identified and confidentiality is maintained throughout the study. At the conclusion of the study, deidentified data will be made available for researchers to understand the effects of aging and head injuries.
The tangible benefits are of a comprehensive assessment of physical and brain health at each assessment time point and this information will be provided to the subject and a copy to their usual GP to follow up on any issues of note. The intangible benefit is an altruistic one of participating in an important study that will help understand the link between head trauma, ageing and long-term brain disease.
Where is the study run from?
The International Concussion and Head Injury Research Foundation (ICHIRF) in association with St Mary’s University, London (UK)
When is the study starting and how long is it expected to run for?
June 2014 to June 2026 (taking into account a period of suspended testing during COVID)
Who is funding the study?
The funding of the project is as follows -
1. Injured Jockeys Fund
2. Godolphin Racing
3. British Association of Sport and Exercise Medicine
4. Irish Injured Jockeys
5. The Players Foundation
6. National Football League
7. The Racing Foundation
8. MARKER AG
9. Private donations
Who is the main contact?
Dr Michael Turner, michael@ichirf.org
Contact information
Dr Michael Turner
Scientific
Scientific
The International Concussion and Head Injury Research Foundation (ICHIRF)
170 Tottenham Court Road
London
W1T 7HA
United Kingdom
 ORCID ID |
0000-0003-2323-2456 |
|---|---|
| Phone | +44-207-383-7654 |
| michael@ichirf.org |
Study information
| Study design | Prospective long-term non-interventional longitudinal study |
|---|---|
| Primary study design | Observational |
| Secondary study design | Longitudinal study |
| Study setting(s) | Community |
| Study type | Screening |
| Participant information sheet | Not available in web format |
| Scientific title | Brain health in retired athletes - ageing and impact related neurodegenerative disease |
| Study acronym | ICHIRF-BRAIN Study |
| Study hypothesis | 1. To determine the incidence of and risk factors for neurodegenerative disease in this population 2. To determine the incidence of age-related cognitive change in this population 3. To develop early predictors for neurodegenerative disease in this population |
| Ethics approval(s) | 1. Approved 01/06/2015 St Mary’s University SMEC (Waldegrave Road, Twickenham, London TW1 4SX, UK; no telephone number provided; no email provided), ref: n/a Amendments: Screening protocol - approved 27/10/2015, ref: SMEC-2015-16-53 Brain donation - approved 12/06/2017, ref: SMEC-2016-17-115 PET Scanning - approved 26/01/2018, ref: SMEC-2017-18-051 2. Approved 22/09/2017, University of Birmingham (Edgbaston, Birmingham, B15 2TT, UK; no telephone number provided; no email provided), ref: 17/EE/0275 3. Approved 10/10/2019, Beacon Hospital REC (Sandyford, Dublin, Ireland; +353 12936600; ethics@beaconhospital.ie), ref: BEA0130 |
| Condition | Neurodegenerative disease |
| Intervention | Current interventions as of 24/01/2025: The examination will consist of the following: Questionnaire - Participants will complete a questionnaire which includes questions on past medical history, injury history, concussion history, playing history, sleep, mood. Additional history and information will be sought from the participant's partner or spouse. Patient reported outcome measures (PROMs) will include DQOL, PDQ, PIMS and MCQ (https://safetyandquality.govcms.gov.au/condition-specific-proms) Sports Concussion Assessment Tool 3/5 (SCAT3/5) Participants will complete the SCAT3 or the latest iteration of the same tool - currently SCAT5. The SCAT3/5 includes the following assessments: Glasgow Coma Scale, Maddock's questions, Standardized Assessment of Concussion, a modified version of the Balance Error Scoring System (mBESS consisting of 3 stances performed on a hard surface), cervical spine examination and modified neurological examination. There are published normative data on this test. Physical and Neurological examination - The neurological examination will be performed by a consultant neurologist following a standardized exam protocol. Physical examination will include visual acuity and colour vision using Isihara plates, urinalysis and University of Pennsylvania - Brief Smell Identification Test. Balance Assessment -In addition to the clinical mBESS assessment (see above), each subject will perform a balance test using the SWAY iPhone app. Sway is a FDA-approved balance test that uses the inbuilt accelerometers in a smart phone or iPad device and objectively measures balance and reaction time Computerized Neurocognitive Screen - Participants will complete the CogState Brief Battery, a validated computerized cognitive assessment, which includes four separate tasks: Processing Speed (simple reaction time), Attention (choice reaction time), Learning (visual recognition memory) and One Back (Working Memory test). Participants will perform the test in a quiet room under the supervision of a study investigator. As per test protocol, participants will complete a practice trial for each task before completing the scored test. The primary outcome measure is the speed and accuracy of responses relative to normative data for that age-group. Neuropsychological assessment - Neuropsychological tests for the current study will be selected on the basis of a study into neuropsychological function following repeat concussion in active jockeys. The total administration time for the neuropsychological battery will be approximately 60 minutes and will be performed by a consultant clinical neuropsychologist. All neuropsychological tests will be administered and scored according to standardised instructions. The following neuropsychological domains assessed: premorbid function (Test of Premorbid Function); vocabulary and verbal ability (Vocabulary subtest from Wechsler Adult Intelligence Scale- Fourth UK Edition WAIS-IV); auditory verbal short term and working memory (Digit Span subtest from the WAIS-IV; processing speed (Symbol Digit Modalities Test); and the Speed of Comprehension Test; verbal learning and memory (California Verbal Learning Test II); response inhibition (Stroop), visual scanning and response alternation (Colour Trails Test); and fluency across both semantic and letter conditions. Administration of the digit span subtest from the WAIS-IV will allow the use of an embedded measure (Reliable Digit Span) sensitive to the application of cognitive effort. Preliminary analysis will compare performance on neuropsychological composites, the number of abnormal scores and performance on individual tests between concussion and control groups. Future analyses will investigate the relationship between neuropsychological test performance and co-morbid factors such as mood, a history of learning difficulties and/or attention deficit hyperactivity disorder, substance use, and pain; and between neuropsychological test performance and sports related factors such as number of concussions, age at first concussion, and type of sport. Finally, relationships between neuropsychological test performance and imaging, neurology, balance and eye movements will also be explored Advanced MR brain imaging - Anatomical and functional magnetic resonance imaging (MRI) will be acquired for all subjects. MRI studies will be performed using a 3.0 Tesla Siemens scanner using a 32-channel head coil and will require a minimum of 45 minutes to complete (normally around 60 minutes). The image sequences will include: Structural scans, consisting of 3D T1-weighted (T1w) high-resolution sequences and fluid-attenuated inversion recovery (FLAIR) sequences with whole brain coverage. The T1w and FLAIR sequences will permit detection of any underlying structural lesion. Volumetric analysis will be performed using the 3D T1-weighted high-resolution sequences Magnetisation Prepared Rapid Gradient Echo (MPRAGE) sequence. Data measurement and analysis will be as per Guo et al. (66). Analysis of structural brain imaging will be undertaken to detect subtle changes in brain morphology and morphometry related to mild TBI, such as by voxel-based morphometry for whole-brain analysis, and FSL-FIRST for analysis of the subcortex. Diffusion weighted imaging (DWI) (B3000), which will allow for mapping of white matter tracts in the brain. Analysis will be undertaken for both tract based spatial statistics and tractography, such as with constrained spherical deconvolution (CSD), a method robust to crossing fibres. T2-relaxometry and susceptibility weighted imaging sequences, which allows detection of regional grey and white matter changes that may reflect long-term changes in the brain following mild TBI. Resting-state functional MRI (rs-fMRI), acquired by blood oxygenation level dependent (BOLD), will be acquired to assess both resting state functional activity and functional connectivity, and its relationship to mild TBI. Analysis of the scans will be performed using standard statistical techniques, such as by non-parametric randomised permutation testing with appropriate statistical correction for multiple comparisons. Visual Saccadic testing - Saccadic latencies (reaction times) will be recorded using a portable, microminiaturised head-mounted saccadometer, in accordance with a standard published methodology.Three lasers projected high-contrast red targets in a horizontal line at -10°, 0° and +10° on a wall in front of the seated participant. Each trial begins with the central target illuminated. After a random delay of 0.5–1.5s, this jumps 10° to the left or right randomly. Participants are instructed to follow the target with their gaze and 200 saccades will be recorded, taking around 7 minutes. The device records saccadic latency using scleral infrared oculometry, with automatic deletion of blinks, movements in the wrong direction and those with an abnormal velocity profile. Each participant's saccadic latency distribution will be analysed using custom-built software, which calculates best-fit parameters using an established model of saccadic latency, as previously described. Blood testing - Participants in this study will have blood drawn and labelled at baseline and each assessment time point. Samples will be anonymised prior to analysis. All blood will be drawn by professional phlebotomists. Routine blood workup will be analysed under the supervision of The Doctors Laboratory Ltd, 60 Whitfield Street, London, W1T 4EU, UK. The blood screen includes: Full blood count + 5-part differential; erythrocyte sedimentation rate; c-reactive protein; sodium; potassium; chloride; bicarbonate; urea; creatinine; bilirubin; alkaline phosphatase; aspartate transaminase; alkaline transaminase; creatine kinase; lactate dehydrogenase; gamma glutamyl transferase; total protein; albumin; globulin; calcium; phosphate; uric acid; random blood glucose; cholesterol; high density lipoprotein; low density lipoprotein; triglycerides; serum iron; total iron binding capacity; ferritin; vitamin D; blood group; free thyroxine (T4); thyroid stimulating hormone; growth hormone; cortisol; prolactin; coeliac disease profile (tissue transglutaminase (IgA), HLA DQ2/DQ8, total immunoglobulin A). In females only, luteinizing hormone and follicle stimulating hormone. In males only, prostate profile - total prostate specific antibody, free prostate specific antibody, calculated ratio. Fluid Biomarkers studies - Participants in this study will have 5ml Serum and 5ml plasma drawn, labelled, stored in cryovials of 0.5ml and frozen at -80°C in liquid nitrogen at baseline and at each assessment time point. Samples will be anonymised prior to analysis. All blood will be drawn by professional phlebotomists. Samples will be batch-tested using ultrasensitive single molecule array (Simoa) methods (Quanterix, Billerica, MA) (69, 70) for the following biomarkers: neurofilament light polypeptide (NFL), tau, ubiquitin carboxyl‐terminal hydrolase isoenzyme L1 (UCH-L1), glial fibrillary acidic protein (GFAP), Aβ40 and Aβ42. Genotyping the apolipoprotein E (APOE) ε4 allele will also be performed . Neuron-specific enolase (NSE) and S100B will be measured using immunoassays with electrochemiluminescence detection. MicroRNA Study – Saliva samples will be obtained from participants and subject to Next Generation Sequencing (NGS) analysis for the identified miRNAs. NGS sequencing libraries will be prepared, quantified and sequenced for all samples. The collected reads will be subjected to quality control, unique molecular index-based correction (to remove PCR replicates), alignment and downstream analysis. Identified miRNA's will be validated by qPCR, in situ hybridization or miRNA inhibition. Genetics - The advantages of using saliva for whole genome sequencing (WGS) include - the ease in obtaining samples non-invasively from participants, the convenience in mailing saliva collection kits and the long-term stability of saliva samples at room temperature. However, as saliva samples have substantially lower DNA yield than blood, and are prone to microbial contamination, a carefully standardised saliva collection protocol is essential for saliva DNA to meet the stringent QC metrics needed to generated good quality WGS data. Saliva samples will therefore be collected from participants using the Oragene DNA Self-Collection kit (tube format OG-500; DNA Genotek Inc., Kanata, Ontario, Canada) and used for DNA extraction. Each sample will be bar-coded, temporarily stored at room temperature and subsequently transferred to a central laboratory for DNA extraction, biobanking and subsequent analysis. DNA will be extracted from a 500 μl aliquot from the Oragene DNA/saliva Self-Collection kits in accordance with the manufacturer's instructions. Extracted samples will be stored at −20°C prior to NGS. WGS will be performed using DNBSEQ-G400RS (BGI, Shenzhen, China) to a target average coverage depth of 30x and a read length of 150 bp. WGS will be used to determine and compare common and rare single nucleotide variants (SNV) and copy number variants (CNV) between cases and controls. Neuropathological brain examination - Participants and control subjects will be given the opportunity to enrol in the brain bank program, which requires specific informed consent through University College London. If willing to participate, the names and contact details will be forwarded to the Queen Square Brain Bank (QSBB) for neurological disorders coordinator who will make contact and provide additional information as required. All further dialogue with the volunteer will be coordinated by the QSBB who will enrol the participant in the brain bank program. In the event of the participant dying, the QSBB coordinator will make the necessary logistical arrangements with the family, hospital, or funeral director for harvesting brain tissue for detailed neuropathological analysis and tissue preservation for future research. All material stored at the QSBB is under HTA licence and any tissue used for research will have ethical approval obtained from the National Research Ethics Service Committee London. The neuropathological assessment, including staining methods, anatomical sampling sites and diagnostic criteria will be in accordance with a recent NIH consensus conference. Previous interventions: The examination will consist of the following: Questionnaire - Participants will complete a questionnaire which includes questions on past medical history, injury history, concussion history, playing history, sleep, mood. Additional history and information will be sought from the participant's partner or spouse. Patient reported outcome measures (PROMs) will include DQOL, PDQ, PIMS and MCQ (https://safetyandquality.govcms.gov.au/condition-specific-proms) Sports Concussion Assessment Tool 3/5 (SCAT3/5) Participants will complete the SCAT3. The SCAT3/5 includes the following assessments: Glasgow Coma Scale, Maddock's questions, Standardized Assessment of Concussion, a modified version of the Balance Error Scoring System (mBESS consisting of 3 stances performed on a hard surface), cervical spine examination and modified neurological examination. There are published normative data on this test. Physical and Neurological examination - The neurological examination will be performed by a consultant neurologist following a standardized exam protocol. Physical examination will include visual acuity and colour vision using Isihara plates, urinalysis and University of Pennsylvania - Brief Smell Identification Test. Balance Assessment -In addition to the clinical mBESS assessment (see above), each subject will perform a balance test using the SWAY iPhone app. Sway is a FDA-approved balance test that uses the inbuilt accelerometers in a smart phone or iPad device and objectively measures balance and reaction time Computerized Neurocognitive Screen - Participants will complete the CogState Brief Battery, a validated computerized cognitive assessment, which includes four separate tasks: Processing Speed (simple reaction time), Attention (choice reaction time), Learning (visual recognition memory) and One Back (Working Memory test). Participants will perform the test in a quiet room under the supervision of a study investigator. As per test protocol, participants will complete a practice trial for each task before completing the scored test. The primary outcome measure is the speed and accuracy of responses relative to normative data for that age-group. Neuropsychological assessment - Neuropsychological tests for the current study will be selected on the basis of a study into neuropsychological function following repeat concussion in active jockeys. The total administration time for the neuropsychological battery will be approximately 60 minutes and will be performed by a consultant clinical neuropsychologist. All neuropsychological tests will be administered and scored according to standardised instructions. The following neuropsychological domains assessed: premorbid function (Test of Premorbid Function); vocabulary and verbal ability (Vocabulary subtest from Wechsler Adult Intelligence Scale- Fourth UK Edition WAIS-IV); auditory verbal short term and working memory (Digit Span subtest from the WAIS-IV; processing speed (Symbol Digit Modalities Test); and the Speed of Comprehension Test; verbal learning and memory (California Verbal Learning Test II); response inhibition (Stroop), visual scanning and response alternation (Colour Trails Test); and fluency across both semantic and letter conditions. Administration of the digit span subtest from the WAIS-IV will allow the use of an embedded measure (Reliable Digit Span) sensitive to the application of cognitive effort. Preliminary analysis will compare performance on neuropsychological composites, the number of abnormal scores and performance on individual tests between concussion and control groups. Future analyses will investigate the relationship between neuropsychological test performance and co-morbid factors such as mood, a history of learning difficulties and/or attention deficit hyperactivity disorder, substance use, and pain; and between neuropsychological test performance and sports related factors such as number of concussions, age at first concussion, and type of sport. Finally, relationships between neuropsychological test performance and imaging, neurology, balance and eye movements will also be explored Advanced MR brain imaging - Anatomical and functional magnetic resonance imaging (MRI) will be acquired for all subjects. MRI studies will be performed using a 3.0 Tesla Siemens scanner using a 32-channel head coil and will require a minimum of 45 minutes to complete. The image sequences will include: Structural scans, consisting of 3D T1-weighted (T1w) high-resolution sequences and fluid-attenuated inversion recovery (FLAIR) sequences with whole brain coverage. The T1w and FLAIR sequences will permit detection of any underlying structural lesion. Volumetric analysis will be performed using the 3D T1-weighted high-resolution sequences Magnetisation Prepared Rapid Gradient Echo (MPRAGE) sequence. Data measurement and analysis will be as per Guo et al. (66). Analysis of structural brain imaging will be undertaken to detect subtle changes in brain morphology and morphometry related to mild TBI, such as by voxel-based morphometry for whole-brain analysis, and FSL-FIRST for analysis of the subcortex. Diffusion weighted imaging (DWI) (B3000), which will allow for mapping of white matter tracts in the brain. Analysis will be undertaken for both tract based spatial statistics and tractography, such as with constrained spherical deconvolution (CSD), a method robust to crossing fibres. T2-relaxometry and susceptibility weighted imaging sequences, which allows detection of regional grey and white matter changes that may reflect long-term changes in the brain following mild TBI. Resting-state functional MRI (rs-fMRI), acquired by blood oxygenation level dependent (BOLD), will be acquired to assess both resting state functional activity and functional connectivity, and its relationship to mild TBI. Analysis of the scans will be performed using standard statistical techniques, such as by non-parametric randomised permutation testing with appropriate statistical correction for multiple comparisons. Visual Saccadic testing - Saccadic latencies (reaction times) will be recorded using a portable, microminiaturised head-mounted saccadometer, in accordance with a standard published methodology.Three lasers projected high-contrast red targets in a horizontal line at -10°, 0° and +10° on a wall in front of the seated participant. Each trial begins with the central target illuminated. After a random delay of 0.5–1.5s, this jumps 10° to the left or right randomly. Participants are instructed to follow the target with their gaze and 200 saccades will be recorded, taking around 7 minutes. The device records saccadic latency using scleral infrared oculometry, with automatic deletion of blinks, movements in the wrong direction and those with an abnormal velocity profile. Each participant's saccadic latency distribution will be analysed using custom-built software, which calculates best-fit parameters using an established model of saccadic latency, as previously described. Blood testing - Participants in this study will have blood drawn and labelled at baseline and each assessment time point. Samples will be anonymised prior to analysis. All blood will be drawn by professional phlebotomists. Routine blood workup will be analysed under the supervision of The Doctors Laboratory Ltd, 60 Whitfield Street, London, W1T 4EU, UK. The blood screen includes: Full blood count + 5-part differential; erythrocyte sedimentation rate; c-reactive protein; sodium; potassium; chloride; bicarbonate; urea; creatinine; bilirubin; alkaline phosphatase; aspartate transaminase; alkaline transaminase; creatine kinase; lactate dehydrogenase; gamma glutamyl transferase; total protein; albumin; globulin; calcium; phosphate; uric acid; random blood glucose; cholesterol; high density lipoprotein; low density lipoprotein; triglycerides; serum iron; total iron binding capacity; ferritin; vitamin D; blood group; free thyroxine (T4); thyroid stimulating hormone; growth hormone; cortisol; prolactin; coeliac disease profile (tissue transglutaminase (IgA), HLA DQ2/DQ8, total immunoglobulin A). In females only, luteinizing hormone and follicle stimulating hormone. In males only, prostate profile - total prostate specific antibody, free prostate specific antibody, calculated ratio. Fluid Biomarkers studies - Participants in this study will have 5ml Serum and 5ml plasma drawn, labelled, stored in cryovials of 0.5ml and frozen at -80°C in liquid nitrogen at baseline and at each assessment time point. Samples will be anonymised prior to analysis. All blood will be drawn by professional phlebotomists. Future consideration to performing fluid biomarkers on CSF will be undertaken. Samples will be batch-tested using ultrasensitive single molecule array (Simoa) methods (Quanterix, Billerica, MA) (69, 70) for the following biomarkers: neurofilament light polypeptide (NFL), tau, ubiquitin carboxyl‐terminal hydrolase isoenzyme L1 (UCH-L1), glial fibrillary acidic protein (GFAP), Aβ40 and Aβ42. Genotyping the apolipoprotein E (APOE) ε4 allele will also be performed . Neuron-specific enolase (NSE) and S100B will be measured using immunoassays with electrochemiluminescence detection. Gut Metabolomic study – Participants will be given a faecal sample collection kit, with instructions regarding collection, storage and transport. Faecal samples will be processed, and DNA extracted and subjected to next generation sequencing to determine the composition and potential function of the gut microbiota. Follow-up work will focus on metabolically active microbes and for this faecal samples will be stored at -80°C for the analysis of microbial metabolites such as short-chain fatty acids and for follow-up work which may focus on metabolically active microbes. Microbes present in faecal samples will also be assessed through culture based (agar) assays to assess their ability to produce antimicrobial peptides. A urine sample may also be collected and stored at -80°C for metabolite analysis at a future date. MicroRNA Study – Saliva samples will be obtained from participants and subject to Next Generation Sequencing (NGS) analysis for the identified miRNAs. NGS sequencing libraries will be prepared, quantified and sequenced for all samples. The collected reads will be subjected to quality control, unique molecular index-based correction (to remove PCR replicates), alignment and downstream analysis. Identified miRNA's will be validated by qPCR, in situ hybridization or miRNA inhibition. Genetics - The advantages of using saliva for whole genome sequencing (WGS) include - the ease in obtaining samples non-invasively from participants, the convenience in mailing saliva collection kits and the long-term stability of saliva samples at room temperature. However, as saliva samples have substantially lower DNA yield than blood, and are prone to microbial contamination, a carefully standardised saliva collection protocol is essential for saliva DNA to meet the stringent QC metrics needed to generated good quality WGS data. Saliva samples will therefore be collected from participants using the Oragene DNA Self-Collection kit (tube format OG-500; DNA Genotek Inc., Kanata, Ontario, Canada) and used for DNA extraction. Each sample will be bar-coded, temporarily stored at room temperature and subsequently transferred to a central laboratory for DNA extraction, biobanking and subsequent analysis. DNA will be extracted from a 500 μl aliquot from the Oragene DNA/saliva Self-Collection kits in accordance with the manufacturer's instructions. Extracted samples will be stored at −20°C prior to NGS. WGS will be performed using DNBSEQ-G400RS (BGI, Shenzhen, China) to a target average coverage depth of 30x and a read length of 150 bp. WGS will be used to determine and compare common and rare single nucleotide variants (SNV) and copy number variants (CNV) between cases and controls. Neuropathological brain examination - Participants and control subjects will be given the opportunity to enrol in the brain bank program, which requires specific informed consent through University College London. If willing to participate, the names and contact details will be forwarded to the Queen Square Brain Bank (QSBB) for neurological disorders coordinator who will make contact and provide additional information as required. All further dialogue with the volunteer will be coordinated by the QSBB who will enrol the participant in the brain bank program. In the event of the participant dying, the QSBB coordinator will make the necessary logistical arrangements with the family, hospital, or funeral director for harvesting brain tissue for detailed neuropathological analysis and tissue preservation for future research. All material stored at the QSBB is under HTA licence and any tissue used for research will have ethical approval obtained from the National Research Ethics Service Committee London. The neuropathological assessment, including staining methods, anatomical sampling sites and diagnostic criteria will be in accordance with a recent NIH consensus conference. |
| Intervention type | Mixed |
| Primary outcome measure | Neurodegenerative disease (e.g. Alzheimer's Disease) will be a clinical diagnosis supported by neuropsychological, radiological, pathological and/or fluid biomarker changes and in line with international diagnostic criteria measured as follows: 1. A questionnaire which includes questions on past medical history, injury history, concussion history, playing history, sleep, mood 2. Sports Concussion Assessment Tool 3/5 3. Physical and Neurological examination - The neurological examination will be performed by a consultant neurologist following a standardized exam protocol. Physical examination will include visual acuity and colour vision using Isihara plates, urinalysis and University of Pennsylvania - Brief Smell Identification Test 4. Balance Assessment: each subject will perform a balance test using the SWAY iPhone app 5. Computerized Neurocognitive Screen - Participants will complete the CogState Brief Battery, a validated computerized cognitive assessment, which includes four separate tasks: Processing Speed (simple reaction time), Attention (choice reaction time), Learning (visual recognition memory) and One Back (Working Memory test) 6. Neuropsychological assessment - Neuropsychological tests for the current study will be selected on the basis of a study into neuropsychological function following repeat concussion in active jockeys. The total administration time for the neuropsychological battery will be approximately 60 minutes and will be performed by a consultant clinical neuropsychologist. 7. Anatomical and functional magnetic resonance imaging (MRI) will be acquired for all subjects. MRI studies will be performed using a 3.0 Tesla Siemens scanner using a 32-channel head coil 8. Visual Saccadic testing - Saccadic latencies (reaction times) will be recorded using a portable, microminiaturised head-mounted saccadometer 9. Blood testing - Participants in this study will have blood drawn and labelled at baseline and each assessment time point. Blood will be tested for: Full blood count + 5-part differential; erythrocyte sedimentation rate; c-reactive protein; sodium; potassium; chloride; bicarbonate; urea; creatinine; bilirubin; alkaline phosphatase; aspartate transaminase; alkaline transaminase; creatine kinase; lactate dehydrogenase; gamma glutamyl transferase; total protein; albumin; globulin; calcium; phosphate; uric acid; random blood glucose; cholesterol; high density lipoprotein; low density lipoprotein; triglycerides; serum iron; total iron binding capacity; ferritin; vitamin D; blood group; free thyroxine (T4); thyroid stimulating hormone; growth hormone; cortisol; prolactin; coeliac disease profile (tissue transglutaminase (IgA), HLA DQ2/DQ8, total immunoglobulin A). In females only, luteinizing hormone and follicle stimulating hormone. In males only, prostate profile - total prostate specific antibody, free prostate specific antibody, calculated ratio 10. Fluid Biomarkers studies - Participants in this study will have 5ml Serum and 5ml plasma drawn, labelled, stored in cryovials of 0.5ml and frozen at -80°C in liquid nitrogen at baseline and at each assessment time point. Samples will be batch-tested using ultrasensitive single molecule array (Simoa) methods (Quanterix, Billerica, MA) (69, 70) for the following biomarkers: neurofilament light polypeptide (NFL), tau, ubiquitin carboxyl‐terminal hydrolase isoenzyme L1 (UCH-L1), glial fibrillary acidic protein (GFAP), Aβ40 and Aβ42. Genotyping the apolipoprotein E (APOE) ε4 allele will also be performed . Neuron-specific enolase (NSE) and S100B will be measured using immunoassays with electrochemiluminescence detection 11. MicroRNA Study – Saliva samples will be obtained from participants and subject to Next Generation Sequencing (NGS) analysis for the identified miRNAs 12. Neuropathological brain examination - Participants and control subjects will be given the opportunity to enrol in the brain bank program. In the event of the participant dying, the QSBB coordinator will make the necessary logistical arrangements with the family, hospital, or funeral director for harvesting brain tissue for detailed neuropathological analysis and tissue preservation for future research Removed 24/01/2025: Gut Metabolomic study – Participants will be given a faecal sample collection kit, with instructions regarding collection, storage and transport. Faecal samples will be processed, and DNA extracted and subjected to next generation sequencing to determine the composition and potential function of the gut microbiota |
| Secondary outcome measures | Age-related cognitive changes in this population will be a clinical diagnosis supported by neuropsychological, radiological, pathological and/or fluid biomarker changes and in line with international diagnostic criteria. Predictors will be based on the study measures listed in the primary outcomes. |
| Overall study start date | 01/06/2014 |
| Overall study end date | 01/06/2026 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Adult |
| Lower age limit | 40 Years |
| Upper age limit | 85 Years |
| Sex | Both |
| Target number of participants | 250 |
| Total final enrolment | 159 |
| Participant inclusion criteria | Current inclusion criteria as of 24/01/2025: 1. Completed the online screening assessment 2. Participated in elite sport or amateur sport on a regular basis 3. Can understand and participate in the testing procedures 4. Are able to provide informed consent for participation 5. Are now retired from active participation in competitive sport Previous inclusion criteria: 1. Completed the online screening assessment 2. Participated in elite sport 3. Can understand and participate in the testing procedures 4. Are able to provide informed consent for participation |
| Participant exclusion criteria | 1. For the questionnaire study if they are aged <18 years and ineligible for the phenotyping <50 years 2. Have a history of previous severe traumatic brain injury 3. Are on current psychotropic medication 4. They have a pre-existing medically-diagnosed neurological disorder (e.g. Alzheimer’s dementia, Parkinson’s disease, Multiple Sclerosis, Motor Neuron Disease) 5. The participant is currently enrolled in a disease modifying therapeutic (drug or interventional) trial 6. Presence of any of the following clinical conditions: Substance abuse within the past year; Unstable cardiac, pulmonary, renal, hepatic, endocrine, hematologic, or active malignancy or infectious disease; AIDS or AIDS-related complex; Unstable psychiatric illness defined as psychosis (hallucinations or delusions) or untreated major depression within 90 days of the screening visit |
| Recruitment start date | 01/06/2015 |
| Recruitment end date | 31/12/2025 |
Locations
Countries of recruitment
- England
- Ireland
- United Kingdom
Study participating centres
International Concussion and Head Injury Research Foundation (ICHIRF)
170 Tottenham Court Road
London
W1T 7HA
United Kingdom
London
W1T 7HA
United Kingdom
Beacon Hospital Research Institute
Suite 13 Beacon Mall
Beacon Hospital
Dublin
Dublin 18
Ireland
Beacon Hospital
Dublin
Dublin 18
Ireland
Sponsor information
The International Concussion and Head Injury Research Foundation (ICHIRF)
Research organisation
Research organisation
170 Tottenham Court Road
London
W1T 7HA
United Kingdom
| Phone | +44 (0)207 3837654 |
|---|---|
| info@ichirf.org | |
| Website | https://www.ichirf.org |
Funders
Funder type
Charity
Injured Jockeys Fund
No information available
Godolphin Racing
No information available
British Association of Sport and Exercise Medicine
No information available
Irish Injured Jockeys
No information available
The Players Foundation
No information available
National Football League
No information available
The Racing Foundation
No information available
MARKER AG
No information available
Private donations
No information available
Results and Publications
| Intention to publish date | 01/06/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Stored in non-publicly available repository, Available on request |
| Publication and dissemination plan | Participants: All volunteers will receive a detailed report, including the results of any tests carried out, within 30 days of the screening. This will include recommendations regarding any further action that may be required as a result of any abnormal findings (e.g. in the event of a raised cholesterol, the volunteer would be advised to consult his/her GP and recommended to have the test repeated). Publication: De-identified trial data will be presented at conferences, seminars and published in the medical literature. |
| IPD sharing plan | The data-sharing plans for this study are under review but will involve access on request via a non-publicly available repository |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol (preprint) | 27/05/2022 | 21/06/2022 | No | No | |
| Results article | 01/09/2022 | 20/09/2022 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No | ||
| Preprint results | 05/11/2024 | 24/01/2025 | No | No |
Editorial Notes
24/01/2025: The following changes were made to the study record:
1. The funders were updated to remove the Professional Footballers Association and EU Erasmus in collaboration with the Galway-Mayo Institute of Technology and add The Players Foundation and Private donations.
2. The primary outcome measures, inclusion criteria and interventions were updated.
3. The recruitment end date was changed from 31/05/2025 to 31/12/2025.
4. The overall study end date was changed from 31/12/2025 to 01/06/2026.
5. The intention to publish date was changed from 01/06/2024 to 01/06/2026.
6. Study website, IPD sharing plan, age limits and preprint added.
7. The secondary study design was changed from Cohort to Longitudinal study.
11/01/2024: The following changes were made to the trial record:
1. The study participating centre The Manchester Institute of Health & Performance was removed.
2. The plain English summary was updated to reflect these changes.
01/11/2023: The study contact confirmed that the record is up to date.
20/09/2022: Publication reference and total final enrolment added.
21/06/2022: Preprint reference added.
20/06/2022: The intention to publish date has been changed from 01/06/2022 to 01/06/2024.
11/08/2020: Trial’s existence confirmed by St Mary's University, London.
