Background Contact sports, including rugby union, are associated with higher rates of neurodegenerative dementia, due to various underlying pathologies such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). New ultrasensitive multiplexed immunoassays may clarify disease mechanisms after repetitive head impacts (RHI) and traumatic brain injury, potentially aiding risk-stratification, early diagnosis and dementia treatment.
Methods Midlife participants in the ABHC cohort underwent plasma biomarker quantification (NULISA – NUcleic acid Linked Immuno-Sandwich Assay; n=124 markers), 3T MRI, trauma exposure ascertainment and phenotyping. Regressions quantified exposure-specific protein expression, relationship to trauma (including position) and brain atrophy, using cluster analysis to test correlates of traumatic encephalopathy syndrome (TES).
Results 197 former elite rugby players and 33 controls were assessed. 24 (12.2%) met criteria for TES but none had dementia. Ex-players returned reduced plasma glial fibrillary acidic protein (GFAP), kallikrein-6 (KLK6) and synaptosomal-associated protein 25 (SNAP25). Ex-forwards specifically showed reduced plasma beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid beta-38 (Aβ38), and increased phospho-tau181 (p-tau181). KLK6 was lower in ex-backs than controls. No biomarkers related to career duration, concussion load or regional brain volume, nor did clustering relate to TES.
Conclusions Ex-players showed distinctive plasma biomarker changes, more prominently in ex-forwards, possibly reflecting greater RHI exposure. Plasma KLK6, an endothelial serine protease, was reduced across the ex-player group, with potential diagnostic or prognostic utility in future. Reduced GFAP and SNAP25 in ex-forwards has an uncertain basis, while elevated p-tau-181 more so than p-tau217 points towards non-AD tau pathology. Our findings motivate longitudinal characterisation, including comparison with other neurodegenerative diseases.
Neil Graham1,2, Karl Zimmerman1,2, Jessica Hain1,2, Erin Rooney1,2, Ying Lee1,2, Martina del Giovane1,2, Thomas Parker1,2, Mathew Wilson3, Maneesh Patel4, Elena Veleva5,6, Owen Swann5,6, Amanda J Heslegrave5,6, Lucia M Li1,2, Henrik Zetterberg5,6, Daniel Friedland1, Richard Sylvester3,7, David Sharp1,2
1Brain Sciences, Imperial College London, London, UK
2UK Dementia Research Institute Centre for Care Research and Technology, Imperial College London, London, UK
3Institute of Sport, Exercise and Health, UCL, London, UK
4Department of Stroke and Neuroscience, Imperial College London NHS Healthcare Trust, London, UK
5UK Dementia Research Institute, UCL, London, UK
6Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
7Acute Stroke and Brain Injury Unit, National Hospital for Neurology and Neurosurgery, London, UK
CSO
Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.
CFO
Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition. He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.