Abstract
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.
Authors and Affiliations
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, and David Sharp¹˒²
¹ Brain Sciences, Imperial College London, London, UK
² UK Dementia Research Institute Centre for Care Research and Technology, Imperial College London, London, UK
³ Institute of Sport, Exercise and Health, UCL, London, UK
⁴ Department of Stroke and Neuroscience, Imperial College London NHS Healthcare Trust, London, UK
⁵ UK Dementia Research Institute, UCL, London, UK
⁶ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
⁷ Acute Stroke and Brain Injury Unit, National Hospital for Neurology and Neurosurgery, London, UK