Neil Graham, Karl Zimmerman, Jessica Hain, Erin Rooney, Ying Lee, Martina Del Giovane, Thomas Parker, Mathew Wilson, Maneesh Patel, Elena Veleva, Owen Swann, Amanda J Heslegrave, Lucia M Li, Henrik Zetterberg, Daniel Friedland, Richard Sylvester, David Sharp
{"title":"中年血浆蛋白质组学分析表明，前精英橄榄球运动员的淀粉样蛋白和tau蛋白加工发生了改变。","authors":"Neil Graham, Karl Zimmerman, Jessica Hain, Erin Rooney, Ying Lee, Martina Del Giovane, Thomas Parker, Mathew Wilson, Maneesh Patel, Elena Veleva, Owen Swann, Amanda J Heslegrave, Lucia M Li, Henrik Zetterberg, Daniel Friedland, Richard Sylvester, David Sharp","doi":"10.1136/jnnp-2025-336593","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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-tau<sub>181</sub> (p-tau<sub>181</sub>). 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.</p><p><strong>Conclusions: </strong>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-<sub>181</sub> more so than p-tau<sub>217</sub> points towards non-AD tau pathology. Our findings motivate longitudinal characterisation, including comparison with other neurodegenerative diseases.</p>","PeriodicalId":16418,"journal":{"name":"Journal of Neurology, Neurosurgery, and Psychiatry","volume":" ","pages":""},"PeriodicalIF":7.5000,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Midlife plasma proteomic profiles indicate altered amyloid and tau processing in former elite rugby players.\",\"authors\":\"Neil Graham, Karl Zimmerman, Jessica Hain, Erin Rooney, Ying Lee, Martina Del Giovane, Thomas Parker, Mathew Wilson, Maneesh Patel, Elena Veleva, Owen Swann, Amanda J Heslegrave, Lucia M Li, Henrik Zetterberg, Daniel Friedland, Richard Sylvester, David Sharp\",\"doi\":\"10.1136/jnnp-2025-336593\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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-tau<sub>181</sub> (p-tau<sub>181</sub>). 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.</p><p><strong>Conclusions: </strong>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-<sub>181</sub> more so than p-tau<sub>217</sub> points towards non-AD tau pathology. Our findings motivate longitudinal characterisation, including comparison with other neurodegenerative diseases.</p>\",\"PeriodicalId\":16418,\"journal\":{\"name\":\"Journal of Neurology, Neurosurgery, and Psychiatry\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":7.5000,\"publicationDate\":\"2025-10-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Neurology, Neurosurgery, and Psychiatry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/jnnp-2025-336593\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Neurology, Neurosurgery, and Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/jnnp-2025-336593","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Midlife plasma proteomic profiles indicate altered amyloid and tau processing in former elite rugby players.
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.
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The Journal of Neurology, Neurosurgery & Psychiatry (JNNP) aspires to publish groundbreaking and cutting-edge research worldwide. Covering the entire spectrum of neurological sciences, the journal focuses on common disorders like stroke, multiple sclerosis, Parkinson’s disease, epilepsy, peripheral neuropathy, subarachnoid haemorrhage, and neuropsychiatry, while also addressing complex challenges such as ALS. With early online publication, regular podcasts, and an extensive archive collection boasting the longest half-life in clinical neuroscience journals, JNNP aims to be a trailblazer in the field.
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