Concussions in retired rugby players linked to higher neurodegenerative disease biomarkers

By Vijay Kumar MalesuReviewed by Benedette Cuffari, M.Sc.Jul 21 2024

In a recent study published in the International Journal of Molecular Sciences, researchers assess differences in specific biomarkers associated with neurodegenerative diseases between United Kingdom-based retired rugby players with a history of concussions and a non-contact sports group.

Study: Concussion-Related Biomarker Variations in Retired Rugby Players and Implications for Neurodegenerative Disease Risk: The UK Rugby Health Study. Image Credit: PeopleImages.com - Yuri A / Shutterstock.com

An overview of concussions

Rugby, a popular contact sport, is associated with a significant risk of injury, including concussions, due to its physical nature of tackling and collisions. Concussions are brain injuries that result from head accelerations and decelerations and are characterized by reflex paralysis, brief consciousness impairment, or memory loss.

Concussion symptoms can include dizziness, headache, sleep disturbances, and cognitive issues. Furthermore, concussions have been linked to long-term cognitive and mental health effects, including an increased risk of neurodegenerative diseases like chronic traumatic encephalopathy (CTE), Alzheimer's (AD), and amyotrophic lateral sclerosis (ALS).

Further research is needed to establish the neurobiological relationships between concussions, persistent adverse behavioral effects, and biomarkers predictive of neurodegenerative diseases.

About the study 

The current study involved analyzing blood biomarkers in retired rugby players with a history of concussions and non-contact sports controls from the U.K. Rugby Health Project, which was initiated in 2016. Male study participants were recruited between September 2016 and December 2018 through various channels.

The concussed group included a total of 30 retired rugby players with five or more diagnosed concussions. Comparatively, the control group was comprised of 26 retired rugby and non-contact sports participants with no reported concussions.

A general health questionnaire gathered information on rugby engagement, injuries, health, and well-being. Serum concentrations of total tau (t-tau), serum amyloid alpha (SAA), retinol-binding protein 4 (RBP-4), retinol, plasma neurofilament light (Nf-L), cytokines, and serum-derived exosomes including beta-amyloid (Aβ42), p-tau181, p-tau217, p-tau231, as well as serum-derived exosome sizes were also measured. Exosomes were isolated from serum using the total exosome isolation reagent, with sizes confirmed through transmission electron microscopy (TEM) analysis and cluster of differentiation 63 (CD-63) antibody marker.

Biomarker assessments were conducted using an enzyme-linked immunosorbent assay (ELISA) and a human Luminex® discovery multiplex assay. Data were statistically analyzed using GraphPad Prism software.

Study findings 

Serum biomarker analysis revealed a highly significant elevation of serum t-tau levels in retired rugby players with multiple concussions as compared to the non-contact control group. Serum RBP-4 concentrations were also significantly lower in the retired rugby group. However, no differences in Nf-L, serum SAA, and retinol levels were observed between the two groups.

Analysis of chemokines and cytokines in plasma samples detected only chemokine (C-C motif) ligand 2 (CCL2)/ monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6), with no significant differences observed. Serum exosomes from a subset of participants were analyzed to concentrate low-level protein markers, including Aβ42 and p-tau proteins.

No statistical differences were observed in exosome Aβ42 concentrations between the groups. However, exosome-derived p-tau181 levels were significantly higher in the concussed group, whereas p-tau217 and p-tau231 levels were not different.

Certain individuals in the concussed group exhibited high levels of multiple markers, such as elevated exosome Aβ42 and p-tau231 and larger exosome size. Exosome morphology analysis revealed that the average diameters of exosomes were significantly larger in players with a history of concussion as compared to controls, with sizes ranging from 22 to 39 nanometers (nm). SEM visualized exosome structures and confirmed significant size differences.

Pearson's correlation analysis showed significant correlations among biomarkers. There was a positive correlation between t-tau levels and exosome size, as well as between Aβ42 and Nf-L. A highly negative correlation was observed between t-tau and RBP-4, as well as between RBP-4 and exosome sizes.

Conclusions 

The current study provides important insights into key biomarkers associated with the long-term consequences of concussions, including neurodegenerative diseases, in retired rugby players. Significant differences were observed in serum t-tau, RBP-4, and exosome p-tau181 levels between the concussed group and the healthy control group. Average serum exosomes were larger in the concussed group, thus indicating greater cellular damage.

The study findings suggest the need to re-evaluate concussion protocols and long-term post-retirement outcomes in sports. Moreover, the current study supports the potential use of these biomarkers for early diagnosis of concussion-based neurodegenerative diseases like CTE, AD, and ALS.