Progress and Significance of Current Concussion Research - Developing a Blood Biomarker for Brain Injury

If you read my post on Concussions in the NHL, you'll know that a concussion is considered to be among the most complex injuries to diagnose in sports medicine. A concussion is a clinical diagnosis based largely on the observed injury mechanism (point of contact, force on head area, etc.), signs, and symptoms. Due to the fact that there is no true [perfect] diagnostic test for a concussion, physicians must rely on patient-reported symptoms and neurological testing to make a diagnosis. Additionally, unlike other neurological injuries, most concussions cannot be identified by advanced neuroimaging techniques such as CT scans or MRIs.

In this post I'll highlight some current research on concussion.

WHAT WE KNOW

Concussion is still an injury that is largely debated. Most debate surrounds the long-term effects of the injury. What isn't debated is that a player suffering from a concussion should never return to play (RTP) the same day as the injury and should take a minimum of a few days off to recover and rest. Concussion in athletes practicing contact sports is a growing problem worldwide and new research has highlighted some important facts about the injury:

• The underlying pathophysiology of a concussion is an acute disturbance of neuronal function combined with damage to neuronal and glial (neuronal support) cells. This acute disturbance may eventually present chronic consequences (Blennow et al.). 
• Most concussions resolve after 7 days or within a couple weeks; however studies have revealed that 10-15% of concussions remain symptomatic more than a year after the injury. The chronic and sometimes even progressive symptoms of concussion have been linked to repeated injury occurring before the brain has properly recovered (Baugh et al.).
• Cerebrospinal fluid (CSF) can show biochemical changes in the central nervous system (CNS). CSF biomarkers such as total tau (T-tau) and neurofilament light (NFL), show elevated levels of axonal damage after acute damage to the brain (Hesse et al. and Nylen et al.) 
• The levels of these biomarkers correlate with the severity of the brain damage and eventually return to normal after a period of rest (Zetterberg et al. Neselius et al.).
• CSF is obtained via a lumbar puncture, a sometimes painful procedure that is invasive and not optimal for routine testing.

A simple biomarker for concussion which can be used routinely and accurately as a diagnostic tool would be extremely useful for team physicians. This test could not only help diagnose a concussion, but also be useful in follow-up for concussed athletes and aid RTP decisions.

A recent study published in the JAMA Neurology Journal had the objective of "determining if sports-related concussion is associated with elevated levels of blood biochemical markers of injury..." The researchers collaborated with the Swedish Hockey League to conduct the research. 

THE STUDY

DESIGN

In the study Blood Biomarkers for Brain Injury in Concussed Professional Ice Hockey Players, Dr. Pashtun Shahim et al. researched an objective biomarker to help in clinical decisions regarding concussion. The study examined three biomarkers to determine their significance: 

• Neuron-specific enolase (NSE) - a biomarker for neuronal injury (elevated levels found in boxers that had been repeatedly hit in the head (Zetterberg et al).
• S-100B - a glial cell biomarker named S-100 calcium-binding protein B, elevated levels found in boxers who took head shots compared with boxers who only took body shots (Graham et al.).
• Plasma T-tau - elevated levels found in Olympic boxers, which then normalized after rest (Neselius et al.).

The research was approved by the Swedish Ice Hockey Association and ran through the University of Gothenburg. With player's consents, team physicians of all 12 teams in the Swedish Hockey League would collect pre-season data, asking all players to take the Standardized Assessment of Concussion. Two of the consenting teams, Frölunda and Lülea, collected baseline blood samples from all their players prior to the start of the season. 

The study asked physicians to document signs and symptoms of concussion as well as any other examination findings when making their diagnosis. For players who suffered a concussion during the season, blood samples were collected at 1, 12, 36, 48, and 144 hours post-injury (or when the player returned to full-contact). 

RESULTS

Of the 288 players in the SHL, 35 had a sports-related concussion for the duration of the study. 28 of these players' samples were used in data analysis, as the remaining 7 players either withdrew consent or had an uncertain diagnosis. Of these 28 concussions,

• Three (10.7%) suffered a loss of consciousness (LOC)
• 25 (89%) experienced symptoms such as headaches, confusion, dizziness, or nausea. 
• 15 (53.5%) had symptoms lasting longer than 6 days.

T-tau levels were significantly higher in post-concussion samples compared with the pre-season samples. Unfortunately, the S-100B and NSE post-concussion samples were not significantly different from the pre-season samples. However, the samples collected immediately after injury (1 hour) showed elevated levels of both T-tau and S-100B when compared with the pre-season samples. The levels of these two biomarkers peaked at this timepoint (1 hour post-concussion). The levels of T-tau 144 hours after injury remained significantly elevated when compared to baseline samples; however, this did not occur in S-100B and NSE samples.

Assessing the severity of a concussion is important in the management of the injury and determination of when to RTP. The level of T-tau was not significantly different post-concussion for different grades of concussion; however, players whose concussions had symptoms for > 10 days or experienced a LOC had some higher levels. The levels of S-100B 1 hour post-concussion were significantly higher in players that experienced a LOC and those players that had symptoms for > 10 days when compared to players whose symptoms resolved in 6 days.


CONCLUSION
The T-tau biomarker displayed a significant diagnostic accuracy level, where T-tau concentrations at 1 hour post-concussion could accurately predict the number of days it took for concussion symptoms to resolve and the players to experience a safe RTP. Plasma T-tau, while highly specific to the Central Nervous System (CNS), is a promising biomarker which can be used in the diagnosis of a concussion and RTP decisions.

The NHL and NHLPA should consider participating in more studies with researchers. The wealth of information that could be learned from just basic investigation on a few blood samples is highly valuable and could not only aid current players experiencing concussion but also help determine the NHL's future plan for limiting injury.


Sources:

1. Baugh CM, Stamm JM, Riley DO, et al. Chronic traumatic encephalopathy; neurodegeneration following repetitive concussive and subconcussive brain trauma. Brain imaging Behav. 2012;6(2): 244-254. 
2. Blennow K, Hardy J, Zetterberg H. The neuropathology and neurobiology of traumatic brain injury. Neuron. 2012;6(5);886-899. 
3. Hesse C, Rosengren L, Vanmechelen E, et al. Cerebrospinal fluid markers for Alzheimer's disease evaluated after acute ischemic stroke. J Alzheimers Dis. 2000;2(3-4): 199-206. 
4. Nylen K, Csajbok LZ, Ost M, et al. CSF-neurofilament correlates with outcome after aneurysmal subarachnoid hemorrhage. Neurosci Lett. 2006; 404(1-2); 132-136. 
5. Zetterberg H, Hietala MA, Jonsson M, et al. Neurochemical aftermath of amateur boxing. Arch Neurol. 2006;63(9): 1277-1280. 
6. Neselius S, BRisby H, Theodorsson A, Blennow K, Zetterberg H, Marcusson K. CSF-biomarkers in Olympic boxing; diagnosis and effects of repetitive head trauma. PLoS One. 2012;7(4):e33606. 
7. Zetterberg H, Tanriverdi F, Unluhizarci K, Selcuklu A, Kelestimur F, Blennow K. Sustained release of neuron-specific enolase to serum in amateur boxers. Brain Inj. 2009:23(9): 723-726. 
8. Graham MR, Myers T, Evans P, et al. Direct hits to the head during amateur boxing is associated with a rise in serum biomarkers for brain injury. Int J Immunopathal Pharmacol. 2011;24(1): 119-125. 
9. Neselius S, Zetterberg H, Blennow K, et al. Olympic boxing is associated with elevated levels of the neuronal protein tau in plasma. Brain Inj. 2013;27(4): 425-433.