When athletes in contact sports suffer multiple head injuries close together, before their brain has recuperated, they are at risk of serious brain damage down the road. To improve physicians’ ability to decide whether a player can return to the game, researchers are looking for practical, objective biomarkers that track with injury. Scientists led by Henrik Zetterberg, University of Gothenburg, Sweden, have evaluated an ultra-sensitive new test that measures tau in the blood. In the March 13 Journal of the American Medical Association, they find that tau correlates with head injury and predicts recovery time in hockey players. “Clinical assessments are imperfect,” said Howard Federoff, Georgetown University, Washington, D.C., who was not involved in the study. “This could add tremendous value as we better understand the temporal relationships between injury, measurement of biomarkers, and symptoms.”
Several biomarkers in cerebrospinal fluid (CSF) correlate with brain injury in athletes. Zetterberg’s group has found that the amount of neurofilament light (NFL) and total tau (t-tau) track with the number and severity of blows to the head in boxers (see Zetterberg et al., 2006, and Neselius et al., 2012). Blood biomarkers would be easier to access, however, so researchers are looking for good candidates. In boxers, plasma levels of both the astroglial marker S-100 calcium-binding protein B (S100B) and the neuronal injury marker neuron-specific enolase (NSE) rise after punches to the head (see Graham et al., 2011). Likewise, the Swedish researchers found that t-tau levels rise in the blood of Olympic boxers after a fight (see Neselius et al., 2013). In this study, first author Pashtun Shahim and colleagues wondered whether these biomarkers correlated with the severity of the injury and could be tracked longitudinally to monitor recovery.
To find out, the authors enlisted all 288 professional ice hockey players from the 12 teams of the Swedish Hockey League. Just before the 2012-2013 season began, the researchers took baseline blood samples from 47 men on two of those teams. Over the next four months, 28 players from the league suffered concussions, often accompanied by nausea, headache, dizziness, or confusion. Each athlete gave blood samples one, 12, 36, 48, and 144 hours after injury, then again if their recovery took longer than that. Team physicians recorded how long it took each player to recuperate from their symptoms and return to regular play.
Shahim and colleagues measured fluctuations in t-tau using an immunoassay recently developed by the diagnostics company Quanterix, based in Lexington, Massachusetts. It detects as little as 0.2 pc/mL using tiny magnetic beads in microwells. A standard immunoassay picked up S100B and NSE in the blood.
Compared with preseason controls, both t-tau and S100B rose in concussed players just one hour after injury. Within the first 12 hours, these levels fell again. Interestingly, tau peaked a second time at 36 hours. Furthermore, the one-hour concentrations of both tau and S100B predicted the number of days it would take for concussion symptoms to subside. NSE tracked with neither injury nor recovery.
Since drawing blood is not always possible just an hour after injury, the authors looked to see if any marker correlated at 144 hours. Only t-tau differed between players who recovered in fewer than six days and those who took longer.
Based on these results, the authors proposed in their paper that t-tau is a promising biomarker that could be used in the diagnosis of concussion and in deciding when an athlete can return to play. They were unsure why the protein peaked twice, but speculated that this could result from an early release of cytosolic tau right after the impact followed by injured axons leaking microtubule-bound tau for several days. Frequently, hockey concussions cause shear forces that overstretch axon tracts.
NSE and S100B, on the other hand, were not specific to neuronal injury, as both also rose after a friendly match without concussion, the authors noted. Shahim said he and colleagues are currently replicating the results in a larger sample and scouting out additional candidates for blood biomarkers. The NFL is one, but the research team is still working on an ELISA to detect it in the blood.
“Blood biomarkers useful in the management of traumatic brain injury (TBI) has been one of the holy grails of the clinical neurosciences for several decades,” wrote Joshua Gatson, University of Texas Southwestern Medical Center, Dallas, and Ramon Diaz-Arrastia, Uniformed Services University of the Health Sciences, Bethesda, Maryland, in an accompanying editorial. They suggest tau markers may be one option for predicting patient outcome, noting that future biomarker panels might include markers of astrocyte, endothelium, and microglial pathology.
In terms of practical use on athletic teams, it is unclear how blood biomarkers will figure into athletic management in the near future. That is because concussions at present are clinically defined, said Charles Bernick, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, who conducts biomarker studies with professional fighters. However, Bernick did suggest that this type of data could be useful to figure out whether lighter blows cause brain damage in the absence of symptoms. Researchers may also want to explore whether tau measurements can predict future conditions such as CTE, he said.
Could this tau immunoassay have implications for a blood test predicting Alzheimer’s disease? Perhaps, Zetterberg said, though his recent work suggests that even with 1,000-fold sensitivity over conventional immunoassays, this test has trouble distinguishing AD patients from those with mild cognitive impairment and controls (see Zetterberg et al., 2013). He suggested that a small chronic release of tau may be hard to detect in blood because it seems to be broken down quickly. However, his group is looking for a more stable fragment of tau that could correlate with disease.—Gwyneth Dickey Zakaib
- Zetterberg H, Hietala MA, Jonsson M, Andreasen N, Styrud E, Karlsson I, Edman A, Popa C, Rasulzada A, Wahlund LO, Mehta PD, Rosengren L, Blennow K, Wallin A. Neurochemical aftermath of amateur boxing. Arch Neurol. 2006 Sep;63(9):1277-80. PubMed.
- Neselius S, Brisby H, Theodorsson A, Blennow K, Zetterberg H, Marcusson J. CSF-biomarkers in Olympic boxing: diagnosis and effects of repetitive head trauma. PLoS One. 2012;7(4):e33606. PubMed.
- Graham MR, Myers T, Evans P, Davies B, Cooper SM, Bhattacharya K, Grace FM, Baker JS. Direct hits to the head during amateur boxing is associated with a rise in serum biomarkers for brain injury. Int J Immunopathol Pharmacol. 2011 Jan-Mar;24(1):119-25. PubMed.
- Neselius S, Zetterberg H, Blennow K, Randall J, Wilson D, Marcusson J, Brisby H. Olympic boxing is associated with elevated levels of the neuronal protein tau in plasma. Brain Inj. 2013;27(4):425-33. PubMed.
- Zetterberg H, Wilson D, Andreasson U, Minthon L, Blennow K, Randall J, Hansson O. Plasma tau levels in Alzheimer's disease. Alzheimers Res Ther. 2013;5(2):9. Epub 2013 Mar 28 PubMed.
- Strathmann FG, Schulte S, Goerl K, Petron DJ. Blood-based biomarkers for traumatic brain injury: Evaluation of research approaches, available methods and potential utility from the clinician and clinical laboratory perspectives. Clin Biochem. 2014 Jul;47(10-11):876-888. Epub 2014 Jan 31 PubMed.
- Britt E, Diwaker M, Baker D, Chang D, Huang M. Signs of mild traumatic brain injury in active duty us marines can be measured with brain MRI magneto-encephalography. Br J Sports Med. 2014 Apr;48(7) PubMed.
- Zetterberg H, Smith DH, Blennow K. Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood. Nat Rev Neurol. 2013 Apr;9(4):201-10. Epub 2013 Feb 12 PubMed.
- Mondello S, Muller U, Jeromin A, Streeter J, Hayes RL, Wang KK. Blood-based diagnostics of traumatic brain injuries. Expert Rev Mol Diagn. 2011 Jan;11(1):65-78. PubMed.
- Tartaglia MC, Hazrati LN, Davis KD, Green RE, Wennberg R, Mikulis D, Ezerins LJ, Keightley M, Tator C. Chronic traumatic encephalopathy and other neurodegenerative proteinopathies. Front Hum Neurosci. 2014;8:30. Epub 2014 Jan 31 PubMed.
- Lucke-Wold BP, Turner RC, Logsdon AF, Bailes JE, Huber JD, Rosen CL. Linking traumatic brain injury to chronic traumatic encephalopathy: identification of potential mechanisms leading to neurofibrillary tangle development. J Neurotrauma. 2014 Jul 1;31(13):1129-38. Epub 2014 Apr 11 PubMed.
- Stein TD, Alvarez VE, McKee AC. Chronic traumatic encephalopathy: a spectrum of neuropathological changes following repetitive brain trauma in athletes and military personnel. Alzheimers Res Ther. 2014;6(1):4. Epub 2014 Jan 15 PubMed.
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- Do Lipids Hold the Key to Blood-Based Alzheimer’s Test?
- Shahim P, Tegner Y, Wilson DH, Randall J, Skillbäck T, Pazooki D, Kallberg B, Blennow K, Zetterberg H. Blood Biomarkers for Brain Injury in Concussed Professional Ice Hockey Players. JAMA Neurol. 2014 Mar 13; PubMed.
- Gatson J, Diaz-Arrastia R. Tau as a Biomarker of Concussion. JAMA Neurol. 2014 Mar 13; PubMed.