Tau as a Biomarker of Concussion

Abstract

The search for 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. Biomarkers are molecules that can be measured in accessible biological fluids that reflect physiological, pharmacological, or disease processes and can suggest the etiology of, susceptibility to, activity levels of, or progress of a disease. According to the US Food and Drug Administration, biomarkers fall into 3 categories, which are notmutually exclusive: prognostic, predictive, and pharmacodynamic.1 Prognostic biomarkers are baseline measurements that categorize patients bydegree of risk for disease progression and informabout the natural historyof thedisorder. Predictivebiomarkers arebaseline characteristics that categorize patients by their likelihood of response to a particular treatment. Finally, pharmacodynamic biomarkers aredynamicmeasurements that show that biological responsehasoccurred in apatient after a therapeutic intervention. Biomarkers have historically been critical to progress in a broad range of clinical conditions. Diagnostic and therapeutic advances in fields as disparate as cardiology and oncology have relied on the ability to measure biomarkers that are reliable indicators of the underlying pathology. Clinicians evaluating and treating patientswho have sustained TBIs in themild end of the spectrum and present after abrief periodof alteredawareness andbrief (orno) loss of consciousness are faced with several questions that could benefit from the availability of validated blood biomarkers. Does thispatientneed tobe transported toahospital (usuallybyambulance and at significant expense) for further evaluation, or is observation in place adequate, either on the sidelines of a sporting event or at home? Does this patient need a neuroimaging study, which is usually a cranial computed tomographic scan that involves radiationand, inyoungchildren,use of sedation topreventmovement? Is thispatient likely tomake a complete recovery after his or her concussion, or is he or she at risk forpersistentpostconcussivesymptoms(PCS) forweeks, months, or longer? While most patients fully recover from a mildTBI (mTBI, a termnowconsideredsynonymouswithconcussion), a significant minority do not, and the ability to predict earlyonwhether there ishigh riskofpersistentPCSwould be very useful for counseling and for the development of preventive strategies. Finally, what about the patient who presents with months or years of cognitive, behavioral, or psychologicalproblemsafter 1ormultipleTBIs?Are thesymptoms primarily due to an organic brain disorder, or should evaluation and treatment be focused on psychological factors? The study by Shahim et al2 in JAMA Neurology represents an important contribution to this field and introduces an innovative technology that may have wide applicability. The investigators studied professional ice hockey players from 2 teams in the Swedish Hockey League. A total of 288 players were studied at baseline, 35 of whom had a concussion during a half season (September 2012 to January 2013). Twenty-eight of these were evaluated after the concussion, and blood was drawn at 1, 12, 36, 48, and 144 hours after injury. This represents a strong study design. The high prevalence of concussion in professional athletes allows the collection of blood prior to the index mTBI (although obviously not prior to concussions they sustained in prior seasons), which increases the confidence in the results. Also importantly, professional athletes are typically psychologically robust and have little or no conscious or unconscious incentive to overreport PCS. While only 3 of the 28 players had a period of unconsciousness, 15 had PCS persisting beyond the time of the last blood collection, indicating the nontrivial nature of these seemingly mild injuries. Themost novel feature of the study is the use of an innovative digital immunoassay technology, which allows measurement of total tau in plasma.3,4 The digital immunoassay for tau is 3000-foldmore sensitive than standard immunoassays, allowing the detection of proteins found in circulation in subfemtomolar concentrations. In addition to assaying plasma total tau, the investigators also studied 2 other biomarkers thathave longbeena focusof research in theTBI field, neuron-specific enolase (NSE), aproductofneurons, andS-100 calcium-binding protein B (S-100B), a product of activated astrocytes. The main finding of the study is that total tau is elevated inplasmaafter a concussion, and theelevationpersists for several (up to 6) days. This is an important finding, as tau is a widelystudiedbrain-specificmolecule involved inawiderange of neurodegenerative conditions, including chronic traumatic encephalopathy.5 Total taumay be useful as a prognostic biomarker, as there was a good correlation between total tau elevations 1 hour after concussion and thenumber of days it took for symptoms to resolve.Using receiver operating characteristic analysis, total tau at 1 hour had high diagnostic accuracy (area under the receiver operating characteristic curve = 0.80) for discriminating players who had a concussion from those who had played in a friendly game and were not concussed, and it had evenbetter prognostic accuracy for identifyingplayerswhohadPCS lasting longer than6days (area under the receiver operating characteristic curve = 0.91) comparedwithnonconcussedplayers.Whatweallwant, of course, is high diagnostic accuracy separating concussed individuals Related article page 684 Opinion