By Halinder S. Mangat, MD

Assistant Professor of Neurology, Weill Cornell Medical College

Dr. Mangat reports no financial relationships relevant to this field of study.

SYNOPSIS: The ongoing search for reliable biomarkers of traumatic brain injury repeatedly has demonstrated the reliability of using plasma phosphor-tau levels to help distinguish injury from normal, and severe injury from mild injury.

SOURCE: Rubenstein R, Chang B, Yue JK, et al. Comparing plasma phosphor tau, total tau, and phospho tau-total tau ratio as acute and chronic traumatic brain injury biomarkers. JAMA Neurol 2017; Jul 24. doi: 10.1001/jamaneurol.2017.0655. [Epub ahead of print].

The TRACK-TBI investigators explored the measurement of plasma tau as a total protein, phosphorylated protein, and the ratio between the two as a correlate of acute and chronic traumatic brain injury (TBI).1 In this study, 196 patients with acute TBI and 21 patients with chronic TBI were enrolled and blood samples were compared with assays from 20 commercially acquired, healthy control samples with no history of TBI. Patients were predominantly male (74%), white (83%) with mild head injury (81% Glasgow Coma Scale [GCS] score 13-15; 3% GCS score 9-12; 6% GCS score < 9), and half had normal CT (55%). Patients with acute TBI had blood collected within 24 hours of injury, and chronic TBI patients had blood collected at an average of 176 days. The investigators developed and used a new high-sensitivity assay: multi-arrayed fiberoptics conjugated with rolling circle amplification (a-EIMAF), which previously has been validated.

Higher hypophosphorylated tau protein (P-tau) and P-tau and total-tau (P-tau-T-tau) ratios both significantly were correlated with abnormal CTs, TBI severity by GCS (13-15, 9-12, 3-8), and CT Marshall score, and were significantly higher in TBI patients than in controls. In addition, both indices could distinguish mild TBI from controls as well as moderate and severe TBI. Analyses of area under the curve (AUC) were 0.9-1.0 for the two indices in discrimination between all acute TBI and healthy controls, 0.7-0.8 in distinguishing between mild and moderate/severe TBI, and 0.9-1.0 in distinguishing patients with normal vs. abnormal CT scans. The two indices also correlated with good outcomes, being inversely proportional, but had poor discrimination by AUC; the latter was significantly better (0.7-0.8) for poor outcome (Glasgow Outcome Scale-Extended < 5). Lastly, and surprisingly, P-tau and P-tau-T-tau ratio both were significantly higher in chronic TBI patients with AUC 0.9-1.0.

COMMENTARY

This study joins a few other outstanding studies exploring reliable and robust blood biomarkers of TBI. The clinical field of TBI, especially acute TBI, has remained at a standstill in terms of improved identification of patients. For several decades, the GCS scale has been used to classify severity, and in the last few decades, CT has been used to identify and classify TBI. Patients with mild TBI who do not have sustained impairment in consciousness frequently have no findings on CT examination. Yet they form up to 80% of the TBI burden. This has been highlighted only recently and brought to the public domain by increased press of sequelae of mild TBI from sports and blast injury in war.2-4 Therefore, development of biomarkers is the pressing need of the hour.

The choice of the protein is appropriate given that tau is a scaffolding axonal microtubule protein whose abnormal posttranslational transformation by hyperphosphorylation and accumulation has been known to play a role in long-term brain injury, as seen in chronic traumatic encephalopathy and Alzheimer’s disease. The consistent association of P-tau and the P-tau-T-tau ratio with clinical condition, lesion on CT, and ability to differentiate mild TBI from more severe TBI makes this study’s results exciting.

A few drawbacks of the study, as stated by the authors, are that the samples from controls and patients were handled differently, and control samples were few and commercially obtained. In the future, the study investigators are validating the assay prospectively using patient family or friends as controls.

However, an extensive network as TRACK-TBI should perhaps look to concomitantly study other biomarkers that have shown recent promise, such as GFAP (with breakdown products),5 ubiquitin C-terminal hydrolase L1,6 and brain-derived neurotrophic factor,7 to validate not only which biomarker provides the highest accuracy and reliability, but also which is most efficient and cost-effective.

REFERENCES

  1. Rubenstein R, Chang B, Yue JK, et. al. Comparing plasma phospho-tau, total tau, and phospho tau-total tau ratio as acute and chronic traumatic brain injury biomarkers. JAMA Neurol 2017; Jul 24. doi: 10.1001/jamaneurol.2017.0655. [Epub ahead of print].
  2. MacDonald CL, Barber J, Jordan M, et al. Early clinical predictors of 5-year outcome after concussive blast traumatic brain injury. JAMA Neurol 2017;74:821-829.
  3. Stamm JM, Bourlas AP, Baugh CM, et al. Age of first exposure to football and later-life cognitive impairment in former NFL players. Neurology 2015;84:1114-1120.
  4. Hart J Jr, Kraut MA, Womack KB, et. al. Neuroimaging of cognitive dysfunction and depression in aging retired NFL players: A cross-sectional study. JAMA Neurol 2013;70:326-335.
  5. McMahon PJ, Panczykowski DM, Yue JK, et. al. Measurement of the glial fibrillary acidic protein and its breakdown products GFAP-BDP biomarker for the detection of traumatic brain injury compared to computed tomography and magnetic resonance imaging. J Neurotrauma 2015;32:527-533.
  6. Diaz-Arrastia R, Wang KK, Papa L, et al. Acute biomarkers of traumatic brain injury: Relationship between plasma levels of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein. J Neurotrauma 2014;31:19-25.
  7. Korley FK, Diaz-Arrastia R, Wu AH, et. al. Circulating brain-derived neurotrophic factor has diagnostic and prognostic value in traumatic brain injury. J Neurotrauma 2016;33:215-225.