Assistant Professor of Neurology, Weill Cornell Medical College

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

SYNOPSIS: Currently, there are no reliable and readily available biomarkers to assist in determining prognosis for neurological recovery after cardiac arrest, but serum tau measurements hold promise for the future.

SOURCE: Mattsson N, Zetterberg H, Nielsen N, et al. Serum tau and neurological outcome in cardiac arrest. Ann Neurol 2017;82:665-675.

Prognostication after cardiac arrest remains a challenge, with most biomarker tests for extent of neural injury having variable sensitivity and specificity. Mattsson et al used a novel single molecule detection assay to quantify serum tau in patients from the Target Temperature Management (TTM) after cardiac arrest trial, which examined the outcomes in patients treated to 33° or 36°C after cardiac arrest.¹ Blood samples were collected from 819 patients at 29 European centers, of whom 689 were eligible for this sub-study. Outcomes were assessed at six months using the Cerebral Performance Categories (CPC) scale.

The mean age of patients was 64 years, 81% were male, and the mean return of spontaneous circulation (ROSC) time was 31 minutes, after 73% received bystander CPR. Higher tau was associated with older age, longer ROSC, and absence of bystander CPR. There were no longitudinal differences in serum tau between 33° and 36°C groups with poor outcome. Overall differences between groups were smaller than that between patients with good (CPC 1-2) and poor (CPC 3-5) outcomes.

Poor outcomes correlated with elevated tau levels drawn within 24 hours of cardiac arrest, and differences in tau between groups increased at 48 hours; 72 hours and later samples had greater sensitivity for poor outcomes. In the CPC 1 group, serum tau decreased significantly between time points (24, 48, 72 hours), while it increased in CPC 4 and 5. Low levels of tau were correlated with lower CPC, and similar correlations also were seen with the modified Rankin Scale. In prognostic accuracy, ROSC analyses at different time points were identical, and false-positive rate of 2% at 72 hours provided a sensitivity of 66%. Adding tau to clinical information improved prediction with AUC of 0.94 in logistic regression models of poor outcome. Models comparing clinical information with NSE or tau yielded similar AUC, as did models including all three.

COMMENTARY

In the search for additional and improved biomarkers, the authors must be commended on this sub-study from the TTM trial. In this study, serum tau showed good correlation with poor outcome after cardiac arrest regardless of therapeutic temperature target, with the best sensitivity seen with high serum levels at 72 hours in CPC 3-5 group. The specificity and sensitivity were 91% and 71%, respectively, at a false-positive rate of 5% at 72 hours. The accuracy was slightly higher for tau compared to NSE. The use of the test in conjunction with clinical data can improve prognostication at 72 hours and may assist in identifying patients who are unlikely to benefit from prolonged intensive care compared to patients who are more likely to survive.

The study has been well performed as part of a multicenter trial and was powered adequately for detection of poor outcomes with tau levels. Temperature management was not found to be a confounder.

One of the critical needs in neuroprognostication is to discover a biomarker that not only has high specificity and sensitivity, but also can be performed readily at any hospital, since cardiac arrest is a ubiquitous illness seen at hospitals globally. The currently used assay is not commercially available and is semi-automated. However, advances in technology likely can deliver this for commercial use.

The promise of tau as a biomarker of severe brain injury also has been demonstrated recently in traumatic brain injury.² Different forms of tau, such as phospho-tau, also may be promising, and although not ready for clinical use, do hold the hope of a biomarker for acute brain injury, regardless of etiology.

REFERENCES

1. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med 2013;369:2197-2206.
2. 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;74:1063-1072.