Stefanie Schulte

Blood-based biomarkers for traumatic brain injury: evaluation of research approaches, available methods and potential utility from the clinician and clinical laboratory perspectives

Blood-based biomarkers for traumatic brain injury (TBI) have been investigated and proposed for decades, yet the current clinical assessment of TBI is largely based on clinical symptoms that can vary widely amongst patients, and have significant overlap with unrelated disease states. A careful review of current treatment guidelines for TBI further highlights the potential utility of a blood-based TBI biomarker panel in augmenting clinical decision making. Numerous expert reviews on blood-based TBI biomarkers have been published but a close look at the methods used and the astonishing paucity of validation and quality control data has not been undertaken from the vantage point of the clinical laboratory. Further, the field of blood-based TBI biomarker research has failed to adequately examine sex and gender differences between men and women with respect to the clinical care settings, as well as differences in physiological outcomes of TBI biomarker studies. Discussions of tried-and-true laboratory techniques in addition to a few new ones already operating in the clinical laboratory are summarized with a consideration of their utility in TBI biomarker assessment. In the context of TBI biomarkers, the central concerns discussed in this review are the readiness of the clinical laboratory, the willingness of the research environment and the inherent ability of each to radically affect patient outcomes in TBI.

Lactate infusion at rest increases BDNF blood concentration in humans

Studies in humans use blood lactate to determine the degree of the exercise intensity, suggesting that exercise with elevated blood lactate concentrations results in increased BDNF plasma concentrations. However, it is not clear if lactate per se or rather other mechanisms are responsible for changes in blood BDNF concentrations. The lactate clamp method at rest is an appropriate method to examine physiological responses of lactate on the human organism without the effects of exercise. Eight male sport students placed in a sitting position received intravenous infusions with a 4 molar sodium-lactate solution in an incremental design starting with an infusion rate of 0.01ml/kgBW/min for the first three minutes, which was increased every three minutes by 0.01ml/kgBW/min up to 0.08ml/kg/min in the 24th minute. All together each subject received 4.2mmol of infusion. Venous blood samples were taken before and immediately after the infusion as well as in the 24th and the 60th min after the infusion period and analysed for BDNF. Blood gases and capillary blood lactate (La) were analysed before the test, every three minutes directly before increasing the infusion rate, at the end of the infusion and in the post infusions period until the 12th min and after 24 and 60min. BDNF and La increased significantly after the infusion and reached baseline values at the end of the experiment (p<0.05, p<0.01, respectively). pH and hydrogen ions increased from the beginning until the end of the infusion period (p<0.01). This data suggest that blood lactate is involved in the regulation of BDNF blood concentrations.

A Systematic Review of the Biomarker S100B: Implications for Sport-Related Concussion Management

OBJECTIVE Elevated levels of the astroglial protein S100B have been shown to predict sport-related concussion. However, S100B levels within an athlete can vary depending on the type of physical activity (PA) engaged in and the methodologic approach used to measure them. Thus, appropriate reference values in the diagnosis of concussed athletes remain undefined. The purpose of our systematic literature review was to provide an overview of the current literature examining S100B measurement in the context of PA. The overall goal is to improve the use of the biomarker S100B in the context of sport-related concussion management. DATA SOURCES PubMed, SciVerse Scopus, SPORTDiscus, CINAHL, and Cochrane. STUDY SELECTION We selected articles that contained (1) research studies focusing exclusively on humans in which (2) either PA was used as an intervention or the test participants or athletes were involved in PA and (3) S100B was measured as a dependent variable. DATA EXTRACTION We identified 24 articles. Study variations included the mode of PA used as an intervention, sample types, sample-processing procedures, and analytic techniques. DATA SYNTHESIS Given the nonuniformity of the analytical methods used and the data samples collected, as well as differences in the types of PA investigated, we were not able to determine a single consistent reference value of S100B in the context of PA. Thus, a clear distinction between a concussed athlete and a healthy athlete based solely on the existing S100B cutoff value of 0.1 μg/L remains unclear. However, because of its high sensitivity and excellent negative predictive value, S100B measurement seems to have the potential to be a diagnostic adjunct for concussion in sports settings. We recommend that the interpretation of S100B values be based on congruent study designs to ensure measurement reliability and validity.

Serum Concentrations of S100B are not Affected by Cycling to Exhaustion With or Without Vibration

Serum Concentrations of S100B are not Affected by Cycling to Exhaustion With or Without Vibration The calcium-binding protein S100B is produced primarily by astrocytes and exerts concentration-dependent paracrine and autocrine effects on neurons and glia. The numerous findings of a correlation between S100B and traumatic brain injury (TBI) have resulted in the employment of this protein as a clinical biomarker for such injury. Our present aim was to determine whether cycling with (V) or without (NV) vibration alters serum concentrations of S100B. Twelve healthy, male non-smokers (age: 25.3±1.6 yrs, body mass: 74.2±5.9 kg, body height: 181.0±3.7 cm, VO2peak: 56.9±5.1 ml·min-1·kg-1 (means ± SD)) completed in random order two separate trials to exhaustion on a vibrating bicycle (amplitude 4 mm and frequency 20 Hz) connected to an ergometer. The initial workload of 100 W was elevated by 50 W every 5 min and the mean maximal period of exercise was 25:27±1:30 min. The S100B in venous blood taken at rest, immediately after the test, and 30, 60 and 240 min post-exercise exhibited no significant differences (p>0.05), suggesting that cycling with and without vibration does not influence this parameter.

Response to the Letter to the Editor of Sorci et al. ''Causes of elevated serum levels of S100B protein in athletes''

We view the interest generated by our paper positively and appreciate the views of Drs. Sorci, Riuzzi and Donato. In their response to our paper (Schulte et al. 2012), Sorci et al. pose three important considerations regarding the contribution of peripheral sources to increased peripheral S100B levels and the function of S100B itself. In the following we address Sorci et al. main points in this response. First, we concur with this suggestion—a point we acknowledge in our article—that S100B is also expressed in soft tissue outside the brain and possibly released by damaged skeletal muscle tissue due to vigorous physical activity. Secondly, findings regarding the connection between lipolysis/fat tissue and S100B are equivocal. That said, we would agree with Sorci et al. as it would be premature to exclude the possibility that increased lipolysis by physical activity might be a potential mechanism in increasing peripheral S100B concentration. Finally, Sorci et al. indicate the functions of S100B regarding tissue repair/regeneration or amplification of the local inflammatory response. Based on the fact that S100B has opposing effects depending on its concentration (neurotoxic and neuroprotective effects), we wholeheartedly embrace the conclusion that S100B may not only be a biomarker of pathological conditions such as concussion/mild traumatic brain injury, but also a potential indicator of neuroprotective processes. Independent of whether S100B has neurotoxic or neuroprotective effects, it is the most widely investigated biomarker in the assessment of traumatic brain injury. A peripheral concentration of S100B in serum less than the recommended cut-off level of 0.1 lg/L has been linked to negative computer tomography (CT) scans regarding TBI with a sensitivity of 96.8 % and a specificity of 42.5 % (Pandor et al. 2011). Early identification of sports-related brain injury, like concussion, is essential in preventing athletes’ poor clinical outcomes and optimizing post-injury performance. The identification of concussed athletes based on S100B assessment requires accurate reference values. Increased peripheral S100B levels C0.1 lg/L do not necessarily imply that an athlete is concussed. Due to the fact that there are multiple factors that potentially influence S100B serum concentration levels (e.g. myocytic damage and lipolysis), S100B levels might exceed the cutoff value of 0.1 lg/L without the contribution of cerebral sources and thus cannot be attributed to concussion. In addition to the influencing factors mentioned by Sorci et al., we want to point out that factors such as sex, age and color of skin (melanocytical activity) may also influence basic peripheral S100B concentrations (Gazzolo et al. 2003). Hence, it is important to establish individual matched reference values of S100B for concussed athletes regarding demographic factors such as sex, age, race, and other salient factors associated with physical activity (e.g. Communicated by Hakan Westerblad.