A Systematic Review of The Biomarker S100B: Implications For Sport-Related Concussion Management

Journal of Athletic Training 2014;49(6):830–850
doi: 10.4085/1062-6050-49.3.33
Ó by the National Athletic Trainers’ Association, Inc systematic review
www.natajournals.org
A Systematic Review of the Biomarker S100B:

Implications for Sport-Related Concussion
Management
Stefanie Schulte, PhD, RN*; Leslie W. Podlog, PhD*; J. Jordan Hamson-Utley,
PhD, LAT, ATC†; Frederick G. Strathmann, PhD*; Heiko K. Strüder, PhD‡
*Department of Exercise and Sport Science, University of Utah, Salt Lake City; †University of St Augustine, FL;
‡German Sport University, Institute of Movement and Neurosciences, Cologne, Germany
Objective: Elevated levels of the astroglial protein S100B Data Extraction: We identified 24 articles. Study variations
have been shown to predict sport-related concussion. However, included the mode of PA used as an intervention, sample types,
S100B levels within an athlete can vary depending on the type sample-processing procedures, and analytic techniques.
of physical activity (PA) engaged in and the methodologic Data Synthesis: Given the nonuniformity of the analytical
approach used to measure them. Thus, appropriate reference methods used and the data samples collected, as well as
values in the diagnosis of concussed athletes remain undefined. differences in the types of PA investigated, we were not able to
The purpose of our systematic literature review was to provide determine a single consistent reference value of S100B in the
an overview of the current literature examining S100B mea- context of PA. Thus, a clear distinction between a concussed
surement in the context of PA. The overall goal is to improve the athlete and a healthy athlete based solely on the existing S100B
use of the biomarker S100B in the context of sport-related cutoff value of 0.1 lg/L remains unclear. However, because of
concussion management. its high sensitivity and excellent negative predictive value,
Data Sources: PubMed, SciVerse Scopus, SPORTDiscus, S100B measurement seems to have the potential to be a
CINAHL, and Cochrane. diagnostic adjunct for concussion in sports settings. We
Study Selection: We selected articles that contained (1) recommend that the interpretation of S100B values be based
research studies focusing exclusively on humans in which (2) on congruent study designs to ensure measurement reliability
either PA was used as an intervention or the test participants or and validity.
athletes were involved in PA and (3) S100B was measured as a Key Words: head injuries, physical activity, exercise mode,
dependent variable. analysis techniques
Key Points
When standardized analytical approaches are applied, measuring peripheral S100B in concussion management is
beneficial.
Determining a single consistent reference value for S100B in the context of physical activity is currently not possible.
Thus, repeated assessments of individual baseline values (eg, in the preseason) should be conducted.
U
ndiagnosed or underreported mild traumatic brain and quick indicators of abnormal cerebral processes after
injury (mTBI; concussion) can lead to a number of mTBI.
severe and long-term consequences for athletes, In the assessment of traumatic brain injury, S100B is the
including headache, speech and motion dysfunction, most widely investigated biomarker.3 A 21-kDa protein
impairment in sensory and cognitive perception, and even abundant in the central nervous system (CNS), S100B is
death.1 Early identification of sport-related concussion is predominantly expressed in astrocytes, with a cerebrospi-
therefore essential to prevent poor clinical outcomes, nal fluid (CSF) to serum ratio of 18:1.4 When secreted by
ensure the health and well-being of athletes suffering from astrocytes, S100B has neurotrophic and neuroprotective
effects at physiologic nanomolar concentrations. Howev-
mTBI, and optimize postinjury performance. Diagnostic
er, higher (micromolar) concentrations of S100B have
imaging can be used to detect brain damage. However, been shown to be neurotoxic and expressed in astrocytic
assessment tools such as computed tomography (CT) scans death.5,6 After a traumatic brain injury, S100B is released
are often not on site or available at sport events; they may or leaked by the cells of the CNS and enters the peripheral
be cost intensive and are not ideal for detecting mTBI as bloodstream by passing through the presumably disrupted
they cannot distinguish subtle changes in brain tissue. Thus, blood-brain barrier (BBB). The mechanisms that lead to
a substantial percentage of sport-related mTBIs go an increase in the peripheral S100B concentration are still
unreported or undiagnosed (or both).2 Difficulties detecting unclear. However, because proteins in general do not
and diagnosing this injury highlight the need for objective easily cross the intact BBB,7 the mechanism of peripheral
830 Volume 49 Number 6 December 2014

S100B increase might be based on an active or passive of 0.1 lg/L in the absence of mTBI. A second aim of the
release of S100B secreting cells, an alteration in the review was to provide an overview of the diverse theories
permeability of the BBB, or a combination of these. that explain increases in peripheral S100B concentrations in
Identifying concussed athletes based on S100B assess- the context of PA. Furthermore, we discuss the effects of
ment requires accurate reference values. A peripheral various methodologic factors, including the timing of
concentration of S100B in serum less than the recommend- sample withdrawal, sample processing and analysis, and
ed cutoff level of 0.1 lg/L3,8,9 has been associated with choice of the analytical technique, all of which have
negative CT scans regarding traumatic brain injury with a considerable influence on S100B values. Finally, we offer
sensitivity of 96.8% and a specificity of 42.5%.3 The examples and recommendations regarding peripheral
sensitivity of peripheral S100B measurement refers to the S100B measurement in sport-related concussion manage-
ability to correctly identify concussed athletes, and the ment.
specificity refers to the ability to correctly identify those
athletes without mTBI. Accordingly, a peripheral S100B METHODS
level greater than 0.1 lg/L does not necessarily mean that
an athlete is concussed and has to be removed from training The systematic review was conducted in accordance with
and competition, because multiple factors can influence the the guidelines outlined in the Cochrane Handbook for
S100B serum concentration level.3,10–13 Serum S100B Systematic Reviews of Interventions.28 Based on these
values have been measured across diverse groups, making guidelines, we defined the hypothesis, developed criteria
determination of accurate values challenging. For example, for study inclusion and data collection, and made
S100B values greater than the recommended 0.1 lg/L have determinations with regard to the presentation and
been measured in healthy individuals of both sexes younger interpretation of the results. Furthermore, 2 researchers
than 20 years,12 in healthy adults of different races,11 and in used the Physiotherapy Evidence Database (PEDro) scale29
patients without head trauma but with extracranial to rate the methodologic quality of the studies. The PEDro
injuries.13 Identification of the appropriate S100B reference scale is an 11-item scale designed for rating the
value in sport-related concussion management is further methodologic quality of randomized controlled trials.
complicated by the fact that various types of physical Studies scoring 9 or 10 are considered to have excellent
activities affect S100B concentrations in apparently healthy internal methodological validity; 6 to 8, good; 4 or 5, fair;
athletes.14–24 and less than 4, poor.30 Initial discrepancies between the
The range of variables found to affect S100B reference reviewers were discussed, and consensus was reached on all
values raises questions concerning the reliability of this PEDro scores.
substance as a marker of mTBI in athletes. However,
S100B testing in the peripheral bloodstream is very Search Strategy
economical (about $20).25 The blood can be sampled
anywhere and anytime by appropriate, certified staff and We searched the following electronic databases with no
S100B concentrations can be measured using commer- date or language limitations: PubMed, SciVerse Scopus,
cially available kits or sent to a reference laboratory. SPORTDiscus, CINAHL, and Cochrane. These databases
More importantly, the S100B blood test will provide an were searched using the following key words: S100B,
indication of whether an athlete requires medical follow- S100b, S100beta, S-100B, S-100beta, S-100b, biomarker,
up, depending on the magnitude of the increase. A assess*, and diagnos*. The references were imported into
prompt posttraumatic assessment of S100B adds value to the literature-management program Endnote (version X5;
the early diagnostic and prognostic analysis of mTBI.26 Thomson Reuters, Carlsbad, CA). After we eliminated
Hence, it is important to establish an individual’s S100B duplicate publications, 2605 potentially relevant abstracts
level via multiple assessments and compare the value remained.
with values for concussed athletes matched on factors
such as sex, age, race, and the specific type of physical Study Selection
activity (PA) (eg, sprint versus endurance sport, contact
versus noncontact sport) to maximize the interpretation The search was restricted to studies focusing on (1)
of the peripheral S100B value. Adding the peripheral humans (2) in which either PA was used as an intervention
S100B measurement to existing concussion management or physically active individuals or athletes were test
could enable trained sport medicine professionals (eg, participants, and (3) studies involving S100B as the
athletic trainers with phlebotomy technician certification) dependent variable. These abstracts were individually
to identify concussed athletes with much greater evaluated by 2 independent reviewers, both experienced
expediency and accuracy and aid in monitoring their researchers in the field of sports medicine. The title,
recovery.27 abstract, and key words of each publication were
The purpose of our systematic literature review was to considered to determine if the inclusion criteria (1–3) were
provide an overview of the current literature describing satisfied. The final data reported in the review were based
S100B measurement in the context of PA. Our primary aim on the reviewers’ consensus. A total of 29 abstracts met
was to synthesize the state-of-the-art knowledge regarding these criteria. Because methods or measurements were not
S100B reference values in distinguishing healthy and completely described in the 29 abstracts, we obtained the
concussed athletes. Our intention was to categorize full-text articles of each to determine if the study should be
peripheral S100B values measured after different types of included in the systematic review. One reviewer completed
PA in healthy athletes. We hypothesized that vigorous PA a full-text article evaluation to assure that all inclusion
increases peripheral S100B levels beyond the cutoff level criteria were met. In the end, 26 articles met the predefined
Journal of Athletic Training 831

criteria and were included in our systematic literature scale.29 This scale has been adopted previously to rate the
review. methodologic quality of randomized controlled trials,
which is a common practice in systematic reviews. Three
Data Extraction of the PEDro scale items—blinding, concealed allocation,
and randomization—have evidence for discriminative
To extract the data, we developed a questionnaire with validity.39 As complete blinding of participants is impos-
the following 4 main categories: sible when assessing modalities of PA and exercise and
1. Filter questions (Is the abstract referring to the biomarker because of deficiencies in the design (eg, no control group)
S100B in its function as a diagnostic tool? Is PA or and description of the study methods (eg, no information
exercise defined as an intervention or an influencing factor regarding the allocation of treatment), we rated most
of S100B?) articles as fair to poor on the PEDro scoring scale. Based
2. Formal information about the articles (year of publication, on the guidelines of the Cochrane Handbook for Systematic
type of document, type of article, research area, name of Reviews of Interventions28 and the PEDro scores, conduct-
journal, address of corresponding author) ing a meta-analysis was inappropriate for this type of
3. Information about the protein S100B (term used for S100 systematic review.
calcium binding protein B, measurement unit, cutoff level,
details of S100B levels—study results, type of sample RESULTS
tissue, time sample was withdrawn, details of sample We found widespread nonuniformity in terms of study
processing, main approaches used to explain alterations of designs, analytical methods used, data samples collected,
S100B levels) and types of PAs examined. Thus, we provide a
4. Information about the study design (type and details of systematic description of the results regarding the
intervention, method of S100B analysis, details about test S100B values, types of PA reported, participants,
participants) explanatory approach for increased S100B values, time
To ensure agreement between the reviewers, we pilot of specimen collection, specimen processing and storage
tested the questionnaire on 5 articles included in the processing, analytical measurement, and methods used for
systematic review before data extraction began. The initial analysis (Table 1).
Holsti coefficient for intercoder reliability31 was 94%.
Discrepancies in data extraction were solved by discussion The S100B Values
between the reviewers. The S100B values described in the articles were based on
We categorized the results in tables using the original a range of study designs (ie, pre-post design, group
descriptions from reviewed articles (eg, no history of comparisons, intervention) and thus, in some studies, there
cardiac, cerebrovascular, respiratory disease32) or sorted were no pretest or posttest values ascertained, descriptions
them into rational categories (eg, group soccer included, eg, regarding S100B values were insufficient, or results were
soccer training session with24,33–36 and without head- expressed in ‘‘differences’’ or ‘‘percentages’’ without
ing35,36). The S100B levels were described in the articles showing total values (Table 1). A categorization of
using different SI units (lg/L, pg/mL, ng/L, ng/mL), so we S100B values according to the kind of PA was statistically
converted these to lg/L with 2 decimal places for impossible. However, there was a tendency toward
standardization purposes. significant increases in peripheral S100B values after
competitive and vigorous PA in the absence of apparent
Statistical Analysis head injury (see ‘‘Mode of PA’’ and Table 2).
According to the Cochrane Handbook for Systematic
Reviews of Interventions,28 4 critical criteria need to be Mode of PA
satisfied to conduct a meta-analysis of existing studies: (1) We identified more than 9 kinds of PA and categorized
identification and selection of studies, (2) heterogeneity of them according to the descriptions provided in the articles.
results, (3) availability of information, and (4) analysis of As mentioned earlier, a trend indicated that vigorous PA
the data.37 Of the articles that met our inclusion criteria, might cause significant increases in peripheral S100B
many failed to address at least 2 of the criteria necessary to values. Conspicuous are those S100B concentrations that
conduct a meta-analysis, namely heterogeneity of results exceed concentrations of more than 0.1 lg/L3,8,9 in the
and availability of information. The dissimilar results absence of apparent head injury (Table 2).
among the articles could be attributed to differences in
the individual study designs. Furthermore, the lack of
Participants
information that we intended to extract (eg, details of the
study design and actual values for S100B) precluded the Participants were described variously as breath-hold and
possibility of conducting a meta-analysis. Finally, the scuba divers (experienced or professional), race walkers
Cochrane Handbook indicates the futility of conducting and runners, wrestlers (Greco-Roman, freestyle), soccer
statistical analyses when the aforementioned criteria have players (professional, amateur), basketball and ice hockey
not been satisfied as ‘‘meta-analyses of poor quality studies players, trained swimmers, boxers (amateur), and as other
may be seriously misleading.’’38 ‘‘professional’’ athletes and ‘‘physically active’’ individuals
In addition to assessing the available literature according (treadmill walking, ergometer bicycling, bungee jumping).
to the 4 criteria outlined above, we assessed the The sex of the participants was described in 22 articles,
methodologic quality of the studies using the PEDro with male participants being investigated disproportionally

(males ¼ 665 versus females ¼ 14). None of the authors Processing of the S100B Sample
provided an explanation for the sex ratio. The age of the To obtain S100B values, the sample processing consisted
participants in the intervention groups ranged from 17 to of several steps. The different types of samples (blood,
52 years. Only 1 article provided information about the saliva, CSF) have to be processed to obtain serum or
race of the participants.35 In 5 articles, previous concus- plasma, which can then be stored or processed further (or
sions and notable findings such as a history of head injury both). The articles described different types of sample
were described.19,22,34,36,48 Apart from that, either the processing.
participants were described as having unremarkable health Some samples were allowed to clot cool 49 or by keeping
histories or we could not obtain any information regarding them on ice or snow,32,46 at 58C,22 or at room temperature18
their health status. The sample sizes in the chosen articles for 30 minutes,35 60 minutes,18 or for 3 hours maximum.49
varied between n ¼ 1 (case control study43) and 535 The following steps of centrifugation were described in
(prospective cohort study35). The sizes of groups exposed slightly different terms according to acceleration, temper-
to an intervention (any kind of PA) ranged between n ¼ 544 ature, and time. Some of the samples were centrifuged
and n ¼ 6935 (Table 3). immediately after the collection3,4 or within 2 hours24 with
an adjustment of 900g for 10 minutes,14 1000g for 10
Explanations of Increased Peripheral S100B Due to minutes at 48C,16 3000g for 10 minutes,35 or 3000g for 7
PA minutes.23 If the samples were transferred for storage,44
they were stored either on dry ice24 or at 08C in a cooler.44
The results of our systematic review revealed diverse In other articles, the procedure of sample processing after
approaches to explaining increases in peripheral S100B obtaining the supernatant was described as an immediate
concentrations in the context of PA. An overview of all freezing 23 or within 2 hours, 35 at 208C, 18,20,46,49
main approaches with which the authors explain increases 708C,14,16,23,36 788C,19,22,34,42,44 or 808C.15,24,33,47 In 1
of peripheral S100B in the context of PA is in Table 4. study, the handling of samples was followed ‘‘according to
Separately or in combination, the explanatory approaches standards and brought to the laboratory for further
refer to cerebral and extracerebral sources and active and processing.’’3,4 Other researchers provided no further
passive release mechanisms, including a possible passage information (see also Table 1).
through the BBB to explain increased peripheral S100B
levels (Table 4). The S100B Analysis
According to the type and size of the sample, different
Timing of Sample Collection methods and principles of the immunoassay techniques
Authors of articles with a pre-post study design were used to assess S100B levels. The collective title
described the time of sample collection before the ‘‘immunoassay’’ represents a specific biochemical testing
intervention as prior, before, pre-exercise, or at the start technique that uses antibodies to identify or quantify
of the intervention,* with few details regarding the exact the presence or concentration of a substance (S100B)
point of time of blood collection (5 and 0 minutes in solutions that frequently contain a complex mixture
before,20 1 to 5 hours before,48 1 to 2 hours before,22 24 of substances, such as biological fluids (eg, serum,
hours before,23 8 to 9 AM at the start 43). In 1 study,20 the plasma, saliva, CSF; Table 1). The immunoassay uses
investigators monitored S100B values during the inter- an antibody, immobilized on a plastic surface, that
binds to its specific targets (eg, S100B; antigen-antibody
vention at 15-minute intervals. The time of measurement
reaction). Another reagent is used to generate a signal
after the intervention was described generally as postex-
from the captured material. The level of signal indicates
ercise,46 end of,45 after,14 next morning,35 or, more the concentration of the substance.50 According to the
precisely, as immediately following,15,47 right after,35 labels used in the system of immunoassays, the methods
immediately after,19,48 or 15 minutes after the race.23 described in the selected articles of our systematic review
Furthermore, points of time of the blood collection were are listed in alphabetic order. Detection limits between
characterized as fixed intervals (5, 10, 15, 30, 60, 120 0.005 and 0.02 lg/L were listed as reference values for
minutes after apnea45; after 20, 60, 80 minutes of the analytic methods, and intra-assay and interassay
recovery18; 0, 1, 3, 20 hours after the race21; 10 minutes coefficients of variation were determined to be approx-
thereafter42; within 15 minutes after44; 20 minutes after16; imately 10% or less (Table 5).
within 1 hour after22; after 0.53 6 0.06 hours, 1.97 6
0.06 hours, 4.02 6 0.07 hours34; 60 and 360 minutes after DISCUSSION
the heading session, 64 and 355 minutes after the exercise
session, and 65 minutes after trauma36; and 71 minutes Categorization of Sport-Related S100B Reference
after49). In addition, the details of the time of blood
Values
collection were described as over the course of time, as
well as after 26 hours,43 48 hours after the end of the To support the use of peripheral S100B measurement in
race,15 after 5 days,43 days 1 and 10 of experimental sport-related concussion management, appropriate refer-
testing,47 7 to 10 days after the training session,33 after 2 ence values are needed. Thus, we reviewed the current
months of resting,33 and at different altitudes32 (see also literature in the context of S100B measurement and PA.
Table 1). Our main goal was to categorize peripheral S100B values
measured before and after different types of PA in healthy
*References 14–17,19,21–24,34–36,42,44–47,49. athletes. Given the nonuniformity in the types of sports,

Table 1. Methods Used to Measure S100B Levelsa Extended on Next Page
Reference Physical Activity Time of Blood Withdrawal Sampling and Storage

40
Schulte et al, 2013 LC to examine lactate-induced Before start LC, after 12 min LC, Serum obtained by centrifugation
changes in serum [S100B] at end of LC, and 6, 12, 24, and frozen and stored for 1 mo
without physical activity and 60 min after LC at 408C until analysis
Schulte et al,41 2011 A: Cycling with vibration Rest, immediately before and Serum prepared from samples by
B: Cycling without vibration after test and at 30, 60, and centrifugation and frozen and
Means: time ¼ 25:27 6 1:30 240 min postexercise stored at 408C until analysis
min, vibration ¼ 20 Hz,
amplitude ¼ 4 mm
Stavrinou et al,42 2011 Recreational scuba diving Before dive and 10 min after Samples allowed to clot,
(conservative dive profile; open centrifuged immediately, 08C,
water) transferred for storage at
Total: 3 dives in 2 d, 12 h 788C until analysis
between sessions
Michetti et al,14 2011 A: Vigorous training Before and after physical activity/ Immediately centrifuged (900g for
B: Sedentary stress 10 min), stored at 708C
Spiropoulos et al,15 2010 A: ‘‘Spartathlon’’ foot race (246 Before start of race and Stored frozen at 808C until
km) mean ¼ 32 h 8 min, Md immediately after and 48 h analysis
¼ 30 h 2 min, range ¼ 25 h after end of race
17 min–34 h 43 min
B: Sedentary
Bjursten et al,32 2010 Hike to 4554 m above sea level At 1155 m after acclimatization, Cooling with snow, centrifugation
3647, 4554, 3647, 1155 m (3000g for 10 min, within 1 h),
stored frozen until analysis
Arslan et al,16 2010 A: Local Greco-Roman wrestling Before and 20 min after matches Centrifugation (1000g for 10 min,
competition þ48C), stored at 708C
B: Freestyle wrestling competition
(3 3 2 min per match)
Zetterberg et al,43 2009 2-mo period of nonparticipation in At the start, after 2 mo of resting nd
boxing from championship/training
boxing
Liner and Andersson,44 2009 International breath-hold diving Within 15 min after LOC, after 26 Handled according to standards
competition (70 m, 90 s) h, after 5 d and brought to laboratory for
resulted in LOC further processing
Andersson et al,45 2009 A: Voluntary, maximum-duration Beginning of recordings, at start Samples kept on ice, centrifuged,
apnea diving 335 6 38 (range and end of apnea, fixed frozen, and later analyzed
¼ 281–403) s intervals (5, 10, 15, 30, 60, 120
B: Resting in supine position min after apnea)
Straume-Naesheim et al,35 2008 A: Head impact occurring during Before the season/training Clot (30 min), centrifugation
a soccer league match session, right after the match/ (3000g for 10 min), frozen
B: Regular league match with no training session, next morning within 2 h until analysis
recorded head trauma
C: High-intensity training session
without heading
D: Low-intensity training session
with heading exercises only
Stålnacke and Sojka,34 2008 A: 5 3 Heading soccer ball Before, after Clot, centrifugation, transport,
falling from 18 m 0.53 6 0.06 h, frozen and stored at 788C
B: No heading 1.97 6 0.06 h, until analysis
4.02 6 0.07 h
Cheuvront et al,46 2008 10 d of heat acclimatization (100 Pre-exercise and postexercise, d Serum stored and frozen (208C)
min of treadmill walking in 1 and d 10 of testing until analyses
458C)

Table 1. Extended From Previous Page and Continued on Next Page
S100B, lg/L
Analysis/Sample Type Significance Pre Post
Immunoluminometric assay/ ns All groups: 0.03 (0.0–0.09) nd
serum
Luminometric assay/serum ns All groups: 0.05 (0.01–0.09) nd
Immunoluminometric analysis/ ns Dive 1, 0.06 6 0.01 Dive 1, 0.11 6 0.06

serum Dive 2, 0.06 6 0.01 Dive 2, 0.07 6 0.01
Dive 3, 0.06 6 0.01b Dive 3, 0.07 6 0.01b
Immunoluminometric assay/ s A: Md ¼ 0.75 A: Md ¼ 2.29

saliva Pre . post, A . B, P , .01 B: Md ¼ 0.30 B: Md ¼ 0.83
Electrochemiluminescence s A: 0.13 6 0.01 A: Postrace ¼ 0.29 6 0.01,
immunoassay/serum Pre-post P , .001 B: nd 48 h after race ¼ 0.13 6
0.01
B: nd
Immunometric process/serum s Increase from baseline of

, .05 versus baseline 122% (SD ¼ 80%), 42%
(SD ¼ 27%), 47% (SD ¼
34%), and 33% (SD ¼
25%), respectively, at
different time points
ELISA method/serum s A: Md 0.04 (0.01–1.26) A: Md 0.9 (0.05–1.67)
Pre-post A: P , .001 B: Md 0.03 (0.01–0.14) B: Md 0.07 (0.03–0.17)
B: P , .01
ns groups
Biochip array technique/serum ns A: 0.07 (0.03–0.24)
B: 0.07 (0.02–0.13)
Electrochemiluminescence Case report 0.1 after 15 min LOC

immunoassay/serum 0.1 after 26 h
0.05 after 5 d
Immunoradiometric assay/ s nd Average pre-post
serum Pre-post A: D 37%
A: ,.05 B: nd
B: ns
Electrochemiluminescence s All groups D B1:
assay/serum Pre-post 0.05 (0.02–0.11) A and B: 0.06 (0.05–0.07)
all groups BL (n ¼ 49), 0.05 (0.03– versus C and D: 0.03
nd 0.09)–0.06 (0.03–0.11) (0.02–0.03)
A and B had higher increases 33.9% elevated B1 .0.12
than C and D, P , .001 (after match with/without
head impacts)
Immunoluminometric assay/ ns A: 0.16 6 0.13 0.5 h after

serum B: 0.16 6 0.08 A: 0.11 6 0.02
B: 0.11 6 0.04
2 h after
A: 0.1 6 0.03
B: 0.1 6 0.04
4 h after
A: 0.11 6 0.04
B: 0.1 6 0.04
ELISA/serum ns Total range ¼ 0.05–0.12 D d 1: 0.02 6 0.04
D d 10: 0.01 6 0.03
Table 1. Extended From Previous Page

Table 1. Continued From Previous Page and Extended on Next Page
Reference Physical Activity Time of Blood Withdrawal Sampling and Storage

33
Zetterberg et al, 2007 Heading (ball kicked from distance of 30 m) CSF and serum: 7–10 d after CSF: stored at 808 until
A: 10 times training session analysis
B: 20 times Serum: nd
Schulpis et al,17 2007 A: Forced training, a-tocopherol (200 mg/24 h os) Pre and post forced training nd
supplement for 30 d before and after a-
B: Forced training tocopherol supplement
Watson et al,18 2006 NF cycling in a climatic chamber (35.08C 6 0.58C), During final minute of each Clot at room temperature (60
55% V̇O2peak for 6 3 15 min without exercise period (pre, post min), centrifuged to yield
replacement of sweat loss 20, 60, 80 min, recovery) serum, stored at 208C
until analysis
Stålnacke et al,19 2006 2 Competitive soccer games Before and immediately after Clot, centrifugation, stored at
game 788C until analysis
Saenz et al,47 2006 Boston Marathon (698F – 708F), mean finishing Before and immediately after Aliquots of samples frozen
time (250 6 33 min) race within 1 h of collection at
808C
Watson et al,20 2005 Sitting in water tank for 30 min immersed to neck 2 samples (5 and 0 min), Centrifuged to yield serum;
(39.08C 6 0.18C) and ‘‘W’’ cycling in a climate during exercise at 15-min kept frozen at 208C until
chamber (358C 6 0.38C), 60% V̇O2peak for 60 min intervals analysis
Stålnacke et al,48 2004 2 Competitive soccer games 1–5 h before, immediately Clot, centrifugation, transport,
after game frozen, stored at 788C
until analysis
Hasselblatt et al,21 2004 Münster Marathon, Md 4:12 (range ¼ 2:56–4:55) h Before and 0, 1, 3, 20 h after nd
race
Stålnacke et al,22 2003 Competitive games of Swedish Elite Ice Hockey 1–2 h before (ie, just before Clot (58C), centrifugation,
League and Swedish Elite Basketball League warming up) and within 1 h frozen and kept at 788C
after game until analysis
Mussack et al,36 2003 A: Controlled heading Md 55 (range ¼ 49–63) min A: Before and 60, 360 min Samples processed to serum,
B: Normal exercise Md 61 (58–66) min after heading session supernatants frozen in
C: TBI CCTþ visible brain damage B: Before and 64, 355 min aliquots at 708C until
D: TBI CCT without visible brain damage after exercise session batch evaluation
C, D: 65 min after trauma
Dietrich et al,23 2003 7600-m swimming race, XIII Travessio do Pontal 24 h before and 15 min after Serum obtained by
de Tapes, March 2002 (107.6 6 3.4 min) race centrifugation (3000g for 7
min), immediately frozen
and stored at 708C
Woertgen et al,49 2002 Bungee jump, 50 m, 2.8g Before, immediately after, 71 Samples were cooled for 3 h
min after jump maximum, serum frozen
and stored at 208C until
analysis
Otto et al,24 2000 A: Boxing competition (5 3 2 min) Before and within 15 min after Samples spun down within 2
B: Boxing sparring bouts (3–5 3 2 min) each exercise h and serum stored first on
C: 25-km race (98–142 min) dry ice and finally at 808C
D: Cross-country jogging (10 km, 55–75 min)
E: Exhaustive running/sprint (33 as fast as
possible for 2 min)
F: Exhaustive ergometer cycling (33 as fast as
possible for 2 min), 200–375 W
G: Headers (203 heading back a 450-g football
7.5 m without jumping)
Abbreviations: BL, baseline; B1, within 1 h after match/game training session; CCT, cranial computed tomography; CI, confidence interval;
CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; LC, lactate clamp; LOC, loss of consciousness; Md, median; nd, no
details; NF, non-fluid; ns, not significant; os, by mouth; s, significant; TBI, traumatic brain injury; W, warm; D, difference.
a
The type of physical activity, the time of blood withdrawal and S100B analysis techniques, and the sample types are described using the
descriptions and terms from reviewed articles. The Significance column indicates if the differences within the S100B data were statistically
significant and provides further information. S100B data are given as mean 6 SD and/or (range) and in lg/L with 2 decimal places
(conversion as needed) unless otherwise indicated.
b
Mean (SD) calculated based on the data in the article.
c
Data not represented here.

S100B, lg/L
Analysis/Sample Type Significance Pre Post
Electrochemoluminescence ns None A: Md 0.06 (0.03–0.12)
immunoassay/serum, CSF B: Md 0.04 (0.01–0.07)
C: Md 0.04 (0.03–0.06)
Immunoluminometric assay/ s A: 0.11 6 0.03 A: 0.28 6 0.06
serum Pre-post B: 0.12 6 0.02 B: 0.18 6 0.04
P , .001
Groups post
P , .001
ELISA/serum s 0.09 6 0.02 0.20 6 0.06
Pre-post
P , .001
Immunoluminometric assay/ s 0.11 6 0.05 0.18 6 0.11

serum Pre-post
P ¼ .000
Biosite Triage stroke panel/ ns 0.06 6 0.14 0.06 6 0.12
plasma
ELISA/serum s 0.07 6 0.05 D 0.12 6 0.10

Pre-post
P ¼ .02
Immunoluminometric assay/ s 0.06 6 0.03 0.12 6 0.04
serum Pre-post
P , .001
Luminometric assay/serum s nd D 0.05
Pre-post
P , .001
Immunoluminometric assay/ s A: 0.22 6 0.04 A: 0.30 6 0.11
serum Pre-post B: 0.22 6 0.04 B: 0.30 6 0.10
A: P ¼ .00004
B: P ¼ .001
Immunoluminometric assay/ s A: Md 0.15 (0.08–0.25) A: Md 0.18 (0.11–0.27)
serum Pre-post in B after age stratificationc B: Md 0.10 (0.03–0.14) B: Md 0.11 (0.06–0.20)
Pre in A, B after age stratificationc C: Md 0.62 (0.46–1.02) C: Md 0.32 (0.19–0.61)
C versus D D: Md 0.10 (0.04–0.27) D: Md 0.08 (0.04–0.17)
Groups
A versus B
C versus D
Monoclonal s 0.07 6 0.02 (0.01–0.25) 0.11 6 0.02 (0.01–0.3)
immunoluminometric assay/ Pre-post P , .001
serum
Radioimmunoassay/serum ns 0.22 6 0.02 (0.2–0.26) Post

0.22 6 0.03 (0.19–0.28)
After 71 min
0.23 6 0.02 (0.2–0.27)
Immunoluminometric assay/ Significant increase after boxing and Mean (Md) D Mean (Md), (range)
serum running disciplines but not after all groups A: 0.12 (0.09), (0–0.26)
cycling or heading (P : nd provided) 0.04 (0.04) B: 0.04 (0.03), (0–0.12)
(0.01–0.17) C: 0.07 (0.06), (0–0.21)
D: 0.04 (0.03), (0–011)
E: 0.02 (0.02), (0–0.07)
F: 0 (0), (0.04–0.06)
G: 1.3 (0), (0.02–0.01)
analytical methods used, and data samples collected, as In the following sections, we will provide a comprehen-
well as the diversity of participants investigated, we were sive theory of increased peripheral S100B levels after PA,
not able to determine a single consistent reference value of including a focus on release mechanisms, sources of
S100B in the context of PA. Thus, a clear distinction S100B, and renal elimination. Furthermore, we will focus
between concussed and healthy athletes based on the on the effects of different methodologic approaches on
existing S100B cutoff value of 0.1 lg/L3,8,9 remains S100B values, as well as the interpretation of peripheral
unclear. S100B increases in clinical practice. We will draw

Table 2. Modes of Physical Activity in Studies of S100B Concentrationsa
S100B . 0.1 lg/L
Mode of Physical Activity Details Pretest Posttest
17
Basketball Forced basketball training with a-tocopherol supplementation
and competitive games of the Swedish Elite Basketball League22
Cycling Prolonged cycling with and without replacement of sweat loss18
Prolonged cycling under temperate and warm conditions20
Exhaustive ergometer cycling24,41
Diving Competitive43 and voluntary breath-hold diving45
Recreational scuba diving42
Hiking/running/walking Ascent at 4554 m32
‘‘Spartathlon’’ foot race15
Boston Marathon47
Münster Marathon21
25-km race, cross-country jogging, and exhaustive sprints24
Prolonged treadmill walking46
Ice hockey Competitive games of the Swedish Elite Ice Hockey League22
Martial arts Competitive wrestling16
Competitive boxing24,43
Soccer Soccer league matches19,35,48
Soccer training session with heading24,33–36
Soccer training session without heading35,36
Swimming 7600-m swimming race23
Other Bungee jumping,49 unspecified vigorous training,14 lactate clamp in sitting participants40
a
The different modes of physical activities are sorted in rational categories, listed in alphabetical order (left column), and described in further
detail (middle column). The right column indicates with an arrow () if S100B concentrations in the peripheral blood unequivocally
exceeded the cutoff level of 0.1 lg/L.
conclusions based on the results and, finally, offer astroglial tissue,60 cerebral brain damage (eg, trauma,
recommendations regarding the use of peripheral S100B ischemia, disease, intoxication) can lead to a peripheral
measurement in sport-related concussion management. increase in S100B levels. 3 Some researchers 21,22,36
suggested that chronic vibration or an acute axial impact
A Comprehensive Overview of S100B-Increasing (or a combination) related to PA (eg, running, jumps,
Mechanisms and Sources heading) might be a source for cell damage and thus an
explanation for the rise in S100B during PA. Contrary to
The results of our systematic review indicate that PA can this theory, a missing correlation between a serum increase
lead to an acute significant increase in mean peripheral in S100B and acceleration–deceleration events in ice
S100B concentration,14,15,17–20,22–24,36,48 exceeding the cut- hockey indicates that a mechanical impact might not be a
off value of 0.1 lg/L,3,8,9 in the absence of apparent head cause of enhanced release of cerebral blood into the
trauma. In addition to acute alterations in S100B concen- peripheral bloodstream.22 Although various theories explain
trations, involvement in intense PA under competitive and increases in serum S100B under pathophysiologic
stressful conditions might also modify S100B baseline conditions such as concussion, researchers concur on the
values. In professional sportsmen, Michetti et al14 and need for further study of the causes, mechanisms, and
Stålnacke et al22 found noticeably high S100B baseline consequences of these increases.
concentrations that exceeded the upper limit for a normal Vigorous PA cannot be regarded as a pathologic
healthy adult population. condition per se that leads to cell damage. Therefore, an
We identified different approaches to explain the increase in peripheral S100B after sports need not
increased S100B levels during PA in the peripheral necessarily result from leakage of the protein out of
bloodstream and combined them into 1 comprehensive damaged cells. Mental and metabolic stress, as occurs in
theory. We considered cerebral and extracerebral sources, competitive sports, increases peripheral S100B levels in the
active and passive release mechanisms, possible passage absence of apparent brain injury.59,61–64 In an experimental
through the BBB or blood-CSF barrier, and renal study, Agawa et al61 found serum serotonin levels increased
elimination (Figure).51 during challenging exhaustive exercise. Teradaira et al64
Cerebral S100B Release. Based on the findings of our showed similar results by exposing sitting students to a
systematic review, we speculate that an elevated S100B stress model using visual display terminals; they noted
level is a sign of cerebral cell death and represents the increased plasma concentrations of serotonin. Because of
passive release of S100B from damaged neurons or glial the features of the enzyme kinetics, Agawa et al61 and
cells (or both, including those from the BBB) without Teradaira et al64 concluded that increased levels of
any stimulated active release into the extracellular peripheral serotonin, among other markers, appeared to
compartment.58,59 Alternatively, elevated S100B may also be induced by mental stress. One approach to explain
be the result of a pathophysiologic cascade that exerts a stress-induced increased peripheral S100B levels is seroto-
neurotoxic effect and leads to secondary brain tissue nin-induced release of intraglial S100B due to activation of
damage.5,59,60 Because S100B is most abundant in cerebral 5-HT1A receptors.65 This receptor activation

stimulates the expression and release of S100B, which, decreasing the occludin protein levels of the BBBs’ tight
accompanied by an alteration in the BBB during stressful junctions during acute, intense PA. Dysfunction of the BBB
conditions,18,20,66 might be a physiologic up-regulation to can expose the brain to hazardous molecules and pathologic
initiate S100B’s neuroprotective effects. Sport competitions organisms, significantly affecting normal brain function.
with mentally challenging situations are closely connected Furthermore, Watson et al18,20 reported an increase in
to metabolic stress. Both aerobic and anaerobic exercise serum S100B concentration after prolonged exercise in a
can induce a state of oxidative stress that leads to the warm environment (relative humidity ¼ 56% 6 5% and
physical reaction of an up-regulation in endogenous 60% 6 5%). Here, S100B is discussed as a peripheral
antioxidant defenses.61 Gerlach et al62 found support for marker of BBB integrity. Shrinking of BBB cells due to
the theory of S100B up-regulation under severe metabolic heat stress concomitant with a loss of body fluid could be a
stress conditions such as hypoxia. They suggested that the mechanism by which the protein S100B passes through and
secretion of S100B up to nanomolar concentrations is an leaks into the peripheral bloodstream. Total body fluid loss
early astroglial response to metabolic injury that initiates from increased sweating and deficient fluid ingestion during
neuroprotective and neurotrophic effects.67 Furthermore, intense or prolonged exercise may lead to shrinkage of
S100B is elevated and released into the blood circulation in barrier endothelial cells, which can cause a temporary gap
a variety of CNS disorders that are accompanied by in the tight junctions and reduce the barrier integrity. In
inflammatory signaling by activating advanced glycation addition to the ways exercise may contribute to increased
end products.68 Is the release of S100B an effect of the BBB permeability (eg, hyperthermia, central serotonergic
condition and thus a passive release by damaged inflam- neurotransmission), Watson et al18,20 stated that exercise in
matory cells or rather the cause, revealing its dose- a warm environment may lead to a loss of body fluid
dependent neuroprotective function? Furthermore, cell (sweat), resulting in plasma hyperosmolality and a shift of
death to eliminate dysfunctional inflammatory cells might fluids from the interstitial and intracellular spaces. Extra-
also be a source of S100B release.69 Increased release after cellular osmolality can influence the volume of the brain75
PA as well as in athletes’ baseline values could be related to and possibly the permeability of the BBB.18 Thus, the
physiologic regulatory mechanisms and might be a sign for possibility that an osmotic fluid shift across the BBB into
a low-grade systemic inflammation in professional and the periphery due to sweating in warm conditions (eg,
competitive conditions of sports.14,22,69 sauna) causes the washout of cerebral S100B has to be
Passage of S100B Through the BBB. The release taken into consideration when using the S100B measure-
mechanisms discussed in the previous paragraph describe a ment in the diagnosis of concussed athletes.
release of S100B in the brain. Increased release of S100B Even though most of the current literature refers to
from brain cells does not necessarily lead to increased S100B as a marker of BBB permeability, the passage of
peripheral levels of S100B because of the protective S100B from the brain to the peripheral bloodstream is not
function of the BBB. This barrier regulates the specifically related to the BBB. The barrier between the
homeostatic, nutritive, and immune environments of the blood and the CSF is made up of leaky capillaries, allowing
CNS and the exchange of molecules between the CNS and a passage for proteins.5,76 Hence, these leaks might be a
peripheral bloodstream. Proteins with molecular weights up passage for S100B to move from the CNS to the peripheral
to 600 Da are known to cross the BBB.7 As a 21-kDa bloodstream and increase S100B concentrations. Neverthe-
protein, S100B cannot pass the intact BBB passively by less, Marchi et al77 concluded that the transthyretin
diffusion, nor are there any indications of an active- monomer is a more appropriate candidate marker for
transport mechanism in any direction.58 blood-CSF barrier alterations, as this protein is primarily
To enter the peripheral bloodstream, cerebral S100B has localized in choroid plexus CSF. However, S100B seems to
to cross the altered BBB with increased permeability. The be a better marker for indicating alterations in the
permeability might be increased because of passive permeability of the BBB.
mechanisms such as sport-related BBB damage.5 Shear Noncerebral S100B Release. Whereas the previous
stress in terms of mechanical impact, axial vibrations, section highlighted the release of S100B from cerebral
accelerations–decelerations, inconspicuous falls, collisions, sources and the passage through physiologic barriers such
or simple jumping or heading may be involved in sport- as the BBB and the blood-CSF barrier, we now focus on the
related head trauma.70 This type of mechanical stress can contribution of S100B from peripheral sources. Activation
affect endothelial physiology and the formation of the tight or exercise-induced damage of peripheral tissue containing
junctions,71 and thus the permeability of the BBB, allowing S100B will likely lead to an increase in serum S100B.78
S100B to pass through the BBB into the peripheral blood Several sources, apart from the brain, could contribute to
flow. the serum S100B content by active or passive release.
Another explanation for facilitated passage of S100B Immunoassays and mRNA quantification of cells have
through the BBB is the effect of vigorous PA.66,72,73 Sharma identified adipocytes, erythrocytes, chondrocytes,
et al72 proposed a mechanism by which PA up-regulates lymphocytes, bone marrow cells, melanocytes, testes,
serotonin levels under severe stressful conditions (ie, forced heart, and aorta as S100B-expressing cells. The
swimming of rats in a water maze). Serotonin binds to the contribution of S100B from adipose tissue due to
5-HT2 receptors, increasing BBB permeability.72 In paral- lipolysis or muscle cell membrane ruptures seems to be
lel, serotonergic activation and the modulation of the most plausible.21,80–83 Because of the low brain specificity
serotonin receptor 5-HT1A promote increased expression of of the protein S100B, a debate has arisen during the last
astroglial S100B (see ‘‘Cerebral S100B Release’’).74 decade as to the origin of serum S100B and its release.
Additionally, initial results from a study by Fontes-Ribeiro Several lines of evidence suggest that S100B serum
et al73 suggest a slight increase in BBB permeability by concentrations can be significantly affected by

Table 3. Participants in Studies of Physical Activity and S100B Concentrationsa Continued on Next Page
Reference Participant Groups Sex and No. Clinical History Age, y
Schulte et al,40 2013 A: Exercise science M8 Participants displaying cerebral 25.8 6 4.1
students and neurophysiologic problems
B: CG: no excluded from study after
medical examination
Schulte et al,41 2011 A: Healthy nonsmoker M 12 No noteworthy medical history, 25.3 6 1.6
B: CG: no especially with respect to
neurologic problems
Stavrinou et al,42 2011 A: Experienced healthy M5 No history 37.2 (23–42)
divers
B: CG: no
Michetti et al,14 2011 A: Professional sportsmen A: M 25 Negative history for nervous A: 23 6 3
B: CG: Healthy controls B: M 50 system diseases/infections and B: 24 6 2
neurodegenerative disorders
Spiropoulos et al,15 2010 A: Runners/healthy race A: M 10 No history of recent infection or A: 42.8 6 1.4 (33–53)
walkers B: M 10 other disease B: 42.2 6 10.4
B: CG: sedentary healthy PR: nd
men
Bjursten et al,32 2010 A: Experienced healthy ?7 No history of cardiac, 42–51
hikers cerebrovascular, respiratory PR: nd
B: CG: no disease; 3 participants
developed acute mountain
sickness 3 y earlier
Arslan et al,16 2010 A: Greco-Roman wrestlers A: M 15 Excluded: smoking, chronic A: Md 19 (19–30)
B: Freestyle wrestlers B: M 16 illness, musculoskeletal B: Md 20 (19–26)
problems, alcohol intake, any PR: nd
medication
Zetterberg et al,43 2009 A: Healthy amateur boxers A: M 44 A: No comorbid conditions/ A: 19 (17–28)
B: CG: Healthy controls B: M 23 medications; bouts: 840 (200– B: 28 (19–50)
2000) PR: nd
B: No TBI/combative sports
Liner and Andersson,44 2009 A: Healthy professional M1 Pre: nd Total: 23
breath-hold diver Post: LOC PR: nd
B: History: no
Andersson et al,45 2009 A: Healthy trained breath- A: M 8, F 1 Healthy participants, no LOC at Total: 31 (7)
hold divers B: M 5, F 1 end of apnea PR: nd
B: CG: limited experienced
divers
Straume-Naesheim et al,35 2008b Norwegian professional A: ? 69 A: Total: 228 head impacts from A: 28.1 (22.5–35.0)
soccer players B: ? 56 352 matches, 13 time-loss B: 26.2 (19.0–33.0)
A: Head impact C: ? 48 injuries, 7 concussions C: 26.1 (18.5–33.6)
B: Match control D: ? 46 B: No recorded head trauma D: 26.1 (18.4–33.7)
C: High-intensity exercise during matches
D: Heading C, D: nd
Stålnacke and Sojka,34 2008 Soccer players A: M 10 Total: No. of previous Total: 22 6 8
A: Heading B: M 9 concussions 0–6 PR: nd
B: No heading
Cheuvront et al,46 2008 A: Healthy volunteers M9 No medications, otherwise 19 (18–21)
B: CG: no healthy on physical PR: nd
examination
Zetterberg et al,33 2007 Healthy amateur soccer A: M 10 All were healthy and none A: Md 26 (19–32)
players B: M 13 showed any signs of focal B: Md 23 (20–28)
A: 103 heading C: M 9 neurologic injury C: Md 24 (22–27)
B: 203 heading PR: nd
C: CG: healthy,
nonathletes
Schulpis et al,17 2007 A: Basketball players M 10 nd 18.5 6 0.6
B: CG: no PR: nd
Watson et al,18 2006 A: Physically active males M8 None accustomed to exercising 25.8 6 6.5
B: CG: no in warm environment at time of PR: nd
study
Stålnacke et al,19 2006 A: 4 Elite Soccer League F 44 No. of previous concussions 1.4 23 6 3
teams 6 1.9 (0–5) for n ¼ 26 PR: nd
B: CG: no
Saenz et al,47 2006 A: Marathon runners F6 No cardiovascular diseases 49 6 7
B: CG: no M 29 PR: nd

Table 3. Continued From Previous Page
Reference Participant Groups Sex and No. Clinical History Age, y
Watson et al,20 2005 A: Active healthy men M7 Excluded: participants with 25.7 6 5.0
B: CG: no history of metabolic disease or PR: nd
psychiatric illness
Stålnacke et al,48 2004 A: 4 Elite Soccer League M 28 No. of previous concussions: 0–7, 26 6 5
teams no concussions during study PR: nd
B: CG: no
Hasselblatt et al,21 2004 A: Runners F4 Neither head injury nor other 39 6 8
B: CG: no M 14 neurologic or medical problem PR: nd
encountered throughout or
after race
Stålnacke et al,22 2003 A: 2 Ice hockey teams A: M 26 No. of previous concussions: 0–4 A: 28 6 4
B: 2 Basketball teams B: M 18 B: 25 6 4
PR: nd
Mussack et al,36 2003 Amateur soccer players A: M 61 Conspicuous findings in A: Md 15.3 (14.8–16.4)
A: Heading group B: M 58 A: 49/61 B: Md 15.9 (15.0–16.8)
B: Exercise group C: M 20 B: 38/58 C: Md 41.8 (32.3–61.1)
C: TBI CCTþ D: M 61 D: Md 37.1 (27.6–53.5)
D: TBI CCT PR: nd
Dietrich et al,23 2003 A: Trained swimmers M 16 Independent of any traumas 25.4 6 2.2
B: CG: no caused by axial vibration of PR: nd
brain
Woertgen et al,49 2002 A: Healthy patients M8 No LOC, no neurologic deficit 28 (16–45)
B: CG: no F3 after jump PR: nd
Otto et al,24 2000 A: Amateur boxers A: M 10 nd A/B: 17–40 (Md 20)
B: Amateur boxers B: M 13 C: 20–44 (Md 32)
C: Volunteers C: M 11 D: 23–52 (Md 30)
D: Volunteers D: M 12 E: 25–52 (Md 30)
E: Volunteers E: M 12 F: 23–52 (Md 28.5)
F: Athletes F: M 12 G: 22–52 (Md 26)
G: Sportsmen G: M 12 PR: nd
Abbreviations: ?, sex not specified; CCT, cranial computed tomography; CG, control group; F, females; LOC, loss of consciousness; M,
males; Md, Median; nd, no details; PR, participants’ races; TBI, traumatic brain injury.
a
Age data are given as mean 6 SD and/or (range) unless otherwise indicated.
b
Percentage of participants who were Norwegian or Scandinavian: A ¼ 79.7, B ¼ 87.8, C ¼ 81.3, D ¼ 80.4. This is the only study for which
details about participants’ race or ethnicity were available.
extracerebral sources. On the one hand, researchers have Renal Elimination. In addition to sources and
shown increases in S100B concentrations and thus mechanisms that contribute to an increase in S100B in
tendencies toward false-positive values of S100B after the peripheral bloodstream, this protein is also subject to
large extracranial injuries13 and multiple trauma84 (see renal elimination and thus a down-regulating mechanism.
review by Gang and Gang78). On the other hand, an The S100B protein is metabolized and eliminated mainly
investigation of 200 participants by Pham et al10 did not via degradation in the proximal tubules of the kidney.
reveal a significant contribution of S100B expressed in Peripheral S100B concentrations need between 25
adipocytes to peripheral S100B levels. Given the minutes86 and 132 minutes87 to fall to half their value as
expression of S100B in adipocytes, Pham et al10 studied measured at the beginning of the time period (half-life).
the relationship between individuals’ fat content and S100B The flow rate of filtered fluid through the kidney
levels by determining body mass index (BMI). However, (glomerular filtration rate) is not related to the half-life of
determining individuals’ fat content by BMI calculation has urinary S100B protein.88 Thus, alteration of the glomerular
to be regarded critically. The BMI is a formula based upon filtration rate by PA has no influence on the clearance of
an individual’s weight and height. The National Institutes urinary S100B protein in sport-related mTBI.
of Health have acknowledged major shortcomings of the Consequently, peripheral S100B concentrations would be
BMI calculation as an individual’s body fat—particularly in chronically increased because of renal dysfunction.
an athlete or athletic individual—may be overestimated.85 Depending on the exercise mode and intensity, PA might
be a risk factor for renal failure due to severe dehydration
Despite the fact that S100B is most abundant in cerebral
from excessive sweating,89 especially in combination with
tissue, previous authors have shown80,83 that contributions
nonsteroidal anti-inflammatory drugs.90
to the serum increases might originate from extracerebral
sources (ie, melanocytes, erythrocytes, fat cells, testes,
heart, and aorta). In sum, further studies are needed to The Influence of Human Biology on S100B Baseline
clarify whether increased peripheral S100B reflects the Values
damage to brain tissue or an opening of the BBB or whether As discussed previously, PA, the methodologic approach
the physiologic side effects of PA increase the release of regarding the choice of sample, the sample-processing
S100B by cerebral or extracerebral sources. procedures, and the analytical techniques used could affect

Table 4. Explanations of Increased Peripheral S100B Due to Physical Activitya
Reference Theory
Schulte et al,40 2013 Variations in brain activity according to serotonergic activity after intensive physical
activity
Muscular origin of S100B after damage due to mechanical mechanisms that force BBB
alterations
Schulte et al,41 2011 Various sports involving rigorous mechanical impact on the head
Physical activity to exhaustion/after competition for approximately 2 h
Stavrinou et al,42 2011 Cumulative neural tissue damage by subclinical neurotrauma
Michetti et al,14 2011 Physiologic up-regulation or inflammatory cascades under condition of stress and/or
physical activity
Acute/chronic hypoxia conditions
Spiropoulos et al,15 2010 Exercise-induced inflammation
Bjursten et al,32 2010 Compromised integrity of BBB by mental stress or hypoxic conditions
Arslan et al,16 2010 Injury of cerebral or extracerebral tissue
Zetterberg et al,33 2007; Zetterberg et al,43 2009 Brain injury caused by heading in soccer/amateur boxing
Liner and Andersson,44 2009 Impaired integrity of central nervous system: BBB disruption not necessarily related to
either neuronal or glial brain damage
Andersson et al,45 2009 Temporary opening of BBB
Straume-Naesheim et al,35 2008 Activities with high intensity and/or number of headers
Stålnacke and Sojka,34 2008; Stålnacke et al,19 2006; Game-associated activities and events
Stålnacke et al,48 2004; Stålnacke et al,22 2003 No. of headers and other trauma events
Direct head trauma (heading) and acceleration/deceleration of body without head
trauma (falls, collisions, jumps, etc)
Opening/increased permeability of BBB during exercise
Cheuvront et al,46 2008 Exercise heat strain, alterations in BBB integrity
Schulpis et al,17 2007 Release from muscle and nerves induced by training
Watson et al,18 2006; Watson et al,20 2005 Alterations in the integrity of BBB due to exercise-induced hyperosmolality/prolonged
exercise in a warm environment
Saenz et al,47 2006 Systemic inflammatory response to exertional rhabdomyolysis
Subclinical central nervous system damage
Hasselblatt et al,21 2004 Extracranial release: skeletal muscle tissue
Mussack et al,36 2003 Transient release due to brain damage after heading
Whole-body stress during regular exercise
Extracranial release: fat, skin, skeletal muscle tissue
Dietrich et al,23 2003 Variations in physiologic brain activity: increased serotonin acting in 5-HT1A receptors
Peripheral sources: lipolysis
Woertgen et al,49 2002 Brain tissue damage after acceleration and deceleration/shear force
Otto et al,24 2000 Mechanical impact to the brain
Abbreviation: BBB, blood-brain barrier.
a
In the cases of multiple authors and publications, the explanatory approaches were condensed.
the assessment of S100B values. Furthermore, several S100B in the serum of adult soccer players increased
factors in human biology, such as age and sex, may equally in both sexes. However, Gazzolo et al95 found
influence S100B baseline levels in the peripheral blood- significant sex differences when S100B concentrations
stream without PA. Most of the participants in the reviewed were correlated with age. The S100B concentrations in the
studies were described as physically active individuals of blood of female pediatric patients monitored from birth to
both sexes and of different ages. Few if any details were 15 years of age differed significantly from those in male
provided regarding participants’ ethnic backgrounds or patients of the same age, suggesting that brain maturation in
race. the pediatric period differs by sex, as it does in the
The results of our review showed a conspicuous male-to- intrauterine and adult periods.
female ratio (based on 22 articles) of 48:1, and therefore a The ages of the participants in the intervention groups
clear underrepresentation of females. None of the authors ranged from 17 to 52 years. Gazzolo et al95 described a
provided a rationale for the sex ratio. The tendency to negative correlation between blood S100B protein concen-
examine male participants and exclude female participants trations and gestational age, with higher concentrations in
in S100B research reflects a gender bias within the broader neonates. This correlation was not apparent in individuals
natural sciences and reveals an ongoing failure to address older than 20 years of age.12,95 Additionally, Wiesmann et
sex differences or similarities in study design and analysis, al92 found a weak correlation between decreasing concen-
leading to a gender bias in research.91 Discrepant tration and increasing age, with no significant differences
information exists regarding the influence of sex on between age groups. The findings of increased S100B
peripheral S100B values. No statistically significant values in children during the first year of life and in
differences between males and females were found in adolescence could indicate alterations in BBB permeabil-
healthy individuals aged 18 to 65 years,92 18 to 80 years,93 ity36 or possible neurotrophic effects of S100B as a
male and female term neonates, children, or adults up to 70 cytokine at physiologic concentrations to induce and
years.12 Additionally, Stålnacke et al48,94 confirmed that support brain maturation and neuronal outgrowth.6 How-

Table 5. Analytical Techniques for Measuring S100B Concentrationsa
Analytical Technique Procedure Validation Characteristics
Biochip array technique43 The biochip array technique was used in 1 of the Intra-assay and interassay CV: 10%43
reviewed studies. The multi-analyte approach by
biochip array technology is based upon ELISA
principles and contains discrete regions of
antibodies specific for different proteins. Thus,
the device allows simultaneous quantification of
the different substances in a single serum
sample.51
Biosite Triage Stroke The Biosite Triage Stroke Panel was described in Biosite Triage Stroke Panel CV: 15%47
Panel47 the methods of 1 article. This assessment panel
is a point-of-care fluorescence immunoassay for
the rapid quantitative measurement of brain
natriuretic peptide and fibrin degradation
products containing D-dimer, MMP-9, and
S100B in EDTA-anticoagulated whole blood or
plasma specimens. The test results are
presented as a multimarker index value in the
assessment and diagnosis of stroke.52
Electrochemiluminescence In 4 publications, the method of Roche Diagnostics
immunoassay15,33,35,43 electrochemiluminescence immunoassays used CV for all biochemical analyses were ,10%33
to analyze the concentration of S100B was Roche Elecsys; Roche Diagnostics, F. Hoffmann-La Roche
described. The technique is based on a solid- Ltd, Basel, Switzerland
phase, streptavidin-coated microparticle and Lower detection limit: 0.005 lg/L35
electro-chemiluminescence technology. The Roche S100 reagent kit; Roche Diagnostics GmbH,
label used in the system enables extremely Mannheim, Germany:
stable reagents compared with enzyme Measurement range: 0.02–39 lg/L
conjugates.53 Total imprecision (CV total) at 0.2 lg/L: 1.29%43
ELISA16,18,20,46 The technique of ELISA was mentioned 4 times in Bio Vendor, Modrice, Czech Republic
the methods of reviewed studies. This Lowest detection limit: 0.005 lg/L
technique is commonly performed in ‘‘wet labs’’ Intra-assay CV for 0.41 lg/L: 4.5%
using antibodies labeled with an enzyme Interassay CV for 0.47 lg/L: 3.1%16
marker. Alterations in biological activity of the Sangtec Medical, Bromma, Sweden:
enzyme are a result of the enzyme-antibody- Intra-assay CV: 3.5–7.2%17,18,20
antigen reaction, which is proportional to the Fujirebio Diagnostics AB, Göteborg, Sweden:
concentration of the antigen.54 Intra-assay CV: 11%46
Immunoluminometric The use of luminometric assays was illustrated in Sangtec Medical, Bromma, Sweden
assay14,17,19,21–24,34,36,42,48 11 publications; it is thus the most common Detection limit: 0.02 lg/L14,22,34,42,48
Immunoradiometric technique for S100B assessment. Detection of Measuring range: 0.02–30 lg/L17
assay45,48 S100B in body fluids by luminometry is based Intra-assay CV: 5.5%
upon counting the emission of light by a Interassay CV:10.1%14
substance not resulting from heat of light via Intra-assay CV: 6.4% at 0.11 lg/L, 2.8% at 1.6 lg/L,
phototubes.55 Depending on the principle and and 3.6% at 18.4 lg/L
technique, different types of luminescence are Interassay CV:11% at 0.11 lg/L, 3.7% at 1.6 lg/L, and
applied (eg, immunoluminometric assay for 3.2% at 18.4 lg/L34
S100B detection). LIA-mat Sangtec 100, Bromma, Sweden
Immunoluminometric assays are based on Intra-assay CV: 5.5% at 0.28 lg/L
labeling and detecting with either Interassay CV: 10.1%
chemiluminescent or bioluminescent molecules Detection limit: 0.2 lg/L24
to identify substances such as S100B in LIA-mat, Byk-Sangtec 100, Dietzenbach, Germany
biological fluids.56 Detection limit: 0.02 lg/L
The application of immunoradiometric assay was CV: 5%23
described in 2 articles. Immunoradiometric CV: 9.5%49
assay is a form of radioimmunoassay in which a Sangtec 100, DiaSorin, Dietzenbach, Germany
specific antibody is added directly to the test Detection limit: 0.02 lg/L21,40
antigen (eg, S100B). Radioimmunoassays Measuring range: 0.02–30 lg/L40
measure antigen-antibody reactions using a CV: ,5%40
radioactively labeled substance to measure the
binding of the unlabeled substance to a specific
antibody or other receptor system.54 The
radioimmunoassay technique is extremely
sensitive and extremely specific but requires
specialized equipment and licensing.
Abbreviations: CV, coefficient of variation; ELISA, enzyme-linked immunosorbent assay.
a
Typical validation characteristics in regards to the analytical procedure are accuracy, precision, specificity, detection limit, quantitation
limit, linearity, and range. Information about these characteristics is provided only if mentioned in the reviewed articles.

Figure. Sport-related S100B increases. Comprehensive overview with possible release mechanisms and sources that might lead to
peripheral S100B increases in the context of physical activity. Once S100B is released from cerebral sources, it has to pass the blood-brain
barrier (BBB) to enter the peripheral bloodstream.57 Additionally, peripheral sources might contribute to an increase in peripheral S100B
levels. In each case, active and passive mechanisms might be involved in the cascade. From http://etc.usf.edu/clipart. Abbreviations: BCB,
blood-cerebrospinal fluid barrier; GFAP, glial fibrillar acidic protein.
ever, Einav et al93 found no correlation between S100B groups A and B had higher serum S100B concentrations
concentration and age. These inconsistent findings suggest than group C. As differences in skin color are reflected by
that S100B baseline concentrations decrease up to the age melanocytic activity and melanocytes from dark-skinned
of 20 years but do not vary beyond that point. individuals have a higher metabolic activity than those of
Information about the citizenship of the participants was fair-skinned individuals,97 the differences in baseline
provided in only 1 article,35 so we were unable to draw peripheral S100B concentrations might be due to the
conclusions regarding the race or the skin color of athletes. different levels of metabolic activity reflected by skin color.
Athletes of different races have similar densities of Together, these results indicate that there may be an
melanocytes, whereas the differences in skin color are
influence of PA, age, sex, and athlete skin color on S100B
reflected by melanocytic activity. As S100B is also
expressed by melanocytes in selected elements of normal baseline values in the peripheral blood and that these are
skin,96 athletes’ skin color might also influence S100B important factors for correctly interpreting athletes’ S100B
baseline concentration in the peripheral bloodstream. Ben values to assess and manage concussion. These factors need
Abdesselam et al11 investigated serum S100B concentra- to be understood for adults as well as for children, with a
tions in 136 healthy individuals divided into 3 groups special focus on the transition at approximately age 20
according to race (the authors offered no further details years, before S100B is routinely measured to aid in
about the group classification) into group A (Asian), B concussion management. Hence, baseline values as a point
(black), and C (Caucasian). Healthy adult individuals in of reference should be assessed on a regular basis.

The Effects of Different Methodologic Approaches on fibrinogen and other clotting factors. Both are extracted by
S100B Values centrifugation, but plasma is prepared by collection in a
tube containing an anticoagulant. Common anticoagulants
To measure the S100B concentration, a variety of
that are used in clinical and laboratory practice are EDTA,
methodologic aspects must be considered regarding the
heparin, and citrate. Tort et al103 evaluated the influence of
timing of the sample collection, sample type, and sample
processing, as well as the analytic technique used. In anticoagulants (EDTA, heparin, citrate) on plasma and
combination, the range of options is huge and differs in serum S100B levels. When anticoagulants were used,
reliability, validity, and economic cost. plasma levels of S100B were higher than serum levels.
Timing of Sample Collection. The results of our However, heparin plasma samples were highly correlated
systematic review provided few details regarding the with serum samples. Thus, they recommended using
appropriate time of sample withdrawal. Authors using a heparin plasma when an anticoagulant is required.103
pre-post study design described the time of sample Improper technique for blood collection can lead to
withdrawal postexercise as a maximum of 24 hours hemolysis: the membranes of the erythrocytes rupture and
before the intervention and inconsistently postexercise. release their hemoglobin into the blood plasma. Based on
Variations in the time between an S100B-level–increasing their results, Beaudeux and colleagues104 concluded that
event and collection of the sample can also be expected to hemolysis might be a cause of increased serum levels of
influence the accuracy of the diagnosis and determination neuron-specific enolase but not of S100B. In 2008, however,
of injury severity in sport-related concussion. The half-life Pfeifer et al105 showed significant increases in both S100B
of S100B has been shown to be 25 minutes,86 whereas and neuron-specific enolase. Thus, because the prediction of
studies of patients with mTBI demonstrated half-lives of 97 mTBI is more accurate when a panel of complementary
minutes98 and 132 minutes.87 However, these investigators biomarkers is used,106 hemolyzed samples should not be
did not discuss the possibility of impairment of renal analyzed as they might produce false-positive results.
function, which would slow the elimination rate. With regard to storage time, unfortunately, authors of the
Furthermore, increased release of S100B has been found studies we reviewed provided few if any details on which to
in cell-culture models within 15 minutes of injury.99 base recommendations for further research. When details
Assuming that the half-life of S100B is less than half an about the storage temperature were provided, most of the
hour, the time elapsed between a potential concussion and samples were stored at temperatures between 708C and
sample collection is likely to affect the accuracy of 808C. Raabe et al107 analyzed S100B serum samples
diagnosis of sport-related concussion based on peripheral (Liaison assay; Byk-Sangtec Diagnostica, Dietzenbach,
S100B measurement. A peripheral S100B level 0.1 lg/L Germany) immediately and after 4, 8, 12, and 24 hours,
within 3 to 4 hours of injury predicts a CT scan that is stored at room temperature, at 48C or frozen, and defrosted
negative for mTBI, but the measurement is more accurate after 24 hours. They found no effect of storing temperatures
if taken within the first 30 minutes after a potential injury, or time periods. Similarly, Ikeda et al108 noted unaltered
based on the short half-life of this protein.3,8,9 Ideally, serum concentrations 7 months after venipuncture and
sport-related concussion assessment includes a combination storage at 708C. However, Müller et al109 showed that
of self-reported symptoms, postural control, and S100B was not stable in frozen serum over 6 years stored at
neurocognitive function.100 Experience has shown that it 208C; values increased during long-term storage. Hence,
takes less than 30 minutes to administer and assess serum samples can be stored without temperature concerns
a combined test battery (eg, Immediate Post-Concussion even overnight and serum S100B concentrations will be
Assessment and Cognitive Testing [ImPACT], Standardized unaffected.109 Long-term storage over years, however, is
Assessment of Concussion [SAC], Balance Error Scoring not recommended.
System [BESS]) using an established process.101,102 In the Techniques for Analyzing S100B. Müller et al109 found
context of this assessment (before or after), an additional that the choice of analytical method might also play a
blood draw to measure S100B would be practical and add significant role in determining S100B levels. Results from
value to the early diagnostic and prognostic analysis of sport- the Liaison Sangtec 100 (enzyme-linked immunosorbent
related concussion. assay) and Elecsys S100 (Roche Diagnostics, Mannheim,
Sample and Sample Processing. The protein S100B can Germany) immunoassays were not interchangeable: S100B
be detected in diverse biological fluids such as CSF, blood concentrations were higher measured using the Liaison
components (serum, plasma), urine, saliva, amniotic fluid, Sangtec 100 test.109 Einav et al93 also found that values
and even human milk.59 We identified 4 different types of measured by the enzyme-linked immunosorbent assay
S100B samples (serum, plasma, saliva, CSF) that have been method (Liaison Sangtec 100) tended to be higher than
investigated and various methods for processing samples those measured by the Elecsys S100, particularly when
(time, centrifugation, temperature). None of the articles S100B levels exceeded 0.7 lg/L. Levels of S100B
provided a precise indication regarding the storage time of exceeding 0.7 lg/L could be interpreted as indicating
the frozen sample. brain injury.93 Consequently, the use of different analytical
Baseline saliva samples seem to contain higher concen- methods is not recommended. Furthermore, test-specific
trations of S100B (test ¼ 0.75 lg/L, control ¼ 0.30 lg/L)14 cutoff values for commercial kits are needed to make
compared with serum (0.12–0.14 lg/L)11 or plasma (0.05 S100B measurement more effective for sport-related
lg/L)92 concentrations in normal healthy adults. However, concussion management.
blood (plasma, serum) and CSF S100B levels are reliable Typical validation characteristics for analytical proce-
biomarkers to predict outcomes in patients with mTBI (see dures are accuracy, precision, specificity, detection limit,
review by Michetti et al59). Plasma is the liquid, cell-free quantitation limit, linearity, and range. The accuracy, also
component of whole blood, whereas serum is also free of called trueness of an analytical procedure, describes ‘‘the

Table 6. Best Practices in Sample Patients with Sport-Related Concussiona
Case 1 Case 2
Individual symptoms of soccer player after head trauma Disorientation Disorientation, blurred vision, dizziness,
headache
Loss of consciousness 30 s 5.5 min
S100B levels 1 h after head trauma 0.5 mg/L 0.12 mg/L
Interpretation Strong indication of brain tissue injury Extremely low risk of intracranial lesion
Recommendations Further investigation or examination with, High probability for good outcome
eg, computed tomography
Special attention: increased risk for long-
term persisting symptoms
a
Modified according to Stålnacke et al.48
closeness of agreement between the value that is accepted, According to several grading scales that are routinely
either as a conventional true value or an accepted reference used for concussion,112 it could be tempting to conclude
value, and the value found.’’110 Whereas accuracy refers to that the player in case 2 has a more severe type of mTBI
the true value, precision describes the repeatability or intra- than the player in case 1. The S100B concentrations are
assay precision (the precision under the same operating above the average in case 1, whereas that in case 2 is still
conditions), the intermediate precision (precision within a within the range of healthy adult individuals.11 This
laboratory), and the reproducibility (precision between indicates a high risk for injured brain tissue only in the
laboratories) of the measurement. The specificity of a test is player case 1 and requires further investigation (eg, CT)
the ability to assess the substance unequivocally in the and special attention regarding decision making about
presence of other components that are expected to be returning to training or game play because of the increased
present. The smallest amount of the substance in a sample risk for long-term, persistent symptoms.
that can be detected is called the detection limit of an
individual analytical procedure. This amount need not be CONCLUSIONS
quantified as an exact value. The smallest amount of the
substance that can be quantitatively determined with After an isolated head injury, S100B levels of less than
suitable precision and accuracy is called the quantitation the current cutoff value of 0.1 lg/L3,8,9 have been
limit of the assay. The linearity of an analytical procedure associated with CT scans that are negative for mTBI.3,113
refers to the test results that are directly proportional to the As such, a peripheral S100B concentration less than 0.1 lg/
levels of the substance in the sample within the upper and L indicates that the patient likely did not suffer an mTBI
lower concentration (range) for which the analytic (high negative predictive value).114,115 Although the
procedure has been demonstrated to have suitable levels conflicting results make it complicated to interpret S100B
of precision, accuracy, and linearity.110 values in the context of sport-related mTBI, the excellent
The articles we reviewed list no information about negative predictive value of changes in S100B levels allows
accuracy, specificity, quantitation limit, or linearity. the possibility of brain injury to be excluded.116,117
However, adequate information was provided for the However, peripheral S100B measurement in athletes based
measuring range, including the lower detection limit, and on a general cutoff level of 0.1 lg/L must be evaluated
the precision, expressed as the coefficient of variation. A critically. Competitive and vigorous PA, in addition to
detection limit up to 0.02 lg/L seems to be a common intraindividual variability, may affect peripheral S100B
reference value for the analytic methods that are currently levels, which may affect the interpretation of S100B levels
available. Additionally, intra-assay and interassay coeffi- among an athletic population. Accordingly, repeated
cients of variation were determined to be approximately assessment of reference values for each athlete is required
10% or less (Table 5). For most analytes, a coefficient of over the course of the athlete’s career. Based on the results
variation less than 5% represents acceptable performance. of our systematic review (for overview, see ‘‘Recommen-
Coefficients of variation up to 10% may be acceptable, but dations’’), we believe that the measurement of peripheral
those exceeding 10% are rarely acceptable, except at very S100B can add value to the early diagnostic and prognostic
low concentrations.111 analysis of sport-related concussion. The peripheral S100B
concentration can be available within an hour of blood
sampling118 and costs around $20,25 making this assessment
Interpreting Peripheral S100B Increases
tool in sport-related concussion management affordable for
The interpretation of S100B values is difficult, as there most in school and mass and professional sports.
are no clear, unambiguous reference values that take into The S100B protein has gained a role as a complementary
account all of the influences discussed previously, espe- specific index of early diagnosis and prognosis in the
cially in the presence of PA. To reliably predict an athlete’s management of mTBI or concussion associated with sports.
diagnosis and outcome, the S100B post–traumatic-event To establish reliable, valid S100B reference values for use
values should be compared with individual baseline values in the management of sport-related concussion, more
using the same analytical approach. How peripheral S100B studies are needed to clarify the details of S100B increases
measurement could provide appropriate information for the in athletes under different conditions. Unraveling the
management of sport-related concussion is illustrated by 2 mechanism of S100B neurotoxicity and assessment of the
cases of patients with concussion who had loss of therapeutic effects of S100B protein are promising research
consciousness (Table 6).48 directions for achieving the optimal clinical treatment of

traumatic brain injury. Because S100B alone is not Athletes of different races and ethnicities may demonstrate
diagnostic for sport-related mTBI, additional eligible differences in serum S100B baseline values.
biomarkers (eg, neuron-specific enolase) need to be Renal dysfunction decreases the rate of S100B elimination
identified to assemble a promising panel of biomarkers to and leads to increased peripheral concentrations.
differentiate among various types and levels of brain injury.
Furthermore, the implementation of point-of-care devices
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Address correspondence to Stefanie Schulte, PhD, RN, Department of Exercise and Sport Science, University of Utah, 250 South 1850
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Journal of Athletic Training 2014;49(6):830–850

A Systematic Review of the Biomarker S100B:

830 Volume 49 Number 6 December 2014

Journal of Athletic Training 831

832 Volume 49 Number 6 December 2014

Journal of Athletic Training 833

Reference Physical Activity Time of Blood Withdrawal Sampling and Storage

834 Volume 49 Number 6 December 2014

Luminometric assay/serum ns All groups: 0.05 (0.01–0.09) nd

Immunoluminometric analysis/ ns Dive 1, 0.06 6 0.01 Dive 1, 0.11 6 0.06

Immunoluminometric assay/ s A: Md ¼ 0.75 A: Md ¼ 2.29

Immunometric process/serum s Increase from baseline of

Electrochemiluminescence Case report 0.1 after 15 min LOC

Immunoluminometric assay/ ns A: 0.16 6 0.13 0.5 h after

Table 1. Extended From Previous Page

Journal of Athletic Training 835

Reference Physical Activity Time of Blood Withdrawal Sampling and Storage

836 Volume 49 Number 6 December 2014

Immunoluminometric assay/ s 0.11 6 0.05 0.18 6 0.11

ELISA/serum s 0.07 6 0.05 D 0.12 6 0.10

Radioimmunoassay/serum ns 0.22 6 0.02 (0.2–0.26) Post

Journal of Athletic Training 837

838 Volume 49 Number 6 December 2014

Journal of Athletic Training 839

840 Volume 49 Number 6 December 2014

Journal of Athletic Training 841

842 Volume 49 Number 6 December 2014

Journal of Athletic Training 843

844 Volume 49 Number 6 December 2014

Journal of Athletic Training 845

846 Volume 49 Number 6 December 2014

Journal of Athletic Training 847

848 Volume 49 Number 6 December 2014

Journal of Athletic Training 849

850 Volume 49 Number 6 December 2014

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