Neurological Research

A Journal of Progress in Neurosurgery, Neurology and Neuro Sciences

ISSN: 0161-6412 (Print) 1743-1328 (Online) Journal homepage: http://www.tandfonline.com/loi/yner20

S100β as a biomarker for differential diagnosis of

intracerebral hemorrhage and ischemic stroke

Saijun Zhou, Jianhong Bao, Yiping Wang & Suyue Pan

To cite this article: Saijun Zhou, Jianhong Bao, Yiping Wang & Suyue Pan (2016): S100β as
a biomarker for differential diagnosis of intracerebral hemorrhage and ischemic stroke,
Neurological Research, DOI: 10.1080/01616412.2016.1152675

To link to this article: http://dx.doi.org/10.1080/01616412.2016.1152675

Published online: 24 Mar 2016.

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 S100β as a biomarker for differential
diagnosis of intracerebral hemorrhage and
ischemic stroke
Saijun Zhou1,2, Jianhong Bao2, Yiping Wang2, Suyue Pan1
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China, 2Department of
1

Neurology, The 1st Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

Objective: To explore the efficacy of S100 calcium-binding protein B (S100β) in differentiating between intracerebral
hemorrhage (ICH) and ischemic stroke (IS).
Methods: From June 2014 to July 2015, 46 ICH and 71 IS patients who had undergone computed tomography
Downloaded by [University of Birmingham] at 11:06 06 May 2016

(CT) scans were enrolled. Patients’ neurological deficits were evaluated by the National Institutes of Health
stroke scale (NIHSS), and the modified Rankin scale (mRS) was used to assess functional disability 90 days after
discharge. Plasma S100β was measured from a blood sample drawn upon arrival at the emergency department.
Results: The plasma S100β concentration in the ICH group was significantly higher than in the IS group (p < 0.001).
There were only significant correlations between S100β and hemorrhage volume (r = 0.820, p < 0.001), NIHSS
score (r = 0.389, p = 0.008), and mRS (r = 0.732, p < 0.001) in the ICH group. Furthermore, receiver-operating
characteristic (ROC) curve analysis revealed that an S100β concentration of 67 pg/ml yielded an area under the
curve (AUC) of 0.903 with 95.7% sensitivity and 70.4% specificity in differentiating between ICH and IS. In the ICH
group, the plasma S100β concentration was significantly elevated in patients with poor functional outcome vs.
those with favorable functional outcome (p < 0.001). ROC curve analysis showed that an S100β concentration
of 133 pg/ml yielded an AUC of 0.924 with 100% sensitivity and 76.2% specificity in identifying ICH patients
with poor functional outcome.
Conclusion: S100β could serve as a potential biomarker for differentiating between ICH and IS and predicting
short-term functional outcome after ICH.
Keywords:  S100β, Stroke, Hemorrhage, NIHSS, Biomarker

Introduction accuracy is largely influenced by physician experience.5,6

Stroke is a condition that seriously threats humans’
health.1,2 The two main subtypes are intracerebral hem-
orrhage (ICH) and ischemic stroke (IS). The latest report
from the American Heart Association still cited the data
of Greater Cincinnati/Northern Kentucky Stroke Study,
which stated that 87 and 10% of all strokes are IS and ICH,
respectively.3 The incidence of ICH in Asian countries is
relatively higher than in western world, which reaches to
20–30%.4 It is widely accepted that the timely and accu-
rate differentiation between the two stroke types is critical
when selecting specific management and treatment strate-
gies. At present, the differential diagnosis of acute stroke
predominantly relies on radiology examinations such as
computed tomography (CT) and magnetic resonance imag-
ing (MRI). Unfortunately, these techniques may waste pre-
cious time because they are not available until patients are
admitted to the hospital. Besides, radiology examination
Correspondence to: Professor Pan Suyue, MD., Ph.D., Department of
Neurology, Nanfang Hospital, Southern Medical University, No.1838,
Guangzhoudadaobei Road, Guangzhou, 510515, China. Email:
pansuyuevip@qq.com
The development of a rapid biochemical diagnostic test
will greatly improve acute stroke management, especially
in circumstances where CT and MRI are not available.
There are continued efforts in the search for reliable
stroke biomarkers, and great progress has been made in
recent years.7,8 Unfortunately, no markers have been widely
accepted and applied in clinical practice. Glial-specific
S100 calcium-binding protein B (S100β) is predominantly
expressed by astrocytes in the mammalian brain.9 This
neurotropic factor participates in intracellular and extracel-
lular processes.10 Previous studies have shown that S100β
serum levels directly correlate with blood–brain barrier
(BBB) disruption; therefore, elevated S100β may indicate
the presence of radiologically detectable BBB leakage.11
S100β has previously been reported to be a biomarker
for IS, ICH, and traumatic head injury.3,12–14 Moreover,
elevated blood S100β is associated with a higher risk
of hemorrhagic transformation and brain edema.4,15 A
recent study indicated that the combination of soluble
receptor for advanced glycation end products (sRAGE)

© 2016 Informa UK Limited, trading as Taylor & Francis Group

DOI 10.1080/01616412.2016.1152675 Neurological Research   2016 1
 Zhou et al.  S100β in differential diagnosis of acute stroke
and S100β could effectively distinguish ICH from IS in
blood samples collected within 3–6 h.14 Even though the
above-mentioned results are encouraging, more evidence
from clinical practice is needed.
In this study, we explored the efficacy of plasma S100β
levels to distinguish ICH from IS and the ability of the
biomarker to predict the short-term function after ICH.
Patients and methods
The prospective, single-center pilot study was performed
at Nanfang Hospital. It was approved by the hospital’s
ethical committee, and all enrolled participants signed
informed consent forms.
Patients
From June 2014 to July 2015, patients admitted to the
emergency department for complaints of acute stroke
symptoms within the first 6 h after symptoms onset were
Downloaded by [University of Birmingham] at 11:06 06 May 2016
screened. The exclusion criteria were as follows: previous
acute stroke within 3 months and previous brain injury,
head trauma, other neurological disease. Patients’ demo-
graphic characteristics such as age, gender, and time win-
dow were collected.
Neuroimaging and clinical protocol
On admission, a definitive diagnosis was made based on
a combination of medical history and a brain CT scan that
was reviewed by an experienced neuroradiologist who was
blinded to the patient’s clinical details and S100β results.
A standard ellipsoid method was utilized to compute hem-
orrhage volume.16 Infarct size was categorized into three
degrees for anterior circulation (<1/3, 1/3–2/3, and >2/3
of middle cerebral artery territory or multiple territories).17
Volumetric measurements of posterior circulation infarcts
were not conducted for the limited cohort. The National
Institutes of Health Stroke Scale (NIHSS) was applied to
evaluate neurological deficit severity on hospital admis-
sion. Functional disability was rated by the modified
Rankin scale (mRS) 90 days after discharge.18 The 90-day
outcome was dichotomized into favorable prognosis (mRS
0–2) and poor prognosis (mRS 3–6 or death). It is impor-
tant to note that all patients were managed according to
the guidelines of the Chinese Society of Neurology, which
was not affected by the research.
Blood sampling and S100β measurement
Blood samples were drawn upon arrival at the emergency
department, cooled at 4 °C, and centrifuged at 3000 rpm
for 15 min. After centrifugation, the plasma was collected
and frozen at −80 °C until further analysis. A commercial
electrochemiluminescence immunoassay kit (Cusabio,
Wuhan, China) was used to measure S100β. The samples
were analyzed in triplicate to avoid bias, and the respon-
sible laboratory technician was blinded to the patients’
medical information.
2 Neurological Research   2016
Statistical analysis
SPSS 18.0 (Chicago, IL, USA) was used for statistical
analyses, and two-tailed p < 0.05 was considered statis-
tically significant. Comparisons between groups were
made using Student’s t-tests for quantitative data and χ2
tests for categorical data. Correlations between S100β and
NIHSS, mRS, infarct size of the anterior circulation, and
hemorrhage volume were assessed by Spearman’s rank or
Pearson’s correlation analyses, as appropriate. Receiver-
operating characteristic (ROC) curve analysis and the
area under the curve (AUC) were applied to determine
the efficacy of S100β in distinguishing ICH from IS and
identifying ICH patients with poor functional outcome.
Results
A total of 46 ICH patients and 71 IS patients were enrolled.
Demographic characteristics were similar between the
two groups, including age (p = 0.913), gender distribu-
tion (p = 0.782), time from symptom onset to admission
(p = 0.414), presence of hypertension (p = 0.905), presence
of diabetes (p = 0.772), and NIHSS score (p = 0.880, Table
1). The radiological findings on admission are presented
in Table 1.
The mean plasma S100β concentration in the ICH
group was significantly higher than in IS group (p < 0.001,
Fig. 1A). In the ICH group, a significant correlation was
found between S100β and hemorrhage volume (r = 0.820,
p < 0.001) and NIHSS (r = 0.389, p = 0.008, Fig. 2A).
There was no significant correlation between S100β and
infarct size (r = 0.005, p = 0.970) or NIHSS (r = 0.225,
p = 0.059, Fig. 2B) in the IS patients. Furthermore, ROC
curve analysis revealed that S100β at the cut point of
67 pg/ml yielded an AUC of 0.903 with 95.7% sensitiv-
ity and 70.4% specificity in differential diagnosis of ICH
and IS (Fig. 3A).
At 90-day follow-up, functional outcome assessment
was favorable and poor in 21 and 25 patients in the ICH
group compared to 38 and 33 patients in the IS group,
respectively (p = 0.406). In the ICH group, the plasma
S100β concentration in patients with poor functional
outcome was significantly elevated compared to those
with favorable functional outcome (210.0 ± 69.6 vs.
103.2 ± 44.5, p < 0.001, Fig. 1B). Correlation analysis
indicated that ICH patients with higher plasma S100β con-
centrations were more likely to experience a poor func-
tional outcome (r = 0.732, p < 0.001), but this phenomenon
was not observed in the IS group (r = 0.088, p = 0.468).
Furthermore, ROC curve analysis indicated that S100β
at the cut point of 133 pg/ml yielded an AUC of 0.924
with 100% sensitivity and 76.2% specificity for identify-
ing patients with higher mRS in the ICH group (Fig. 3B).
Discussion
We observed a significantly higher mean plasma S100β
concentration in ICH patients compared with IS patients
 Zhou et al.  S100β in differential diagnosis of acute stroke

Table 1  Patient characteristics

Characteristic ICH (n = 46) IS (n = 71) p

Age(years) 68.1 ± 11.6 69.3 ± 10.9 0.913
Gender
Male 30 47 0.782
Female 16 24
Time between symptoms onset and admission 135.4 ± 57.3 144.4 ± 58.4 0.414
Patient with hypertension, n 28 44 0.905
Patients with diabetes, n 15 25 0.772
Median NIHSS, (interquartile range) 8 (6, 13) 8 (6, 14) 0.880
IS etiology, n
Large vessel 22
Cardio-embolic 35
Small vessel 0
Unknown 14
Infraction size, n
<1/3 MCA 21
1/3–2/3 MCA 30
>2/3 13
Posterior circulation 7
Hemorrhage location, n
Basal ganglia 38
Lobar 8
Brain stem 0
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Hemorrhage volume, ml 29.4 ± 12.7

S100β, pg/ml 161.2 ± 79.7 61.7 ± 37.3 <0.001
Prognosis 0.406
Favorable (mRS 0–2) 21 38
Poor (mRS 3–5 or death) 25 33

Notes: ICH: intracerebral hemorrhage, IS: ischemic stroke, NIHSS: National Institutes of Health Stroke Scale, MCA, middle cerebral artery
territory S100β: glial-specific S100 calcium-binding protein B.

Figure 1  Comparison of plasma S100β concentrations between groups. A, Comparison between ICH and IS (161.2 ± 79.7 vs.
61.7 ± 37.3 pg/ml, respectively, p < 0.001) groups; B, Comparison between ICH patients with favorable or poor functional outcomes
(103.2 ± 44.5 vs. 210.0 ± 69.6 pg/ml, respectively, p < 0.001)

within 6 h after acute stroke symptom onset. Moreover,
plasma S100β concentration was correlated with hem-
orrhage volume and NIHSS and mRS in ICH patients.
Plasma S100β concentration was also able to distinguish
ICH from IS and identify ICH patients with poor func-
tional outcome.
The first question regarding the utility of S100β in the
differential diagnosis of ICH and IS is the time window.
Kanner and colleagues found that S100β was directly cor-
related with the extent and temporal sequence of hyperos-
motic BBB dysfunction, suggesting that S100β is a useful
biomarker of BBB function.11 In other words, BBB impair-
ment could result in S100β leakage and consequent eleva-
tions in plasma S100β concentration. It has been reported that
plasma S100β concentration in ICH cases increased within
6 h, peaked at 24 h, plateaued at day 2, and then gradually
decreased.12 In contrast, necrotic cell lysis and death mostly
occur 6–12 h after ischemia.19,20 Significant elevations in
S100β are mostly observed 24 h after symptom onset in IS
patients.13,21 Therefore, we hypothesized that determination of
plasma S100β concentration within 6 h after symptom onset
may be useful for distinguishing between ICH and IS patients.

 Neurological Research  2016 3
 Zhou et al.  S100β in differential diagnosis of acute stroke

Figure 2  Scatter diagram showing plasma S100β concentration versus NIHSS in the ICH (A, r = 0.389, p = 0.008) and IS (B,
r = 0.225, p = 0.059) groups
Downloaded by [University of Birmingham] at 11:06 06 May 2016

Figure 3  ROC curve analysis for the efficacy of S100β in the differential diagnosis of ICH and IS (A, AUC: 0.903, sensitivity:
95.7%, specificity: 70.4%) and identification of patients with poor functional outcome in the ICH group (B, AUC: 0.924, sensitivity:
100%, specificity: 76.2%)

We found that S100β rapidly increased in ICH patients
within 6 h of symptom onset, but no significant elevation
was observed in IS patients. A similar result was reported
in a previous study; Montaner et al. found that S100β
increased and sRAGE decreased within 6 h after symptom
onset in ICH patients.22 In that study, the sensitivity and
specificity of the combination of S100β and sRAGE in
the differential diagnosis of ICH and IS were 22.7% (95%
confidence interval [CI], 15.9–31.0) and 80.2% (95% CI,
77.0–83.0), respectively.22 Our study found that S100β
could effectively distinguish ICH from IS with high sen-
sitivity (95.7%) and specificity (70.4%). Many factors may
contribute to the differences in these two studies, such as
race, disease status, test time, and biomarker measurement.
One possible factor may be the inclusion and exclusion
criteria: acute stroke patients with previous acute stroke
within 3 months, previous brain injury, head trauma, and
other neurological disease were excluded in our study,
while no definite exclusion criteria were described by
Montaner et al. As mentioned above, the time window is
crucial in applying S100β to differentiate ICH from IS.
Montaner et al. recruited patients admitted to the emer-
gency department within the first 24  h after symptoms
onset, while only patients admitted within the first 6  h
after symptoms onset entered into our study. The pro-
longed time window might allow more leakage of S100β
into blood in IS patients, which reduced the efficiency
of S100β in the differential diagnosis of ICH and IS. Of
note, patients’ medical data were blinded to laboratory
technician in order to avoid artificial bias in our study.
Even though the sensitivity and specificity determined
by ROC curve analysis were relatively high, we can-
not ignore the large overlap of S100β data between the
ICH and IS group as shown in Fig. 1A. This indicates
that the misdiagnosis rate may be not low when solely
applying S100β for the differential diagnosis of ICH and
IS. Therefore, it is irresponsible and arbitrary to select a
treatment protocol based solely on S100β measurement.
Besides, the calculated sensitivity and specificity may
decrease after enlarging the sample size. However, this

4 Neurological Research   2016


study indicated the potential of S100β in the differential
diagnosis of ICH and IS, especially in the pre-hospital
setting.
We found that plasma S100β concentration in ICH
patients correlated with hemorrhage volume and NIHSS
score. As a reflection of clinical symptoms, the NIHSS
score is mostly determined by hemorrhage volume.23 A
previous study also indicated that plasma S100β levels
were highly associated with Glasgow Coma Scale scores
and ICH volumes.12 Moreover, cerebrospinal fluid S100β
is a well-known biomarker for assessing traumatic brain
injury severity.14 Additionally, serum S100β determined
by 48 and 72 h after stroke onset was found to be asso-
ciated with infarct size.13 Even though the diseases cat-
egories, inclusion and exclusion criteria, determination
time point selection, and test methods varied among the
above studies, they all confirmed the utility of S100β in
evaluating brain injury severity. S100β is a noninvasive
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biomarker of BBB function and brain lesions,11 and an
early increase in plasma S100β level reflects the abrupt
release of the protein from necrotic neuroglial cells into
the blood. BBB damage in patients with larger hemorrhage
volume is greater than in patients with smaller hemorrhage
volume, which means that more S100β is released into the
circulation of patients with larger hemorrhage volume. In
contrast, neuroglial cell destruction is a gradual process
in IS, and S100β release is relatively lower in the early
stage. Notably, there were few severe ICH cases in this
study, which might be a reason for the results shown in
Fig. 2A. More data from severely injured patients might
flatten the curve.
S100β was also found to be associated with mRS;
patients with high blood S100β concentrations were more
likely to experience poor functional outcome. Besides,
ROC curve analysis indicated that S100β at the cut point
of 133 pg/ml could identify patients with poor functional
outcomes in the ICH group; the sensitivity and specific-
ity were 100 and 76.2%, respectively. As described by
Foerch et al., S100β levels determined 48 and 72 h after
symptom onset correlated with mRS in IS patients.13 It is
obvious that the time point for S100β determination differs
between ICH and IS. Even though the S100β range in ICH
patients with poor functional outcomes greatly overlaps
the range in those with favorable functional outcomes, we
cannot deny the potential of this measurement in helping to
identify patients who need adequate neuroprotective drugs
and rehabilitation training in clinical practice.
Even though the results are encouraging, several limita-
tions need to be considered. First, there is a doubt whether
the enrolled patients could represent the entire population.
Second, the study’s reliability is greatly limited by the
small sample size. Larger multicenter studies are needed.
Third, there is a lack of discussion on the effects of other
clinical parameters on S100β levels, including medication,
infection, renal function, chronic disease, and alcohol use.
Fourth, S100β is elevated in trauma patients and those
 Neurological Research  2016
Zhou et al.  S100β in differential diagnosis of acute stroke
with sepsis-associated encephalopathy.24,25 Given that we
only considered acute stroke, the conclusions are limited
with regard to the diagnostic and predictive sensitivity and
specificity of S100β.
Conclusions
Our findings demonstrate that S100β measured within 6 h
after stroke onset could be a potential biomarker for dis-
tinguishing between ICH and IS, evaluating ICH severity,
and predicting short-term functional outcome in patients
who have experienced ICH.
Disclosure statement
Notes On Contributors
Saijun Zhou is a doctoral student at Nanfang Hospital,
Southern Medical University. Her research interest mainly
includes cerebrovascular disease. Her recent publica-
tion appears in Biochemical and Biophysical Research
Communications with the title ‘CXCR7 suppression mod-
ulates microglial chemotaxis to ameliorate experimental-
ly-induced autoimmune encephalomyelitis’.
Jianhong Bao is a medical master at the 1st Affiliated
Hospital of Wenzhou Medical University. Her research
interest mainly includes cerebrovascular disease. Her
recent publication appears in Biochemical and Biophysical
Research Communications with the title ‘CXCR7 sup-
pression modulates microglial chemotaxis to ameliorate
experimentally-induced autoimmune encephalomyelitis’.
Yiping Wang is a medical graduate student at the 1st
Affiliated Hospital of Wenzhou Medical University. At
present, she has no definite research direction and pub-
lishes no work.
Suyue Pan is a medical professor working at the
Nanfang Hospital, Southern Medical University. His
research interest mainly includes cerebrovascular disease.
His recent publication appears in Neuroscience Letters
with the title ‘Mild hypothermia decreases the total clear-
ance of glibenclamide after low dose administration in
rats’.
Conflicts of Interest
All authors declare that there are no competing financial
interests.
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