Curr Med Chem. 2016;23(15):1571-96.
Identifying S100B as a Biomarker and a Therapeutic Target For Brain Injury and Multiple Diseases.
The calcium binding protein S100B has attracted great attention as a biomarker for a variety of diseases. S100B is mainly expressed in glial cells and functions through intracellular and extracellular signaling pathways. The biological roles of S100B have been closely associated with its concentrations and its physiological states. The released S100B can bind to the receptor of advanced glycation end products and induce the initiation of multiple cell signaling transductions. The regulation of S100B bioactivities has been suggested through phosphoinositide 3 kinase/Akt, p53, mitogen-activated protein kinases, transcriptional factors including nuclear factor-kappaB, and cyclic adenosine monophosphate. The levels of S100B in the blood may function to predict the progress or the prognosis of many kinds of diseases, such as cerebrovascular diseases, neurodegenerative diseases, motor neuron diseases, traumatic brain injury, schizophrenia, depression, diabetes mellitus, myocardial infarction, cancer, and infectious diseases. Given that the activity of S100B has been implicated in the pathological process of these diseases, S100B should not be simply regarded as a biomarker, it may also function as therapeutic target for these diseases. Further elucidation of the roles of S100B may formulate innovative therapeutic strategies for multiple diseases.
Neurol Sci. 2016 Apr;37(4):533-9. doi: 10.1007/s10072-016-2521-1. Epub 2016 Feb 29.
Re-exposure to the hypobaric (Long Haul Flights) hypoxic brain injury of high altitude: plasma S100B levels and the possible effect of acclimatisation on blood-brain barrier dysfunction.
Winter CD1,2, Whyte T3, Cardinal J4,5, Kenny R6, Ballard E7.
Hypobaric hypoxic brain injury results in elevated peripheral S100B levels which may relate to blood-brain barrier (BBB) dysfunction. A period of acclimatisation or dexamethasone prevents altitude-related illnesses and this may involve attenuation of BBB compromise. We hypothesised that both treatments would diminish the S100B response (a measure of BBB dysfunction) on re-ascent to the hypobaric hypoxia of high altitude, in comparison to an identical ascent completed 48 h earlier by the same group. Twelve healthy volunteers, six of which were prescribed dexamethasone, ascended Mt Fuji (summit 3700 m) and serial plasma S100B levels measured. The S100B values reduced from a baseline 0.183 µg/l (95 % CI 0.083-0.283) to 0.145 µg/l (95 % CI 0.088-0.202) at high altitude for the dexamethasone group (n = 6) and from 0.147 µg/l (95 % CI 0.022-0.272) to 0.133 µg/l (95 % CI 0.085-0.182) for the non-treated group (n = 6) [not statistically significant (p = 0.43 and p = 0.82) for the treated and non-treated groups respectively]. [These results contrasted with the statistically significant increase during the first ascent, S100B increasing from 0.108 µg/l (95 % CI 0.092-0.125) to 0.216 µg/l (95 % CI 0.165-0.267) at high altitude].
In conclusion, an increase in plasma S100B was not observed in the second ascent and this may relate to the effect of acclimatisation (or hypoxic pre-conditioning) on the BBB. An exercise stimulated elevation of plasma S100B levels was also not observed during the second ascent. The small sample size and wide confidence intervals, however, precludes any statistically significant conclusions and a larger study would be required to confirm these findings.
BMC Neurol. 2016 Jun 17;16:93. doi: 10.1186/s12883-016-0614-3.
Kinetic modelling of serum S100b after traumatic brain injury.
An understanding of the kinetics of a biomarker is essential to its interpretation. Despite this, little kinetic modelling of blood biomarkers can be found in the literature. S100b is an astrocyte related marker of brain injury used primarily in traumatic brain injury (TBI). Serum levels are expected to be the net result of a multi-compartmental process. The optimal sample times for TBI prognostication, and to follow injury development, are unclear. The purpose of this study was to develop a kinetic model to characterise the temporal course of serum S100b concentration after primary traumatic brain injury.
Data of serial serum S100b samples from 154 traumatic brain injury patients in a neurointensive care unit were retrospectively analysed, including only patients without secondary peaks of this biomarker. Additionally, extra-cranial S100b can confound samples earlier than 12 h after trauma and were therefore excluded. A hierarchical, Bayesian gamma variate kinetic model was constructed and the parameters estimated by Markov chain Monte Carlo sampling.
We demonstrated that S100b concentration changes dramatically over timescales that are clinically important for early prognostication with a peak at 27.2 h (95 % credible interval [25.6, 28.8]). Baseline S100b levels was found to be 0.11 μg/L (95 % credible interval [0.10, 0.12]).
Even small differences in injury to sample time may lead to marked changes in S100b during the first days after injury. This must be taken into account in interpretation. The model offers a way to predict the peak and trajectory of S100b from 12 h post trauma in TBI patients, and to identify deviations from this, possibly indicating a secondary event. Kinetic modelling, providing an equation for the peak and projection, may offer a way to reduce the ambiguity in interpretation of, in time, randomly sampled acute biomarkers and may be generally applicable to biomarkers with, in time, well defined hits.
J Clin Neurosci. 2017 Jan;35:104-108. doi: 10.1016/j.jocn.2016.09.006. Epub 2016 Sep 30.
Elevation of oxidative stress indicators in a pilot study of plasma following traumatic brain injury.
Traumatic brain injury (TBI) encompasses a broad range of injury mechanisms and severity. A detailed determination of TBI severity can be a complex challenge, with current clinical tools sometimes insufficient to tailor a clinical response to a spectrum of patient needs. Blood biomarkers of TBI may supplement clinical assessments but currently available biomarkers have limited sensitivity and specificity. While oxidative stress is known to feature in damage mechanisms following TBI, investigation of blood biomarkers of oxidative stress has been limited. This exploratory pilot study of a subset of 18 trauma patients with TBI of varying severity, quantifies circulating concentrations of the structural damage indicators S100b, and myelin basic protein (MBP), and the biomarkers of oxidative stress hydroxynonenal (HNE), malondialdehyde (MDA), carboxy-methyl-lysine (CML), and 8-hydroxy-2'-deoxy-guanosine (8-OHDG). Significant increases in circulating S100b, MBP, and HNE were observed in TBI patient samples compared to 8 uninjured controls, and there was a significant decrease in CML. This small exploratory study supports the current literature on S100b and MBP elevation in TBI, and reveals potential for the use of peripheral oxidative stress markers to assist in determination of TBI severity. Further investigation is required to validate results and confirm trends.
Neurol Res. 2016 Apr;38(4):327-32. doi: 10.1080/01616412.2016.1152675. Epub 2016 Mar 24.
S100β as a biomarker for differential diagnosis of intracerebral hemorrhage and ischemic stroke.
To explore the efficacy of S100 calcium-binding protein B (S100β) in differentiating between intracerebral hemorrhage (ICH) and ischemic stroke (IS).
From June 2014 to July 2015, 46 ICH and 71 IS patients who had undergone computed tomography (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.
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.
S100β could serve as a potential biomarker for differentiating between ICH and IS and predicting short-term functional outcome after ICH.
Neurol Res. 2016 Feb;38(2):130-7. doi: 10.1080/01616412.2016.1144410. Epub 2016 Mar 4.
S100B and Neuron-Specific Enolase as mortality predictors in patients with severe traumatic brain injury.
To determine temporal profile and prognostic ability of S100B protein and neuron-specific enolase (NSE) for prediction of short/long-term mortality in patients suffering from severe traumatic brain injury (sTBI).
Ninety-nine patients with sTBI were included in the study. Blood samples were drawn on admission and on subsequent 24, 48, 72, and 96 h.
15.2% of patients died in NeuroCritical Care Unit, and 19.2% died within 6 months of the accident. S100B concentrations were significantly higher in patients who died compared to survivors. NSE levels were different between groups just at 48 h. In the survival group, S100B levels decreased from 1st to 5th sample (p < 0.001); NSE just from 1st to 3rd (p < 0.001) and then stabilized. Values of S100B and NSE in non-survival patients did not significantly vary over the four days post sTBI. ROC-analysis showed that all S100B samples were useful tools for predicting mortality, the best the 72 h sample (AUC 0.848 for discharge mortality, 0.855 for six-month mortality). NSE ROC-analysis indicated that just the 48-h sample predicted mortality (AUC 0.733 for discharge mortality, 0.720 for six-month mortality).
S100B protein showed higher prognostic capacity than NSE to predict short/long-term mortality in sTBI patients.
BMC Neurol. 2016 Oct 20;16(1):200.
The addition of S100B to guidelines for management of mild head injury is potentially cost saving.
Mild traumatic brain injury (TBI) is associated with substantial costs due to over-triage of patients to computed tomography (CT) scanning, despite validated decision rules. Serum biomarker S100B has shown promise for safely omitting CT scans but the economic impact from clinical use has never been reported. In 2007, S100B was adapted into the existing Scandinavian management guidelines in Halmstad, Sweden, in an attempt to reduce CT scans and save costs.
Consecutive adult patients with mild TBI (GCS 14-15, loss of consciousness and/or amnesia), managed with the aid of S100B, were prospectively included in this study. Patients were followed up after 3 months with a standardized questionnaire. Theoretical and actual cost differences were calculated.
Seven hundred twenty-six patients were included and 29 (4.7 %) showed traumatic abnormalities on CT. No further significant intracranial complications were discovered on follow-up. Two hundred twenty-nine patients (27 %) had normal S100B levels and 497 patients (73 %) showed elevated S100B levels. Over-triage occurred in 73 patients (32 %) and under-triage occurred in 39 patients (7 %). No significant intracranial complications were missed. The introduction of S100B could save 71 € per patient if guidelines were strictly followed. As compliance to the guidelines was not perfect, the actual cost saving was 39 € per patient.
Adding S100B to existing guidelines for mild TBI seems to reduce CT usage and costs, especially if guideline compliance could be increased.
Ann Vasc Surg. 2016 Oct;36:175-181. doi: 10.1016/j.avsg.2016.02.044. Epub 2016 Jul 6.
Perioperative Embolization Load and S-100β Do Not Predict Cognitive Outcome after Carotid Revascularization.
Cognitive changes after carotid revascularization have been reported in 10-20% of patients. The etiology of cognitive impairments remains largely unknown. This study evaluates the predictive value of S-100β serum values and perioperative microembolization on cognition after carotid revascularization.
Forty-six patients with significant carotid stenosis underwent carotid endarterectomy (CEA, n = 26), transfemoral carotid artery stenting with distal protection (CASdp, n = 10), or transcervical carotid stenting with dynamic flow reversal (CASfr, n = 10). Twenty-six matched vascular patients without carotid stenosis were recruited as controls. All patients underwent comprehensive cognitive testing on the day before and 1 month after carotid revascularization. S-100β analysis was performed in 31 cases pre-, peri-, and 2, 6, and 24 hr after carotid surgery, and in 25 patients transcranial Doppler monitoring was done during surgery.
In the 3 treatment groups similar transient increases in S-100β values were observed. CASdp was associated with a higher embolic load than CEA and CASfr, while CEA was also associated with less microembolization than CASfr. Cognitive improvement or deterioration could not be predicted by S-100β or perioperative embolic load for any of the investigated cognitive domains.
Cognitive deterioration could not be predicted using perioperative embolic load and S-100β changes. A similar inverted u-curve of the S-100β levels was observed in the 3 groups and may be caused by impairment in the blood-brain barrier during intervention, and not due to cerebral infarction. Distal protection CAS is associated with a higher embolic load than transcervical CAS using dynamic flow reversal and CEA, but the long-term impact of this higher embolic load is yet unknown. Perfusion-related measures seem promising in their ability to predict cognitive decline.
Fluids Barriers CNS. 2016 Nov 30;13(1):21.
Improving the clinical management of traumatic brain injury through the pharmacokinetic modeling of peripheral blood biomarkers.
Blood biomarkers of neurovascular damage are used clinically to diagnose the presence severity or absence of neurologicaldiseases, but data interpretation is confounded by a limited understanding of their dependence on variables other than the disease condition itself. These include half-life in blood, molecular weight, and marker-specific biophysical properties, as well as the effects of glomerular filtration, age, gender, and ethnicity. To study these factors, and to provide a method for markers' analyses, we developed a kinetic model that allows the integrated interpretation of these properties.
The pharmacokinetic behaviors of S100B (monomer and homodimer), Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase L1 were modeled using relevant chemical and physical properties; modeling results were validated by comparison with data obtained from healthy subjects or individuals affected by neurological diseases. Brain imaging data were used to model passage of biomarkers across the blood-brain barrier.
Our results show the following: (1) changes in biomarker serum levels due to age or disease progression are accounted for by differences in kidney filtration; (2) a significant change in the brain-to-blood volumetric ratio, which is characteristic of infant and adult development, contributes to variation in blood concentration of biomarkers; (3) the effects of extracranial contribution at steady-state are predicted in our model to be less important than suspected, while the contribution of blood-brain barrier disruption is confirmed as a significant factor in controlling markers' appearance in blood, where the biomarkers are typically detected; (4) the contribution of skin to the marker S100B blood levels depends on a direct correlation with pigmentation and not ethnicity; the contribution of extracranial sources for other markers requires further investigation.
We developed a multi-compartment, pharmacokinetic model that integrates the biophysical properties of a given brain molecule and predicts its time-dependent concentration in blood, for populations of varying physical and anatomical characteristics. This model emphasizes the importance of the blood-brain barrier as a gatekeeper for markers' blood appearance and, ultimately, for rational clinical use of peripherally-detected brain protein.
J Pak Med Assoc. 2011 Mar;61(3):276-81.
Usefulness of S100B protein in neurological disorders.
In recent years, there has been an increased interest in the clinical use of brain markers. The S100B is a calcium-binding peptide and is used as a parameter of glial activation and/or death in many disorders of the central nervous system (CNS). It plays important roles in normal CNS development and recovery after injury. Although S100B is mainly found in astroglial and Schwann cells, it also has extracerebral sources. S100B is a useful neurobiochemical marker of brain damage such as in circulatory arrest, stroke and traumatic brain injury. S100B is also associated with neurodegenerative diseases like Alzheimer's disease or other chronic neurological diseases. Moreover, S100B may have a potential in predicting the efficiency of treatment and prognosis. In this review, an updated overview of the role of S100B in human neurological disorders is presented.
Life Sci. 2013 May 20;92(17-19):923-8. doi: 10.1016/j.lfs.2013.03.004. Epub 2013 Apr 1.
Brain changes in BDNF and S100B induced by ketogenic diets in Wistar rats.
We investigated the effects of ketogenic diet (KD) on levels of tumor necrosis factor alpha (TNF-α, a classical pro-inflammatory cytokine), BDNF (brain-derived neurotrophic factor, commonly associated with synaptic plasticity), and S100B, an astrocyte neurotrophic cytokine involved in metabolism regulation.
Young Wistar rats were fed during 8 weeks with control diet or two KD, containing different proportions of omega 6 and omega 3 polyunsaturated fatty acids. Contents of TNF-α, BDNF and S100B were measured by ELISA in two brain regions (hippocampus and striatum) as well as blood serum and cerebrospinal fluid.
Our data suggest that KD was able to reduce the levels of BDNF in the striatum (but not in hippocampus) and S100B in the cerebrospinal fluid of rats. These alterations were not affected by the proportion of polyunsaturated fatty acids offered. No changes in S100B content were observed in serum or analyzed brain regions. Basal TNF-α content was not affected by KD.
These findings reinforce the importance of this diet as an inductor of alterations in the brain, and such changes might contribute to the understanding of the effects (and side effects) of KD in brain disorders.
Prog Neuropsychopharmacol Biol Psychiatry. 2010 Dec 1;34(8):1433-9. doi: 10.1016/j.pnpbp.2010.07.033. Epub 2010 Aug 20.
Differential regulation of neurotrophin S100B and BDNF in two rat models of depression.
Several clinical studies have demonstrated that serum brain-derived neurotrophic factor (BDNF) levels are decreased and serum S100B levels are increased in patients with major depression. In this study, we investigated whether these findings could be replicated in animal models of depression.
We measured BDNF and S100B protein levels in the serum, prefrontal cortex, striatum and hippocampus of rats in models of depression, i.e., olfactory bulbectomy (OBX) and chronic unpredictable stress (CUS) models. Serum BDNF levels were significantly increased in the OBX rats, as were hippocampal BDNF levels in the CUS rats, in comparison with their respective controls. Significant increases in serum S100B levels were observed in both the OBX and CUS rats as compared with their respective controls; however, S100B levels were decreased in the prefrontal cortex of the CUS rats. No significant correlation was found between serum and regional brain S100B/BDNF levels.
Our findings suggest that both of these animal models of depression, in which similar serum S100B level changes to those in depressed patients were observed, could be used as valid models to explore the role of S100B underlying major depression. Neither serum S100B nor BDNF levels reflect their levels in the brain, and changes in their levels in patients with neuropsychiatric diseases should be interpreted cautiously.
Neurosci Res. 2004 Dec;50(4):375-9.
Ketogenic diet fed rats have low levels of S100B in cerebrospinal fluid.
Ketogenic diets have been used to treat seizure disorders of children resistant to conventional anti-epileptic drug treatment. The mechanism of action of this diet, however, is unknown. Gliosis is a very common characteristic in tissues associated with epileptogenesis and glial cytokines may be involved in the pathology of seizure disorders. We investigate herein, whether ketogenic diet fed rats demonstrate changes in the immunocontent of S100B, an astrocyte-derived cytokine elevated in the temporal lobe of refractory epilepsy. Lower levels of S100B were observed in cerebrospinal fluid with no significant changes in S100B and GFAP content in brain tissue.
Ketogenic fed rats presented a lower seizure severity induced by pentylenetetrazole and no change in cerebrospinal fluid S100B after pentylenetetrazole administration. These results support the concept that the ketogenic diet is neuroprotective in seizure disorders. Since S100B has an extracellular activity in neuronal excitability and synaptic plasticity, it would be reasonable to conceive that a decrease in the S100B could be involved in the mechanism of action of the ketogenic diet. However, it is not possible to establish a direct link between reduced CSF S100B and decreased severity of PTZ-induced attacks at present moment. Regardless of this, CSF S100B could be proposed as an index of efficacy of ketogenic diet for seizure disorders.
J Cardiothorac Vasc Anesth. 2011 Dec;25(6):908-16. doi: 10.1053/j.jvca.2011.06.017. Epub 2011 Aug 25.
Preconditioning with repeated hyperbaric oxygen induces myocardial and cerebral protection in patients undergoing coronary artery bypass graft surgery: a prospective, randomized, controlled clinical trial.
To evaluate the cerebral and myocardial protective effects of hyperbaric oxygen preconditioning in both on-pump and off-pump coronary artery bypass graft surgery.
A prospective, randomized, single-blinded study including patients scheduled for elective on-pump or off-pump surgery between December 2007 and February 2009.
A tertiary care university teaching hospital.
Forty-nine elective on-pump or off-pump coronary artery bypass graft surgery patients.
Patients were randomized to either the control (15 patients with on-pump procedure and 10 patients with off-pump procedure, respectively) or hyperbaric oxygen (HBO; 14 patients with on-pump procedure and 10 patients with off-pump procedure, respectively) groups. Patients in the HBO groups underwent preconditioning for 5 days before surgery.
MEASUREMENTS AND MAIN RESULTS:
On-pump coronary artery bypass graft surgery patients preconditioned with HBO had significant decreases in S100B protein, neuron-specific enolase, and troponin I perioperative serum levels compared with the on-pump control group. Postsurgically, patients in the on-pump HBO group had a reduced length of stay in the intensive care unit and a decreased use of inotropic drugs. Serum catalase activity 24 hours postoperatively was significantly increased compared with the on-pump control group. In the off-pump groups, there was no difference in any of the same parameters.
Preconditioning with HBO resulted in both cerebral and cardiac protective effects as determined by biochemical markers of neuronal and myocardial injury and clinical outcomes in patients undergoing on-pump coronary artery bypass graft surgery. No protective effects were noted in off-pump coronary artery bypass graft surgery.
Crit Care Med. 2006 Aug;34(8):2228-30.
S100B protein in conscious carbon monoxide-poisoned rats treated with normobaric or hyperbaric oxygen.
To evaluate S100B, an astroglial structural protein, during normobaric and hyperbaric oxygen therapy of conscious carbon monoxide (CO)-poisoned rats. So far, the usefulness of hyperbaric oxygen therapy in conscious CO-poisoned patients has been shown with neuropsychological testing. The S100B protein has been demonstrated as a possible biochemical marker and prognostic parameter in CO-poisoned rats.
Randomized, controlled interventional trial.
: Male Wistar rats weighing 254 +/- 14 g.
The rats were exposed to a mixture of 3,000 ppm CO in air for 60 mins. After CO exposure, the first group of eight conscious rats was exposed to ambient air for 30 mins, the second group of six conscious rats was exposed to 100% normobaric oxygen for 30 mins, and the third group of six conscious rats was exposed to 100% hyperbaric oxygen at 3 bars for 30 mins. Blood samples were taken from the jugular vein just before CO exposure and immediately after oxygen therapy. The level of consciousness was evaluated at the end of exposure, and the survival rate was monitored for 14 days. The S100B concentrations were measured with a commercial immunoluminometric assay.
MEASUREMENTS AND MAIN RESULTS:
Analyses of differences in S100B levels between different kinds of therapy before and after treatment showed a global significant difference (p = .002). The post hoc test results showed that S100B levels after therapy of the first group treated with ambient air (0.16 +/- 0.07 microg/L) and the second group treated with normobaric oxygen (0.19 +/- 0.05 microg/L) were similar (p = .741), and both of them were significantly different, with much higher values of S100B levels after therapy, from the third group treated with hyperbaric oxygen (0.06 +/- 0.03 microg/L; p = .018 and p = .002, respectively). All the rats survived.
S100B is elevated in conscious CO-poisoned rats left on ambient air or treated with normobaric oxygen, but not in conscious CO-poisoned rats treated with hyperbaric oxygen.