Assessment of non-BDNF neurotrophins and GDNF levels after depression treatment with sertraline and transcranial direct current stimulation in a factorial, randomized, sham-controlled trial (SELECT-TDCS): an exploratory analysis.

The neurotrophic hypothesis of depression states that the major depressive episode is associated with lower neurotrophic factors levels, which increase with amelioration of depressive symptoms. However, this hypothesis has not been extended to investigate neurotrophic factors other than the brain-derived neurotrophic factor (BDNF). We therefore explored whether plasma levels of neurotrophins 3 (NT-3) and 4 (NT-4), nerve growth factor (NGF) and glial cell line derived neurotrophic factor (GDNF) changed after antidepressant treatment and correlated with treatment response. Seventy-three patients with moderate-to-severe, antidepressant-free unipolar depression were assigned to a pharmacological (sertraline) and a non-pharmacological (transcranial direct current stimulation, tDCS) intervention in a randomized, 2 × 2, placebo-controlled design. The plasma levels of NT-3, NT-4, NGF and GDNF were determined by enzyme-linked immunosorbent assay before and after a 6-week treatment course and analyzed according to clinical response and allocation group. We found that tDCS and sertraline (separately and combined) produced significant improvement in depressive symptoms. Plasma levels of all neurotrophic factors were similar across groups at baseline and remained significantly unchanged regardless of the intervention and of clinical response. Also, baseline plasma levels were not associated with clinical response. To conclude, in this 6-week placebo-controlled trial, NT-3, NT-4, NGF and GDNF plasma levels did not significantly change with sertraline or tDCS. These data suggest that these neurotrophic factors are not surrogate biomarkers of treatment response or involved in the antidepressant mechanisms of tDCS.

Assessment of serum S100B and neuron specific enolase levels to evaluate the neurotoxic effects of organic solvent exposure.

OBJECTIVES: Long-term organic solvent exposure may cause toxic effects in central nervous system . Trichloroethylene (TCE) is known to be one of the neurotoxic chlorinated organic solvents. Trichloroacetic acid (TCA) is an oxidative pathway metabolite of TCE. S100B, a calcium-binding protein in glial cells, and neuron specific enolase (NSE) in neuron cytoplasma are protein markers of astrocyte and neuron damage, respectively. MATERIALS AND METHODS: Clinical and laboratory assesments were performed in 25 participants with organic solvent exposure history. Control group included 25 healthy age and sex-matched individuals. Measurements of serum S100B and NSE were performed using Roche Cobas E 601 compatible kits and elechtrochemiluminescence immunoassay. The levels of TCA in urine were measured by the headspace GC technique, after methyl esterification by methanol. RESULTS: Median value of urine TCA in solvent-exposed group was 12.30 mg/L with 10.20 mg/L and 35.00 mg/L minimum and maximum values, respectively. The difference between serum S100B levels of solvent-exposed group (0.064 µg/L) and control group (0.049 µg/L) was statistically significant (p < 0.05). Serum NSE levels of control group (15.61 ng/ml) were higher than solvent-exposed group (13.90 ng/ml) but difference was not statistically significant (p > 0.05). CONCLUSIONS: Serum S100B levels were found to be higher in solvent-exposed group when compared with control group. NSE levels were comparable between two groups. Increased Serum S100B levels in organic solvent exposure may indicate a preventive response to neuronal damage caused by reactive oxygen species (ROS) produced through oxidative metabolic pathways of organic solvents.

Serum S100B determination in the management of pediatric mild traumatic brain injury.

BACKGROUND: The place of serum S100B measurement in mild traumatic brain injury (mTBI) management is still controversial. Our prospective study aimed to evaluate its utility in the largest child cohort described to date. METHODS: Children younger than 16 years presenting at a pediatric emergency department within 3 h after TBI were enrolled prospectively for blood sampling to determine serum S100B concentrations. The following information was collected: TBI severity determined by using the Masters classification [1: minimal or Glasgow Coma Scale (GCS) 15, 2: mild or GCS 13-15, and 3: severe or GCS <13]; whether hospitalized or not; good or bad clinical evolution (CE); whether cranial computed tomography (CCT) was prescribed; and related presence (CCT+) or absence (CCT-) of lesions. RESULTS: For the 446 children enrolled, the median concentrations of S100B were 0.21, 0.31, and 0.44 µg/L in Masters groups 1, 2, and 3, respectively, with a statistically significant difference between these groups (P < 0.05). In Masters group 2, 65 CCT scans were carried out. Measurement of S100B identified patients as CCT+ with 100% (95% CI 85-100) sensitivity and 33% (95% CI 20-50) specificity. Of the 424 children scored Masters 1 or 2, 21 presented "bad CE." S100B identified bad CE patients with 100% (95% CI 84-100) sensitivity and 36% (95% CI 31-41) specificity. Of the 242 children hospitalized, 81 presented an S100B concentration within the reference interval. CONCLUSIONS: Serum S100B determination during the first 3 h of management of children with mTBI has the potential to reduce the number of CCT scans, thereby avoiding unnecessary irradiation, and to save hospitalization costs.

S100-B protein as a screening tool for the early assessment of minor head injury.

STUDY OBJECTIVE: A computed tomography (CT) scan has high sensitivity in detecting intracranial injury in patients with minor head injury but is costly, exposes patients to high radiation doses, and reveals clinically relevant lesions in less than 10% of cases. We evaluate S100-B protein measurement as a screening tool in a large population of patients with minor head injury. METHODS: We conducted a prospective observational study in the emergency department of a teaching hospital (Bordeaux, France). Patients with minor head injury (2,128) were consecutively included from December 2007 to February 2009. CT scans and plasma S100-B levels were compared for 1,560 patients. The main outcome was to evaluate the diagnostic value of the S100-B test, focusing on the negative predictive value and the negative likelihood ratio. RESULTS: CT scan revealed intracranial lesions in 111 (7%) participants, and their median S100-B protein plasma level was 0.46 µg/L (interquartile range [IQR] 0.27 to 0.72) versus 0.22 µg/L (IQR 0.14 to 0.36) in the other 1,449 patients. With a cutoff of 0.12 µg/L, traumatic brain injuries on CT were identified with a sensitivity of 99.1% (95% confidence interval [CI] 95.0% to 100%), a specificity of 19.7% (95% CI 17.7% to 21.9%), a negative predictive value of 99.7% (95% CI 98.1% to 100%), a positive likelihood ratio of 1.24 (95% CI 1.20 to 1.28), and a negative likelihood ratio of 0.04 (95% CI 0.006 to 0.32). CONCLUSION: Measurement of plasma S100-B on admission of patients with minor head injury is a promising screening tool that may be of help to support the clinician's decision not to perform CT imaging in certain cases of low-risk head injury.

Assessment of biocorrelates for brain involvement in female patients with rheumatoid arthritis.

Central nervous system (CNS) abnormalities are rare in patients with rheumatoid arthritis (RA). Direct studies done to investigate brain involvement in RA are few or even absent. We hypothesized that CNS is not excluded from the inflammatory disease process in RA. Thus we systematically investigated markers of brain involvement in 55 females with RA. We examined patients' cognition using battery of sensitive psychometric testing [Mini-Mental State Examination, Stanford-Binet test (fourth edition) and Wechsler Memory Scale-Revised] and by recording P300 component of event-related potentials, a neurophysiological analogue. We also measured the serum levels of S100B and neuron-specific enolase (NSE), markers of glial and neuronal cells. Compared to control subjects, lower scores in cognitive testing were reported in 71% of the patients (n=39) and abnormal P300 latency and amplitude (P<0.001, 0.050). Patients had higher levels of S100B (P<0.029) and higher levels of S100B were correlated with lower total scores of cognitive functions (P<0.01), P300 latency (P<0.05), and NSE concentrations (P<0.01). However, cognitive scores did not correlate with disease activity or severity. Although depression scores were significant in patients with RA (P<0.001), but they did not correlate with cognitive scores. Seven patients had white matter hyperintensities in MRI brain suggesting vasculitis, ischemic brain lesions and dots of demyelination, and all had higher levels of S100B. Results of this study directly indicate that the disease process (inflammation and demyelination) is associated with cognitive deficits observed with RA.

Functional assessment of a promoter polymorphism in S100B, a putative risk variant for bipolar disorder.

Calcium-binding protein S100B has been implicated in the pathology of bipolar affective disorder (BPAD) and schizophrenia (SZ). S100B protein levels are elevated in serum of patients with both disorders compared to controls. We previously reported genetic association of a SNP in the promoter of S100B, rs3788266, with a psychotic form of BPAD. To test for genotypic effects of rs3788266 in vivo, S100B serum protein levels were measured in 350 Irish and German subjects of known S100B genotype. The functional effect of rs3788266 on S100B promoter activity was studied using the luciferase reporter system in U373MG glioblastoma and SH-SY5Y neuroblastoma cell lines. Allelic effects of rs3788266 on protein complex formation at the S100B promoter were investigated by an electrophoretic mobility shift assay. Higher mean serum S100B levels were associated with the risk G allele of rs3788266 in BPAD cases (P = 0.0001), unaffected relatives of BPAD cases (P < 0.0001) and unrelated controls (P < 0.0001). Consistent with the in vivo findings, luciferase gene expression was significantly increased in the presence of the G allele compared to the A allele in SH-SY5Y (P = <0.0001), and in U373MG (P = <0.0008) cell lines. The binding affinity of both SH-SY5Y and U373MG protein complexes for the S100B promoter was significantly stronger in the presence of G allele compared to the A allele promoter fragments. These data support rs3788266 as a functional promoter variant in the S100B gene where the presence of the G allele promotes increased gene expression and is associated with increased serum levels of the protein.

S100b immunoassay: an assessment of diagnostic utility in minor head trauma.

BACKGROUND: Over 1.4 million patients present annually to United States (US) emergency departments with minor head trauma. Many undergo unnecessary head computed tomography (HCT). OBJECTIVES: We sought to determine the diagnostic accuracy of S100B, a central nervous system peptide, to screen for HCT+ head injury. METHODS: This study was a prospective observational study of adults with minor head trauma. Patients presenting within 6h of injury and undergoing HCT for evaluation were eligible. All HCTs were blindly reviewed for presence of a priori defined intracranial injury (HCT+). Quantitative S100B levels were determined by enzyme-linked immunosorbent assay. RESULTS: A total of 346 patients were enrolled over 12 months, mean age 48 years (± 23 years), 62% male. Twenty-two (6.4%) were HCT+. Vomiting, headache, anterograde amnesia, Glasgow Coma Scale score<15, nausea, and loss of consciousness were associated with HCT+ results. Median S100B levels were significantly elevated in HCT+ (115 ng/dL) vs. HCT- (56.0 ng/dL) patients (p=0.032). Receiver operator characteristic analysis demonstrated an area under the curve of 0.643. Sensitivity and specificity were 86% (95% confidence interval [CI] 67-96) and 37% (95% CI 29-45%) at 42 ng/dL, 91% (95% CI 72-98%) and 24% (95% CI 17-31%) at 32 ng/dL, and 96% (95% CI 78-100%) and 13% (95% CI 9-20%) at 24 ng/dL, respectively. CONCLUSION: The study demonstrates that S100B may be a sensitive but non-specific marker of HCT+ injury.

The economic impact of S-100B as a pre-head CT screening test on emergency department management of adult patients with mild traumatic brain injury.

Recent research suggests that serum S-100B may serve as a good pre-head computed tomography (CT) screening test because of its high sensitivity for abnormal head CT scans. The potential economic impact of using S-100B in the emergency department setting for management of adult patients with isolated mild traumatic brain injury (mTBI) has not been evaluated despite its clinical implementation in Europe. Using evidence from the literature, we constructed a decision tree to compare the average cost per patient of using S-100B as a pre-head CT screening test to the current practice of ordering CT scans based on patients' presenting symptoms without the aid of S-100B. When compared to scanning 45-77% of isolated mTBI patients based upon their presenting symptoms, using S-100B as a pre-head CT screen does not lower hospital costs ($281 versus $160), primarily due to its low specificity for abnormal head CT scans. Sensitivity analyses showed, however, that S-100B becomes cost-lowering when the proportion of mTBI patients being scanned exceeds 78%, or when final CT scan results require 96 min or more than the wait for blood test results. Generally speaking, if blood test results require less time than imaging, and if head CT scan rates for patients with isolated mTBI are relatively high, using S-100B will lower costs. Recommendations for using S-100B as a screening tool should account for setting-specific characteristics and their consequent economic impacts. Despite its high sensitivity and excellent negative predictive value, serum S-100B has low specificity and low positive predictive value, limiting its ability to reduce numbers of CT scans and hospital costs.

[Brain injury marker S100B can reduce the use of computer tomography in minor head injuries--secondary publication]. / Hjerneskademarkøren S100B kan mindske brugen af computertomografi ved lette hovedtraumer--sekundaerpublikation.

The risk of acute intracranial complications after minor head injury (MHI) is low. Despite this, computed tomography (CT) is generally recommended with clinical observation as a secondary option. Both options have disadvantages. Clinical studies have shown the potential advantages of using the biomarker S100B. The specificity of S100B is low, but a high sensitivity for brain damage results in a clinically useful, high negative predictive value (NPV). Integration of S100B into existing management routines can reduce the need for CT scans or admission by over 30%.

Clinical usefulness of a biomarker-based diagnostic test for acute stroke: the Biomarker Rapid Assessment in Ischemic Injury (BRAIN) study.

BACKGROUND AND PURPOSE: One of the significant limitations in the evaluation and management of patients with suspected acute cerebral ischemia is the absence of a widely available, rapid, and sensitive diagnostic test. The objective of the current study was to assess whether a test using a panel of biomarkers might provide useful diagnostic information in the early evaluation of stroke by differentiating patients with cerebral ischemia from other causes of acute neurological deficit. METHODS: A total of 1146 patients presenting with neurological symptoms consistent with possible stroke were prospectively enrolled at 17 different sites. Timed blood samples were assayed for matrix metalloproteinase 9, brain natriuretic factor, d-dimer, and protein S100beta. A separate cohort of 343 patients was independently enrolled to validate the multiple biomarker model approach. RESULTS: A diagnostic tool incorporating the values of matrix metalloproteinase 9, brain natriuretic factor, d-dimer, and S-100beta into a composite score was sensitive for acute cerebral ischemia. The multivariate model demonstrated modest discriminative capabilities with an area under the receiver operating characteristic curve of 0.76 for hemorrhagic stroke and 0.69 for all stroke (likelihood test P<0.001). When the threshold for the logistic model was set at the first quartile, this resulted in a sensitivity of 86% for detecting all stroke and a sensitivity of 94% for detecting hemorrhagic stroke. Moreover, results were reproducible in a separate cohort tested on a point-of-care platform. CONCLUSIONS: These results suggest that a biomarker panel may add valuable and time-sensitive diagnostic information in the early evaluation of stroke. Such an approach is feasible on a point-of-care platform. The rapid identification of patients with suspected stroke would expand the availability of time-limited treatment strategies. Although the diagnostic accuracy of the current panel is clearly imperfect, this study demonstrates the feasibility of incorporating a biomarker based point-of-care algorithm with readily available clinical data to aid in the early evaluation and management of patients at high risk for cerebral ischemia.

Chemotherapy response assessment in stage IV melanoma patients-comparison of 18F-FDG-PET/CT, CT, brain MRI, and tumormarker S-100B.

PURPOSE: This study aims to compare the use of 18F-FDG-PET/CT, CT, brain MRI, and tumormarker S-100B in chemotherapy response assessment of stage IV melanoma patients. METHODS: In 25 patients with stage IV melanoma, FDG-PET/CT and S-100B after 2-3 months (three cycles) of chemotherapy was compared with baseline PET/CT and baseline S-100B. Retrospectively, the response was correlated with the outcome. In patients with clinical suspicion for brain metastases, MRI or CCT was performed. RESULTS: There was agreement between FDG-PET/CT and CT regarding response to chemotherapy in all patients. There was a clear trend to a longer OS of PET/CT responders (n=10) compared with PET/CT non-responders (n=15; p=0.072) with remarkably better 1-year OS of 80% compared to 40% (p=0.048). There was a significant longer PFS of PET/CT responders compared with PET/CT non-responders (p=0.002). S-100B was normal at baseline in eight of 22 patients where it was available. Chemotherapy response assessment with S-100B failed to show correlation with OS or PFS. Eleven patients developed brain metastases during treatment, first detected by PET/CT in two and by MRI or CCT in nine of 11 patients. Appearance of brain metastases was associated with a poor survival. CONCLUSIONS: 18F-FDG-PET/CT and CT alone are equally suitable for chemotherapy response assessment in melanoma patients and clearly superior to S-100B. PET/CT responders have better early survival, but this is shortlived due to late therapy failure--often with brain recurrence. Additional brain MRI for therapy response assessment in such high-risk patients is mandatory to detect brain metastases missed by PET/CT.

[Evaluation of relevance in concussion and damage of health by monitoring of neuron specific enolase and S-100b protein]. / Hodnocení závaznosti otresu mozku a poruchy zdraví pomocí monitorování hladin neuron specifické enolázy a proteinu S-100b v séru.

INTRODUCTION: Proteins released to the circulation from affected glial (neuron specific enolasis, NSE) or ganglial cells (S-100b protein) during traumatic brain injury might be used in diagnosis of traumatic brain injury in cases with negative finding on computer tomography scan (concussion) or in patients where the serious clinical status does not corresponde with mild changes on CT scan (diffuse axonal injury, DAI). Classification of DAI according Gennarelli considered the concussion as lower degree of DAI. MATERIALS AND METHOD: 15 patients were divided into group I of mild conccussion (n=3) with 1-day duration of hospitalisation, group II of serious concussion (n=4) with more days duration of hospitalisation with negative findings on CT scan and group III of patients with diagnosis of DAI (n=8). Blood samples were investigated by immunoanalysis for NSE and protein S-100b (Elecsys 2010, Roche). RESULTS: Values of NSE (16.30 +/- 2.33 vs. 110.48 +/- 34.99 vs. 24.07 +/- 6.29 microg/l), and protein S-100b (0.207 +/- 0.03 vs. 0.945 +/- 0.69 vs. 0.736 +/- 0.36 microg/l) overdrow the reference value in cases of group I, II, and III. We discuss the biomechanics of trauma and the blood brain barrier damage in comparison with values of NSE and S-100b protein. CONCLUSION: [corrected] We proved the significantly higher values of the NSE in group of serious concussion compared to group of DAI. We demonstrated that concussions in some cases lead to serious damage of health.

S-100B and FDG-PET/CT in therapy response assessment of melanoma patients.

OBJECTIVE: To compare the value of the tumor marker S-100B protein and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in patients treated for melanoma metastases. METHODS: In 41 patients with proven melanoma metastases, S-100B measurements and FDG-PET/CT were performed before and after therapy. The change of S-100B levels (DeltaS-100B) was assessed. In all patients, therapy response was assessed with PET/CT using visual criteria and change of maximal standard uptake value (DeltaSUV(max.)) or total lesion glycolysis (DeltaTLG). RESULTS: In 15 of 41 patients (37%), S-100B values were not suitable because they were normal before and after therapy. In 26 patients, S-100B was suitable for therapy response assessment. PET/CT was suitable for response assessment in all patients. Correlations between DeltaS-100B and DeltaTLG (r = 0.850, p < 0.001) and between DeltaS-100B and DeltaSUV(max.) (r = 0.818, p < 0.001) were both excellent. A complete agreement between S-100B and PET/CT response assessment was achieved in 22 of 26 patients. In 4 patients, therapy response differed between the S-100B and PET/CT findings, but subsequent S-100B measurements realigned the S-100B results with the later PET/CT findings. CONCLUSION: In a third of our patients with metastases, the S-100B tumor marker was not suitable for therapy assessment. In these patients, imaging techniques remain necessary, and FDG-PET/CT can be used for response assessment.

Tei index for prenatal diagnosis of acute fetal hypoxia due to intermittent umbilical cord occlusion in an animal model.

OBJECTIVE: To study the effectiveness of the pulsatility index for veins of ductus venosus (DV-PIV) and the Tei index in a prospective assessment of fetal hypoxic-ischemic brain damage in a near-term ovine fetus model with intermittent umbilical cord occlusion (UCO). METHODS: Twelve fetal sheep were studied with umbilical cord occlusion performed in the experimental group animals by complete inflation of an occluder cuff for 90 s, every 30 min for approximately 2.5 h. Fetal arterial blood was sampled at 5 min before the first umbilical cord occlusions, approximately 60 s of the first umbilical cord occlusions, and 3 min after each occlusion for blood gas, pH, neuron-specific enolase (NSE) and S100B. Doppler measurements and Doppler echocardiographic examinations were performed 5 min before the first umbilical cord occlusions and 3 min after each successive occlusion. RESULTS: In experimental group animals, UCO caused a large decline in arterial PaO(2) (to approximately 7.70 mmHg, p < 0.01), a modest decline in pH (to approximately 7.24, p < 0.01), and a modest rise in PaCO(2) (to approximately 53.31 mmHg, p < 0.01), with a return more or less to baseline after occluder release. and there was significant change as compared with the control animals (all p < 0.01) with cumulative changes in responses to repetitive cord occlusions. The DV-PIV waveforms, right ventricle (RV) and LV Tei indices, the serum levels of NSE and S100B increased with cord occlusions (all p < 0.05), and were significantly higher than the control animals (all p < 0.05) with a cumulative changes in responses to repetitive cord occlusions. RV and LV Tei indices were significantly correlated with PaO(2) (r = - 0.684, p < 0.01 and r = - 0.725, p < 0.01), PaCO(2) (r = 0.682, p < 0.01 and r = 0.780, p < 0.01), pH (r = - 0.538, p < 0.01 and r = - 0.681, p < 0.01), NSE (r = 0.653, p < 0.01 and r = 0.687, p < 0.01), and S100B (r = 0.606, p < 0.01 and r = 0.640, p < 0.01). Significant but weaker correlations were also present between DV-PIV and the parameters considered. CONCLUSION: Umbilical cord occlusion during the latter part of the pregnancy, enough to cause significant hypoxemia and acidosis, results in a significant increase of DV-PIV, RV and LV Tei indices, and the serum levels of NSE and S100B. There was a strong correlation between the RV and LV Tei indices and blood gas, pH, and NSE, S100B with hypoxia. Therefore, the Tei index might be an easy and useful quantitative parameter for assessing fetal hypoxic ischemia.

Assessment of cerebral S100B levels by proton magnetic resonance spectroscopy after lateral fluid-percussion injury in the rat.

OBJECT: After traumatic brain injury (TBI), S100B protein is released by astrocytes. Furthermore, cerebrospinal fluid (CSF) and serum S100B levels have been correlated to outcome. Given that no data exist about the temporal profile of cerebral S100B levels following TBI and their correlation to serum levels, the authors examined whether proton magnetic resonance (MR) spectroscopy is capable of measuring S100B. METHODS: Results of in vitro proton MR spectroscopy experiments (2.35-tesla magnet, 25 G/cm, point-resolved spatially localized spectroscopy) revealed an Sl00B-specific peak at 4.5 ppm and confirmed a positive correlation between different S100B concentrations (10 nM-1 microM) and the area under the curve (AUC) for the S100B peak (r = 0.991, p < 0.001). Thereafter, proton MR spectroscopy was performed in male Sprague-Dawley rats (7 X 5 X 5-mm voxel in each hemisphere, TR 3000 msec, TE 30 msec, 256 acquisitions). Exogenously increased CSF S100B levels (approximately 200 ng/ml) through the intraventricular infusion of S100B increased the AUC of the S100B peak from 0.06 +/- 0.02 to 0.44 +/- 0.06 (p < 0.05), whereas serum S100B levels remained normal. Two hours after lateral fluid-percussion injury, serum S100B levels increased to 0.61 +/- 0.09 ng/ml (p < 0.01) and rapidly returned to normal levels, whereas the AUC of the S100B peak increased to 0.19 +/- 0.04 at 2 hours postinjury and 0.41 +/- 0.07 (p < 0.05) on Day 5 postinjury. CONCLUSIONS: Proton MR spectroscopy proves a strong correlation between the AUC of the S100B peak and S100B concentrations. Following experimental TBI, serum S100B levels increased for only a very short period, whereas cerebral S100B levels were increased up to Day 5 postinjury. Given that experimental data indicate that S100B is actively released following TBI, proton MR spectroscopy may represent a new tool to identify increased cerebral S100B levels in patients after injury, thus allowing its biological function to be better understood.