Influence of Blood-Brain Barrier Integrity on Brain Protein Biomarker Clearance in Severe Traumatic Brain Injury: A Longitudinal Prospective Study.

Brain protein biomarker clearance to blood in traumatic brain injury (TBI) is not fully understood. The aim of this study was to analyze the effect that a disrupted blood-brain barrier (BBB) had on biomarker clearance. Seventeen severe TBI patients admitted to Karolinska University Hospital were prospectively included. Cerebrospinal fluid (CSF) and blood concentrations of S100 calcium binding protein B (S100B) and neuron-specific enolase (NSE) were analyzed every 6-12 h for ∼1 week. Blood and CSF albumin were analyzed every 12-24 h, and BBB integrity was assessed using the CSF:blood albumin quotient (QA). We found that time-dependent changes in the CSF and blood levels of the two biomarkers were similar, but that the correlation between the biomarkers and QA was lower for NSE (ρ = 0.444) than for S100B (ρ = 0.668). Because data were longitudinal, we also conducted cross correlation analyses, which indicated a directional flow and lag-time of biomarkers from CSF to blood. For S100B, this lag-time could be ascribed to BBB integrity, whereas for NSE it could not. Upon inferential modelling, using generalized least square estimation (S100B) or linear mixed models (NSE), QA (p = 0.045), time from trauma (p < 0.001), time from trauma2 (p = 0.023), and CSF biomarker levels (p = 0.008) were independent predictors of S100B in blood. In contrast, for NSE, only time from trauma was significant (p < 0.001). These findings are novel and important, but must be carefully interpreted because of different characteristics between the two proteins. Nonetheless, we present the first data that indicate that S100B and NSE are cleared differently from the central nervous system, and that both the disrupted BBB and additional alternative pathways, such as the recently described glymphatic system, may play a role. This is of importance both for clinicians aiming to utilize these biomarkers and for the pathophysiological understanding of brain protein clearance, but warrants further examination

Secondary insults following traumatic brain injury enhance complement activation in the human brain and release of the tissue damage marker S100B

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.OBJECT: Complement activation has been suggested to play a role in the development of secondary injuries following traumatic brain injury (TBI). The present study was initiated in order to analyze complement activation in relation to the primary brain injury and to secondary insults, frequently occurring following TBI. METHODS: Twenty patients suffering from severe TBI (Glasgow coma score ≤ 8) were included in the study. The "membrane attack complex," C5b9, which is the cytolytic end product of the complement system was analyzed in cerebrospinal fluid (CSF). The degree of brain tissue damage was assessed using the release of S100B and neuron-specific enolase (NSE) to the CSF and blood. The blood-brain barrier was assessed using the CSF/serum quotient of albumin (Q (A)). RESULTS: Following impact, initial peaks (0-48 h) of C5b9, S100B, and NSE with a concomitant loss of integrity of the blood-brain barrier were observed. Secondary insults at the intensive care unit were monitored. Severe secondary insults were paralleled by a more pronounced complement activation (C5b9 in CSF) as well as increased levels of S100B (measured in CSF), but not with NSE. CONCLUSION: This human study indicates that complement activation in the brain is triggered not only by the impact of trauma per se but also by the amount of secondary insults that frequently occur at the scene of accident as well as during treatment in the neurointensive care unit. Complement activation and in particular the end product C5b9 may in turn contribute to additional secondary brain injuries by its membrane destructive properties

Imaging brain functions during neuropsychological testing

Imaging brain functions during neuropsychological testing Per Hamid Ghatan This thesis has dealt with the development of tools for assessing cognitive functions(attention and working memory) using functional imaging and the evaluation of themodulatory effects of performance, nicotine, alcohol, brain injury and auditory interference.Two cognitive tasks commonly used in the assessment of patients with brain injury,the externally-generated Perceptual Maze Test (PMT) and an internally-generated arithmeticaltask, Serial -7, were used as activation paradigms. Regional cerebral blood flowwas used as an index for neuronal activity and [ 15 O] butanol was the flow tracer.The imaging processing and statistical analysis was performed with a method developedat the Karolinska Hospital based on the computerized brain atlas and by statisticalparametric mapping (SPM). The externally-generated PMT task is a highly visuoperceptual task which elicitedcortical activations representing visuospatial decoding, attention and motor performance,with only minor involvement of the frontal cortex outside the frontal eye fields.The internally-generated Serial -7 task elicited bilateral activations in fronto-parietalregions, which reflect involvement of attention, working memory and inner speech. The PMT and the Serial -7 elicited different activation patterns representingthe recruitment of different aspects of cognition, but a similar deactivation pattern.The activations of the Serial -7 task were modulated by disturbing irrelevant speech,which may be indicative of an attention-based modulation of activity in regions attributedto task-irrelevant processing. These findings stress the importance of consideringthe activations as well as the deactivations elicited by a task when interpretingfunctional imaging data. Differences attributed to performance in the PMT were observed in regions involvedin handling different levels of perceptual complexity. Differences attributed toperformance in the Serial -7 task were found in regions that regulate aspects ofattention. These findings suggest an increased level of automaticity in high thanin low performers, the latter relied more on a higher level of perceptual processingand willed attention. Nicotine elicited a specific rCBF response in regions pertaining to attentionand vision in both non smokers and smokers. These findings are consistent with thewell-known behavioural effects of nicotine. Alcohol elicited behavioral disturbancesexpressed as CBF increases in prefrontal regions and the antenor cingulate cortexand decreases in the posterior regions. Despite these effects of nicotine and alcohol,the activation patterns elicited by the PMT and Senal -7 were unaffected. The effectof nicotine and alcohol on the anterior cingulate cortex was lateralized to the righthemisphere, which is consistent with a drug interaction with the cerebral rewardsystems. The increases with alcohol were attributed to the euphoriant effects ofthe drug, whereas the effects of nicotine may represent a more subtle effect on e.g.attention mechanisms. Patients with previous episodes of severe hypoglycaemia activated the same regionsas two control groups, when solving to the PMT task. Subtle inter-group differencesin the level of activation were however observed. The prefrontal cortex was moreactivated in patients with severe hypoglycaemia. These activations did not overlapwith those attributed to performance. When studying functional recovery after braininjury with functional imaging techniques, it is of considerable importance to usetasks and analysis that differentiate between influences from performance, compensatorystrategies as well as the restoration of function. Keywords: Keywords: Positron Emission Tomography, Cognition, Alcohol, Nicotine,Brain injury, Interference ISBN 91-628-2792-

Neuron-Specific Enolase Is Correlated to Compromised Cerebral Metabolism in Patients Suffering from Acute Bacterial Meningitis; An Observational Cohort Study

<div><p>Introduction</p><p>Patients suffering from acute bacterial meningitis (ABM) with a decreased level of consciousness have been shown to have an improved clinical outcome if treated with an intracranial pressure (ICP) guided therapy. By using intracranial microdialysis (MD) to monitor cerebral metabolism in combination with serum samples of biomarkers indicating brain tissue injury, S100B and Neuron Specific Enolase (NSE), additional information might be provided. The aim of this study was to evaluate biomarkers in serum and MD parameters in patients with ABM.</p><p>Methods</p><p>From a prior study on patients (n = 52) with a confirmed ABM and impaired consciousness (GCS ≤ 9, or GCS = 10 combined with lumbar spinal opening pressure > 400 mmH₂O), a subgroup of patients (n = 21) monitored with intracerebral MD and biomarkers was included in the present study. All patients were treated in the NICU with intracranial pressure (ICP) guided therapy. Serum biomarkers were obtained at admission and every 12 hours. The MD parameters glucose, lactate, pyruvate and glycerol were analyzed. Outcome was assessed at 12–55 months after discharge from hospital. Mann-Whitney U-Test and Wilcoxon matched-pairs signed rank test were applied.</p><p>Results</p><p>The included patients had a mean GCS of 8 (range, 3–10) on admission and increased ICP (>20 mmHg) was observed in 62% (n = 13/21) of the patients. Patients with a lactate:pyruvate ratio (LPR) >40 (n = 9/21, 43%) had significantly higher peak levels of serum NSE (p = 0.03), with similar, although non-significant observations made in patients with high levels of glycerol (>500 μmol/L, p = 0.11) and those with a metabolic crisis (Glucose <0.8 mmol/L, LPR >25, p = 0.09). No associations between serum S100B and MD parameters were found. Furthermore, median MD glucose levels decreased significantly between day 1 (0–24h) and day 3 (48–72h) after admission to the NICU (p = 0.0001). No correlation between MD parameters or biomarkers and outcome was found.</p><p>Conclusion</p><p>In this observational cohort study, we were able to show that cerebral metabolism is frequently affected in patients with ABM. Furthermore, patients with high LPR (LPR>40) had significantly higher levels of NSE, suggesting ongoing deterioration in compromised cerebral tissue. However, the potential clinical impact of MD and biomarker monitoring in ABM patients will need to be further elaborated in larger clinical trials.</p></div

Neuro-intensive treatment targeting intracranial hypertension improves outcome in severe bacterial meningitis: an intervention-control study.

OBJECTIVE: To evaluate the efficacy of early intracranial pressure (ICP)-targeted treatment, compared to standard intensive care, in adults with community acquired acute bacterial meningitis (ABM) and severely impaired consciousness. DESIGN: A prospectively designed intervention-control comparison study of adult cases from September 2004 to January 2012. PATIENTS: Included patients were confirmed ABM-cases, aged 16-75 years, with severely impaired mental status on admission. Fifty-two patients, given ICP-targeted treatment at the neuro-intensive care unit, and 53 control cases, treated with conventional intensive care, were included. All the patients received intensive care with mechanical ventilation, sedation, antibiotics and corticosteroids according to current guidelines. Additional ICP-treatment in the intervention group included cerebrospinal fluid drainage using external ventricular catheters (n = 48), osmotherapy (n = 21), hyperventilation (n = 13), external cooling (n = 9), gram-doses of methylprednisolone (n = 3) and deep barbiturate sedation (n = 2) aiming at ICP <20 mmHg and a cerebral perfusion pressure of >50 mmHg. MEASUREMENTS: The primary endpoint was mortality at two months and secondary endpoint was Glasgow outcome score and hearing ability at follow-up at 2-6 months. OUTCOMES: The mortality was significantly lower in the intervention group compared to controls, 5/52 (10%) versus 16/53 (30%; relative risk reduction 68%; p<0.05). Furthermore, only 17 patients (32%) in the control group fully recovered compared to 28 (54%) in the intervention group (relative risk reduction 40%; p<0.05). CONCLUSIONS: Early neuro-intensive care using ICP-targeted therapy, mainly cerebrospinal fluid drainage, reduces mortality and improves the overall outcome in adult patients with ABM and severely impaired mental status on admission

Outcome.

<p>Outcome.</p

Outcome.

<p>Outcome.</p

MD parameters, fever and serum glucose over time.

<p>Illustrating parameter change over time (median 0–24h, Day 1, vs median 48–72h, Day 3) from insertion of microdialysis (MD) catheters. MD-glucose (2A) and serum-glucose (2B) levels were significantly lower on Day 3 compared to Day 1 (p<0.01 respectively, Wilcoxon matched-pairs signed rank test). No other parameter presented any significant difference over time. For all parameters n = 15 patients are compared except pyrexia (n = 13).</p

Biomarkers vs MD parameters.

<p>Illustrates NSE (A-C) and S100B (D-F) levels in patients (n = 21) with either increased LPR (>40), metabolic crisis (LPR >25, MD-glucose <0.8 mmol/L) and increased glycerol (>500 μmol/L). In general, increased NSE levels were correlated to worse metabolic conditions.</p

Demographics.

<p>Demographics.</p