Cerebrospinal fluid apolipoprotein E concentration decreases after traumatic brain injury

The APOE epsilon4 allele has been associated with unfavorable outcome after several types of acute brain injury, yet the biological mechanisms underlying this observation are poorly understood. Postmortem and experimental brain injury studies suggest the presence of increased amounts of apolipoprotein E (apoE) within the neuropil after acute brain injury. We assayed the concentration of apolipoprotein E in the cerebrospinal fluid (CSF) of non-injured controls and patients with traumatic brain injury (TBI) to determine whether differences exist, and if these differences correlate with injury severity and clinical outcome. CSF apoE and S100B, a marker of injury severity, were measured by enzyme linked immunosorbant assay. CSF was sampled from 27 traumatic brain injury patients (mean age 32, median 25, range 16-65 years) within 3 days of injury, and 28 controls (mean age 40, median 37, range 19-73 years). The TBI patients all had a Glasgow Coma Score (GCS) of less than eight (i.e., severe head injury). Clinical outcome was determined using the Glasgow Outcome Score (GOS). The average concentration of apoE in the CSF of controls was 12.4 mg/L (95% CI: 10.5-14.3 mg/L) and in TBI patients was 3.7 mg/L (95% CI: 2.1-4.1 mg/L; Mann-Whitney: p < 0.0001). In contrast, the concentration of S100B in the CSF of TBI patients was significantly higher than that of controls (Mann-Whitney: p < 0.0001). We speculate that apoE is retained within the parenchyma of the central nervous system in response to injury where in view of previous data, it may have a protective role.     

Remodeling of cerebrospinal fluid lipoprotein particles after human traumatic brain injury

The association between possession of the APOE epsilon4 allele and unfavourable outcome after traumatic brain injury (TBI) suggests that the apolipoprotein E protein (apoE) plays a key role in the response of the human brain to injury. ApoE is known to regulate cholesterol metabolism in the periphery through its action as a ligand for receptor mediated uptake of lipoprotein particles (Lps). Greater understanding of cholesterol metabolism in the human central nervous system may identify novel treatment strategies applicable to acute brain injury. We report findings from the analysis of lipoproteins in the cerebrospinal fluid (CSF) of patients with TBI and non-injured controls, testing the hypothesis that remodeling of CSF lipoproteins reflects the response of the brain to TBI. CSF Lps were isolated from the CSF of controls and patients with severe TBI by size exclusion chromatography, and the lipoprotein fractions analysed for cholesterol, phospholipid, apoAI, and apoE. There was a marked decrease in apoE containing Lps in the TBI CSF compared to controls (p=0.002). After TBI there was no significant decrease in apoAI containing CSF Lps (CSF LpAI), but the apoAI resided on smaller sized particles than in control CSF. There was a population of very small sized Lps in TBI CSF, which were associated with the increased cholesterol (p=0.0001) and phospholipid (p=0.040) seen after TBI. The dramatic loss of apoE containing Lps from the CSF, and the substantial increase in CSF cholesterol, support the concept that apoE and cholesterol metabolism are intimately linked in the context of acute brain injury. Treatment strategies targeting CNS lipid transport, required for neuronal sprouting and synaptogenesis, may be applicable to traumatic brain injury.     

Increased adrenomedullin in cerebrospinal fluid after traumatic brain injury in infants and children

Adrenomedullin is a recently discovered 52-amino acid peptide that is a potent vasodilator and is produced in the brain in experimental models of cerebral ischemia. Infusion of adrenomedullin increases regional cerebral blood flow and reduces infarct volume after vascular occlusion in rats, and thus may represent an endogenous neuroprotectant. Disturbances in cerebral blood flow (CBF), including hypoperfusion and hyperemia, frequently occur after severe traumatic brain injury (TBI) in infants and children. We hypothesized that cerebrospinal fluid (CSF) adrenomedullin concentration would be increased after severe TBI in infants and children, and that increases in adrenomedullin would be associated with alterations in CBF. We also investigated whether posttraumatic CSF adrenomedullin concentration was associated with relevant clinical variables (CBF, age, Glasgow Coma Scale [GCS] score, mechanism of injury, and outcome). Total adrenomedullin concentration was measured using a radioimmunometric assay. Sixty-six samples of ventricular CSF from 21 pediatric patients were collected during the first 10 days after severe TBI (GCS score < 8). Control CSF was obtained from children (n = 10) undergoing lumbar puncture without TBI or meningitis. Patients received standard neurointensive care, including CSF drainage. CBF was measured using Xenon computed tomography (CT) in 11 of 21 patients. Adrenomedullin concentration was markedly increased in CSF of infants and children after severe TBI vs control (median 4.5 versus 1.0 fmol/mL, p < 0.05). Sixty-two of 66 CSF samples (93.9%) from head-injured infants and children had a total adrenomedullin concentration that was greater than the median value for controls. Increases in CSF adrenomedullin were most commonly observed early after TBI. CBF was positively correlated with CSF adrenomedullin concentration (p < 0.001), but this relationship was not significant when controlling for the effect of time. CSF adrenomedullin was not significantly associated with other selected clinical variables. We conclude adrenomedullin is markedly increased in the CSF of infants and children early after severe TBI. We speculate that adrenomedullin participates in the regulation of CBF after severe TBI.     

Influence of apolipoprotein E and its receptors on cerebral amyloid precursor protein metabolism following traumatic brain injury

Traumatic brain injury (TBI) is the leading cause of mortality and disability among young individuals in our society,and globally the incidence of TBI is rising sharply.Mounting evidence has indicated ...     

Serum and cerebrospinal fluid magnesium in severe traumatic brain injury outcome

Serum magnesium concentration has a neuroprotective effect in experimental models of traumatic brain injury (TBI). This study was designed to assess the relationship between initial serum magnesium, cerebrospinal fluid (CSF) magnesium, neurological outcome and the efficacy of magnesium replacement therapy (MgSO4). A retrospective analysis was performed on a prospectively collected dataset from 216 patients admitted during 1996-2006 to the University of Pittsburgh Medical Center with severe TBI. Admission serum and CSF magnesium were dichotomized into low and normal magnesium concentration groups for serum and normal and high concentration groups for CSF. A logistic-regression analysis was performed with 6-month Glasgow Outcome Scale (GOS) scores as outcome variable. The outcome of a subset of 31 patients who presented with low serum magnesium and who were rapidly corrected within 24 h of admission was also analyzed. Low initial serum magnesium was measured in 56.67% of all patients. Patients with an initial serum magnesium of <1.3 mEq/L were 2.37 times more likely to have a poor outcome (CI: 1.18-4.78, p = 0.016). The prognostic significance of depressed serum magnesium remained, even in patients whose serum magnesium levels were corrected within 24 h (OR = 11.03, CI: 1.87-68.14, p = 0.008). Patients with an initial high CSF magnesium were 7.63 more likely to have a poor outcome (p = 0.05). Elevated CSF magnesium correlated with depressed serum magnesium only in patients with poor outcome (p = 0.013). Patients with low serum magnesium and high CSF magnesium are most likely to have poor outcome after severe TBI. Rapid correction of serum magnesium levels does not reverse the prognostic value of these markers.     

Genetic susceptibility to traumatic brain injury and apolipoprotein E gene

Traumatic brain injury (TBI) is defined as an injury caused by a blow or jolt to the head or a penetrating head injury that disrupts the normal function of the brain. It is a common emergency and severe case in neurosurgery field. Nowadays, there are more and more evidences showing that TBI, which is apparently similar in pathology and severity in the acute stage, may have different outcomes.     

Clinical significance of alphaII-spectrin breakdown products in cerebrospinal fluid after severe traumatic brain injury

Following traumatic brain injury (TBI), the cytoskeletal protein alpha-II-spectrin is proteolyzed by calpain and caspase-3 to signature breakdown products. To determine whether alpha -II-spectrin proteolysis is a potentially reliable biomarker for TBI in humans, the present study (1) examined levels of spectrin breakdown products (SBDPs) in cerebrospinal fluid (CSF) from adults with severe TBI and (2) examined the relationship between these levels, severity of injury, and clinical outcome. This prospective case control study enrolled 41 patients with severe TBI, defined by a Glasgow Coma Scale (GCS) score of < or =8, who underwent intraventricular intracranial pressure monitoring. Patients without TBI requiring CSF drainage for other medical reasons served as controls. Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, and 120 h following TBI and analyzed for SBDPs. Outcome was assessed using the Glasgow Outcome Score (GOS) 6 months after injury. Calpain and caspase-3 mediated SBDP levels in CSF were significantly increased in TBI patients at several time points after injury, compared to control subjects. The time course of calpain mediated SBDP150 and SBDP145 differed from that of caspase-3 mediated SBDP120 during the post-injury period examined. Mean SBDP densitometry values measured early after injury correlated with severity of injury, computed tomography (CT) scan findings, and outcome at 6 months post-injury. Taken together, these results support that alpha -II-spectrin breakdown products are potentially useful biomarker of severe TBI in humans. Our data further suggests that both necrotic/oncotic and apoptotic cell death mechanisms are activated in humans following severe TBI, but with a different time course after injury.     

Association between apolipoprotein E genotype and outcome of traumatic brain injury

Summary ¶Background. The prognosis of traumatic brain injury is quite variable and not fully explained by the known factors. This study is to examine if the polymorphism of apolipoprotein E (apoE) influences the outcome of traumatic brain injury. Methods. Over a period of twelve months, we prospectively studied 100 patients who sustained traumatic brain injuries and were admitted to our neurosurgical unit. Findings. Nineteen patients were apoE4(+) and 81 patients were apoE4(–). There was no significant difference between apoE4(+) and apoE4(–) groups in the cause of injury (p=0.288), type of brain injury (p=0.983) and choice of treatment (p=0.88). The proportion of patients with a lower GCS (<13), indicating a poor prognosis, was higher in the apoE4(+) group (73.7%) than that in apoE4(–) group (61.7%), although the difference was not significant (p=0.654). Six patients (7.4%) in the apoE4(–) group and 5(26.3%) in the apoE4(+) group had been drinking alcohol at the time of injury (p=0.018). The mean duration of hospital stay for apoE4(+) patients was significantly longer than for apoE4(–) patients (p<0.001). Six months after injury, 10 of 19 patients (52.6%) with apoE4 had an unfavorable outcome (dead, vegetative state, or severe disability) compared with 20 of the 81 (24.1%) patients without apoE4 (p=0.017). The apoE4(+) patients had a significantly longer hospital stay and unfavorable outcomes after brain injury. Interpretation. This study discloses a significant genetic association between the apoE genotypes and outcomes of traumatic brain injury. Patients with apoE4 allele are more likely to have an unfavorable clinical outcome after brain injury.Published online July 23, 2003     

Association between cerebrospinal fluid interleukin-6 concentrations and outcome after severe human traumatic brain injury

Acute inflammation plays a significant role in the pathophysiology of traumatic brain injury (TBI). However, the specific relationships between inflammatory mediators and patient outcome following TBI have not been fully established. In this study, we measured plasma and cerebrospinal fluid interleukin-1 (IL-1) and interleukin-6 (IL-6) concentrations in 36 patients, following severe TBI. Patients were monitored with continuous measurements of somatosensory-evoked potentials (SSEP) to derive an established surrogate outcome measurement, the 96-h evoked potential (SSEP96). Clinical outcomes were assessed at 3 months using the Glasgow Outcome Scale (GOS). Peak cerebrospinal fluid (CSF) IL-1 and IL-6 concentrations were significantly higher than those observed in the plasma [median 6.5 pg/mL (range 1.4-25.0) vs. 3.0 (0.8-7.6) for IL-1, and 650 (130-7,214) vs. 253 (52-1,506) for IL-6, p < 0.001 for both]. Peak CSF IL-6 levels correlated with SSEP96 (r = 0.42; p = 0.0133), and peak CSF IL-6 levels were higher with improved GOS (p = 0.024). Multiple regression analysis identified that age (p = 0.0072), pupillary abnormality (p = 0.021), the presence of mass lesion (p = 0.023), and peak CSF IL-6 concentrations (p = 0.026) were all statistically significant predictors of clinical outcome following TBI. These results suggest that peak CSF IL-6 concentrations correlate with improved outcome following TBI. This finding helps to characterize the inflammatory reaction associated with TBI and may help to develop improved treatment strategies for patients with TBI.     

Alterations of acetylcholinesterase activity after traumatic brain injury in rats

Objective: The cholinergic system is highly vulnerable to traumatic brain injury (TBI). However, limited information is available to what extent the degrading enzyme acetylcholinesterase (AChE) is involved. The present study addresses this question.

Method: Thirty-six anaesthetized Sprague-Dawley rats were subjected to sham operation or to TBI using controlled cortical impact (CCI). The AChE activity was histochemically determined in frozen brain slices at 2, 24 and 72 hours after TBI.

Results: High enzyme activity was observed in regions rich in cholinergic innervation such as the olfactory tubercle, basal forebrain, putamen and superior colliculi. Low activity was found in the cortex, cerebellum and particularly in the white matter. A decrease of AchE activity (20-35%) was found in the hippocampus and hypothalamus already at 2 hours after TBI. An increase of ∼30% was found in the basal forebrain at 2 and 24 hours. No changes occurred at 72 hours.

Conclusion: The findings are consistent with impairment of the cholinergic neurotransmission after TBI and suggest the involvement of the AChE in short-term regulatory mechanisms.     

Sex and genetic associations with cerebrospinal fluid dopamine and metabolite production after severe traumatic brain injury

OBJECT: Dopamine (DA) pathways have been implicated in cognitive deficits after traumatic brain injury (TBI). Both sex and the dopamine transporter (DAT) 3' variable number of tandem repeat polymorphism have been associated with differences in DAT protein density, and DAT protein affects both presynaptic DA release, through reverse transport, and DA reuptake. Catecholamines and associated metabolites are subject to autooxidation, resulting in the formation of reactive oxygen species that may contribute to subsequent oxidative injury. The purpose of this study was to determine associations between factors that affect DAT expression and cerebrospinal fluid (CSF) DA and metabolite levels after severe TBI. METHODS: Sixty-three patients with severe TBI (Glasgow Coma Scale score < or = 8) were evaluated. The patients' genotypes were obtained using previously banked samples of CSF, and serial CSF samples (416 samples) were used to evaluate DA and metabolite levels. High-performance liquid chromatography was used to determine CSF levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) during the first 5 days after injury. Mixed-effects multivariate regression modeling revealed that patients with the DAT 10/10 genotype had higher CSF DA levels than patients with either the DAT 9/9 or DAT 9/10 genotypes (p = 0.009). Females with the DAT 10/10 genotype had higher CSF DA levels than females with the DAT 9/9 or DAT 9/10 genotypes, and sex was associated with higher DOPAC levels (p = 0.004). Inotrope administration also contributed to higher DA levels (p = 0.002). CONCLUSIONS: In addition to systemic administration of DA, inherent factors such as sex and DAT genotype affect post-TBI CSF DA and DA metabolite levels, a phenomenon that may modulate susceptibility to DA-mediated oxidative injury.     

Vascular endothelial growth factor is increased in cerebrospinal fluid after traumatic brain injury in infants and children

OBJECTIVE: Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis, the formation of which is triggered by hypoxia, cytokines, and growth factors and is also induced by activation of the adenosine 2B receptor. VEGF is neuroprotective in several models of experimental brain injury and is increased in brain after traumatic brain injury (TBI) in humans and experimental animals. Adenosine is a neuroprotective purine metabolite that increases in cerebrospinal fluid (CSF) after clinical TBI in children. We hypothesized that VEGF levels would 1). be increased in CSF after TBI in infants and children, and 2). be preceded by increases in CSF adenosine. To test this hypothesis, we designed a case-control study to compare the CSF of infants and children after severe TBI with that of uninjured children. METHODS: Using an Institutional Review Board-approved protocol, we compared CSF concentrations of VEGF (by enzyme-linked immunosorbent assay) and adenosine (by high-performance liquid chromatography) in 73 samples from 14 infants and children with severe TBI (Glasgow Coma Scale score 相似文献   

Ubiquitin reduces fluid shifts after traumatic brain injury

BACKGROUND: Ubiquitin has well-described intracellular properties. Recent data also suggest pleiotropic effects of extracellular ubiquitin, including induction of apoptosis, regulation of immune functions, and therapeutic potential during fluid resuscitation from severe trauma. However, the actions of exogenous ubiquitin after traumatic brain injury (TBI) are unknown. METHODS: Series 1: Thirty-five minutes after TBI and hemorrhage, 1.5 mg ubiquitin/kg (n = 5) or albumin (n = 5) intravenous was followed by fluid resuscitation to maintain mean arterial and cerebral perfusion pressure. Series 2: Ubiquitin (n = 5) or vehicle (n = 6) was administered after TBI only. Ubiquitin was measured with enzyme-linked immunosorbent assay in serum, urine (series 1), and cerebrospinal fluid (series 2) for 300 minutes. RESULTS: Series 1: After intravenous bolus, serum ubiquitin peaked at t = 45 minutes with a half-life of 54 minutes. Recovery in urine was 10%. With albumin versus ubiquitin, 85% more resuscitation fluid was required to stabilize systemic and cerebral hemodynamics (P < .05 for t = 150 to 300 minutes), but hematocrit was similar. With albumin there were progressive increases in intracranial pressure, peak inspiratory pressure, and decreases in oxygenation. All were significantly attenuated by ubiquitin (all P < .05 vs albumin). Series 2: Intravenous ubiquitin altered cerebrospinal fluid ubiquitin with an increased time to peak (t = 88 +/- 13 min vs 45 +/- 7 min, P < .05) and area under the concentration-time curve (82 +/- 22 vs 23 +/- 11 microg/min(1)/mL(-1), P < .05). CONCLUSIONS: After TBI, intravenous ubiquitin crossed the blood-brain barrier and significantly reduced third spacing of fluid into the brain and lung during resuscitation.     

F2-isoprostane and neuron-specific enolase in cerebrospinal fluid after severe traumatic brain injury in infants and children

It has been hypothesized that oxidative stress plays an important role in mediating secondary damage after traumatic brain injury (TBI). To study the relationship between lipid peroxidation, clinical variables, and neuronal damage in pediatric TBI, we measured levels of F2-isoprostane, a marker of lipid peroxidation, and neuron-specific enolase (NSE), a marker of neuronal damage, in serial cerebrospinal fluid (CSF) samples from 23 infants and children with severe TBI (Glasgow Coma Scale score <8). These were compared to CSF samples from 10 uninjured pediatric controls. On d1 after injury, F2-isoprostane was increased 6-fold vs. control (36.59+/-8.96 pg/ml vs. 5.64+/-8.08 pg/ml, p=0.0035) and NSE was increased 10-fold (100.62+/-17.34 ng/ml vs. 8.63+/-2.76 ng/ml, p=0.0002). Multivariate analysis of F2-isoprostane levels and selected clinical variables showed a trend toward an inverse association with time after injury (p=0.0708). Multivariate analysis of NSE levels and selected variables showed a positive association between d1 NSE and F2-isoprostane (p=0.0426). CSF F2-isoprostane increases early after TBI in infants and children and is correlated with NSE, supporting a role for oxidative stress in the evolution of secondary damage early after severe TBI in infants and children.     

Pathophysiology of cerebrospinal fluid in head injury: Part 1. Pathological changes in cerebrospinal fluid solute composition after traumatic injury

After head injury, many complex neurochemical events occur locally, at the site of initial injury, and globally, as a result of secondary phenomena. Neurochemical alterations in the cerebrospinal fluid after injury can be utilized to reflect these events. The authors review the role of the cerebrospinal fluid in the treatment of head injury as it relates to the diagnosis, prognosis, and further elucidation of the pathophysiological manifestations of head injury at the cellular and biochemical level.     

Alterations of A-type potassium channels in hippocampal neurons after traumatic brain injury

Traumatic brain injury (TBI) is associated with cognitive deficits, memory impairment, and epilepsy. Previous studies have reported neuronal loss and neuronal hyperexcitability in the post-traumatic hippocampus. A-type K+ currents (I(A)) play a critical role in modulating the intrinsic membrane excitability of hippocampal neurons. The disruption of I(A) is reportedly linked to hippocampal dysfunction. The present study investigates the changes of I(A) in the hippocampus after TBI. TBI in rats was induced by controlled cortical impact. The impact induced a reproducible lesion in the cortex and an obvious neuronal death in the ipsilateral hippocampus CA3 region. At one week after TBI, immunohistochemical staining and Western blotting showed that the expression of I(A) channel subunit Kv4.2 was markedly decreased in the ipsilateral hippocampus, but remained unchanged in the contralateral hippocampus. Meanwhile, electrophysiological recording showed that I(A) currents in ipsilateral CA1 pyramidal neurons were significantly reduced, which was associated with an increased neuronal excitability. Furthermore, there was an increased sensitivity to bicuculline-induced seizures in TBI rats. At 8 weeks after TBI, immunohistochemical staining and electrophysiological recording indicated that I(A) returned to control levels. These findings suggest that TBI causes a transient downregulation of I(A) in hippocampal CA1 neurons, which might be associated with the hyperexcitability in the post-traumatic hippocampus, and in turn leads to seizures and epilepsy.     

Markers for cell-mediated immune response are elevated in cerebrospinal fluid and serum after severe traumatic brain injury in humans

The brain is believed to be an immunologically privileged organ, sheltered from the systemic immunological defense by the blood-brain barrier (BBB). However, there is increasing evidence for a marked inflammatory response in the brain after traumatic brain injury (TBI). Markers for cellular immune activation, neopterin, beta2-microglobulin (beta2M), and soluble interleukin-2 receptor (sIL-2R), were measured for up to 3 weeks in cerebrospinal fluid (CSF) and serum of 41 patients with severe TBI in order to elucidate the time course and the origin of the cellular immune response following TBI. Neopterin gradually increased during the first posttraumatic week in both CSF and serum. Concentrations in CSF were generally higher than in serum, suggesting intrathecal release of this marker. beta2M showed similar kinetics but with higher serum than CSF concentrations. Nonetheless, intrathecal release as assessed by the beta2M index could be postulated for most of the patients. The mean levels of sIL-2R in both CSF and serum were elevated during the whole study period, serum concentrations being up to 2 x 10(4) times higher than in CSF. No significant intrathecal production of sIL-2R could be detected. The present data shows that severe TBI leads to a marked cell-mediated immune response within the brain and in the systemic circulation. In the intrathecal compartment the activated cells appear to be predominantly of the macrophage/microglia lineage, while the immune activation in the systemic circulation seems to involve mainly T-lymphocytes.     

Genetics and brain injury: apolipoprotein E

Apolipoprotein E (apo E) is a lipoprotein produced by astrocytes and microglia and has a proposed role in transporting lipids to injured neurons. There are three known isoforms of apo E, coded for by the APOE epsilon2, APOE epsilon3, and APOE epsilon4 genes. The APOE epsilon4 genotype has been implicated as a risk factor for Alzheimer's disease. Recent studies have suggested that APOE epsilon4 may influence the central nervous system's response to injury. This article presents an overview of the relationship between apo E, Alzheimer's disease, and head injury and reviews recent studies implicating APOE epsilon4 as a possible genetic determinant in recovery from head injury.