Andrew Kay

Head Injury in the United Kingdom

This paper reviews aspects of head injury management and research in the United Kingdom (UK). We discuss evidence about the scale and etiology of head injury in Britain and how this information has supported a triage-based approach, incorporating risk analysis. A Cohesive organization based upon nationally accepted, yet regionally flexible head injury management guidelines is important. Research in the United Kingdom has clarified the effect of head injury on the brain and how this can be reduced. This clarification follows from improved understanding of the neurobiology of injury, of secondary damage and recovery, and information gained from new techniques aimed at investigating events in patients. Outcome is an important perspective and we highlight the increasing focus upon recovery and the extent of disability after so called mild head injury. Although we retain a UK perspective, comparisons with aspects of European head injury emphasize the increasing importance of an international approach in the future.

Alterations in Cerebrospinal Fluid Apolipoprotein E and Amyloid β-Protein after Traumatic Brain Injury

There is evidence that apolipoprotein E (apoE) and amyloid beta-protein (Abeta), which are implicated in the pathology of chronic neurodegenerative disorders, are involved in the response of the brain to acute injury; however, human in vivo evidence is sparse. We conducted a prospective observational study to determine the magnitude and time-course of alterations in cerebrospinal fluid (CSF) apoE and Abeta concentrations after traumatic brain injury (TBI), and the relationship of these changes to severity of injury and clinical outcome. Enzyme linked immunosorbant assay (ELISA) was used to assay apoE, Abeta(1-40) and Abeta(1-42) in serial CSF samples from 13 patients with TBI and 13 controls. CSF S100B and tau were assayed as surrogate markers of brain injury. There was a significant decrease in CSF apoE (p < 0.001) and Abeta (p< 0.001) after TBI contrasting the observed elevation in CSF S100B (p < 0.001) and tau (p < 0.001) concentration. There was significant correlation (r = 0.67, p = 0.01) between injury severity and the decrease in Abeta(1-40) concentration after TBI. In vivo, changes in apoE and Abeta concentration occur after TBI and may be important in the response of the human brain to injury.

Temporal Alterations in Cerebrospinal Fluid Amyloid β-Protein and Apolipoprotein E After Subarachnoid Hemorrhage

Background and Purpose— The mechanism underlying the association between possession of the APOE &egr;4 allele and less favorable outcome after subarachnoid hemorrhage (SAH) remains to be determined. After SAH the level of apolipoprotein E (apoE) in the cerebrospinal fluid (CSF) is decreased, and lower levels are associated with more severe injury and less favorable outcome. This study examined serial CSF samples to determine the time course for the decrease in CSF apoE and the relationship between CSF apoE and amyloid &bgr;-protein (A&bgr;), testing the hypothesis that apoE-A&bgr; interactions occur in vivo after SAH. Methods— Enzyme-linked immunosorbent assay was used to assay apoE, A&bgr;1–40, and A&bgr;1–42 in serial ventricular CSF samples from 19 patients with SAH and 13 controls. CSF S100B and &tgr; were assayed as surrogate markers of brain injury. Results— There was a sustained decrease in CSF apoE (P <0.001) and A&bgr; (P <0.001) after SAH in contrast to the observed elevation in CSF S100B (P <0.001) and &tgr; (P <0.001) concentration. There was significant correlation between CSF A&bgr; concentration and clinical outcome (r =0.65, P <0.01), and the decrease in CSF A&bgr; concentration correlated significantly with that of apoE (r =0.85, P <0.0001). Conclusions— After SAH both apoE and A&bgr; levels decrease in the CSF, supporting the concept that interactions between these proteins occur in vivo. The possibility that apoE and A&bgr; influence outcome after SAH warrants further investigation.

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.

Decreased Cerebrospinal Fluid Apolipoprotein E After Subarachnoid Hemorrhage. Correlation With Injury Severity and Clinical Outcome

Background and Purpose— The apolipoprotein E (APOE) &egr;4 allele has been associated with unfavorable outcome after subarachnoid hemorrhage (SAH), suggesting that apoE plays an important role in the response of the brain to SAH. We determined the concentration of apoE in the cerebrospinal fluid (CSF) of patients with SAH and a control group to test the hypothesis that alterations in CSF apoE reflect the response of the brain to SAH and are correlated with the severity of injury and outcome. Methods— ApoE and S100B (a marker of brain injury) were measured by ELISA in CSF from a non–brain-injured control group and patients with SAH. The severity of SAH was determined from the Glasgow Coma Scale, and the clinical outcome was determined from the Glasgow Outcome Scale. Results— In contrast to increased CSF concentration of S100B, CSF apoE concentration was significantly lower in patients after SAH than in control subjects (Mann-Whitney test, P <0.0001). SAH patients with more severe injury and less favorable outcome had lower CSF apoE concentration than did patients with milder injury and better clinical outcome (Fisher exact test, P =0.02). Conclusions— The concentration of apoE in the CSF decreases after SAH, despite the likely leakage of plasma apoE into the CSF. 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.

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.

Cerebrospinal fluid nitrite/nitrate correlated with oxyhemoglobin and outcome in patients with subarachnoid hemorrhage

The findings of various studies reporting temporal changes in CSF total nitrite/nitrate (NOx) levels after subarachnoid hemorrhage (SAH) vary considerably. The study group comprised 10 patients with SAH and 10 control subjects. Total nitrite/nitrate concentration was measured by a vanadium-based assay with the colorimetric Griess reaction. CSF oxyhemoglobin level was assessed by spectrophotometry. After an initial peak (22.6+/-10.1 microM) within first 24 h after SAH, CSF NOx decreased gradually during the period of observation. There was a significant correlation between CSF concentrations of NOx and OxyHb in the entire observation period (R=0.87, p<0.001). When the impact of bleeding into CSF was considered, patients with very good outcome [Glasgow Outcome Scale (GOS)=5] had significantly lower CSF NOx (11.1+/-1.3 microM) than those with worse outcome (GOS<5) (21.8+/-11.2 microM, p<0.01). In conclusion, this study demonstrates that after aneurysm rupture CSF NOx levels correlate with OxyHb. We suggest this as a novel interpretation of other variable findings in relation to NO metabolites in the central nervous system (CNS) post SAH, and hence it could usefully be incorporated into the planning of future studies, correlating NOx with clinical outcome.

Remodelling of cerebrospinal fluid lipoproteins after subarachnoid hemorrhage

Lipoprotein particles (Lps) in normal human cerebrospinal fluid (CSF) are distinct from those found in plasma and include unique apolipoprotein E (apoE indicates protein; APOE, gene) containing lipoproteins rarely seen in human plasma. Less favourable neurological recovery after subarachnoid hemorrhage (SAH) has been observed in patients who possess the APOE epsilon4 allele raising the possibility that apoE influences neuronal survival after brain injury. We analysed Lps from control and SAH CSF testing the hypotheses that following brain injury CSF Lps undergo remodelling and apoE containing Lps are selectively depleted from brain injury CSF. Lipoproteins were fractionated using CSF from six control pools and six patients with SAH on a sepharose 6HR 10/30 size exclusion column. Fractions were assayed for total cholesterol (TC), free cholesterol (FC), phospholipid, triglyceride (TG), apoE, apolipoprotein B (apoB), and apolipoprotein AI (apoAI). Compared to control CSF there were significant (P<0.05) increases in TC, FC, TG, and apoAI in SAH CSF. Plasma sized apoB-containing lipoproteins and a very small apoAI-containing Lps were identified in the SAH CSF, which were not present in controls. However, despite the release of plasma lipoproteins into the subarachnoid space, there was no significant increase in CSF apoE. These data provide novel indirect evidence suggesting that after SAH CSF Lps undergo remodelling and apoE containing Lps are selectively reduced in brain injury CSF. The remodelling of CSF Lps and selective reduction of apoE containing lipoproteins may reflect an important response of the human brain to injury.

ROLE OF GENETIC BACKGROUND: INFLUENCE OF APOLIPOPROTEIN E GENOTYPE IN ALZHEIMER'S DISEASE AND AFTER HEAD INJURY

Severe traumatic brain injury (TBI) represents an emergent situation whereby health team members are challenged to optimize cerebral perfusion and prevent secondary brain injury. Despite intense interest in furthering our understanding of the pathogenesis of the events that occur after injury, results from multiple clinical trials based on current pathophysiological principles have failed to uncover therapies that improve outcomes in this population.