Temporal alterations in cerebrospinal fluid amyloid beta-protein and apolipoprotein E after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The mechanism underlying the association between possession of the APOEepsilon4 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 beta-protein (Abeta), testing the hypothesis that apoE-Abeta interactions occur in vivo after SAH. METHODS: Enzyme-linked immunosorbent assay was used to assay apoE, Abeta1-40, and Abeta1-42 in serial ventricular CSF samples from 19 patients with SAH and 13 controls. CSF S100B and tau were assayed as surrogate markers of brain injury. RESULTS: There was a sustained decrease in CSF apoE (P<0.001) and Abeta (P<0.001) after SAH in contrast to the observed elevation in CSF S100B (P<0.001) and tau (P<0.001) concentration. There was significant correlation between CSF Abeta concentration and clinical outcome (r=0.65, P<0.01), and the decrease in CSF Abeta concentration correlated significantly with that of apoE (r=0.85, P<0.0001). CONCLUSIONS: After SAH both apoE and Abeta levels decrease in the CSF, supporting the concept that interactions between these proteins occur in vivo. The possibility that apoE and Abeta influence outcome after SAH warrants further investigation.

Decreased cerebrospinal fluid apolipoprotein E after subarachnoid hemorrhage: correlation with injury severity and clinical outcome.

BACKGROUND AND PURPOSE: The apolipoprotein E (APOE) epsilon4 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.

Alterations in cerebrospinal fluid apolipoprotein E and amyloid beta-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.

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.

Serum S100B in primary progressive multiple sclerosis patients treated with interferon-beta-1a.

S100B belongs to a family of calcium-binding proteins implicated in intracellular and extracellular regulatory activities. This study of serum S100B in primary progressive multiple sclerosis (PPMS) is based on data obtained from a randomized, controlled trial of Interferon beta-1a in subjects with PPMS. The key questions were whether S100B levels were associated with either disability or MRI findings in primary progressive MS and whether Interferon beta-1a has an effect on their S100B levels. Serial serum S100B levels were measured using an ELISA method. The results demonstrated that serum S100B is not related to either disease progression or MRI findings in subjects with primary progressive MS given Interferon beta-1a. Furthermore there is no correlation between S100B levels and the primary and secondary outcome measures.

Identification of the structural requirements for mutagenicity by incorporating molecular flexibility and metabolic activation of chemicals I: TA100 model.

Traditional attempts to model genotoxicity data have been limited to congeneric data sets, primarily because the mechanism of action was ignored, and frequently, the chemicals required metabolism to the active species. In this exercise, the COmmon REactivity PAtterns (COREPA) approach was used to delineate the structural requirements for eliciting mutagenicity in terms of ranges of descriptors associated with three-dimensional molecular structures. The database used to build the mutagenicity model includes 1196 structurally diverse chemicals tested in the Ames assay by the National Toxicology Program. This manuscript describes the development of the TA100 model that predicts the results of mutagenicity testing using only the Ames TA100 strain. The TA100 model was developed using 148 chemicals that tested positive in TA100 strain without rat liver enzymes (S-9) and 188 chemicals that tested positive in TA100 strain with rat liver enzymes. A decision tree was developed by first comparing the reactivity profile of chemicals that were positive in TA100 without rat liver enzymes to the reactivity profile of the remaining 1048 chemicals. This approach correctly identified 82% of the primary acting mutagens and 94% of the nonmutagens in the training set. The 188 chemicals in the training set that are positive only in the presence of metabolic activation would pass through the decision tree as negative. The next step was to identify the chemicals that are positive only in the presence of metabolic activation. To accomplish this, a series of hierarchically ordered metabolic transformations were used to develop an S-9 metabolism simulator that was applied to each of the 1048 chemicals. The potential metabolites were then screened through the decision tree to identify reactive mutagens. This model correctly identified 77% of the metabolically activated chemicals in a training set. A computer system that applies the COREPA models and predicts mutagenicity of chemicals, including their metabolic activation, was developed. Each prediction is accompanied by a probabilistic estimate of the chemical being in the structural domain covered by the training set.