Sheila Alexander

The effects of admission alcohol level on cerebral blood flow and outcomes after severe traumatic brain injury

This study examined the relationship between admission serum alcohol level (ETOH) and cerebral blood flow (CBF) and outcomes in the adult traumatic brain injured (TBI) population. We hypothesized that individuals with ETOH > 100 mg/dL will have decreased blood flow on admission and poorer outcomes. Eighty subjects, age 16-65, with severe TBI (Glasgow Coma Score [GCS] </= 8) were entered into the study. Correlational analysis assessed the relationship between ETOH and admission severity of injury scores as measured by Marshall and APACHE III scores, CBF, and outcomes. Comparison of CBF and outcomes between groups based on admission serum ETOH level was conducted with analysis of variance and post hoc Scheffé analyses as well as regression analysis. There was a significant relationship between serum ETOH level and GCS (p = 0.02), but not APACHE III scores (p = 0.12) or Marshall scores (p = 0.27). There was a significant correlation between global CBF and serum ETOH level (p = 0.02). There was no statistically significant association between serum ETOH level and GOS at 3 (p = 0.97), 6 (p= 0.56), or 12 (p = 0.73) months after injury. The data indicated that serum ETOH levels > 100 mg/dL at the time of admission after a TBI were associated with a decrease in global CBF. Elevated serum ETOH level at time of injury did not, however, impact outcomes.

Neuroglobin Genetic Polymorphisms and Their Relationship to Functional Outcomes after Traumatic Brain Injury

Neuroglobin has shown rich neuroprotective effects against cerebral hypoxia, and therefore has the potential to impact outcomes after traumatic brain injury (TBI). However, to date an association between genetic variation within the human neuroglobin (NGB) gene and recovery post-TBI has not been reported. The purpose of this study was to explore the relationship between NGB genotypes and outcomes (as assessed by the Glasgow Outcome Scale [GOS], the Disability Rating Scale [DRS], and the Neurobehavioral Rating Scale-Revised [NRS-R]) after severe TBI. Genotyping using TaqMan allele discrimination for two tagging single nucleotide polymorphisms (tSNPs) that represent the two haplotype blocks for NGB (rs3783988 and rs10133981) was completed on DNA obtained from 196 Caucasian patients recovering from severe TBI. Patients were dichotomized based on the presence of the variant allele for each tSNP. Chi-square and Fishers exact tests were used to compare characteristics between groups. Multivariate linear regression was used to examine NGB tSNPs and recovery from severe TBI. Subjects with the TT genotype (wild-type) for rs3783988 were more likely to have better GOS and DRS scores at 3, 6, 12, and 24 months, while rs10133981 genotype was not significantly related to functional outcome. After controlling for age, gender, and Glasgow Coma Scale (GCS) score, those subjects with the rs3783988 TT genotype had more than a 2.65-times greater likelihood of better functional outcomes than individuals with genotypes harboring a variant allele. Data suggest that the haplotype block represented by rs3783988 in NGB appears to influence recovery after severe TBI. Represented within this haplotype block of NGB is the region that codes for the oxygen-binding portion of NGB.

Traumatic brain injury research: a review of clinical studies.

There is a growing volume of research on trauma brain injury (TBI) as evidenced by a recent Medline search that reported over 6000 articles published on TBI in the past 5 years.

BCL2 Genotypes: Functional and Neurobehavioral Outcomes after Severe Traumatic Brain Injury

Traumatic brain injury (TBI) triggers a cascade of apoptotic-related events that include BCL2 expression, a pro-survival protein in the apoptosis pathway. The purpose of this study was to use tagging single nucleotide polymorphism (tSNP) genotypes to screen the BCL2 gene to determine if genetic variability in the BCL2 gene influences outcomes in 205 patients with severe TBI. Outcomes (Glasgow Outcome Scale [GOS], Disability Rating Scale [DRS], mortality, and Neurobehavioral Rating Scale-Revised [NRS-R]) were analyzed at 3, 6, 12, and 24 months. Multivariate analysis demonstrates that there were four tSNPs of significant interest: rs17759659, rs1801018, rs7236090, and rs949037. Presence of the variant allele for rs17759659 was associated with poorer outcomes (GOS p = 0.001; DRS p = 0.002), higher mortality (p = 0.02; OR = 4.23; CI 1.31,13.61), and worse NRS-R scores (p = 0.05). Presence of the variant allele for rs1801018 was associated with poorer outcomes (GOS p = 0.02; DRS p = 0.009), and mortality (p = 0.03; OR = 3.86; CI 1.18,12.59). Being homozygous for the wild-type allele for rs7236090 was associated with favorable outcomes on the NRS-R (p = 0.007), while homozygosity for the variant genotype was associated with favorable outcomes on the GOS (p = 0.007) and DRS (p = 0.006). The homozygous variant for rs949037 was associated with favorable outcomes (GOS p = 0.04; DRS p = 0.03), and the homozygous wild-type was associated with increased mortality at 3 months (p = 0.005; OR = 3.67; CI 1.08,12.49). The only finding that stood up to Bonferroni correction was rs17759659 for GOS. These data support the possibility that genetic variability for pro-survival proteins, particularly genetic variation in the BCL2 gene, impacts outcomes after severe TBI.

Haptoglobin genotype and functional outcome after aneurysmal subarachnoid hemorrhage

OBJECT Haptoglobin allele heterogeneity has been implicated in differential reactive oxidant inhibition and inflammation. Haptoglobin α2-α2 has a lower affinity for binding hemoglobin, and when bound to hemoglobin, is cleared less easily by the body. The authors hypothesized that haptoglobin α2-α2 genotype should be less protective for downstream injury after aneurysmal subarachnoid hemorrhage (aSAH) and should portend a worse outcome. METHODS Patients with Fisher Grade 2 or higher aSAH were enrolled in the study. Genotyping for haptoglobin genotype was performed from blood and/or CSF. Demographic information, medical condition variables, and hospital course were abstracted from the medical record upon enrollment into the study. Outcome data (modified Rankin Scale score, Glasgow Outcome Scale score, and mortality) were collected at 3 months posthemorrhage. RESULTS The authors enrolled 193 patients who ranged in age from 18 to 75 years. Only Caucasians were used in this analysis to minimize bias from variable haptoglobin allele frequencies in populations of different ancestral backgrounds. The sample had more women than men (overall mean age 54.45 years). Haptoglobin α2 homozygotes were older than the other individuals in the study sample (57.27 vs 53.2 years, respectively; p = 0.02) and were more likely to have Fisher Grade 3 SAH (p = 0.02). Haptoglobin α2-α2 genotype, along with Fisher grade and Hunt and Hess grade, was associated with a worse 3-month outcome compared to those with the haptoglobin α1-α1 genotype according to modified Rankin Scale score after controlling for covariates (OR 4.138, p = 0.0463). CONCLUSIONS Patients with aSAH who carry the haptoglobin α2-α2 genotype had a worse outcome. Interestingly, the presence of a single α-2 allele was associated with worse outcome, suggesting that the haptoglobin α-2 protein may play a role in the pathology of brain injury following aSAH, although the mechanism for this finding requires further research. The haptoglobin genotype may provide additional information on individual risk of secondary injury and recovery to guide care focused on improving outcomes.

APOE Genotype and Functional Outcome Following Aneurysmal Subarachnoid Hemorrhage

Apolipoprotein E (apoE), the major apolipoprotein in the central nervous system, has been shown to influence neurologic disease progression and response to neurologic injury in a gene-specific manner. Presence of the APOE4 allele is associated with poorer response to traumatic brain injury and ischemic stroke, but the association between APOE genotype and outcome following aneurysmal subarachnoid hemorrhage (SAH) remains unclear. The purpose of this project was to investigate the association between APOE genotype and outcome after SAH. We also explored the association of APOE4 genotype and cerebral vasospasm (CV) presence in a subsample of our population with available angiographic data. A sample of 206 aneurysmal SAH participants had APOE genotyping performed, Glasgow outcome scores (GOS) and modified Rankin scores (MRS) collected at 3 and 6 months after aneurysm rupture. No significant association was found between the presence of the APOE4 genotype and functional outcomes controlling for age, race, size of hemorrhage (Fisher grade), and severity of injury (Hunt & Hess grade). However when controlling for CV and the covariates listed above, individuals with the APOE4 allele had worse functional outcomes at both time points. The presence of the APOE2 allele was not associated with functional outcomes even when considering presence of CV. There was no difference in mortality associated with APOE4 presence, APOE2 presence, or presence of CV. These findings suggest APOE4 allele is associated with poor outcome after aneurysmal SAH.

Genomic, transcriptomic, and epigenomic approaches to recovery after acquired brain injury.

Genomics and its related fields have expanded rapidly, primarily because of the potential utility for clinical decision making and improving our understanding of the pathophysiology of complex conditions. The state of the science and technology associated with this field is such that current and future health care providers, when consulting with new patients about their acquired brain injury and options for rehabilitation, will use genetic information as a routine part of the process, which may include information received from a laboratory report that uses transcriptomic data, informs regarding patient prognosis, and makes recommendations for individualized therapeutic approaches to optimize recovery. This may sound like science fiction, but, in the field of oncology, it is the norm for breast cancer and, more recently, for colon cancer, with expansion to other types of cancer on the horizon as research data continue to contribute to the understanding of the pathophysiology of these conditions. Something similar for rehabilitation after acquired brain injury is much further off on the horizon. However, it is a possibility that will never be realized if the community of scientists and health care providers who work with these patients do not have the knowledge or expertise to embrace genomics and related approaches. This article discusses these approaches, some practical considerations for using such approaches, and what is currently published in this area with regard to brain injury.

Endothelial Nitric Oxide Synthase Tagging Single Nucleotide Polymorphisms and Recovery From Aneurysmal Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage (SAH) is a hemorrhagic stroke subtype with a poor recovery profile. Cerebral vasospasm (CV), a narrowing of the cerebral vasculature, significantly contributes to the poor recovery profile. Variation in the endothelial nitric oxide (NO) synthase (eNOS) gene has been implicated in CV and outcome after SAH. The purpose of this project was to explore the potential association between three eNOS tagging single nucleotide polymorphisms (SNPs) and recovery from SAH. We included 195 participants with a diagnosis of SAH and DNA and 6-month outcome data available but without preexisting neurologic disease/deficit. Genotyping was performed using an ABI Prism 7000 Sequence Detection System and TaqMan assays. CV was verified by cerebral angiogram independently read by a neurosurgeon on 118 participants. Modified Rankin Scores (MRS) and Glasgow Outcome Scale (GOS) scores were collected 6 months posthemorrhage. Data were analyzed using descriptive statistics, analysis of variance (ANOVA) and chi-square analysis as appropriate. The sample was primarily female (n = 147; 75.4%) and White (n = 178; 91.3%) with a mean age of 54.6 years. Of the participants with CV data, 56 (47.5%) developed CV within 14 days of SAH. None of the SNPs individually were associated with CV presence; however, a combination of the three variant SNPs was significantly associated with CV (p = .017). Only one SNP (rs1799983, variant allele) was associated with worse 6-month GOS scores (p < .001) and MRS (p < .001). These data indicate that the eNOS gene plays a role in the response to SAH, which may be explained by an influence on CV.

Interleukin 6 and Apolipoprotein E as Predictors of Acute Brain Dysfunction and Survival in Critical Care Patients

BACKGROUND Delirium occurs in up to 80% of intensive care patients and is associated with poor outcomes. The biological cause of delirium remains elusive. OBJECTIVES To determine if delirium and recovery are associated with serum levels of interleukins and apolipoprotein E over time and with apolipoprotein E genotype. METHODS The sample consisted of 77 patients with no previous cognitive deficits who required mechanical ventilation for 24 to 96 hours. Daily serum samples were obtained for enzyme-linked immunosorbent assay measurements of interleukins 6, 8, and 10 and apolipoprotein E. DNA extracted from blood was analyzed for apolipoprotein E genotyping. The Confusion Assessment Method for the Intensive Care Unit was administered daily on days 2 through 9. RESULTS Among the 77 patients, 23% had no delirium, 46% experienced delirium, and 31% experienced coma. Additionally, 77% had delirium or coma (acute brain dysfunction), and compared with other patients, had fewer ventilator-free days (P = .03), longer stay (P = .04), higher care needs at discharge (P = .001), higher mortality (P = .02), and higher levels of interleukin 6 (P = .03), and the APOE*3/*3 apolipoprotein E genotype (P = .05). Serum levels of apolipoprotein E correlated with levels of interleukins 8 and 10. Patients with the E4 allele of apolipoprotein E had shorter duration of delirium (P = .02) and lower mortality (P = .03) than did patients without this allele. CONCLUSIONS Apolipoprotein E plays a complex role in illness response and recovery in critically ill patients. The relationship between apolipoprotein E genotype and brain dysfunction and survival is unclear.

Gene Expression Profiling for Discovery of Novel Targets in Human Traumatic Brain Injury

Several clinical trials have failed to demonstrate a significant effect on outcome following human traumatic brain injury (TBI) despite promising results obtained in preclinical animal studies. These failures may be due in part to a misinterpretation of the findings obtained in preclinical animal models of TBI, a misunderstanding of the complexity of the human response to TBI, limited knowledge about the biological pathways that interact to contribute to good and bad outcomes after brain injury, and the effects of genomic variability and environment on individual recovery. Recent publications suggest that data obtained from gene expression profiling studies of complex neurological diseases such as stroke, multiple sclerosis (MS), Alzheimer’s and Parkinson’s may contribute to a more informed understanding of what affects outcome following TBI. These data may help to bridge the gap between successful preclinical studies and negative clinical trials in humans to reveal novel targets for therapy. Gene expression profiling has the capability to identify biomarkers associated with response to TBI, elucidate complex genetic interactions that may play a role in outcome following TBI, and reveal biological pathways related to brain health. This review highlights the current state of the literature on gene expression profiling for neurological disease and discusses its ability to aid in unraveling the variable human response to TBI and the potential for it to offer treatment strategies in an area where we currently have limited therapeutic options primarily based on supportive care.