Matthew J. Gallek

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.

Endothelin-1 and Endothelin Receptor Gene Variants and Their Association With Negative Outcomes Following Aneurysmal Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease that affects approximately 30,000 people a year in the United States. Delayed cerebral ischemia (DCI) and cerebral vasospasm (CV) are common complications after aSAH. In addition, aSAH patients have a high risk of poor long-term outcomes. Endothelin-1 (ET-1), a potent vasoconstrictor, or its two types of receptors, ET receptor A (ETA ) and ET receptor B (ETB), may play a role in the pathogenesis of DCI and CV. Genetic variations within the ET-1, ETA, or ETB genes may also account for variance observed in the outcomes of aSAH patients. The purpose of this study was to describe the distribution of the Lys198Asn polymorphism, a known functional SNP in the ET-1 gene, and tagging SNPs of the ET-1, ETA, and ETB genes in individuals recovering from aSAH. This study also investigated the relationships among the ET polymorphisms, DCI, and global functional outcomes measured at 3 and 6 months after aSAH. Participants included individuals aged 18–75 years with a diagnosis of aSAH. There was a trend found between the variant allele of an ET-1 SNP (rs6912834) and angiographic vasospasm. There were also associations found between two ETB SNPs (rs9574124 and rs3027111) and poor outcomes as measured by the Glasgow Outcome scale at 3 months. These findings support the role of ET-1 and ETB in recovery following aSAH.

Cortical gene expression correlates of temporal lobe epileptogenicity

INTRODUCTION Despite being one of the most common neurological diseases, it is unknown whether there may be a genetic basis to temporal lobe epilepsy (TLE). Whole genome analyses were performed to test the hypothesis that temporal cortical gene expression differs between TLE patients with high vs. low baseline seizure frequency. METHODS Baseline seizure frequency was used as a clinical measure of epileptogenicity. Twenty-four patients in high or low seizure frequency groups (median seizures/month) underwent anterior temporal lobectomy with amygdalohippocampectomy for intractable TLE. RNA was isolated from the lateral temporal cortex and submitted for expression analysis. Genes significantly associated with baseline seizure frequency on likelihood ratio test were identified based on >0.90 area under the ROC curve, P value of <0.05. RESULTS Expression levels of forty genes were significantly associated with baseline seizure frequency. Of the seven most significant, four have been linked to other neurologic diseases. Expression levels associated with high seizure frequency included low expression of Homeobox A10, Forkhead box A2, Lymphoblastic leukemia derived sequence 1, HGF activator, Kelch repeat and BTB (POZ) domain containing 11, Thanatos-associated protein domain containing 8 and Heparin sulfate (glucosamine) 3-O-sulfotransferase 3A1. CONCLUSIONS This study describes novel associations between forty known genes and a clinical marker of epileptogenicity, baseline seizure frequency. Four of the seven discussed have been previously related to other neurologic diseases. Future investigation of these genes could establish new biomarkers for predicting epileptogenicity, and could have significant implications for diagnosis and management of temporal lobe epilepsy, as well as epilepsy pathogenesis.

Central nervous system genomics.

In the past 25 years, remarkable progress has been made in our understanding of genomics and its influence on central nervous system diseases. In this chapter, common diseases of the central nervous system will be reviewed along with the genomics associated with these diseases. The diseases/injuries that will be investigated include neurovascular disorders such as ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, and traumatic brain injury. This chapter will also explore Apolipoprotein E (APOE), a 299-aminoacid protein encoded by the APOE gene, and its associations with many of the previously named diseases. APOE was first tied to the risk of Alzheimers disease and has since then been investigated in traumatic brain injury and hemorrhagic strokes. In addition, we will discuss the future of genomic research in central nervous system diseases.

The Relationships Between BNP and Neurocardiac Injury Severity, Noninvasive Cardiac Output, and Outcomes After Aneurysmal Subarachnoid Hemorrhage

Introduction: Neurocardiac injury, a type of myocardial dysfunction associated with neurological insult to the brain, occurs in 31–48% of aneurysmal subarachnoid hemorrhage (aSAH) patients. Cardiac troponin I (cTnI) is commonly used to diagnose neurocardiac injury. Brain natriuretic peptide (BNP), another cardiac marker, is more often used to evaluate degree of heart failure. The purpose of this study was to examine the relationships between BNP and (a) neurocardiac injury severity according to cTnI, (b) noninvasive continuous cardiac output (NCCO), and (c) outcomes in aSAH patients. Method: This descriptive longitudinal study enrolled 30 adult aSAH patients. Data collected included BNP and cTnI levels and NCCO parameters for 14 days and outcomes (modified Rankin Scale [mRS] and mortality) at discharge and 3 months. Generalized estimating equations were used to evaluate associations between BNP and cTnI, NCCO, and outcomes. Results: BNP was significantly associated with cTnI. For every 1 unit increase in log BNP, cTnI increased by 0.05 ng/ml (p = .001). Among NCCO parameters, BNP was significantly associated with thoracic fluid content (p = .0003). On multivariable analyses, significant associations were found between BNP and poor mRS. For every 1 unit increase in log BNP, patients were 3.16 times more likely to have a poor mRS at discharge (p = .021) and 5.40 times more likely at 3 months (p < .0001). Conclusion: There were significant relationships between BNP and cTnI and poor outcomes after aSAH. BNP may have utility as a marker of neurocardiac injury and outcomes after aSAH.

Transitions of care for stroke and TIA

Purpose:The purpose of this study was to identify elements of a stroke population that may affect transitions of care (TOC). Data sources:A retrospective analysis of the demographic characteristics of patients from an urban primary stroke center with an admitting diagnosis of transient ischemic attack, acute ischemic stroke, subarachnoid hemorrhage, or intracerebral hemorrhage was performed over an 8‐month period (N = 276). A subset of this patient sample participated in a telephone survey 1 month after discharge. Conclusion:Hospital length of stay, age, insurance status, discharge disposition, comorbidities, and readmission rates were identified as important elements affecting TOC for stroke and TIA. Information from patient surveys indicated that emotional health, follow‐up with care providers, stroke education, and point of contact are important elements during the transition periods after stroke and TIA. Implications for practice:Both providers and patients should inform the development of a comprehensive TOC program that spans in‐hospital to multiple care settings, including the home, which is essential. The advanced practice nurse is ideally suited to successfully lead these programs.

Endothelin-1 Gene Polymorphisms Influence Cerebrospinal Fluid Endothelin-1 Levels Following Aneurysmal Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage is a type of stroke with high morbidity and mortality. Increased endothelin-1 (ET-1) levels have been associated with increased risk of cerebral vasospasm, which is associated with increased morbidity. The purpose of this study was to investigate the relationships between ET-1 genotypes and ET-1 protein levels in cerebrospinal fluid (CSF) measured 72 hr before angiographic vasospasm measurement in subjects at high risk of cerebral vasospasm. Specifically, this study evaluated the differences between variant positive and variant negative groups of nine different ET-1 single-nucleotide polymorphisms (SNPs) in relationship with the ET-1 protein exposure rate. The CSF ET-1 protein levels were quantified using enzyme-linked immunosorbent assay. One functional SNP and eight ET-1 tagging SNPs were selected because they represent genetic variability in the entire ET-1 gene. The variant negative group of SNP rs2070699 was associated with a significantly higher ET-1 exposure rate than the variant positive group (p = 0.004), while the variant positive group of the rs5370 group showed a trend toward association with a higher ET-1 exposure rate (p = 0.051). Other SNPs were not informative. This is the first study to show differences in ET-1 exposure rate 72 hr before angiography in relation to ET-1 genotypes. These exploratory findings need to be replicated in a larger study; if replicated, these differences in genotypes may be a way to inform clinicians of those patients at a higher risk of increased ET-1 protein levels, which may lead to a higher risk of angiographic vasospasm.