Author ORCID Identifier

https://orcid.org/0000-0002-9388-0232

Year of Publication

2020

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Behavioral Science

First Advisor

Dr. Peter Morris

Second Advisor

Dr. Joshua Lile

Abstract

Aneurysmal subarachnoid hemorrhage (aSAH) is a severe form of hemorrhagic stroke resulting from the spontaneous rupture of an intracranial aneurysm and release of oxygenated blood into the subarachnoid space. In the United States alone, aSAH occurs in approximately 30,000 patients each year and occurs, primarily, in otherwise healthy adults, frequently without warning. Sadly, approximately 40% of patients with aSAH will die in the first 30 days. Of those who survive, only about 75% will be able to live semi-independently again and only about 60% will be able to return to work.

Delayed brain injuries (DBI), which may affect up to 70% of aSAH patients, are an important cause of these devastating outcomes. DBI include delayed cerebral vasospasm (DCV) and delayed cerebral ischemia (DCI). Despite intensive research, effective preventative and treatment therapies for DBI have not been identified, in part due an incomplete understanding of their pathophysiology. Although a number of mechanisms have been proposed, a strong correlation between DBI and inflammatory mediators has been most frequently observed, suggesting an important role of inflammation in the development of DBI.

Because intracranial blood is a key feature of aSAH, haptoglobin (Hp) has emerged as a potential patient-specific modifier of DBI risk. Hp is a naturally occurring acute phase reactant that binds to free hemoglobin (Hb) molecules to facilitate Hb metabolism by circulating macrophages. In humans, there are 3 different Hp phenotypes, Hp1-1, Hp1-2 and Hp2-2. Recent clinical observations suggest that different Hp phenotypes affect the incidence of DBI after aSAH. While the mechanism for this observation remains unknown, one potential explanation is that Hp may alter the neuroinflammatory response, reflected in plasma, CSF, or parenchymal concentrations of pro-inflammatory cytokines. Macrophage CD163 binds Hp-Hb complexes and a free-floating version of CD163, termed soluble CD163 (sCD163), can also be isolated from plasma and other body tissues in response to stress and as a result of inflammatory injury. The relationship between sCD163 and different Hp phenotypes is unknown but sCD163 may also have an important role in modulating DBI risk after aSAH.

The objective of this dissertation, therefore, is to investigate the hypothesize that the different haptoglobin phenotypes modify the risk of DBI through a differential effect on sCD163 and inflammatory cytokines. To achieve this objective, three specific aims were completed and are described in detail in this dissertation. First, a prospectively collected aSAH biobank was established at the University of Kentucky. This biobank was necessary to facilitate current and future observational aSAH studies. Second, using data and patient samples from the established biobank, plasma and CSF concentrations of 3 different neuroinflammatory cytokines were determined at pre-specified time points and compared against Hp phenotype, clinical outcome, and DBI diagnoses. Finally, using data and patient samples from the established biobank, plasma and CSF concentrations of sCD163 was determined at pre-specified time points and were also compared against Hp phenotype, clinical outcome, and DBI diagnoses.

The proposed biobank successfully recruited 25 patients over a 2-year period. Of these patients, 3 (12%) were Hp1-1 phenotype, 14 (56%) were Hp1-2 phenotype, and 8 (32%) were Hp2-2 phenotype. There were no statistically significant differences in plasma or CSF concentrations of any of the measured cytokines at any time point when subjects were compared by their DCV status, DCI status, Hp phenotype, Hp class, or a combination of Hp class and DCV or DCI. While there were significant differences in plasma sCD163 concentration when subjects were compared by a combination of Hp class and DCV, there were no other statistically significant differences in plasma or CSF concentration of sCD163 at any time point when subjects were compared by their DCV status, DCI status, Hp phenotype, Hp class, or a combination of Hp class and DCV or DCI. These findings are most likely related to the relatively small number of patients included in these analyses. Future studies should include more patients to better evaluate the roles that the different Hp phenotypes play in the development of DBI after aSAH.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.467

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Neurosurgery Commons

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