Multimodal characterization of central nervous system inflammation in patients with aneurysmal subarachnoid hemorrhage

Yale University, New Haven CT

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating type of hemorrhagic stroke with high rates of morbidity and mortality, and after initial stabilization, the mainstay of care is supportive. Early elevation of pro- inflammatory cytokines in the central nervous system is associated with adverse outcomes after hemorrhage. Whether time-to-resolution of this pro-inflammatory phase is a determinant of outcomes remains uncertain. The goal of this research project and training plan is to provide Dr. Magid-Bernstein, an Assistant Professor of Neurology at Yale University and a Physician-Scientist with expertise in immunology and neurocritical care with the critical skills to become an independent investigator at the juncture of neuroimmunology and acute brain injury. Her career development aims are: (1) to learn advanced statistical methods to analyze neuroimaging, (2) to obtain expertise in advanced statistical techniques including analysis of large datasets and computational transcriptomic analysis, (3) to gain skills in managing clinical research cohorts and clinical trial design, and (4) to develop the leadership and academic skills to lead a research program. To achieve these goals, the PI has assembled a mentorship team of experts in translational research in inflammation and stroke, neuroimaging, and advanced biostatistical methods including transcriptomics. Our preliminary data show that pro-inflammatory cytokines including interleukin-6, interleukin-8, C-C motif chemokine ligand-2, and vascular endothelial growth factor are elevated in the cerebrospinal fluid (CSF) of patients with aSAH within the first 3 days after ictus. The proposed study will investigate the duration of the pro- inflammatory phase as a potentially modifiable determinant of outcome after hemorrhage. Our central hypothesis is that failure to transition from a pro-inflammatory state to a reparative and anti- inflammatory CSF profile in patients with aSAH will be associated with poor neurologic outcome, persistent hydrocephalus, and inflammation on magnetic resonance imaging (MRI). We will test this hypothesis by collecting serial CSF samples from 200 aSAH patients and measuring cytokines and numbers of immunologic cells within the CSF to characterize the trajectory of inflammation over time and its relationship to outcome (Aim 1). We will investigate the relationship between this immune profile, persistent post-hemorrhagic hydrocephalus on computed tomography (CT) images, and on vessel wall MRI (Aim 2). Finally, in an exploratory aim, we will investigate the relationship between the above inflammatory CSF profiles, hydrocephalus on CT imaging, inflammation on vessel wall MRI, and outcome (Aim 3). The proposed research is significant because no disease modifying interventions exist for critically ill patients with aSAH, and identification of CSF and imaging markers associated with poor outcome will enable development of targeted interventions to modify the course of this devastating disease. This project is innovative because it will identify multimodal markers of neuroinflammation after aSAH, paving the way for novel intervention.