AQP4 and glymphatic function in post-stroke recovery

点击翻译按钮获取中文摘要

SUMMARY Stroke is a leading cause of death and long-term disability. Brain edema is the most common life- threatening complication following an acute stroke event. It leads to elevated intracranial pressure that will affect the spared areas surrounding the stroked tissue. The preservation of such areas is critical in reducing brain injury and promoting long-term recovery. Understanding the pathophysiology of brain edema is key to identifying therapeutic targets and reducing the final disability burden related to acute stroke. The glymphatic system is a recently discovered waste clearance pathway in the brain. It removes interstitial metabolic waste products, as well as excessive interstitial fluid (ISF), by facilitating the exchange of ISF and cerebrospinal fluid (CSF). With drastically increased metabolic byproducts and the development of cerebral edema, the glymphatic system may play a critical role in post-stroke recovery. Further, aquaporin-4 (AQP4), a water channel protein that has been recognized to be involved in cerebral edema, also drives the glymphatic system. However, due to the limited means of evaluating the glymphatic function in vivo, our current understanding of the role of AQP4 and the glymphatic system in post-stroke recovery is still quite limited. The goal of this project is to develop novel MRI methods for quantitative assessment of the glymphatic function in vivo and to apply these methods to investigate the role of AQP4 and the glymphatic system in post-stroke edema formation and reabsorption. Specifically, we will develop and validate a 3D magnetic resonance fingerprinting (MRF) method for dynamic and simultaneous tracking of a gadolinium (Gd)-based, large molecular weight (MW) paravascular tracer (GadoSpin, MW=200 kDa, primarily a T1 contrast agent) and oxygen-17 (17O) enriched water (H217O, MW=19 Da, a T2 contrast agent) in mouse brain (Aim 1). This approach will enable the simultaneous evaluation of CSF flow in the paravascular space and CSF-ISF exchange between the paravascular space and brain parenchyma in a single MRF scan. Kinetic analysis methods will be developed for quantitative assessment of the glymphatic function from MRF measurements, including the CSF flow in the paravascular conduits and the CSF-ISF exchange rate and water transport in the glymphatic pathway (Aim 2). These methods will be applied to evaluate the effects of AQP4 knockout and inhibition on edema formation and reabsorption in two mouse models of ischemic (cytotoxic edema) and hemorrhagic (vasogenic edema) stroke (Aim 3). Successful completion of the project will give rise to a novel MRI method for in vivo quantification of glymphatic function. Application of this method to the investigation of post-stroke pathophysiology will lead to new insights into the role of AQP4 and the glymphatic system in post-stroke edema.