Contrast Agent Clearance Dynamics and Diffusion in the Mouse Brain After Ventricular Administration

Abstract Fluid and solute exchange between cerebrospinal fluid (CSF) spaces and the central nervous system (CNS) parenchyma are critical for maintaining neural homeostasis and clearing metabolites. Nevertheless, the pathways and mechanisms underlying fluid and solute exchange between these compartments remain poorly understood. Historically, solute exchange between CSF spaces and the CNS parenchyma has been attributed to diffusion primarily driven by concentration gradients. Recently, the glymphatic hypothesis has challenged this concept by proposing that fluid and solutes move through the brain parenchyma via bulk flow, with influx along arterial perivascular spaces (PVS) and efflux along venous PVS. In this study, we used dynamic contrast‐enhanced MRI to investigate the distribution of two different contrast agents of molecular weights <1 kDa and 17 kDa injected into the lateral ventricle under awake, low‐dose, and high‐dose anesthesia conditions. Our findings revealed an increased CSF bulk flow of both contrast agents from the lateral ventricles to the circle of Willis under awake and low‐dose anesthesia states. In contrast, solute movement into different regions of the brain parenchyma was size‐dependent and affected by the rate of clearance from the ventricles. These observations support the CSF sink hypothesis, emphasizing diffusion‐driven solute exchange as a key mechanism over glymphatic circulation.