The Association between Glymphatic System and Perivascular Macrophages in Brain Waste Clearance

The glymphatic system suggests the convective bulk flow of cerebrospinal fluid (CSF) through perivascular spaces and the interstitial spaces of the brain parenchyma for the rapid removal of toxic waste solutes from the brain. However, the presence of convective bulk flow within the brain interstitial spaces is still under debate. We first addressed this argument to determine the involvement of the glymphatic system in brain waste clearance utilizing contrast-enhanced 3D T1-weighted imaging (T1WI), diffusion tensor imaging (DTI), and confocal microscopy imaging. Furthermore, perivascular macrophages (PVMs), which are immune cells located within perivascular spaces, have not been thoroughly explored for their association with the glymphatic system. Therefore, we investigated tracer uptake by PVMs in the perivascular spaces of both the arteries/arterioles and veins/venules and the potential association of PVMs in assisting the glymphatic system for interstitial waste clearance. Our findings demonstrated that both convective bulk flow and diffusion are responsible for the clearance of interstitial waste solutes from the brain parenchyma. Furthermore, our results suggested that PVMs may play an important function in glymphatic system-mediated interstitial waste clearance. The glymphatic system and PVMs could be targeted to enhance interstitial waste clearance in patients with waste-associated neurological conditions and aging.