Perivascular spaces around arteries exceed perivenous spaces in the mouse brain.

The perivascular space (PVS) surrounds cerebral blood vessels and plays an important role in clearing waste products from the brain. Their anatomy and function have been described for arteries, but PVS around veins remain poorly characterized. Using in vivo 2-photon imaging in mice, we determined the size of the PVS around arteries and veins, and their connection with the subarachnoid space. After infusion of 70 kD FITC-dextran into the cerebrospinal fluid via the cisterna magna, labeled PVS were evident around arteries, but veins showed less frequent labeling of the PVS. The size of the PVS correlated with blood vessel size for both pial arteries and veins, but not for penetrating vessels. The PVS around pial arteries and veins was separated from the subarachnoid space by a thin meningeal layer, which did not form a barrier for the tracer. In vivo, FITC-dextran signal was observed adjacent to the vessel wall, but minimally within the wall itself. Post-mortem, there was a significant shift in the tracer's location within the arterial wall, extending into the smooth muscle layer. Taken together, these findings suggest that the PVS around veins has a limited role in the exchange of solutes between CSF and brain parenchyma.

Cerebrospinal fluid turnover as a driver of brain clearance.

Cerebrospinal fluid (CSF) has historically been considered to function as a sink for brain-derived waste disposal. Recent work suggested that CSF interacts even more intensely with brain tissue than previously recognized, through perivascular spaces that penetrate the brain. Cardiac pulsations, vasomotion, and respiration have been suggested to drive CSF flow in these perivascular spaces, thereby enhancing waste clearance. However, the intrinsic role of CSF production in relation to its distribution volume (turnover) is not an explicit component of recent concepts on brain clearance. Here, we review the work on CSF turnover and volume, focusing on preclinical evidence. Herein, we highlight the use of MRI in establishing CSF-related parameters. We describe the impact of sleep, effect of anesthesia, aging, and hypertension on CSF turnover, and how this relates to brain clearance. Evaluation of the available evidence suggests that CSF turnover is a major determinant in brain clearance. In addition, we propose that several putative drivers of brain clearance, but also conditions associated with impaired clearance, such as aging, may actually relate to altered CSF turnover.