Figure 1. The glymphatic pathway.

Rodent studies have shown that CSF from the subarachnoid space is driven into the perivascular space of major cerebral arteries on the brain surface from where it flows along the artery as it branches into penetrating arteries.^12,13,22,39A similar pattern of CSF flow has been shown in patients undergoing MRI in combination with intrathecal contrast agent.^15,46 In these patients it was observed that the CSF contrast agent flows along the large leptomeningeal cerebral arteries in an anterograde fashion, and that presence of contrast agent in the subarachnoid space precedes parenchymal uptake in adjacent brain regions.¹⁵ The microscopic details of CSF flow within the brain thus far all stem from animal research. These studies have shown that the perivascular space runs along the entire penetrating artery, known as the Virchow-Robin space, and continues to follow the vessel as it branches into arterioles and capillaries.^12,13,21 In the murine brain, CSF influx into the extracellular space happens at every level of the perivascular space after entry to the brain parenchyma and is facilitated by a polarized expression of the AQP4 water channel towards the astrocytic end-feet that line the perivascular space.¹² Whether a similar parenchymal CSF flow occurs in human brain has not yet been proven, but humans also harbor intracerebral perivascular spaces and polarized AQP4 expression towards astrocytic end-feet.^55,58 The basis of fluid movement within the interstitium is still a matter of debate. Bulk flow clearance of ISF is a long-standing observation, which could be driven by multiple factors such as CSF inflow, arterial pulsatility, hydrostatic pressure gradients between the arterial and venous perivascular spaces, and osmotic gradients.⁸ Rodent studies show that ISF and its solutes move towards the venous perivascular space, where the fluid is taken up and drained by convection out of the brain parenchyma.¹² This directional flow removes solutes from the brain parenchyma accumulated during neural activity.¹²

CSF, cerebrospinal fluid; ISF interstitial fluid, PVS: perivascular space; AQP4, aquaporin-4.