Table 1.

Limitations in knowledge related to glymphatic clearance and BBB clearance (adapted [73])

Limitations for glymphatic clearance	Limitations for BBB clearance
Fluorescent tracing has demonstrated size-dependent flow of tracers consistent with diffusion coefficients, suggesting a diffusion model of transport instead of the glymphatic model	Fluorescent tracing has demonstrated similar rate constants for the transport of solutes with large size variations, suggesting a convective model
AQP4 cannot transport macromolecules and AQP4-null mice have demonstrated no qualitative or quantitative variation in solute clearance	AQP4-null mice have demonstrated impaired solute clearance
Bulk flow is unlikely with the high hydraulic resistance of such narrow pathways, even with a major pressure difference	Diffusion transport is only short range and thus cannot explain how solutes are cleared over the long distance between IF and the BBB
There may be insufficient coverage of cerebral blood vessels by astrocytic endfeet to justify their role in “sieving” interstitial solutes	Diffusion of solutes into the CSF for clearance is exclusive to small and/or lipophilic molecules, suggesting the sieving effect of astrocytic endfeet

BBB, blood-brain barrier; AQP4, aquaporin-4; IF, interstitial fluid; CSF, cerebrospinal fluid.