FIGURE 23.
Reframing the contributions of advection and diffusion to glymphatic clearance. A: 2-dimensional representation of the glymphatic pathway, composed of a brain-wide network of perivascular spaces that branch along the cerebral vasculature. Cerebrospinal fluid (CSF) flows into the system (Qin) through the large surface perivascular spaces of the cerebral arteries flowing at several microns per second (µm/s) and transports solutes like oxygen and carbon dioxide by a primarily advective process. As the flow pathways bifurcate and divide into daughter branches, glymphatic fluid flow slows down perhaps up to several nanometers per second (nm/s) near the capillaries in the tissue where diffusion would dominate transport of most solutes. The flow continues along the closed system toward the outflow routes and coalesces increasing in speed. The total outflow rate (Qout) might not be exclusively composed of fluid coming from perivenous spaces but might also include white matter tracts and subependymal pathways. The sum of all these outflow pathways should theoretically equal the inflow rate (Qin = Qout). B: ions and small molecules (e.g., H2O: 18 Da; Na: 23 Da; O2: 32 Da; and K: 39 Da) can be transported quickly and efficiently across short distances via diffusion, while larger molecules (e.g., lactate: 90 Da, and glucose: 180 Da), peptides and protein aggregates (e.g., Aβ1-40: 4.3 kDa; Aβ1-42: 4.5 kDa; albumin: 66.5 kDa, Aβ oligomers: 100-200 kDa; and tau aggregates: 242 kDa) might rely more so on the advective modes of transport for clearance. C: glymphatic function is dependent on the interplay between effective advective transport via perivascular spaces and adequate access to the extracellular space. Dysfunction in glymphatic clearance could be due to variations in either or both of these processes. RBCs, red blood cells; AQP4, aquaporin 4.