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IMAGING THE PERIVASCULAR SPACE 65

of the glymphatic flow. Nevertheless, both systems flow, which has been implicated in the removal of
require proficient passage along perivascular spaces. Aβ (4,10,11,28,29,53), a protein well-known for its
role in AD (72). ISF bulk flow pathways are thought
Perivascular and Glymphatic Clearance to originate in the walls of cerebral vessels, running
As mentioned above, previous studies derived along the basement membrane of capillaries and
mostly from a single group of researchers have arteries that drive ISF toward CSF compartments.
shown that ISF can move along the perivascular While the removal of ISF along periarterial path-
spaces of arteries in the opposite direction of blood ways provides one mechanism for solute and waste

Figure 1. Perivascular and Glymphatic Flow
Perivascular clearance comprises perivascular drainage and glymphatic pathways. The perivascular drainage pathway (white arrows) moves
waste into the periarterial space (located along smooth muscle cells and the capillary basement membrane) and towards the subarachnoid
space in the direction opposite to blood flow. The glymphatic pathway (black arrows) clears waste from the ISF through the brain paren-
chyma, and comprises three functional components. (1) CSF influx, unidirectionally with blood flow, into the periarterial space (between
the basement membrane of smooth muscle cells and pia mater), where the water component of CSF crosses astrocytic AQP4 channels
to enter the brain parenchyma. CSF solutes can be cleared with astroglial transporters or channels, or can pass through the astrocytic
endfeet clefts. (2) CSF–ISF exchange within the brain parenchyma. (3) CSF–ISF movement into the perivenous space of deep-draining
veins. Effluxed waste can then recirculate with the CSF, or eventually be absorbed into the lymphatic system. Arrows indicate direction
of flow. Abbreviations: AQP4, aquaporin-4; CSF, cerebrospinal fluid; ISF, interstitial fluid. Adapted with permission from AAAS: Science
(Nedergaard, M. Garbage truck of the brain. Science. 2013;340:1529-1530). Reprinted by permission from Macmillan Publishers Ltd: Nature
Reviews Neurology (Tarasoff-Conway, J.; Carare, R.; Osorio, R.; Glodzik, L.; Butler, T.; Fieremans, E.; Axel, L.; Rusinek, H.; Nicholson, C.;
Zlokovic, B.; Frangione, B; Blennow, K.; Ménard, J.; Zetterberg, H.; Wisniewski, T.; Leon, M. Clearance systems in the brain—implications
for Alzheimer disease. Nature Reviews Neurology. 2015;11:457-470), copyright 2015.