Rapid lymphatic efflux limits cerebrospinal fluid flow to the brain

Abstract

The relationships between cerebrospinal fluid (CSF) and brain interstitial fluid are still being elucidated. It has been proposed that CSF within the subarachnoid space will enter paravascular spaces along arteries to flush through the parenchyma of the brain. However, CSF also directly exits the subarachnoid space through the cribriform plate and other perineural routes to reach the lymphatic system. In this study, we aimed to elucidate the functional relationship between CSF efflux through lymphatics and the potential influx into the brain by assessment of the distribution of CSF-infused tracers in awake and anesthetized mice. Using near-infrared fluorescence imaging, we showed that tracers quickly exited the subarachnoid space by transport through the lymphatic system to the systemic circulation in awake mice, significantly limiting their spread to the paravascular spaces of the brain. Magnetic resonance imaging and fluorescence microscopy through the skull under anesthetized conditions indicated that tracers remained confined to paravascular spaces on the surface of the brain. Immediately after death, a substantial influx of tracers occurred along paravascular spaces extending into the brain parenchyma. We conclude that under normal conditions a rapid CSF turnover through lymphatics precludes significant bulk flow into the brain.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1916-x) contains supplementary material, which is available to authorized users.

Intracranial pressure elevation alters CSF clearance pathways

“…We note that lumbar intrathecal contrast delivery during infusion to assess glymphatic function in humans was proposed in Yang et al [70]. Further, as suggested by Ma et al [38] increased flow, and a possible change in ICP, may alter the distribution of CSF to different outflow pathways. In addition, if the glymphatic circulation is a main outflow route for CSF, the outflow resistance R out is a direct measure of glymphatic dysfunction, which in turn has been linked to neurodegenerative disorders [33].…”

“…In addition, pressure gradients in the SAS are likely less than 3 mmHg/m [44,55], and the transmantle pressure difference has been estimated to be no more than 0.03 mmHg [64]. Glymphatic circulation driven by local differences in pulsatile pressure of several mmHg also seems implausible, as the ICP wave is almost identical in time everywhere in the brain [13], with a maximal estimated pulsatile difference of approximately 0.2 mmHg [68] Ma et al [38] suggest that outflow through the cribriform plate dominates, but only when the total outflow from the SAS is large. We also found the relative distribution of flow to the different outflow pathways to be affected by infusion, but there are important differences.…”

“…In sheep it has been reported that outflow through the cribriform plate plays a major role in CSF absorption, whereas the importance of the AG is unclear [59]. Flow through the cribriform plate has been suggested to dominate the paravascular flow route when total CSF efflux is large [38]. In addition, the Bulat-Klarica-Orešković hypothesis states that production and absorption is present everywhere in the CSF system, especially over the capillary wall due to its large surface area [9].…”

Paravascular spaces: entry to or exit from the brain?

“…Such open communication would effectively eliminate potential pressure differences, which are necessary to drive glymphatic flow (Faghih & Sharp, 2018). In agreement with this view, recent work shows that even at very early time points, tracers are present in the paravascular spaces of both arteries and veins at the level of the SAS (Ma et al, 2018). Thus, it appears that these physical and anatomical features do not concur with the proposed bulk flow through the parenchyma according to the glymphatic theory.…”

“…Again, net flow at the brain surface does not provide evidence for inflow along paravascular spaces around arteries into the brain. In fact, recent work shows that tracers do not appreciably enter the brain parenchyma after injection into the cisterna magna and rapidly leave the brain via the cribriform plate and other perineural pathways (Ma et al., ). However, the oscillations in pressure in the CSF compartment could play a role in the transport of solutes along paravascular spaces of penetrating arteries.…”