Review Fluid transport in the brain, 2022, Rasmussen, Mestre, Nedergaard

[SNT Gatchaman]

Fluid transport in the brain

Spoiler: Authors

Martin Kaag Rasmussen; Humberto Mestre; Maiken Nedergaard

The brain harbors a unique ability to, figuratively speaking, shift its gears. During wakefulness, the brain is geared fully toward processing information and behaving, while homeostatic functions predominate during sleep. The blood-brain barrier establishes a stable environment that is optimal for neuronal function, yet the barrier imposes a physiological problem; transcapillary filtration that forms extracellular fluid in other organs is reduced to a minimum in brain. Consequently, the brain depends on a special fluid [the cerebrospinal fluid (CSF)] that is flushed into brain along the unique perivascular spaces created by astrocytic vascular endfeet.

We describe this pathway, coined the term glymphatic system, based on its dependency on astrocytic vascular endfeet and their adluminal expression of aquaporin-4 water channels facing toward CSF-filled perivascular spaces. Glymphatic clearance of potentially harmful metabolic or protein waste products, such as amyloid-β, is primarily active during sleep, when its physiological drivers, the cardiac cycle, respiration, and slow vasomotion, together efficiently propel CSF inflow along periarterial spaces. The brain’s extracellular space contains an abundance of proteoglycans and hyaluronan, which provide a low-resistance hydraulic conduit that rapidly can expand and shrink during the sleep-wake cycle.

We describe this unique fluid system of the brain, which meets the brain’s requisites to maintain homeostasis similar to peripheral organs, considering the blood-brain-barrier and the paths for formation and egress of the CSF.

Web | DOI | PDF | Physiological Reviews | Open Access

 

[Jonathan Edwards]

The blood-brain barrier establishes a stable environment that is optimal for neuronal function, yet the barrier imposes a physiological problem; transcapillary filtration that forms extracellular fluid in other organs is reduced to a minimum in brain. Consequently, the brain depends on a special fluid [the cerebrospinal fluid (CSF)] that is flushed into brain along the unique perivascular spaces created by astrocytic vascular endfeet.

This, surely, is utter nonsense. All fluid in the brain parenchyman has to come from transcapillary filtration. The fluid that comes from transcapillary filtration in choroid plexus merely passes through the ventricular system, it does not wash through deep brain parenchyma.

 

[Jonathan Edwards]

I am still very puzzled by this. I am prepared to believe that they are describing a real fluid flux system but I cannot see how it works.

My first query is about the claim tht water flow is reduced to a minimum because of the blood brain barrier. (It might be minimal, but for other reasons such as positive CSF pressure.) Water molecules are smaller than oxygen and carbon dioxide molecules, which have to zip across the BBB continually. Is the BBB really impervious to water?

The other puzzle is the route for the glymphatic. I tried reading the review but got bogged down because it did not give a simple explanation at the beginning. Brain tissue is fed by blood vessels and drained by blood vessels. In all other tissues these run together until they become large arteries and veins, so at the level of fluid flux, i.e. capillaries and venules, there is only one perivascular space around both the in and the out vessels. So if glymphatics run in this space there is no through route, only the same route in as out. Pumping fluid along a perivascular space with a blind end would be an extremely inefficient method of 'flushing' because the fluid would have to come back out the same way. Rapid shunting phases would just push to fluid back and forth a bit without achieving much. This cannot be what is proposed but I have yet to understand what IS proposed.

 

[Kitty]

Does this figure, or the paper it's from, help explain anything?

https://www.researchgate.net/figure/Amyloid-beta-clearance-via-the-glymphatic-system-Aquaporin-4-AQP4-water-channels_fig1_374625222

 

[jnmaciuch]

Water molecules are smaller than oxygen and carbon dioxide molecules, which have to zip across the BBB continually. Is the BBB really impervious to water?

It’s primarily through aquaporins if I’m remembering correctly. Passive diffusion is also possible depending on various factors contributing to permeability but accounts for a much lower percentage of total water influx

[Edit: cross-posted with @Kitty ]

 

[Jonathan Edwards]

It’s primarily through aquaporins

What are aquaporins? And what is primarily through them? And from where to where? I want to understand the anatomical routes.

 

[Kitty]

Is it possible the movement is only one way?

It's just that the diagram suggests CSF goes in via arterial spaces and exits via venous ones—but interstitial fluid is only shown on the out route.

(The diagram's got nothing to do with this study tho.)

 

[Jonathan Edwards]

It's just that the diagram suggests CSF goes in via arterial spaces and exits via venous ones—but interstitial fluid is only shown on the out route.

Interstitial fluid only on the out route would be the old theory - coming in through the blood vessels. If it comes in alongside arteries how would the pump work - since the arteries come in from underneath in the circle of Willis, not through the CSF ventricles? And it is hard to see how pushing fluid in along arteries helps push it out along veins? In between there are capillaries with no perivascular space.

 

[Kitty]

To be honest I only looked it up because wanted to know what astrocytic vascular endfeet were. The pictures didn't disappoint, though I still think the name is a tautology.

 

[jnmaciuch]

What are aquaporins? And what is primarily through them? And from where to where? I want to understand the anatomical routes.

Aquaporins are channels in cell membranes that can open to allow selective passage to water and other solutes. Present on nearly all cells, but especially on endothelial/epithelial cells of blood vessels and astrocytes.

What's being described is: blood vessels project into the brain parenchyma. In other tissues, solutes can exit the blood vessel directly into the parenchymal interstitial space. But around each blood vessel in the brain, there is an additional sheath, made of up the endfeet of astrocytes.

The space between the blood vessel wall and the astrocytic endfeet is the "perivascular" space. The fluid in this perivascular space is what is referred to as the "lymphatic fluid" in the brain.

Water and other solutes from this lympathic fluid enter the actual body of the astrocytes via aquaporins on these endfeet. Water and solutes can then exit the astrocyte into the parenchymal space via aquaporins on other parts of the astrocyte. The astrocytic body effectively serves as a customs area--intracellular regulation of aquaporins/other channel proteins can regulate which solutes and how much pass through either end.

 

[Eddie]

Cerebrospinal fluid (CSF) flow according to the conventional view (left) and including the glymphatic model (right). According to the conventional model, CSF is produced in the ventricles and flows to the subarachnoid space to be directly reabsorbed into the bloodstream. In the updated glymphatic model, part of CSF flows into the brain along the perivascular spaces of penetrating arteries. In a high glymphatic flow state (for example, natural sleep), CSF enters brain tissue supported by aquaporin 4 (AQP4) water channels. CSF mixes with interstitial fluid (ISF) and drains from the brain along perivenous spaces. The elongated and elliptical shape of the periarterial spaces and the eccentric localization of arteries within the periarterial spaces reduce resistance to fluid flow. Although peripheral arteries and veins generally occur side by side, along with nerves, blood vessels of the central nervous system (CNS) are not confined together in fascia but located separately and follow distinct trajectories. This unique organization of vasculature in the CNS has been hypothesized to generate a pressure gradient for fluid flow from the periarterial to the perivenous spaces through the interstitium.

The glymphatic system: implications for drugs for central nervous system diseases - Nature Reviews Drug Discovery

Evidence for a fluid clearance pathway in the central nervous system known as the glymphatic system has grown in the past decade. Nedergaard and colleagues overview the evidence for the glymphatic system and its role in disease, and discuss opportunities to harness the glymphatic system...

www.nature.com

This is the reference for how the fluid flows across the ISF:

A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β - PubMed

Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF...

pubmed.ncbi.nlm.nih.gov

 

[jnmaciuch]

So then the argument re: the glympathic system and waste clearance is that some (but likely not all) waste products don’t pass back through the endothelial right junction of the blood vessel endothelium into the circulation, they just pass through astrocytes into the “brain lymph” and get cleared out from there?

[Edit: I guess that’s where the discussion of dorsal dura mater lymphatic vessels comes in to answer the question of “clears out to where?” Seems like an incompletely answered question]

 

[Eddie]

So then the argument re: the glympathic system and waste clearance is that some (but likely not all) waste products don’t pass back through the endothelial right junction of the blood vessel endothelium into the circulation, they just pass through astrocytes into the lymph and get cleared out from there?

[Edit: I guess that’s where the discussion of dorsal dura mater lymphatic vessels comes in to answer the question of “clears out to where?” Seems like an incompletely answered question]

From what I can understand it seems like after moving from the periarterial space to the perivenous space it flows back into the subarachnoid space. From here CFS is being reabsorbed into the superior sagittal sinus through arachnoid granulations which takes some "waste" with it. Lymphatic vessels also directly remove the CFS from the perivenous space removing more of the fluid.

The fluid in the subarachnoid space would contain waste from the perivenous efflux side. So the fluid that the astrocytes move across would already have some waste in it. Fresh CFS is constantly being produced and old CFS removed from the subarachnoid space. Given that waste comes from the ISF, then it would seem that the concentration of waste in the ISF will be higher than the waste in the CFS (as you are constantly adding some clean fluid into the system). So when the fluid goes from the periarterial to the perivenous side the concentration of waste increases. The net outflow of waste would just depend on how much fresh CFS was entered into the system and how much waste is in the CFS that is removed from the system.

Maybe there are some ways that the outflow from the perivenous space can be more efficiently funneled to lymphatics or into the venous system but I can't find much on that. Another thought might be that astrocytes can "block" some of the waste from entering the ISF when traveling from the periarterial to the perivenous side creating much more of a "waste" gradient.