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

[Jonathan Edwards]

My reading was that amyloid was used as a sort of proxy for general "waste" clearance because advanced tracers have been developed for that molecule.

Thanks for the comments.


I think amyloid is investigated because there has been a theory that amyloid accumulation causes Alzheimer's. That brings in billions in funding. I am not actually aware of any other 'waste' produce that has been suggested to be bad in the brain. Nobody worried about it much before. And now there is a lot of doubt about amyloid being important as a causal driver. The amyloid animal models may have dementia but if you mess about with any protein you may get that.

much harder to see small differences in more common metabolites.

I don't think this is about 'metabolites' which are small molecules that can cross vascular walls. What are usually called 'waste' metabolites are small molecules that leave the tissue and are further degraded by liver or excreted by kidney as for urate and urea. There aren't that many others because burning organic chemicals mostly produces water, CO2 and urea for the nitrogen.

I am not suggesting the brain can do anything special. Maybe just that microglia (brain macrophages) can pinocytose and degrade proteins like macrophages in any tissue

If it is true that the arterial pulsation drives the surrounding fluid in the direction of flow could that not be enough to create some very small flow through the parenchyma by itself?

It could, but is there really a good basis for saying it is important? Brain arteries are relatively inelastic at their point of entry at the circle of Willis. They may be more elastic at smaller caliber deeper in but It would seem a pretty inefficient way of trying to get water in when the whole brain is already bathed in that water and diffusion under oncotic gradient is available.

I remain uncertain why the astrocytes matter much other than as structural guides for convective flow. Maybe water goes through their aquaporins but maybe it mostly goes between them. on the brain surface. I don't see it mattering much.

 

[Eddie]

I think amyloid is investigated because there has been a theory that amyloid accumulation causes Alzheimer's. That brings in billions in funding. I am not actually aware of any other 'waste' produce that has been suggested to be bad in the brain. Nobody worried about it much before. And now there is a lot of doubt about amyloid being important as a causal driver. The amyloid animal models may have dementia but if you mess about with any protein you may get that.

I don't think this is about 'metabolites' which are small molecules that can cross vascular walls. What are usually called 'waste' metabolites are small molecules that leave the tissue and are further degraded by liver or excreted by kidney as for urate and urea. There aren't that many others because burning organic chemicals mostly produces water, CO2 and urea for the nitrogen.

I am not suggesting the brain can do anything special. Maybe just that microglia (brain macrophages) can pinocytose and degrade proteins like macrophages in any tissue

Those are useful points, I think that is where the disagreement existed. I agree that if the role of the glymphatic system is solely to remove amyloid it seems relatively uninteresting.

I know waste is an oversimplification. But for the sake of argument I am right in thinking the pathways to remove waste are either to cross vascular walls or to be reused by glia? If that is roughly the case I have a few questions about if that 'waste' removing capacity is enough.

Are there byproducts of brain activity that can accumulate faster than they can be processed by glia cells? Certain researchers in ME/CFS have pursued lactate buildup in the brain. I know lactate is used by neurons as fuel. But since lactate buildup can occur in certain conditions like acute head injury could that be a reason to think glia cells don't have much excess capacity to remove lactate from within brain tissue? Maybe there is some build up during the day that requires more than removal by glia.

Is the vascularization of the brain enough to ensure that metabolites can be removed through vascular walls in the deep parts of the brain?

I understand that you aren't suggesting the brain can do anything special but it seems to be you are suggesting the brain can rid itself of metabolites without a system present in other tissues. Do you think the lymphatic system plays a role in clearing waste in the periphery? And if so why is it necessary for it to play that role? Is it because in regions father away from veins, the differences in concentrations are not strong enough to draw some metabolites back into the veinous system? Could a similar issue exist in the brain that required a similar system to solve?

 

[jnmaciuch]

But since lactate buildup can occur in certain conditions like acute head injury could that be a reason to think glia cells don't have much excess capacity to remove lactate from within brain tissue? Maybe there is some build up during the day that requires more than removal by glia.

This thread might be of interest? I just started reading through it.

Post in thread 'Glymphatic clearance controls state-dependent changes in brain lactate concentration, 2017, Lundgaard et al.'

Dec 1, 2025

During physiological conditions, O2 and glucose are normally consumed in a ratio of 5.5:1, suggesting that 9% of glucose is consumed anaerobically in CNS. During a period of activation, the O2:glucose ratio declines even further leading to the concept that increased neural activity is, at least in part, supported by less efficient ATP production by glycolysis and that brain activity therefore is linked to generation of surplus lactate. However, it is unclear how the excess lactate leaves the brain.

The expression of MCTs in brain endothelial cells is high and lactate is able to...

• SNT Gatchaman

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I think it's also worthwhile to be specific about what waste management by glia means--in the context of amyloids, it would be utilizing the already-extent protein degradation capacity (mostly in microglia), and then the raw materials would be largely released to the extracellular environment to be taken up by other cells or end up back in the circulation. But the only way glia could handle small molecule "waste" is converting it to other forms through their own metabolic pathways. Which basically means that all they could possibly do is take a problem of excess lactate and convert it to a problem of excess (spins the wheel) pyruvate.

All of which is to say that a problem of too-high small metabolite concentration (more than astrocytes could feasibly take up as "buffer" reservoirs, anyways) could really only be dealt with by shuttling the excess to some fluid flow system. The paper from the thread I linked mentions some other findings of lactate clearance through the circulation. But like I speculated earlier in this thread, there is the possibility that glymphatics handle a small but important percentage of that job as well--it's just a matter of how good the evidence of that is.

 

[Jonathan Edwards]

But for the sake of argument I am right in thinking the pathways to remove waste are either to cross vascular walls or to be reused by glia? If that is roughly the case I have a few questions about if that 'waste' removing capacity is enough.

Neurons may pinocytose as well but this is roughly my assumption, yes.

Are there byproducts of brain activity that can accumulate faster than they can be processed by glia cells?

Glia would not be implicated in getting rid of small metabolites like lactate. Those will either diffuse out into venules or be utilised by neurons themselves. I do not see it as credible for a feeble trickly glymphatic system to be removing small molecular metabolites being produced continually during basic respiratory processes. That is not proposed in any other tissue I know of.

 

[Jonathan Edwards]

Is the vascularization of the brain enough to ensure that metabolites can be removed through vascular walls in the deep parts of the brain?

Capillaries and venules penetrate deep tissues much better than perivascular spaces around arteries, arterioles and veins. Venules normally remove all products of respiration in the vast majority of tissues. I just don't think this is something anyone seriously thinks glymphatics would be important for (at least I hope not). The more plausible thing is that glymphatics are needed to remove large molecules like proteins. That would be an integral part of an oncotic story but these proteins need not be 'waste'. They may be perfectly healthy proteins that can be recirculated.

but it seems to be you are suggesting the brain can rid itself of metabolites without a system present in other tissues.

The lymphatics in other tissues are not there to remove waste as far as I know. They are there for oncotic control and immune cell transit. The brain looks as if it is much the same. Immune cells exiting from brain may travel along perivascular spaces rather than being in lymphatic tubes until they get to dura but I think that is what was always assumed to be happening.

 

[Jonathan Edwards]

Is it because in regions farther away from veins, the differences in concentrations are not strong enough to draw some metabolites back into the veinous system?

There aren't any areas further away from venules. Venules permeate everywhere at a microscopic level.

 

[Eddie]

Thanks for the discussion. I don't have any other ideas about why the glymphatic system would be relevant for removing waste.

I didn't realize that there are about as many capillaries as neurons in the brain. I was imagining that on the scale of induvial cells, some would be closer or further away from a capillary. And if that were the case maybe some directional flow might be useful in speeding up diffusion. But with that not being the case, an extra removal system for molecules that can cross the blood brain barrier does seem quite unnecessary.

I still think that these perivascular spaces exist and probably serve some function (maybe the immune function), but I do now understand your skepticism in tying that to waste removal. Hopefully one of these papers can spell out what they mean by waste and why that is such an important function that it required a separate system.

 

[jnmaciuch]

I still think that these perivascular spaces exist and probably serve some function (maybe the immune function), but I do now understand your skepticism in tying that to waste removal. Hopefully one of these papers can spell out what they mean by waste and why that is such an important function that it required a separate system

I also don’t think we can discount the possibility that the glymphatic channels might have just been unintended byproducts of evolving a system which added extra checkpoints and barriers between the brain parenchyma and the circulation to keep the extracellular space around neurons relatively stable and insulated. That system might end up taking on some assorted functions without having been evolved for anything in its own right. The glymphatic perivascular space “appears” as soon as we evolved an additional barrier of astrocytes around a far-less-permeable-than-usual blood vessel endothelium. The only criteria is that this byproduct does not end up being overly detrimental to the organism’s reproductive prospects

 

[Jonathan Edwards]

In the model I am envisaging glymphatic channels would be an important part of maximising an oncotically driven diffusion process to maintain low brain ECF 'oncolarity'. Cortical grey matter is bathed directly in low protein CSF. Deep grey matter is fed by the ventricular CSF but arterial glymphatics would allow a further convective inflow into all areas that at the point where arterioles become capillaries and perivascular space ceases to exist converts to an oncotically drive diffusion. Venous glymphatics would provide an outflow route a bit like a cistern overflow that ensured hydrostatic pressures could be optimally smoothed out.

The bit I would like Levick's input on is the possibility that this all centres around a net reabsorption of CSF into blood vessels which would be the reverse of other tissues where there is a net efflux. The supra-atmospheric CSF pressure might dictate this. The implication would be that without CSF production by choroid, brain would gradually be sucked 'dry' by venules - to the extent of being starved of low protein water. Whether this is right depends on the sort of pressure and permeability calculations Rodney spent his life on.