Ep. 223: The Glymphatic System and Brain Injury

00:00:00: Welcome to EAMcast, your weekly source for education research and updates from the European Academy of Neurology.

00:00:36: to many clinical neurologists, the glimphatic system.

00:00:40: To help us explore this topic we are joined today by Professor Gaia Ringstedt who is head of neurobiology at Jocelyn University Hospital and one of leading scientists in the world on this field.

00:00:54: Professor Ringstedtt thank you very much for joining us today!

00:00:57: Thanks for having me Well.

00:01:00: before speaking specifically about brain injury which is one of the main topic for our episode today, I would like to start more broadly.

00:01:10: Why should neurologists care about a lymphatic system?

00:01:14: Yeah...I think that reason is that brain fluid transport is relevant surprisingly wide range on neurological conditions.

00:01:27: you know every organ needs mechanisms extracellular environment and remove metabolic waste.

00:01:36: And the brain is particularly interesting because it does not have conventional lymphatic vessels, as you know within a brain tissue itself.

00:01:44: so instead cerebral spinal fluid interstitial fluid and perivascular transport appears to be parts of an integrated system for fluid homeostasis and molecular clearance.

00:01:59: then this potentially connects the glymphatic system to several major areas of neurology.

00:02:06: You know, in neurodegenerative disease we are interested in a clearance of proteins such as amyloid beta and tau In hydrocephalus another CSF disorders.

00:02:17: fluid transport is obviously central And sleep appears to have an important influence on molecular clearance normal fluid on your stasis.

00:02:34: And increasingly we are also asking whether these pathways can be used in the opposite direction, not only to remove substances from the brain but also deliver therapeutic molecules into it?

00:02:48: So perhaps a broader question is simply what is the gluten-phatic system and how does human brain exchange substances with zero spinal fluid?

00:02:59: And how do those substances enter, move through and ultimately leave the brain?

00:03:05: I think that question should potentially concern almost every neurologist actually.

00:03:09: I

00:03:09: understand from the beginning this is a relatively new concept... ...and the term lymphatic system has become more popular but it also seems like its not always used in exactly same way.

00:03:25: So what we mean by the lymphatic systems?

00:03:29: Yeah, that's an important question because I think the term is sometimes used to loosely.

00:03:37: The original glymphatic model came from the animal experiment showing that CSF enters the brain along peri-arterial pathways and then exchanges with interstitial fluid... ...and also participates in removal of solutes from brain tissue.

00:03:52: at this time a major conceptual advance.

00:03:57: but I would avoid thinking about the brain as a simple plumbing system, you know with fluid entering through one pipe and leaving to another.

00:04:07: There are several interconnected processes You know.

00:04:10: first CSF has to be distributed around the brain.

00:04:14: second molecules can move from csf towards brain tissue And third there is exchange and transport within the extracellular spaces of the brain.

00:04:24: Importantly, finally substances have to leave brain tissue and ultimately lead the central nervous system.

00:04:31: And this leads to a distinction that I think is fundamental – That CSF influx transport within brain tissue….

00:04:40: …and molecular clearance are related processes but they're not synonymous.

00:04:45: So if you see high concentration of tracer as we use in the brain... ...that could mean that a lot of tracers entered equally mean that clearance of it is slow.

00:04:57: So whenever an imaging method is describing as measuring lymphatic function, I think we should ask which part of the process are actually measuring here?

00:05:06: Very interesting!

00:05:08: One field where neurologists probably more familiar with the lymphatic system is lip medicine.

00:05:15: Why sleep so important for this system and what happens to these processes during sleep?

00:05:21: I think that has attracted most attention as probably one of the most fascinating aspects... ...of this field of gluntatic research.

00:05:30: Some of the original experimental observations were really quite striking, there was in twenty thirteen a landmark mouse study by she and colleagues that was in science where natural sleep or anesthesia.. ..was associated with about a sixty percent increase in the volume of interstitial space And at the same time CSF interstitial exchange increased substantially and amyloid beta was cleared from the brain approximately twice as rapidly during sleep, as during wakefulness.

00:06:02: That led to this very attractive idea that one important function of sleep might be create a physiological state that facilitates removal or metabolic waste.

00:06:16: Well, our human tracer studies we compare people who are allowed to sleep normally with individuals that underwent one night of total sleep deprivation for twenty four hours.

00:06:26: And interestingly the initial enrichment of tracer within their brain was quite similar between groups and a difference appeared later.

00:06:35: so after one night without sleep Clearance of the tracer was impaired across large parts of brain, including cortex white matter and limbic structures.

00:06:46: And a difference still present after participants were subsequently allowed to sleep.

00:06:51: So I think we reproduced an important part of animal observations in humans that sleep seems to matter for molecular clearance from their brains.

00:07:03: However...I would also emphasize that there are species differences, obviously.

00:07:10: The effects we observe in humans do not appear to have the dramatic magnitude suggested by some of their early animal experiments and the experiments aren't directly comparable.

00:07:20: you know these are different species, different tracers, different spatial and temporal resolution.

00:07:26: In our study we examined sleep deprivation rather than experimentally measuring clearance during defined sleep stages.

00:07:33: I would say human data support biological principle, but we should be cautious about just simply transferring the quantitative effects seen in mice directly to humans.

00:07:44: And this may be clinically important because disturbed sleep is extremely common in many neurological diseases as you are well aware of including your generation.

00:07:54: and also traumatic brain injury which perhaps will discuss a little later

00:08:05: does to move from animal experiments, humans.

00:08:09: And what have these studies taught us about?

00:08:12: CSF actually reaches and moves within the human brain?

00:08:17: I think one of the most striking findings here is that distribution is highly structured anatomically.

00:08:27: after a tracer is introduced into the lumbar CSF it moves cranially and reaches the basal cisterns.

00:08:35: And from there we see particularly early transport around large arteries at surface of brain, We have identified a distinct compartment surrounding these arteries within subarachnid space which is called perivascular subaracnide space.

00:08:50: Tracer can move rapidly in an integrated direction with this compartment along arterial tree.

00:08:59: This tracer enrichment within this compartment precedes the enrichment of adjacent cerebral cortex.

00:09:05: So, these speeds are transport of tracers and compartments around these arteries.

00:09:11: Another observation that I find particularly interesting is close interaction between basal cistern C-SF and medial temporal lobes.

00:09:22: The middle temporal lobe structures lie immediately adjacent to the basal cysterns as you know and we observe substantial CSF interstitial exchange in these regions.

00:09:33: And that is anatomically intriguing because the medial temporal lobe, including the entorhinal and hippocampal regions are critically involved with memory and this affected early on disorders such as Alzheimer's disease.

00:09:50: but I will of course be very cautious not to infer causality from an anatomical proximity.

00:09:57: an interesting question.

00:09:58: Could regions that are particularly dependent on exchange with basal cisternal CSF also be particularly sensitive to disturbances of CSF transport or clearance?

00:10:11: Very, very interesting and new to me.

00:10:14: so we're talking about fluid substances moving towards within the brain.

00:10:21: but there's probably another part.

00:10:24: Where do these fluids and molecules actually go when they lead the brain?

00:10:30: Yeah, you know this is a million dollar question.

00:10:34: This where I think that concept needs to become broader than their traditional lymphatic model.

00:10:41: You're not moving in molecule out of brain tissue.

00:10:43: That's only one part of clearance.

00:10:44: And eventually... ...that molecule has to leave the craniospinal system and reach the systemic circulation.

00:10:52: There appear be several parallel pathways.

00:10:56: These seem to include cranial and meningiol roots, lymphatic drainage towards cervical lymph nodes perhaps direct CSF to blood transport.

00:11:08: And we see a very substantial clearance actually along the spinal compartment.

00:11:13: Of course We injected it at lumbar level.

00:11:16: that might dominate our observations but in the end I increasingly think of brain clearance as a chain rather than one particular pathway.

00:11:28: And that has, you know, an important implication because if there is downstream bottleneck it could potentially affect what happens upstream and this makes for instance cervical lymphatic drainage biopal surgery particularly interesting You know?

00:11:47: One rather provocative example the attempts in China to treat Alzheimer's disease by creating deep cervical lymphatic venous anastomosis.

00:11:59: You know, essentially providing alternative route from surgical lymphatic vessels into the venous circulation.

00:12:06: I want to emphasize that this remains very experimental and controversial and we do not currently have convincing evidence.

00:12:14: it is effective treatment for Alzheimer's diseases at a group level but The physiological idea is fascinating.

00:12:21: I mean, if you improve drainage downstream in the neck can that influence molecular clearance upstream of a brain?

00:12:31: If particular surgical treatment ultimately fails then I think the physiological question remains highly relevant and the basal cisterns again may be particularly important.

00:12:44: they appear to represent something of a crossroads here.

00:12:47: It's both the source of CSF for this periarticular transport, as I said towards the brain and also the CSF compartment communicating closely anatomically with these extra cranial drainage pathways through that base of the skull.

00:13:04: Sounds very complex!

00:13:06: We have mainly spoken about transport clearance removing substances from the brain.

00:13:13: but

00:13:15: Perhaps these pathways could be also useful in the other direction.

00:13:19: Could they be used, for instance to improve delivery of drugs into your brain?

00:13:25: That is a question with some interesting prospects.

00:13:31: I think this may become one of the most exciting applications on this physiology that we are now discussing.

00:13:40: Drug Delivery To The Brain notorious, the difficult because of the blood-brain barrier that prevents so many molecules.

00:13:46: That we administer in blood from reaching therapeutic concentrations and brain tissue on the other side of a blood-brain barrier.

00:13:54: but We have seen at this CSF provides another access route to The brain.

00:14:01: if molecules introduced into the CSF naturally distribute along the surface of the brain and then enter the periarterial pathways in exchange with brain tissue, than perhaps we can exploit these mechanisms therapeutically.

00:14:16: Then we have sort of bypassed a blood-brain barrier.

00:14:20: when you entered the brain from outside... We are already outside vessels!

00:14:25: And recently demonstrated an interesting proof of principle just published, it was by Kira Emblem and the co-workers that were in cancer letters.

00:14:40: We had there a patient with an oligodendroglioma And she received intracecal gatherbook troll, MRI contrast agent as a CSF imaging tracer.

00:14:50: The tracer reached the tumor from the CSS side.

00:14:54: It entered the extravascular tumor compartment then remained detectable within the tumor for more than forty eight hours.

00:15:03: Of course, gallibutrile and MR-contrast agent is not an anti-cancer drug.

00:15:07: But the important observation is that a molecule introduced into CSF could reach tissue within human brain tumor without first having to cross on their bloodstream through the tumor vasculature.

00:15:20: And this suggests you know completely different way of thinking about drug delivery.

00:15:25: Perhaps the lymphatic and CSF transport systems are not only pathways for taking substances out from the brain.

00:15:31: they may also be pathways to bringing molecules into it.

00:15:34: And that principle could potentially be relevant not only to brain tumors, but also other neurological disorders that you neurologists treat where this systemic delivery is more or less restricted by the blood-brain and the barrier.

00:15:52: Very very interesting!

00:15:53: Another interesting point is that these transport and clearance processes might not be the same in everyone.

00:16:00: they make different probably between individuals and also, between different pathological conditions.

00:16:07: Can we actually measure brain clearance in an individual patient?

00:16:12: Yes!

00:16:12: We think that this is possible... And it's something which has been particularly interesting.

00:16:19: if the field is going to become clinically relevant then just group averages will not be sufficient.

00:16:28: ultimately What is the clearance capacity of this particular individual, right?

00:16:34: And here in Oslo we developed a pharmacokinetic approach.

00:16:39: In which an imaging traceric antrosagent is administered intrathepally into CSF and its subsequent appearance in blood is measured over time.

00:16:52: With Galbert Rohl, the MRI antrosageant And that's interesting.

00:16:56: We found substantial differences between individuals in its clearance, the CSFs to blood clearance and Galibur Troll is off-label use.

00:17:08: but more recently we have demonstrated essentially the same principle using iodinated CT contrast agent which is unlabeled.

00:17:17: That's important because the concept is therefore not restricted one particular MRI contrast agent The clearance measurement we obtain with Galbutrol and iodics and all were related, supporting the idea that we are observing an individual physiological property of CSF clearance rather than just simply a peculiar pharmacokinetics or one tracer.

00:17:42: And the blood measurement does not tell us exactly which anatomical route the molecule took from CSF to blood.

00:17:47: it's like integrated downstream endpoint but I'd like to describe this relationship in a very simple way.

00:17:56: You know, imaging tells us where the molecule goes and blood sampling tells that it has actually left.

00:18:04: And by combining these spatial imaging with pharmacokinetic measurements we may eventually be able to characterize several parts of the clearance chain In the same individual... That's interesting, I think.

00:18:20: Now what we'll talk about several neurological conditions and I would like to move specifically to neuro trauma.

00:18:28: Why should traumatic brain injury affect this transport and clearing system?

00:18:32: And what could this mean for a patient after

00:18:37: TBI?".

00:18:38: Yeah, yeah big question!

00:18:41: It's complex because as far as I know the traumatic brain injuries might change almost every... physiological factor that could influence brain fluid transport.

00:18:54: So, after injury we can see a manure radiologist and... We can see cerebral edema.

00:19:02: you can see blood-brain barrier dysfunction.

00:19:05: We know there is altered vascular pulse utility and breakdown of the auto regulation, astrocytical responses inflammation changes in ICP sleep change, so it would actually be surprising if brain fluid transport remained completely normal.

00:19:23: And there are here some animal experiments that have shown that rheumatic transport can be substantially impaired after TBI and as some abnormalities can persist also well beyond the acute phase.

00:19:39: This race is what I think an important biological question.

00:19:44: Is impaired clearance simply just a consequence of injury or can it become part of the secondary injured process?

00:19:51: So if injured tissue becomes less efficient at removing extracellular proteins and inflammatory mediators, cellular debris this could potentially prolong inflammation and tissue dysfunction.

00:20:06: And over long periods, impaired clearance has also been proposed as one possible contributor to pathological protein accumulation, amylobate tau-alpha-synuclein and so on.

00:20:16: And we know that traumatic brain injury is associated epidemiologically with increased late risk of dementia this well known.

00:20:25: then.

00:20:25: all these mechanisms are of course multifactorial.

00:20:28: So I would not say that lymphatic dysfunction explains post-traumatic dementia alone but it's a biologically plausible component Of the much larger chain which connects acute brain injury with chronic brain disease.

00:20:44: This is where what we talked about earlier, sleep might become relevant again because sleep disturbances are extremely common after GBI.

00:20:54: so if sleep itself contributes to maintain molecular clearance then the chronic disturbance of sleep could potentially interact with other post-traumatic abnormalities in brain fluid homostasis.

00:21:07: that's a very interesting hypothesis but One that still needs to be tested directly in patients, of course.

00:21:15: Very interesting!

00:21:17: There have been several very interesting paper in recent years about TBI and lymphatic system.

00:21:23: What I find particularly interesting is the idea that lymphatic drainage may be impaired after TBI but that this impairment might contribute secondary damage.

00:21:34: for instance, like you were saying, can you explain how it happened?

00:21:40: Yeah, I can try.

00:21:43: You know there's one interesting paper by Hussain and colleagues that was... ...I think it was in Nature XXIII-XIV.

00:21:55: That is at least one of the most interesting recent experimental studies since this year And its constantly a research environment The Danish super researcher who discovered the lymphatic system, the group of Mike and Nedegard.

00:22:11: In this study following traumatic brain injury in mice they observed a pronounced adrenergic response And it was associated with suppression of both lymphatic transport and downstream cervical lymphatic drainage.

00:22:30: They also found even reduced contractility of cervical lymphatic vessels by imaging, very fascinating.

00:22:36: And when adrenergic signaling was pharmacologically inhibited, a lymphatic and lymphatic drainage improved brain edema was reduced and functional outcome improved.

00:22:51: There were even enhanced removal of cellular debris I think unless subsequent inflammation or less accumulation of phosphorylated tau.

00:23:00: For me, the most interesting implication is conceptual because traditionally when we think about cerebral edema We ask why it's too much fluid entering or accumulating with the injured brain?

00:23:11: But this study adds another question Could part of a problem be that two little fluid Is leaving?

00:23:18: and My colleague he's neurosurgeon Peterson either.

00:23:23: And I will discuss his proposed mechanism using the term lymphatic stagnated edema.

00:23:30: I would not emphasise by no means that this is an established new clinical category of cerebral edema, but you know it's a mechanistic concept based primarily on experimental evidence.

00:23:41: But i think it adds some important dimension to our understanding.

00:23:45: just post-traumatic fluid homostasis

00:23:48: To conclude... It seems to me that these are very interesting experimental fields and open field.

00:23:58: Today we also have different ways to study fluid transport and clearance in humans.

00:24:04: How close are we actually using this data clinically?

00:24:09: Yeah, how close are you?

00:24:13: Here I think the research field... We all should be both a little optimistic but also disciplined.

00:24:22: The experimental literature from the animal world has given us Powerful biological framework, but you know the direct evidence in patients is still much more limited.

00:24:34: and a major problem is that many studies use indirect imaging measurements.

00:24:40: And they call them markers of lymphatic function.

00:24:44: There are several methods for example that DTI alps diffusion technique may show some differences between patient groups and some others have shown an increased load of visible periscule spaces at MRI.

00:24:57: And these may contain some useful information, but neither are.

00:25:01: those methods directly measure molecular clearance from the brain.

00:25:05: so this distinction is particularly important after traumatic brain injury because tissue diffusion can change for many reasons.

00:25:12: you know axonal injury edema, gliosis changes in extracellular water content None of which necessarily means that glymphatic clearance has changed.

00:25:23: So I think the next phase must have some priorities and we need to distinguish, as i said earlier CSF delivery enhancement on brain We need look at this CSF interstitial exchange that tissue transport and the clearance.

00:25:42: And we need to have measurements at level of individual patients, instead simply saying this yeast group has reduced lymphatic function... ...we should ultimately be able ask where in the clearance change?

00:25:56: Sorry!

00:25:57: Where is a chain problem with this particular person?

00:26:05: In the end down the road We would need some intervention studies, right?

00:26:10: I mean if someone claims that an intervention improves brain clearance whether it's sleep or pharmacological treatment.

00:26:16: Or something or lymphatic drainage ideally we should demonstrate and actual change in transport of Clarence rather than relying you know only on Some indirect imaging survey markers.

00:26:29: so perhaps the main message is That the glymphatic system should not simply be viewed as just a waste disposal pathway.

00:26:38: It's part of much larger brain fluid transport system that may influence neurological disease, recovery sleep and potentially even the way we deliver drugs to the brain.

00:26:51: so The challenge now is to move from very attractive biological concept To some more quantitative human physiology in individual patients and that is something we are, you know thinking very thoroughly about these days.

00:27:10: Very interesting.

00:27:12: thank you very much Professor Riesent.

00:27:15: Thank You very much for being here today with us And for helping to better understand this complex very complex and fascinating field I hope the Glyphatic system.

00:27:27: Yes i hope this glyphatic systems now a little less mysterious for all of us.

00:27:35: Thank you again,

00:27:57: You can also listen to this and all of our previous episodes on the EAN campus, E&Cast.

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