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Today we are honored to welcome Dr. Milan ho for

1:10

a lecture on the lymphatic system Anatomy physiology

1:13

and imaging.

1:15

Dr. Ho is a professor of radiology and an

1:18

international physician leader scientists and educator who

1:21

specializes in translational Advanced Imaging

1:24

and Precision Health

1:26

Dr. Ho trained in chemical engineering at Stanford and

1:29

MIT medicine at Washington University radiology at

1:32

bi-dmc Harvard and neuro

1:35

radiology at UCSF.

1:37

Her books include Radiology signs

1:40

the AAW pocket mentor and pediatric Nur

1:43

Imaging state of the art.

1:46

At the end of the lecture join Dr. Hoenna Q&A session where she

1:49

will address questions you may have on today's topic.

1:52

Please remember to use the Q&A feature to submit your questions so

1:55

we can get to as many as we can before our time is up.

1:58

With that we are ready to begin today's lecture Dr.

2:01

Hope please take it from here.

2:04

So thank you everyone today. I'll be talking about the gloomphatic system,

2:07

which is a fairly newly described entity just

2:10

in the last decade responsible for brain homeostasis

2:13

and a lot of disease processes as

2:16

well. So I'm going to try to provide a broad overview of

2:19

the neuro Anatomy neurobiology physiologic implications

2:23

and variation and then how we're interrogating this

2:26

very interesting system with imaging.

2:29

over the next hour

2:32

All right. So these are my Grands nothing related to this talk. I'd like

2:35

to acknowledge several physicists that

2:38

I work with a different institutions who have been very helpful in collaborations.

2:43

All right. So today we will be reviewing lymphatic systems

2:47

structure and function. What is it? What does it

2:50

do?

2:51

What are the clinical implications for brain health for brain disease

2:54

and for Interventional therapies, and then

2:57

we will discuss emerging and

3:00

current Imaging techniques that are relevant to neurofluid circulation

3:03

and Dynamics.

3:06

So I'm going to start very big picture, you know, what are

3:09

the contents of the cranial Vault? Right? We have

3:12

neurons which are the nerve cells we have glia

3:15

which are the supporting cells which help with maintenance and

3:18

Regulation and so forth. We have the vessels

3:21

right? This is the Monroe Kelly Doctrine essentially. So we

3:24

have the arteries veins and capillaries and then we have everything else

3:27

which is the interstitial space. Right and we don't really think about

3:30

this. It's almost like a negative space. It's really everything everything else

3:33

the fluid and the extra cellular space beyond and

3:36

so that's what we're really going to magnify on

3:39

in this talk.

3:41

So when we look at neural cells as

3:44

I mentioned there are neurons and so essentially these consists of dendrites that

3:47

collect incoming signals. They conduct that to

3:50

the cell body which processes them and then sends out, you

3:53

know transmits new signal outgoing

3:56

signals through the axon which in mature children

4:00

and adults as Mile and needed right? So we have fat and protein

4:03

that enable salt tutorial or skip conduction to make this faster and

4:06

then they synapse either to another neuron or

4:09

an effect or cell like a nerve or a muscle.

4:12

Then we also have a lot of glial cells are supporting cells,

4:15

right? So in this central nervous system, we have astrocytes

4:18

which have many different functions. They help with nerve development

4:21

nerve regulation vessel responses response

4:24

to injury, right? So gliosis astrogliosis.

4:27

We also have oligodendocites. So

4:31

these are the ones that actually create Mile and they wrap around the accents

4:34

and help myelinate with age. They're microglia,

4:37

which are responsible for immune presentation macrophage reaction

4:40

and then the appendable cells which

4:43

are you know, kind of lining the the ventricles and

4:46

the central Canal of the spinal cord and helping with

4:49

that CSF barrier.

4:51

And then in the peripheral nervous system the analogs

4:54

of the exercise of the satellite cells. So they have a lot of different supportive functions.

4:57

And then the Schwann cells are like the

5:00

oligodendrocytes. So they myelinate the peripheral nerves.

5:04

Okay, so when we look at the vessels, it's fairly simple. Right? So

5:07

we have the large arteries like the carotides for vertebral arteries

5:10

The Circle of Willis and they bring to the arterials and

5:13

then at the level of the kaplers. This is where all the gas exchange

5:16

happens oxygen and carbon dioxide and then

5:19

the capillaries, you know reconverge into small venules

5:22

and then draining veins. And so that seems very

5:25

simple right but in everywhere else

5:28

in the body, but the central nervous system a capillaries

5:31

are leaky and so in addition to the auction

5:34

exchange they are able to leak these waste

5:37

into the interstitium and then the lymphatic system

5:40

right the peripheral lymphatic system actually collects those waste

5:43

and drains them.

5:45

To the venous system ultimately. However, in

5:48

the brain, there are actually capillary type Junctions

5:51

part of the blood-brain barrier, which do not

5:54

allow that leakage to happen. Right? And so that's why you don't this

5:57

basically helps the brain to be a

6:00

sanctuary site so that you're not exposed to you know,

6:03

drugs or toxins or pathogens in the blood that enter

6:06

the CNS, you know without a lot of resistance. The

6:09

problem is from that if you have that

6:12

blood-brain bear that's very tight. How are you actually getting

6:15

the nutrients, you know, the macromolecules or even

6:18

at the small molecules into the brain parenchyma

6:21

and how are you draining weight? So that was a

6:24

critical question that was actually not answered until the last

6:27

decade or so.

6:28

So when you think about that a little bit, okay, so in

6:31

the brain, we have many fluid compartments, right? We all know

6:34

about the cerebrospinal fluid is produced at the level of the chord

6:37

Plexi in the ventricular system. So we have your lateral

6:40

ventricles, they drink through the frame of Monroe to the midline third

6:43

ventricle and then down through the Super Bowl Aqueduct or the fourth

6:46

ventricle and then into the Freeman Magnum and then a lot of that 80%

6:49

of the CSF then kind

6:52

of comes up the cerebral convexities and is resorbed of

6:55

very mechanisms, right and then maybe

6:58

20% or so comes down through the spinal canal and coats the

7:01

cord in the central canal and so forth.

7:03

So that's the CSF, right? That's 10%

7:07

of all of your fluid in the

7:10

in the cranial Vault. Then you have the the blood

7:13

right? So we have water in the blood as well.

7:16

So the arteries of veins the capillaries circulating and then

7:19

the rest of the fluid, right? So a good amount of it in

7:22

the brain is within the the neural cell so both the neuro

7:25

and neurons and the glia right they have cell bodies. They

7:28

have all this like fluid within, you know encapsulated in the cell memories

7:31

and all of this.

7:32

However, there's still some flute on accounted for

7:35

as I mentioned the negative space, right? That's the interstitial fluid

7:38

and that's everything else. It's between the neuroglia

7:41

and the vessels as all of this interstitial extracellular

7:44

space, you know, all of

7:47

this other stuff that when added up constitutes about

7:50

12%

7:52

of the total volume

7:53

All right. So when we look at neurofluid circulation

7:56

the female Danish scientist Michael

7:59

Netter guard who works part-time at the University of Rochester

8:02

actually discovered this in rodents in 2012,

8:05

and she named it the glimphatic system

8:08

which is short for glio + lymphatic because it serves the

8:12

function of the peripheral lymphatics in the CNS, which

8:15

you know doesn't have the normal lymphatics. There are some Dural lymphatics

8:18

but the glia the supporting glial cells play a

8:21

really critical role in communicating with the

8:24

peripheral and Dural emphatics. And so those processes

8:27

together essentially accomplish exchange between

8:30

the cerebral spinal fluid in the brain

8:33

and the interstitial fluid surrounding in

8:36

those, you know, pair of vascular spaces. And so that process is

8:39

very complex and we'll get more into it in a second but that enables brain

8:42

nutrition it enables waste clearance

8:45

and various, you know, Dynamics and mechanics the mechanical

8:48

processes involve dispersion,

8:51

which is really a com.

8:53

Question of advection so not convection because

8:56

it's temperature changes but advection which is bulk

8:59

flow due to velocity changes as well

9:02

as diffusion, which we see all the time across the membranes more with small

9:05

molecules than large but it's really combination of bulk flow

9:08

and diffusion.

9:09

And so as a reminder, the peripheral emphatics

9:12

are very leaky. And so they can communicate, you know

9:15

with the capillaries and drain waste but

9:18

in the brain you have these tight junctions

9:21

and so, you know, there are all these supporting glial

9:24

cells in that para vascular space that

9:27

assist with this exchange process. So it does

9:30

not happen in the same way as the periphery

9:32

and this is really important because it allows the CNS to be

9:35

really a very stereotyped environment, you

9:38

know, very consistent homeostatic environment,

9:41

but very different from the rest of the body because the CNS has

9:44

to regulate many peripheral functions, right? It has to communicate with

9:47

the cardiovascular system the gastrointestinal system and then

9:50

the immune system and it has to do all of those things in different

9:53

ways and yet maintain its own homeostasis at the same

9:56

time.

9:58

So here's another nice little example. So, you know going back to you know,

10:01

physical chemistry or whatever, but the the

10:04

plasma membrane the cell membrane

10:07

is nonpolar, right? So small little molecules, like if they're

10:10

very small they can diffuse quickly and go through membranes and

10:13

stuff. If they're nonpolar so diffusion properties

10:16

can happen with small nonpolar molecules, but very

10:19

rarely with large or polar molecules, right? They're just not going to go through so

10:22

that process happens with bulk flow.

10:25

So, you know the cardiac cycle like pumping the blood through pumping

10:28

the CSF pulsations that really helps a lot with both

10:31

small and large molecules.

10:34

All right. So now I'm going to get to barrier system. So we always talk

10:37

about blood brain barrier, but they're actually many other barriers as

10:40

well. So I'm going to talk about each one in a little bit of detail. So the

10:43

word barrier is a little bit of a misnomer because

10:46

it's not it's not a complete, you know, bear like impenetrable

10:49

barrier, but it's a semi-permeable interface. Right

10:52

and the idea is to selectively regulate the

10:55

neural environments that you can have different compartments with different

10:58

functions and micro environments. And so

11:01

the blood-brain barrier as I mentioned is at the

11:04

level of the vasculature and the perivascular space. So you have these

11:07

tight capillary Junctions, which restrict exchange of

11:10

fluids and other you know,

11:13

molecules between the blood and the

11:16

rest of the brain

11:18

You also have a blood CSF barrier. That's

11:21

the choroid plexus right? Because the chord plexus is a highly

11:24

vascular organ that's produces CSF

11:27

and is the only place where blood and CSF actually

11:30

directly contact each other. And so it's a very intimately

11:33

kind of convoluted epithelial endothelial

11:36

convolute that has a very unique functions in

11:39

terms of specialized and specialized epider epidermal

11:42

cells

11:44

And then you have brain CSF barriers,

11:47

right? So there's both outer and inner so the outer barrier

11:50

between the brain of the CSF is the

11:53

leptomening. She's at the Pia matter arachnoid matter. That's the

11:56

basement membrane and then the inner CSF

11:59

brain Bearer is the ventricular pendulum, right? So the

12:02

lining of the ventricles which really restricts, you

12:05

know, the CSF from actually getting into the principle

12:08

under normal circumstances, you know to changes in

12:11

hydrocephalus and so forth, but

12:13

Okay, so here, you know pictures with a thousand words. So here's another

12:16

kind of summary of what's happening with

12:19

these four different brain barriers, right? So the outer meningual

12:22

barrier where you have the leptomeningese a

12:25

bunch of supporting cells and then the reacting

12:28

with granulations and all that are at the periphery.

12:31

You have the inner blood blood CSF

12:34

barrier, which is the chord plexus right producing all

12:37

of this fluid and having the

12:40

blood right next to it the ventricular

12:43

barrier, which is the ependimal cells of the ventricles of

12:46

budding the CSF and the Brain in each side and then our

12:49

favorite the blood-brain barrier. We're we're gonna

12:52

talk more about this, but essentially you have tight junctions and then you

12:55

have pericites right around the capillary wall

12:58

modulating it and then you have astrocyte foot processes

13:01

that are actually sitting there and sitting on

13:04

the surface of that complex and regulating The

13:07

Exchange process the fluid exchange.

13:10

Okay, so let's drill down more into this blood-brain barrier

13:13

that this is what Mike and nedegard looked at with the rodents. And

13:16

so this has been determined to be closely regulated

13:19

by aquapore and for water channel. So aquaporn

13:22

channels are essentially they provide selective

13:25

osmosis right at their embedded in the cell membrane

13:28

and most of them live in the kidney with all these collecting tubals and

13:31

stuff. But the Aquaphor and four you see throughout the body and you

13:34

also see that with for example, neuromyelitis Optica, right the

13:37

autoimmune disorder with a lot of water dysregulation.

13:40

So Aquaphor and foreign channels play a critical

13:43

role in here. And so now I want to get into the astrocites

13:47

in the parasites. So the parasites are the glia that

13:50

directly modulate The Vessel constriction the

13:53

wall, you know, and the astrocide foot processes actually coordinate

13:56

everything between and Surround this

13:59

complex and regulate the fluid exchange. So there's

14:02

a perivascular space the so-called vocal

14:05

Robina spaces, right? They're extensions of the subarachnoid

14:08

space that go into the brain and that's the blue right

14:11

here this kind of light blue color and in fact

14:14

recover and at Imaging we typically describe

14:17

the Perry arterial spaces that you

14:20

know, the the subtracting space is surrounding the penetrating arteries,

14:23

but in fact, there are also pair of Venus spaces and they're contiguous the

14:26

we don't know if there's a Perry capillary space.

14:29

It hasn't been described yet. It doesn't mean it doesn't exist because the

14:32

thing is the capillaries are 8 to 10 microns, so it could

14:35

be that there's just so small. We're not resolving them yet. So

14:38

they be a micron or less or it could be

14:40

That they're you know permeable because

14:43

that's what the exchanges happening so we don't know yet. So no one

14:46

knows if there is or isn't a pericapillary space for sure, but

14:49

there are definitely para our

14:52

periterial and perivenous faces.

14:55

And then there's the pair of vascular space right

14:58

next to the vessels. These are all these adjacent glial

15:01

cells the pericites the astrocytes this interstitial space

15:04

and that's what does the bulk of the fluid exchange so Netter guard

15:07

basically did fluorescent.

15:09

CSF Tracer injection studies in rodents and

15:12

saw this exchange process. So we all set the vertical robot

15:15

spaces.

15:16

We're doing the exchange but they're actually, you know, kind of sealed right

15:19

by the by the membrane. So at the level of the capillaries, there's this

15:22

exchange process that happens between the perivascular spaces

15:25

and the para vascular spaces and they see the

15:28

Tracer actually going out into the parenchyma and that's basically

15:31

where the waste are getting cleared in the nutrients are getting delivered at that level

15:34

of the capillaries, but it's really the pair of vascular space that

15:37

does the majority of that work.

15:39

Okay, so here's a little bit of a busy

15:42

diagram but it's a nice reflection of what I just said. So essentially you

15:45

have the subarachnoid space things go into the vercare Open Spaces

15:48

in the arterial and then we don't know what happens at the

15:51

capillary space but somehow right The Exchange is

15:54

happening between the CSF and these that's

15:57

in the vercarobind spaces and the interstitium.

16:01

Regulated by these glial cells and then everything

16:04

drains back out into the pair of Venus spaces again along the

16:07

CSF and then drains back out. Now. It may

16:10

not be even the simple as unidirectional flow. So there's a

16:13

lot of bulk flow kind of pushing this process forward but there's even some studies

16:16

suggesting that this is not purely like a Ford process

16:19

and it's really like everything is just exchanging in the interstitution and

16:22

it may even be bi-directional, you know, just more

16:25

forward than back. But again, there's a lot we still don't know

16:28

about this. It's very interesting very exciting very humbling as

16:31

well.

16:32

All right. So I wanted to mention there is a that are

16:36

some exceptions to blood-brain barrier where you

16:39

actually have direct contact between certain

16:42

structures and the

16:45

blood and this is because as I mentioned the brain has to regulate

16:48

the periphery, right? So it has to know what's going on in terms

16:51

of the humoral like the immunity and endocrine stuff and all of that.

16:54

And so these are called the circumventricular organs most of them live in

16:57

and around the third and fourth ventricles in the midline because that's where most of

17:00

the flow happens. So there's just from av3b. It's

17:03

basically Antero ventral third ventricle.

17:06

So that's like where most of these guys live, right

17:09

and they're highly exposed to blood circulation in

17:12

CSF. So they can really help regulate a lot of endocrine and

17:15

immune type reaction. So they have fenestrated capillaries

17:18

highly permeable capillaries so

17:21

that they can actually, you know, see what's going on in the periphery.

17:24

Right? So like the pituitary the time you going why

17:27

do they all in hands right because they don't have a intact blood brain

17:30

barrier there that's normal the

17:32

Any sites in the hypothalamus have specialized eponymous that they have neural projections

17:35

as well. So the circumventricular organs are

17:38

cvos consist of sensory ones. So the area prostrema

17:41

is one of the most well known right and the roof of the

17:44

fourth ventricle that causes vomiting right and some disorders actually

17:47

nmo classically has aeropostrema lesions and has

17:50

vomiting the there's an organ below

17:53

the fornics. There's one in the limit terminals at

17:56

the hypothalamus. There's also secretory organs, right?

17:59

So these are actually secreting like hormones and

18:02

stuff to the periphery. So there's there's one in the posterior

18:05

commissure obviously at the pituitary has

18:08

a lot of them the median Eminence at

18:11

the hypothalamus and then the pineal glands. So some are sensory summer

18:14

secretary summer sensory summer both but the idea

18:17

is that they they actually are exceptions to that blood brain barrier

18:20

for specific communication with the periphery.

18:23

Okay, so now let's drill down into the other barrier. So

18:26

we have the the chord plexus which forms the blood CSF barrier

18:29

as I mentioned. It's highly convoluted fenestrated capillary.

18:32

So this is actually the only place in your

18:35

brain that is permeable normally permeable to

18:38

macromolecules. So this is why when you're doing some of these Gene

18:41

therapies or large molecular therapies, they actually

18:44

will put in a ventricular catheter and inject directly, but you're

18:47

just gonna bypass all the other barriers and inject these large

18:50

molecules and they can get absorbed by the chord plexus. So that's

18:53

the most effective rather than trying to disrupt the blood brain barrier

18:56

and they also produce CSF

18:59

So the two CSF and

19:02

brain Bears to enter in the outer, right? So again, here's the

19:05

chord plexus. The inner barrier here is the ventricular

19:08

Panama. So there are Gap Junctions between cells that

19:11

are tight. So they restrict restrict passage,

19:14

but there are also strap Junctions which

19:17

selectively allow certain molecular sizes through between

19:20

cells and not others. So it's pretty complex. And then

19:23

the outer barrier right again is the glial basement remembering

19:26

so there's like a basement remember that restricts restricts communication

19:29

of along the priorectomy matter and

19:32

the Brain

19:33

and that is actually disrupted in some things like zika virus infection and

19:36

some developmental things like Cobblestone cortex, actually

19:39

these muscular dystrophies.

19:42

All right. So there's also extra cranial berries, right?

19:45

So the orbit the eyes are actually

19:48

extension of the CNS, right? And so there are this very well in an

19:51

Ophthalmology. It's talked about a lot in terms of drug delivery, right? Because it's very

19:54

hard to get drugs into the eye Gene therapies,

19:57

you know direct injection and stuff and then if you have an

20:00

eye infection, right if you have end up the Midas, it's very

20:03

hard to get antibiotics there. So there's a blood

20:06

aqueous barrier in the front right in the anterior chamber and

20:09

that restricts, you know, essentially toxins and

20:13

infection to the ciliary body out here and then

20:16

in the back, you know back here.

20:20

And the posterior part the the majority of the

20:23

globe the vitreous chamber, you actually have two blood retinal

20:26

barriers. The inner barrier is the retinal vascular

20:29

epithelium. So it has a lot of those like astrocytes parasites

20:32

and stuff like we were talking about and the outer barrier

20:35

is the retinal pigment epithelium. So like the choroid brick

20:38

membrane all of that like more tough stuff that is restricting

20:41

flow through the choreo capillaries.

20:45

There's the blood Labyrinth barrier. So the inner ear right another area.

20:48

So the street of vascularis in the Scala media

20:51

of the inner ear secretes endolymph,

20:54

right? So there's perilymph which

20:57

communicates with this ESF in the brain

21:00

and then there's endolymph which is like and that difference in

21:03

concentrations between those two actually enables the

21:06

electric, you know signals that power your cochlear

21:09

hair cells and you can transmit that into essentially you

21:12

can conduct that and transmit that into the perception of sound so

21:15

maintaining that difference in electric potential between

21:18

endolymph and Imperial limit is very very important. So inner ears

21:21

also another Infamous place where you know, it's hard to get drugs when

21:24

you have labyrinthitis and stuff and people have done

21:27

trains to panic injections maneer disease right where

21:30

you have Endo lymphatic hydrops, right and they're been studies

21:33

showing delayed gadolinium enhancement, or you can do trains

21:36

competing injections again right for that. So there are studies about

21:39

that as well. But very similar or analogous kind

21:42

of barrier.

21:43

The blood spinal cord barrier. So basically the barrier

21:46

does come down through the cord. It's similar

21:49

like it's analogous with the parasites and the astrocytes

21:52

but it's looser than the brain right. So there's

21:55

more susceptibility to disease to injury it's a

21:58

little bit more permeable, which is why when we're trying to do a lot of the CNS

22:01

therapies, you know, chemo gene therapy,

22:04

whatever we often will inject like

22:07

do an LP and an inject either at the level of the lumbar or sometimes

22:10

like C12 punctures, but it's a little bit easier to access

22:13

and deliver to the level the chord then within the brain.

22:17

And then there's a blood nerve barrier. So even the peripheral nerves

22:20

like as they come out, right? There's the door sword gangling and then you have a nerve

22:23

Berry which again is even looser. Right? But this is very important

22:26

for people who are doing like peripheral nerve injections and stuff like that that you

22:29

have the the epineurium the endinurium, right?

22:32

And so they're there is actually this interstitial space. And again, it is

22:35

regulated by the Perry sites and the endothelial cells.

22:40

Okay. So the other thing I want to mention is CNS

22:43

egress, right? So we have this process of exchange

22:46

modulated by the glimphatic system, but

22:49

there are other Pathways by which

22:52

CNS can exit the brain and they also kind of help support,

22:55

you know, the waste clearance and so forth. So the arachnic

22:58

granulations which we all know about and which we thought was doing

23:01

this we're doing this process but actually is a more supplementary Downstream role.

23:04

So these are little projection sort

23:08

of a recording Mata into the durometer so they can actually but the

23:11

the veins running in the dura the venison is

23:14

directly and help with more drainage, but that's only after

23:17

the CSF interstitial exchange has happened

23:20

in the Perry capillary region. There are meningual

23:23

lymphatics and Dural spaces particularly

23:26

as I'll show you later along the pair sagittal midline

23:29

area of the brain and those also help communicate with

23:32

the peripheral lymphatics. They drain down through

23:35

cervical lymphatics, and then they go to the like the SVC and you

23:38

know, like thoracic duct Venus system.

23:41

As I mentioned about 20% or so

23:44

of CSF actually goes not into the you know through the brain but actually

23:47

goes down and codes the spinal cord the central Canal the peripheral

23:50

nerves and then there's also some exit via these

23:53

neurovascular frame and I write through your skull base and whatnot. So

23:56

vascular adventitia also carry out a little bit of CSS

23:59

Windows of minority. And so all of

24:02

these Pathways end up during these peripheral circulation

24:05

peripheral lymphatics and provide additional CSF

24:08

drainage and solute clearance capability. So

24:11

to summarize the eragonal granulations, which you know

24:14

project into the dura and about the veins, here's

24:17

those pair sagil spaces. So they live kind of in and around the superior

24:20

sagittal sinus and so forth. I'll show you some MRI examples

24:23

later around the cranial nerves and around

24:26

the Dural lymphatics and actually very interestingly.

24:29

There are quite a few nasal lymphatics

24:32

in year. This has been recently described in year, like olfactory groove

24:35

right where all the nerves come down. So

24:38

actually the CSF leaks you can

24:41

like very kind of leaking you can actually detect some of that coming

24:44

out and image it as well particularly at the level of the, you know

24:47

olfactory plate.

24:49

All right. So we talked about this a lot in functional MRI neurovascular

24:52

coupling slash uncoupling

24:55

right? So it's really not the neurovascular unit.

24:58

It's the neurogliovascular unit. Right? So the

25:01

ngvu so we're we really are starting to

25:04

understand the extremely Central role that the glia as

25:07

I mentioned the pericite, you know modulating the capillary

25:10

and then the astrocyte foot process really controlling that

25:13

whole complex that really enables the communication between the

25:16

neuron right the capillary slash vascular

25:19

system and everything else. And so the ngvu

25:22

is the

25:24

The single most you know, basic structural and

25:27

functional unit of the brain right and provides

25:30

multi-level communication for molecular cellular all

25:33

the way to like, you know brain system wide and so in a

25:36

normal healthy brain, right this enables cerebral

25:39

Auto regulation the hemodynamic response, right? So in functional

25:42

MRI, if you let's say you, you know move your hand right

25:45

then you're using more oxyhemoglobin, right?

25:48

So the deoxyhemoglobin percentage increases

25:51

oxygen limit drops and then after five to

25:54

15 seconds, you haven't at a regulatory response where the

25:57

brain delivers more blood to that area and you can see that as a

26:00

increased signal slightly increased on Bold fmri or ASL

26:03

or any other perfusion steady. And so

26:06

that's how you that's how you know, you have a healthier neurogliovascular unit

26:09

now in in some conditions, like

26:12

let's say tumor right with neovascularity or

26:15

you know, chronic brain injury or whatever you may actually

26:18

have disruption of this of this normal signaling process, right? So

26:21

that's neurovascular uncoupling and so that's the idea that

26:24

You know just because you're let's say moving your hand,

26:27

but the motor cortex was injured or something or has a tumor

26:30

you may not actually get it to light up on fmri because of

26:33

the lack of the normal physiological response and that's a false negative

26:36

fmri. That's a situation where the it's

26:39

not it's not necessarily that there is no motor

26:42

function there that but you're not actually sensing it at fmri because the Assumption

26:45

you're making with the Bold fmri is not valid right that you

26:48

have a healthy ngvu. So this is very important, right because it

26:51

really has a lot of implications for function and the

26:54

glial cells really play a huge role in it.

26:57

So in terms of the cell types involved, it's

27:00

very complex. People are still doing a lot of research on this but I mentioned the

27:03

endothelial wall to astrocytes and pericites. There

27:06

are many different barrier types. So we usually talk about endothelial bears

27:09

but there are epithelial even mesothelial and

27:12

glial barriers that we're seeing. So this is a lot of work going

27:15

on in cell biology. It's extremely complex and many

27:18

different kinds of Transporter types to right so things embedded in

27:21

the membranes tight junctions fence and

27:24

gate functions. So both barriers at the

27:27

level of the cell membrane and then between cells as well.

27:30

All right. So now I want

27:33

to get into physiology. Right? So the thing is that the lymphatic system

27:36

very the function varies a lot

27:39

even in normal individuals, right? So as you can imagine with cardiac cycle

27:42

right systole diastole with the

27:45

respiration brain activity, right? So, you know, if you're if

27:48

you're active with your brain or your or not the body

27:51

position sitting standing, you know exercise right

27:54

physical activity diet lifestyle all of

27:57

these actually impact lymphatic function quite a bit and there have

28:00

been studies on each one of these individually sleep

28:03

is a huge one, right? So this is what made the news,

28:06

you know in the last decade right that in the rats that

28:09

she was looking at the in the

28:12

interstitial space, right? That was be essentially the

28:15

drainage it increased 60% in volume.

28:18

So essentially lymphatic function more than doubled in these

28:21

rats during sleep. So essentially, you know, if you're

28:24

not getting your sleep, you're not clearing your waist, right? So you're your brain waste or

28:27

building up and building up and I had written an editorial for aw.

28:30

Slash asnr talking about some of the history in terms

28:33

of you know, you hear about these video Gamers who die in their

28:36

chairs after playing for three two or three days straight or in

28:39

Japan death from over work is like a thing, right?

28:42

So they just they keep working and they're like, oh I'm working. I'm drinking

28:45

coffee. I'm good, and then suddenly they just dropped it and it's actually a well-known phenomenon.

28:48

So, you know sleep

28:51

is important, right? If you take one thing from this talk the Circadian

28:54

rhythm. So most most mammals

28:57

and even many plants right have like a diurnal Rhythm

29:00

so like the day in the night and so the lymphatic functions,

29:03

you know changes right depending on on when

29:06

they're awake and asleep.

29:08

Other lifestyle things so exercise stress is you know,

29:11

a big problem A drugs, you know things like caffeine right

29:14

or you know recreational drugs and aging so

29:17

over the course of Our Lives even for a very healthy normal person,

29:20

right the lymphatic system degenerates like

29:23

like everything else.

29:25

All right. So normal is a relative term.

29:28

Okay, so I wanted to show you just some

29:31

examples or some schematics, right? So basically the glymphatic

29:34

system, so when it's active versus inactive,

29:37

right so basically aquapore and four channels will

29:40

restrict fluid exchange. Let's say when you're awake

29:43

and you're busy or you're stressed or whatever you're doing and then

29:46

when you're sleeping, right and and you have the ability to exchange

29:49

these ways, so it's kind of a dynamic thing,

29:52

right? So at some times when when you're not

29:55

busy doing something else and you have the you know, there's more

29:58

downtime shall we say, right? Then the lymphatic system

30:01

is more active and all of these different modulators, right

30:04

the cardiac cycle the respiratory cycle a neural

30:07

activity awake asleep thinking not thinking as

30:10

much right and the vase the Dynamics all of these things as you can see

30:13

from how to describe to the physiology earlier are going

30:16

to have a big impact.

30:18

Okay, so, you know, this is a Hot

30:21

Topic and actually people have linked lymphatic system to pretty

30:24

much everything in their mother right in terms of neurologic diseases. It's

30:27

like oh the lymphatic system is responsible for everything and I think it's

30:30

true in a way that ever that it is it is a biomarker which

30:33

maybe either director indirect right?

30:36

So we know that every neurologic disease has been linked to

30:39

disturbance of lymphatic function. The problem is this is

30:42

a chicken or the egg because even in a normal, you know,

30:45

normal individual we see so much variation. So where's the

30:48

threshold for calling disease? And then if you let's say there's a

30:51

lot of work looking at for example, sleep and lifestyle interventions

30:54

in Parkinson's disease is the disordered

30:57

sleep a symptom or is it a Cause right?

31:00

And if you if you essentially do sleep rehab

31:03

do they actually have better outcomes? So there's a lot of questions. We

31:06

still don't understand and then how do you how where's the cut point

31:09

diagnostically right and and therapeutically between normal

31:12

and disease that there's a lot of financial questions here from a

31:15

practical, you know clinical standpoint, but

31:18

there have been papers linking disordered lymphatic

31:21

function, you know impaired waste

31:24

clearance to disorders of CSF pressure not surprisingly,

31:27

right? So hydrocephalus

31:30

CSF hypertension CSF hypotension strokes

31:33

and vasculopathies, right all sorts of you know,

31:36

ischemias and strokes and cardiovascular disease

31:39

infection Ottawa means so I mentioned neuromyelitis Optica

31:42

because of the aqua p*** for but all sorts of different, you know,

31:45

CNS infections that break down the blood brain barrier autoimmune disorders,

31:48

right?

31:50

Post traumatic brain injury the response to

31:53

the recovery from Pain disorders, right the perception of

31:56

pain metabolic and toxic disorders, right?

31:59

Obviously, you know how to how do these toxins affect

32:02

the CNS? Why do some people respond, you know more adversely than

32:05

others?

32:06

Even during development, right? There's a lot we don't know because a lot

32:09

of this work has been done in like adult or mature animal models or

32:12

humans, right? So how does how does lymphatic function

32:15

evolve and we know it's not matured birth, right? So

32:18

over the first several years of life these barriers develop and

32:21

progress. So there are a lot of implications for neurodevelopmental disorders

32:24

and the their inverse neurogenic disorders

32:27

quite a bit of work done in the dimensions for this as well

32:30

as Neuropsychiatric, you know mood disorders personality disorders

32:33

Etc.

32:35

So there's a nice little summary article in the Japan

32:38

Journal which calls these all glimpedema,

32:41

right? Because the idea is that the globatic system doesn't work. So the fluid

32:44

the you know, the waste Laden fluid builds up

32:47

and so the idea is it's a common pathway because it could

32:50

be anything like maybe you're not sleeping enough. Maybe you had a trauma

32:53

maybe an old Hemorrhage you have issues with

32:56

your membranes your barriers, right? You have some underlying

32:59

vascular issues you have inflammation or something else, whatever the

33:02

initial primary insult, right? It leads

33:05

to secondary neural injury it impairs the interstitial

33:08

fluid exchange. And essentially what happens is the waste

33:11

proteins build up they build up it's like a positive feedback. And

33:14

so there's a final common pathway of glimpedema where

33:17

you get essentially irreversible neural damage.

33:23

So some examples so these are all different etiologies,

33:26

right? So an acute stroke, right? So you get like cytotoxic

33:29

edema, and then you get impaired drained

33:32

your fluid because everything's swollen acute Hemorrhage

33:35

where because of the fibrin from the red blood

33:38

cells, you're you know, aquacorn Transporters are

33:42

blocked and you can't drain traumatic brain injury where

33:45

you have all sorts of like inflammatory, you know, like disruptions and

33:48

stuff and so like the drainages impaired or chronic

33:51

things normal aging right where the Aquaphor and four cells

33:54

sorry Transporters that I'm Miss localized and they don't work right

33:57

the dimensions where you have, you know,

34:00

amyloid beta or alpha synuclean or whatever impairing the

34:03

drainage, you know, because of these plaques and things that are are

34:06

accumulating in the cells or hydrocephalus where you have,

34:09

you know, altered CSF pressures and

34:12

differentials and now you can't drain so you can see these are all different molecular mechanisms,

34:15

but they have that common, you know

34:18

Common pathway in terms of you can't drain correctly

34:21

waste accumulate.

34:23

The AMOLED beta right it's not unique to ad right

34:26

you can see it in any of these things. Right? So the whole point is these are

34:29

common pathway waste products and once they're

34:32

there they just keep building up and it's a positive feedback and you can't

34:35

drain you get more waste and then you're the your brain is damaged

34:38

but all sorts of different acute and

34:41

chronic insults and even normal physiologic aging could lead to

34:44

that common pathway. It's just a matter of like how fast right and

34:47

how severe

34:49

okay, so I just did this PubMed again this morning

34:52

because it's always this numbers all increasing but there have been almost 1,200

34:55

papers, you know on the

34:58

lymphatic system since in the last decade and

35:01

Over a quarter of those in the last six months. It's a very hot topic,

35:04

you know very future of Interest. I hope to stimulate more

35:07

interest through talks like this. A lot of this I

35:10

think is being done in the kind of basic science side and

35:13

even some of the Imaging physics but less on the clinical because as I mentioned

35:16

there are a lot of questions about clinical applications clinical practice

35:19

ability, but I think a deeper understanding of that translation

35:22

from bench to bedside is really key for us as a

35:25

radiologist and referring Physicians to really sort of

35:28

rethink how we've approached a lot

35:31

of neurological diseases and therapies. And so I just

35:34

wanted to point that out. So these are just some of

35:37

the, you know best and greatest articles on the top

35:40

which I just talked about. So like, you know, neurogenic diseases

35:43

immune diseases and drugs,

35:46

you know cocaine alcohol Etc, you know,

35:49

so there's on every topic at just mentioned

35:52

there's tons of papers that you can look at if you would like but I've kind

35:55

of looked at many of them already and I've tried to synthesize it for you so you

35:58

didn't have to all right. So then the last

36:01

Part is really diagnosis in therapy. Right? So I wanted to

36:04

mention that you know, understanding of the blood-brain barrier

36:07

and other CNS Bears is actually very important right for

36:10

our understanding of intervention, right?

36:14

It could be as minimally invasive as lifestyle. Right? So we talked about, you know, Sleek rehab

36:17

and died and things and and how does that affect the natural

36:20

course of the disease, but of course drug delivery,

36:23

right? So CNS Direct Delivery is you know

36:26

infamously difficult, right? And so we can

36:29

do things like the ventricular access device. But you know, there's a

36:32

risk of infection these things clog after a while. It's very invasive, right? So

36:35

are there ways to deliver things to the

36:38

periphery, but then still get them through their blood brain barrier, you know,

36:41

or can we modulate let's say if we do a surgery we

36:44

do an ablation or even you know adjuvent therapies,

36:47

how can we improve the effectiveness of these,

36:50

you know targeted treatments? So there's a lot

36:53

of work being done for example with a focus ultrasound because like Mannitol,

36:56

right it translates disrupts the

36:59

blood when bear but only translate right? So if you actually want to

37:02

deliver something to the through the blood brain barrier to the CNS, you can

37:05

do a focus ultrasound and then, you know, the intervention or the drug

37:08

delivery or whatever. There's all sorts of other things like, you know Nano Nano

37:11

particles and how does how can you

37:13

Late or how can you do minimally invent

37:16

invasive interventions and so forth that I just wanted to provide some

37:19

awareness of that because the more we understand about how

37:22

this process works normally has to started by disease. We

37:25

can also selectively disrupt or Target these

37:28

things to really improve the effectiveness of the

37:31

existing therapies or developing therapies that we have.

37:35

All right. So last part is Imaging techniques, which is

37:38

what maybe you're all here for since it's an MRI lecture. And so there

37:41

are many different new and

37:44

emerging technologies that can be used to interrogate different aspects of neurofluence circulation

37:47

and lymphatic system. So there's structure

37:50

there's flow and there's metabolism. Right? So

37:53

structure obviously the higher field Imaging right

37:56

high performance gradients will give you really nice micro

37:59

structure. So 17 has been used a lot particularly for

38:02

looking at Perry vascular spaces. You can see them in very, you

38:05

know, small resolution diffusion type diffusion

38:08

plus approaches can look at

38:11

the directionality, you know a flow within and around the periovascular

38:14

spaces and then a susceptibility to actually see

38:17

the traversing vessels and you can do some of these in in concert

38:20

to actually correlate between the different, you know structural.

38:23

Findings in terms of flow. We have non-contrast, you

38:26

know perfusion, which is are sure spin labeling.

38:29

We can also do face counters or bold more for

38:32

fmri, but there's actually an ultra fastball that can be done as

38:35

well to look at lymphatic, you know pulsations. You

38:38

can do Gad right? But obviously there's there's

38:41

some you know, like are you gonna do

38:44

that for research right. Are you gonna actually give someone Gad for research special even

38:47

might deposit long term in the body. Well, you know, but there

38:50

are studies that have been done right just in normal,

38:53

you know in patients coming through where you look at over time,

38:56

like, you know one hour three hours 24 hours and you're

38:59

looking at where where these where the Gad

39:02

goes as it partitions out from the intravascular to the interstitial space,

39:05

right? So that's actually a very nice demonstration of

39:08

the partitioning and the exchange process so

39:11

you can do intravenous get but you can also inject interest,

39:14

you know interest external Gad right

39:17

like around C12 or even internal to look

39:20

at, you know lymphatic type, you know lymphatic drainage.

39:23

And then we have you know dynamic, you know,

39:26

either T2 star awaited or T1 waited to look at, you

39:29

know over time like how you know, if you want to actually quantify that

39:32

exchange process and then metabolic wise,

39:35

right? We have chemical change saturation transfer, which is an MRI technique

39:38

right to look at different different sizes that

39:41

exchange with free water and you can look at the concentrations of

39:44

various things like peptides or whatnot. We have

39:47

Beyond proton MRI,

39:50

right? We can do other nuclei Imaging to look at metabolism or

39:53

or other types of cell processes. And then we of

39:56

course we have nuclear medicine techniques as well again.

39:59

For research only right? It's hard to justify like

40:02

giving dad or you know doing a radio pharmaceutical injection.

40:05

But if you're doing this as part of like a clinical trial or like in

40:08

part of patient care, right we do we do sometimes do these

40:11

but it just depends on what the use cases.

40:13

Here the challenges right? So as I mentioned the lymphatic

40:16

function is a multi-scale process. It's

40:19

like everything from molecular cellular all the way to you know, organs

40:22

and tissues and so

40:25

there's no one Imaging modality that

40:28

will look at every scale right you can have things like histology or

40:31

like, you know, single whatever like two Photon

40:34

microscopy and that looks like really small stuff. But then you're gonna be doing xvivo

40:37

right like little like pathologic specimens,

40:40

you know after the animal sacrificing I can

40:43

do humans like that. So in humans, right, we're looking more macro scale

40:46

stuff another problems, right?

40:49

Is that even with that like even with 70 right?

40:52

You can try to get to microscopic and resoscopic resolution, but

40:55

you also have good temper resolution usually spatial and

40:58

temporal resolution imaging as you know, or trade-offs, right so looking

41:01

at both very rapid temporal Dynamics as well

41:04

as high spatial resolution is quite challenging and you know

41:07

things like pet are are not going to be good spatial resolution.

41:10

And then finally, how do you get contrasting the Inn?

41:13

Official space because you're looking at the exchange between CSF and

41:16

interstitial so you cannot directly inject the interstitial space.

41:19

So you have to access one of these other spaces and then watch The

41:22

Exchange over time and be able to resolve that

41:25

using Imaging so it is very challenging that being said

41:28

we do have a lot of emerging techniques. So as

41:31

you can see it depends on what you're trying to do. Are you

41:34

trying to image the blood compartment the CSF or the interstitial space?

41:37

Do you want to give a tracer or not? You know

41:40

what sort of you know, do you want to use like face contrast or diffusion

41:43

technology? There's all these different possibilities and physicists actually

41:46

are doing a whole bunch of different stuff on this. So I think we should get on

41:49

board and try to look at these things as well. So and

41:52

then what part of the CNS are you looking at? Right? Are you looking at kind of

41:55

the pair of vascular exchange, you know in the parenchyma. Are

41:58

you looking at interstitial fluid transport bulk flow?

42:01

Right. We do a lot of face contrast like CSF flow

42:04

studies. You want to look at the flex from the olfactory, you

42:07

know plate, you know look down here at the spine you want

42:10

to do this Ultra fast bold sequence that can actually

42:13

Get pulsations at the entire brain you want

42:16

to look at bulk flow and it's fine. So they're for every single use case.

42:19

There are at least one if not multiple approaches. It

42:22

just depends on what your clinical question is and what your disease

42:25

process and then really defining, you know, the patient population and

42:28

how you're going to approach this.

42:31

All right. So as we all know we've all seen these cases right CSF

42:34

flow. Kiary one where you have impaired, you know

42:37

flow at the level of the cranny cervical Junction. You can have you know, interstitial tonsil

42:40

or pulsatility. So Chiari one

42:43

Chiari 2 aqueductal stenosis, here's

42:46

a nice example where you know, the flow's not getting through the level of aqueducts. So

42:49

we're getting proximal hydrocephalus and then,

42:52

you know poster ventricular last and we're looking at the success of you

42:55

know, flow through the floor of third ventricle and the membrane of liliquis. So

42:58

we all know CSF flow studies face contrast

43:01

studies Perry vascular spaces, right? So at

43:04

70, I mean even at 3T you can

43:07

see these but 17 they actually done some machine learning and deep

43:10

learning approaches to try to Auto segment all these perivascular spaces

43:13

and then sum them up right to look

43:16

at total volume and also the the average

43:19

diameter the average torch velocity. So they've been able to correlate, you

43:22

know, the Perry vascular Space volume burden tortillocity

43:25

length Etc with normal aging,

43:28

you know, what age as well as disease processes like

43:31

Ed severity so obviously, you know, this is

43:34

not the kind of thing. We're going to see here and measure these ourselves but having some sort of

43:37

automated process could be helpful for PVS burden.

43:40

All right. This is a actually very straightforward way

43:43

to look at perivascular space

43:46

index. It's called the Alps or the along the

43:49

perivascular spaces index and it's very simple. So essentially you

43:52

take your run-of-the-mill DTI, right? And this

43:55

is the fa map. Right? So you have the red is the you know, Left Right

43:58

decisations blue is the you know, cortical spinal

44:01

track as it's going Superior. And then AP is

44:04

is the green right? So like the you know Superior launching

44:07

with vesiculous, so they basically said okay at the level the center

44:10

of semio valley, right? You have these perivascular spaces

44:13

that are kind of going in this x direction right like this. And

44:16

so you can distinguish these areas of Interest the Chronicles

44:19

final track, which is like a vertical projection the association

44:22

area like the slf which is going anterior

44:25

posterior and the subcortical association which is kind of going along the

44:28

prayer vascular spaces. And so if you were to

44:31

divide right the the essentially

44:34

the average flow like the fusional

44:37

flow along the periovascular spaces from the

44:40

Other two areas right? There should

44:43

be like essentially all the flow. All the CSF

44:46

flows should be going along the periovascular spaces and not perpendicular and there

44:49

should be no real difference between these two

44:53

unless it's the contribution of this paravascular exchange.

44:56

So essentially they're saying,

44:59

you know, they're there's this selected diffusion along the

45:02

pair of vascular space. How does it really differentiate from you know,

45:05

how does that pair of vascular exchange process actually

45:08

affect this flow. So it's really what does that relationship?

45:11

You know, how how much flow is there that's actually being exchanged because

45:14

there's no way to actually gonna go through, you know

45:17

through through the axon or perpendicular to axon unless you

45:20

have an active glimphatic process going on to facilitate that

45:23

exchange right? It doesn't make any sense. So basically, you know,

45:26

how much if this assumed pair of vascular flow

45:29

is now being supplemented by The

45:32

Exchange essentially in the perpendicular Direction. So it's

45:35

a very simple reproducible easy for a clinician

45:38

to measure even metric just doing these Ro

45:40

race and essentially you average, you know,

45:43

you average the two x the two x

45:46

measurements from the Y and Z and that can be easily done at the

45:49

workstation. It's pretty reproducible and there have

45:52

been some nice studies. I'm actually reviewing a couple now on different disease processes

45:55

like temporal lobe epilepsy the Alps index once the

45:58

effect is unaffected or like different stages of

46:01

Alzheimer things like that.

46:03

All right. There's also Mr. Elastography rights.

46:07

So brain on elastography which is essentially looking at tissue stiffness. And

46:10

what I wanted to point out here was that when you

46:13

look at like a normal each match control, if you look at different

46:16

types of hydrocephalos, it could be communicating it could be obstructive whatever

46:19

but essentially you have increased interstitial

46:22

pressures and that's forcing at the fluid from

46:25

the periovascular spaces. So the remaining brain tissue actually looks

46:28

stiffer than a normal patient in these various

46:31

types of hydrocephalus. And so again that has

46:34

implications right for the effective drainage the fact

46:37

that there's less interstitial fluid on board to be exchanged.

46:41

Perfusion. Okay. So as I mentioned we have

46:44

actually spin labeling which actually looks at endogenous blood

46:47

water as a tracer and so you can actually measure absolute

46:50

cerebral blood flow you have DSC which

46:53

we use a lot for tumors, right? So it's negative contrast from the

46:56

first pass of gadolinium and you look at relative cerebral

46:59

blood volume and then Dynamic countries and hands

47:02

Imaging which is T1 weighted. We do this a lot with like breast and liver

47:05

for example or research in the brain and it's T1 when

47:08

it's now you're looking at positive contrast to Gad but the thing is that not

47:11

just the first fast but over time right Gad will

47:14

actually partition from the intravascular space

47:17

where you injected it to the interstitial space,

47:20

right? And so that partition coefficient looking at

47:23

that exchange can be very helpful for the lymphatic function. And so actually all three

47:26

of these you have to repurpose them for a gloomphatic

47:29

applications. But all three of these can actually be used

47:32

to help look at that.

47:34

So in terms of this was a very well known study on

47:37

actually clinical patients, right? What are they looked at? Just Gad

47:40

injection and then they actually re-image them three and 24

47:43

hours post post-injection. It's

47:46

again, see how that initial the

47:49

initial intravenous injection actually partitions out

47:52

into the CSF and then even into you know, the the

47:55

Globes right the vitreous humor and so forth and so

47:58

on and here's a closer look right so initially, it's actually the

48:01

aqueous humor and later the vitreous humor right over time.

48:04

You can see other things like the cavernous sinuses.

48:07

You can see the inner ears and so forth. So there's a

48:10

Time dependent entry right exchange of

48:13

with different barriers time-dependent

48:16

and then eventually clearance, but

48:19

it's all very Dynamic and temporal and different for each barrier

48:22

system.

48:25

The chord plexus as I mentioned, right? That's the that's the blood

48:28

CSF barrier. So normalcard plexus is

48:31

very hypervascular. It's like five six times more perfused than

48:34

normal brain parenchyma on ASL and

48:37

then obviously a papaloma or or carcinoma right

48:40

is even more like this plastic, right? So this is

48:43

actually in a typical one because it's getting some leptomanage you'll seeing but you can see the high

48:46

amount of flow that's happening. So on ASL there

48:49

have been many studies looking at, you know, the the normal increase

48:52

for Fusion of the chord plexus and even

48:55

alterations and like Dimensions. Therefore, you can also

48:58

look at the things like the proton concentration. This is a essentially

49:01

amide proton Imaging so looking at how much protein there is

49:04

and so in a papaloma, there's you know increase protein

49:07

and then in the carcinoma there's even more. So again, it

49:10

just depends on what you're really trying to look for. What's your clinical

49:13

question?

49:14

Um in terms of a different types of

49:17

tumors, right? So normally we use DSC but

49:20

you can actually use any perfusion technique. They just measure slightly different things. So

49:23

this is helpful for surgeons in terms of staging right

49:26

making sure they don't under biopsy when they're when they're

49:29

trying to assess the tumor. So this was a pxa this

49:32

was a actually an infantile getting gluclioma,

49:35

right? But again, you're really looking at these

49:38

areas of increased perfusion and this was a glioblastoma so

49:41

you can actually see all of the different exchange constants in

49:44

the brain. So you can use this to look at blood perfusion. You

49:47

can use this to look at CSF refusion just depends on how you're setting your parameters

49:50

and so forth. So work with your physicists.

49:53

And then ivim is actually just a form

49:56

of diffusion where we do both low and high

49:59

B values. So normally you do diffusion weighted Imaging

50:02

at high B values, right? And so you're looking at random

50:05

molecular water diffusion, but there's actually a small component

50:08

from the blood microcirculation which actually forms a

50:11

pseudo diffusion coefficient. So if you actually measure low

50:14

B values as well, like multiple B values you

50:17

can actually do this exponential correction and do a more standardized or

50:20

corrected thing for clinical trials. And so you can normalize things

50:23

to look at, you know, corrected ADC kurtosis

50:26

Etc and actually a

50:29

develop a normalized index that looks at both

50:32

perfusion and diffusion characteristics. You can imagine how this will be very

50:35

helpful for cereal. You know, tumor Imaging post treatment

50:38

Etc.

50:40

Here's a nice example from Danny Wong who

50:43

does a lot of Alzheimer work over at USC Loney. So

50:46

I'm here. He's looking at amyloid beta in

50:49

the CSF, right? And so basically the more you because Emily

50:52

beta is bad, right? It can form like a five roles and plaques in

50:55

the brain. So if you're clearing it, that means you're lymphatic function is better, right? So

50:58

they they correlated the CSF levels of

51:01

amyloid beta and so they correlated with

51:04

higher overall cerebral blood flow and higher overall

51:07

blood-brain permeability. So basically the better

51:10

the glimpatic function the better the exchange and flow

51:13

the healthier the brain was so the Neuropsychiatric outcomes were also better.

51:17

Here's another thing with apoe. So apoe basically is helping

51:20

you to remove your you know, your plaques and stuff.

51:23

And so if you have the APO E4 mutation heterozygous

51:26

or even worse homozygous, right?

51:29

It's a poor outcome. So here he was showing

51:32

that essentially the mutational load of apoe for correlated

51:35

with poorer, you know, blood-brain barrier

51:38

permeability. So worse lymphatic function there was

51:41

increased iron deposition in the brain. So worst neurodegeneration

51:44

at decreased iron and removal right

51:47

Toxin and removal and then increased amyloid plaques on

51:50

the Pittsburgh, PA pet.

51:54

This is a nice work from John Hua. Right? So if you do a post

51:57

contrast T1, right you can do this

52:00

on any patient, right? Everything will light up all the vessels and somewhere

52:04

in here are those meningul emphatics I told you about but you

52:07

can't tell them apart from the vessel because everything enhancing if

52:10

you do a post-contrust flare, so this is a postcounter CD flare

52:13

you suppress the vessels but you actually see the surrounding managerial

52:16

lymphatic. So these are those pair of sagittal Journal

52:19

lymphatics managerial lymphatics. I told you about so these are the ones that communicate

52:22

with the sagittal sinus and actually are able

52:25

to drain out to the cervical lymphatic so you can see them actually quite nicely.

52:28

And so John actually did a DSC study to actually quantify The

52:32

Exchange, you know during a Gad like first

52:35

passive Gad to actually look at different types of

52:38

disease processes and show that you know, drop in signal with the

52:41

get injection within the meningeal lymphatics to show

52:44

the essentially the healthiness of the lymphatic system.

52:48

You can also look at you know, just normal disease processes.

52:51

This was actually a patient. We saw at my institution with

52:54

covid-19 who had retinitis. So these kind of like, you know

52:57

ill defined sort of natural or fluffy deposits are

53:00

our characteristic of covid-19 retinitis. There's a

53:03

paper and radiology. And again, this is the vitreous humor, right? So essentially the

53:06

blood retinal barrier has been broken down and you're getting these inflamed like

53:09

plaque like deposits. Here's a

53:12

labyrinthitis case. So again, like normal you're should have

53:15

nice CSF signal, right? But that has been broken down

53:18

right by this middle ear infection, right?

53:21

So we have meningo genic labyrinthitis. And so now you're getting

53:24

enhancement and this can actually sometimes ossify out,

53:27

right?

53:29

Here's the classic normalized Optica. Right? So the aquaporn

53:32

for autoimmunity leads to these patchy sometimes,

53:35

you know cloudy enhancement all along the

53:38

ventricular system because that's where the appenda and the you

53:41

know, the blood brain blood pendemal barriers are

53:44

right. So all those transport processes are degenerating to get

53:47

a lot of like fluffy ill-defined Perry ventricular

53:50

type cloudy things

53:53

and also characteristically the as I mentioned the aeropostrema, right

53:56

and the back of the third sorry back of

53:59

the fourth and and then you can also have like some chord

54:02

stuff like just patchy chord things especially along

54:05

that's Central Canal right? Everything's kind of like along that appendable lining

54:08

Central Canal. Everything's kind of the permeation is

54:11

happening with those faulty aquaporn channels.

54:14

And then here's a so that your brachial plexus. So outside

54:17

of the dorsal root ganglia and your your

54:20

Your peripheral notion of enhanced right? So this is a case where there's

54:23

like a parsonage Turner, right and essentially like post viral and

54:26

then they had like some, you know, pear infectious

54:29

like issues with a break of plexus. So you're getting blood nerve

54:32

very breakdown. And so you have enhancement and edema in

54:35

the brachial plexus.

54:37

And then for dce, right? This is a well-known patient

54:40

who was like in the news and stuff with a face transplant and out

54:43

of interest, you know, I wanted to see what the kind of exchange processes were.

54:46

So we did dce and you could see you know,

54:49

whenever you basically they replanted this midface, right?

54:52

So the site the sinus, you know, once you break the

54:55

you know, break the connections like those those cilia of

54:58

the sinuses are never gonna be like normal anymore. So there's

55:01

a lot of you know, retention CIS and whatnot.

55:04

But the vessels hook up and then in terms of the radiation

55:07

there is some third spacing as you would expect at the transplant, but the perfusion

55:10

to the flap is good and here you can kind

55:13

of see the drainage and everything in the exchange to the cervical lymphatic. So

55:16

basically the facial things are draining in the cervical lymphatic. So all

55:19

of this is basically hooking up,

55:22

And then we have Mr. Lymphangiography, right? So

55:25

this is the poor child with a very extensive head and neck lymphatic

55:28

malformation as you can see and then there was some

55:31

actually, you know leakage happening, you know leakage exchange through

55:34

these disorganized cervical lymphatics, right? So as they

55:37

were coming down right there was a lot of leak into the lymphatics and

55:40

the thoracic duct and so forth. And so you can inject either,

55:43

you know nodes like in the cervical region or in the growing depending

55:46

on what you're looking for. You're looking for peripheral you're looking for cervical but the

55:49

ideas that you can actually image lymphatic flow, you know

55:52

in the cervical cervical lymphatics of the period over time as well. If

55:55

you're looking for Downstream Downstream flow. So again, it's

55:58

all about what's your clinical question? How do you want to characterize it work with

56:01

your physicists to tailor those techniques based on the

56:04

you know, underlying mechanisms. So my last slide,

56:07

you know, the idea is that we have all of these complex, you know

56:11

processes all the way from cellular all the way to organ

56:14

systems which we typically do with radiology and

56:17

then population Health, right and we interrogate these through

56:20

a combination of

56:22

Ideally quantitative techniques, right our Radiology digital pathologies

56:25

coming down the pike a lot of genomic epigenomic stuff

56:28

and then clinical metrics and lab values and

56:31

ideally we all work together to synthesize this information. So it essentially

56:34

allows us

56:37

to provide earlier more accurate disease diagnosis risk assessment

56:41

and prognosis and then targeted therapies, right

56:44

so minimally invasive interventions molecular Therapeutics

56:47

so forth and so on to optimize our

56:50

long-term patient outcomes, and that's really the vision

56:53

of Precision Health

56:55

And so, you know into the future, right? So I talked

56:58

about 70. They're actually a few systems out there which are above

57:01

10t. Right and they're mostly scanning like animals and

57:04

fruits and stuff right now not human stuff. But the idea

57:07

of these right is that you can Bridge

57:10

the microscale in the microscale to really achieve what we

57:13

call the Meza scale. Right? So we will have the ability to

57:16

look at cellular molecular level processes and then link them through

57:19

brain systems brain networks to really understand the

57:22

underpinnings of neurologic and psychiatric disorders at

57:25

a much higher level than we currently do and I think the gloemfatic

57:28

system plays a huge huge role in that and these sorts

57:31

of technologies will be required to interrogate them.

57:34

So in conclusion a glimphatic system

57:37

with many barrier systems helps to

57:40

regulate the brainy homeostasis via selective fluid

57:43

exchange between different stereotype compartments.

57:46

Neurofluid circulation varies quite a bit physiologically, right?

57:49

So there's a lot of normal variation, but it can also be disrupted by

57:52

diseases and interventions, right so we can use this to help

57:55

optimize our therapies, but also various diseases

57:58

can create insults that lead to a final

58:01

common path. We have a glimp edema and multimodal imaging

58:04

very things that I showed in terms of flow structure and function

58:07

can be tailored to help us provide quantitative characterization for

58:10

targeted diagnosis and treatment in

58:13

various disorders. Thank you so much for your attention, and I'm happy to take

58:16

some questions now.

58:19

After how we have a couple questions and I

58:22

can start us off by reading the first one to

58:25

you.

58:28

I thought fungal meningitis gets to a periovascular VR spaces

58:31

because there's some connection to the subarachnoid space.

58:34

What is the mechanism of cryptococcal or gelatinous

58:37

pseudosist?

58:38

That's a great question. So I agree macroscopically you

58:42

do see a lot of like, you know thick nodular, you know,

58:45

fungal type meningitities and basilar so you often will

58:48

see them dazzler right like because they're heavy right

58:51

and they deposit and there's a lot of more flow around the basilar sisters. So

58:54

with the with the pseudosis essentially

58:57

they're very like sticky and you know gelatinous and

59:00

you see something you see something like this too with for example, um,

59:03

Mico polysaccharidosis, right? So that's basically the glycoso amino

59:06

glycans, right and they accumulate and they actually

59:09

accumulate in the period vascular spaces and swell them and so the lymphatic

59:12

fail first there, but then if you think about something like

59:15

metacromatic liquid dystrophy where you know, like all

59:18

of the like all of the myeliness is just

59:21

trophic but then the CSF is okay. You

59:24

actually have this Thai grade pattern where you have preservation of brain around

59:27

the fair spaces and everything else is affected. So

59:30

you're absolutely right. I think from a macroscopic standpoint. I'm sure

59:33

that over time those things can leak and and they

59:36

would impair the Perry.

59:38

Larry space exchange as well and I'm sure that actually probably

59:41

contributes if someone wanted to do a study of

59:44

you know, what is the are there more printable deposits

59:47

like beta amyloid or whatnot in a chronic crypto case, but

59:50

I think you're right. It's like basically it's a primary CSF process.

59:53

There's a lot of you know, sticky, you know, gelatinous infection

59:56

kind of in and around, you know, the basal cisterns

59:59

and later as a surprise faces and crawls into the perivascular spaces, but

60:02

you're absolutely right that over time that could have, you know, secondary effects

60:05

on the parenchymal drainage as well. So it's all about you know, where does

60:08

the disease process start? And then how does that affect lymphatic drainage,

60:11

you know on top of everything else?

60:15

awesome

60:16

Our next question is do we all leak CSF into

60:19

our sinuses in very small amounts through the Kirby form

60:22

plate. And if so, do we have an idea of the normal rates

60:25

and could that be a non-invasive measure of

60:28

CSF movement?

60:30

That's a great question. So I was actually just at a school-based meeting with a

60:33

surgeon who mentioned that he had a patient who didn't have any defect

60:36

but was leaking like had beta transferred going

60:39

through. So yes, we do all leak normal amounts and

60:42

there was a rat study that talked

60:45

about this and I think they they fed them something and

60:48

then they measured it in their nose. So we definitely all do because

60:51

there are these normal, you know foremena for

60:54

the through the olfactory Groove and you do get drainage that the

60:57

problem is that I think everyone varies obviously some people have like the

61:00

very thin, you know a factory plates and some people have CSF leaks,

61:03

you know from like little to hissences and then maybe if you

61:06

had your covid swab up there you would actually create an ayatrogenic one so

61:09

forth and so on so it's definitely a normal variant but

61:12

like I don't think anyone knows what the kind of

61:15

the threshold is for calling, you know normal versus abnormal, but I think

61:18

it also depends on whether you can see the discreet bone defect you're not but

61:21

some people have more for M&S and people have larger for Amana,

61:24

you know, some people have less so I this there's clearly gonna

61:27

be a normal man A variation so it is one factor for

61:30

And maybe could even have implications in terms

61:33

of you know, like CSF hypertension and other

61:36

types of symptoms. I think there are some like migrant nerves

61:39

and things or some people with like CNS infection

61:42

who have had more leakage. The only

61:45

problem is it's not it's not a gonna be

61:48

a direct or it's only one factor right in the overall CSF Dynamics.

61:51

If you're looking overall csiences, there are many other things but this particular

61:54

drainage traffic is just one of many so I absolutely agree

61:57

that for a targeted research project and maybe in correlation

62:00

with either normal variation or disease processes, or maybe

62:03

let's say patients who you're doing the myelogram and you want to see you know,

62:06

what even like if they have no bone defect

62:09

but they still have symptoms of CSF hypotension. I'd be really interested to

62:12

see I bet we do have some patients who have maybe just like more patchless

62:15

for him and or something like that. So I think it'd be

62:18

very interesting Heroes, you know classification. Like how does all

62:21

of that correlate but yeah, it is a normal variant and there's still a

62:24

lot. We don't know about it.

62:27

Do you think that the time slip MRI sequence has

62:30

any utility in the study of the lymphatic systems?

62:33

Yeah, that's a great question. So time slope is basically a version of

62:36

face contrast, you know, so non-contrust flow and so it could be used right

62:39

you just have to work with your physicists to understand. You know, what's the question

62:42

like which part of the brain or central nervous system. Are you

62:45

wanting to measure the CSF flow or exchange and then

62:48

figuring out the directionality because you have do have to set you know,

62:51

like a bank in a Direction. So I think and there's also like 2D

62:54

3D 40 even 5D for a cardiac

62:57

flow now, right? So each of these has like pros and cons

63:00

and so it's just a measure. It's just a matter of you know, what kind of

63:03

volunteers or disease processing you're looking at. What do you

63:06

want to show? Where do you want to show it? You know and what direction you want to show it

63:09

and then having your physicists work out those kings, but absolutely it's one

63:12

of the many techniques that has these particularly in Japan. There's a lot of papers on

63:15

it.

63:16

but one final question

63:19

I want to do a research about the spread of PVS in the

63:22

brain patients with migraine. How can I measure them? What program do

63:25

you recommend?

63:27

This is a good question. So there's not I know there's a few papers

63:30

in the literature about I think institutions that

63:33

have done like the Deep learning, you know machine learning how to

63:36

segmentation if you're not doing it at 70. I think it would

63:39

be very hard. I mean, I guess you could do a fiest or something

63:42

but that takes a long time and there could be artifacts. So I would say from

63:45

a practical standpoint. What a lot of people have done is just have ratings like

63:48

radio just ratings to say like, you know number you

63:51

could even do ordinal rating. So like, you know, like a

63:54

few many, you know for for age or

63:57

whatever. It's a like, you know, small moderate large

64:00

and like how many there are something like that but clearly there

64:03

are qualitative changes we see so it's just that it's easier

64:06

to quantify these, you know by Auto

64:09

segmentation automatically, but you need kind of like a nice high resolution

64:12

sequence 3D sequence and 70 which we often don't

64:15

get so if you're looking at something like migraine again, this is challenging because

64:18

they're a lot of reasons people get migrants. It could be like basketball blah,

64:21

but let's say you're excluding.

64:24

You know all of the other cases so you're talking about like idiopathic migraine

64:27

and then you want to talk about the subtypes of migraine, but you need some normal

64:30

controls and you need the migrainers and maybe it

64:33

even want to follow them, you know pre-post a treatment and like how

64:36

long have they been what are their symptoms? So there's a lot of I think clinical trial design

64:39

issues. You have to think about first but ultimately in terms

64:42

of the PVS question, right? I think you could get ordinal Raiders

64:45

and beaches fine for your conventional Imaging.

64:48

Hey Dr. Ho I lied. There's one more question. Okay, you

64:51

ready for it? Okay. Yes. Can you comment on the relation between

64:54

the lymphatic system and multiple sclerosis?

64:58

Yeah, so multiple sclerosis. I talked to more about nmo just

65:01

because of the aquaporn for thing, but you're absolutely right. I think multiple sclerosis is another

65:04

one. I mean, there's a there's a kind of theorized like viral, you know,

65:07

potentially viral aspect to that now to but absolutely, you

65:10

know inflammatory changes just like with infection,

65:14

right? So I don't even disorders do involve some level of

65:17

disturbed barrier function, right and

65:20

I think with Ms. There's some other clearly there's

65:23

like that very venular sign. So, you know, they're

65:26

the Peri venial or modeling plaque. So clearly there is some

65:29

aspect of glimphatic function slash dysfunction involved in

65:32

there. I think we understand less about that and we also are

65:35

wondering you know, what are the other, you know underlying viral /

65:38

autoimming etiology, but I totally agree that Ottawa

65:42

mean slash and find her conditions also our implicated

65:45

and there are a number of papers on Ms. And disturbedical emphatic

65:48

Disturbed sleep. I just don't think they've made

65:51

as clear of a connection as with MMO or some of the other disorders and

65:54

maybe that's an area that you know, you could start looking into but but

65:57

I'm sure

65:58

There will be factors. You could even look at something like the Alps index. The

66:01

only problem is that right? The MS lesions are

66:04

everywhere, right? So you can't there's not really a control but let's say for early Ms.

66:07

Maybe you'd be able to let's say

66:10

like for a patient who at the level of center of some of your Valley

66:13

right? Maybe in an area where there is an MS lesion

66:16

doing the Alps index versus the contralater area

66:19

where there's not, you know, like an early Ms. We might be able to find differences. So I

66:22

think you should be able to demonstrate theoretically

66:25

Disturbed people lymphatic function. There's

66:28

well, I think that the the tiny lesions and the global disease

66:31

burden have limited a lot of the you

66:34

know, research applications in that area, but I'm

66:37

quite sure that you would be able to demonstrate some findings as well.

66:41

Awesome, Dr. Ho thanks for answering all those questions and thank you

66:44

so much for your lecture today. And thanks for

66:47

everyone for participating in our new conference and a special

66:50

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67:06

Mohan Mather on Imaging of uncommon gig

67:09

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