Being ly-mphatic about drainage issues

# # # # The lymphatic network is an important part of our body’s defense system. It is made up of an enormous web of vessels and nodes which help to protect us from infection and disease. This network transports a colourless fluid (called lymph), which serves two primary functions: 1.) it contains infection-fighting white blood cells that help in immune responses, and 2.) it functions as a ‘drainage system’ – allowing excess fluid from organs to be extracted and shifted to the blood system for excretion. Recently, researchers reported something interesting about the lymphatic system in people with Parkinson’s: the rate of flow around the brain is slower. In today’s post, we will discuss what the lymphatic system is, review what the new research found, and look at how this new information could potentially be used to help treat conditions like Parkinson’s. # # # #

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Source: Thinkery

So picture this if you will:

The weather reporter would later say that it was “a month of rain in the matter of an hour“, but in the midst of the summertime mêlée I was standing bare foot, ankle deep in my rapidly flooding courtyard, trying to clear the blocked storm drain with a long metal pole.

My tee-shirt and shorts were soaked, and… oh yeah, there was lots of thunder and (more importantly) lightning.

Source: KalingaTV

Now, I am a rather tall individual (6’8 ~ 2m 7cm on my good days), and looking back now I can appreciate that standing ankle deep in water holding a long metal pole high in the air (to gather enough downward force to unplug the drain) in the middle of a lightning storm was probably not one of my best moments.

Luckily, my neighbour – a plumber and 3-4 fold smarter than me – kindly decided to take pity on his slow-witted nearby resident. He leapt into the situation and resolved it all in the blink of an eye.

Source: Independent

Since that moment I have religiously maintained a clear storm drain, and taken to deriving great pleasure in keeping other drainage systems about the house clear and flowing free.

I’m happy for you, but what does this have to do with Parkinson’s?

Well, very recently researchers have reported that a different kind of drainage issue might be at play in many cases of Parkinson’s.

What on Earth do you mean?!?

On Martin Luther King Day this year, an interesting research report was published:

Title: Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease.
Authors: Ding XB, Wang XX, Xia DH, Liu H, Tian HY, Fu Y, Chen YK, Qin C, Wang JQ, Xiang Z, Zhang ZX, Cao QC, Wang W, Li JY, Wu E, Tang BS, Ma MM, Teng JF, Wang XJ.
Journal: Nat Med. 2021 Jan 18. Online ahead of print.
PMID: 33462448

In this study, the researchers were interested in the meningeal lymphatic system and the influence it may be having in Parkinson’s.

What is the meningeal lymphatic system?

To answer this question, we need to go way back in time – to Italy in the 18^th century.

What?!?

Just go with me on this, it’s a curious little detour that explains a lot about “discovery” in science.

Towards the end of the 18^th century, an Italian physician and anatomist named Paolo Mascagni made a rather amazing discovery.

Paolo Mascagni. Source: Italyonthisday

After graduating from the University of Siena, Mascagni turned his attention to researching and mapping out the human lymphatic system.

The lymphatic system is a network of thin tubes and nodes that runs throughout our bodies. The tubes are called lymphatic vessels, and they contain a liquid called (surprise!) lymph.

The human lymphatic system. Source: Wikipedia

The lymphatic system is similar to our blood circulation, with lymphatic vessels branching throughout our bodies like the arteries and veins.

The lymphatic system has two main functions:

• Fighting infections – lymph contains a type of white blood cells called lymphocytes, which help to fight infections and kill rogue cells
• Remove waste -the lymphatic system serves as a drainage system for the body, collecting waste products and excess fluid from all of the tissues and organs

In addition to the lymphatic vessels, there are also the lymph nodes. These are small bean-shaped glands, scattered throughout the body, which filter the lymph fluid as it passes through them. White blood cells within the lymph node attack any viruses or bacteria that they find in the lymph. One can imagine some pretty epic battles in lymph nodes.

A lymph node. Source: CRUK

The big take away message is that the lymphatic system is critical to keeping our bodies healthy and free of waste.

This short video explains it all better than I do:

Now getting back to Mascagni.

One of his most important findings was the discovery of the meningeal lymphatic system.

This is the lymphatic component of the meninges.

What are the meninges?

The meninges are three layers of membranes that cover the brain, protecting it from impact and damage. The three layers are called the dura mater, the arachnoid mater, and the pia mater.

Meninges. Source: Wikipedia

Before Mascagni came along, it was believed that the brain did not have a lymphatic component. By finding the meningeal lymphatic system, Mascagni added a whole new realm for researchers to explore and build theories around.

Before Mascagni (left), after Mascagni (right). Source: Eurekalert

So the research community were excited by the discovery of the meningeal lymphatic system?

Despite the precision of his anatomical wax models (which are still on display at the Josephinum Medical Museum in Vienna), Mascagni’s report that lymphatic vessels were present in the meninges of the brain were…..

…firstly rubbished and then later forgotten…

…for almost 200 years!

Mascagni’s wax collection. Source: Josephinum Medical Museum

It was not until 1953, that another Italian scientist re-discovered Mascagni’s finding while inspecting samples of human meninges. And this was followed several years later by research describing the existence of a connection between the brain lymphatic component and rest of the lymphatic system, which allowed for the drainage of CNS-related molecules.

And then the research community got excited?

You would think, wouldn’t you.

But no.

Even that work was met with skepticism.

It was not until the 1996 (more than 200 years after Mascagni’s discovery in 1787), when researchers used scanning electron microscopy to finally and definitively establish that there was a meningeal component to the lymphatic system that it was eventually accepted.

And recently the research community has been making up for lost time with their enthusiasm.

# RECAP #1: The lymphatic system is a network of thin tubes and nodes that run throughout our bodies. The tubes are called lymphatic vessels, and they contain a liquid called lymph. The system has two functions: fighting infections and acting as a drainage system for waste and excess fluid from organs. Recently, research has focused on the lymphatic system around the brain. #

So what did the new report on Parkinson’s find?

This is the new report:

Title: Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease.
Authors: Ding XB, Wang XX, Xia DH, Liu H, Tian HY, Fu Y, Chen YK, Qin C, Wang JQ, Xiang Z, Zhang ZX, Cao QC, Wang W, Li JY, Wu E, Tang BS, Ma MM, Teng JF, Wang XJ.
Journal: Nat Med. 2021 Jan 18. Online ahead of print.
PMID: 33462448

In this study, the researchers were interested in what role the meningeal lymphatic system may have in Parkinson’s.

They began their study by collecting brain imaging data (dynamic contrast-enhanced magnetic resonance imaging) from 371 non-affected controls and compared them with brain imaging data from hundreds of cases of Parkinson’s and Parkinson’s-like conditions (including 375 patients with sporadic (or idiopathic) Parkinson’s, 152 cases of multiple system atrophy (or MSA), 136 patients with progressive supranuclear palsy (or PSP), 8 cases of dementia with Lewy bodies (or DLB), 4 patients with corticobasal degeneration, and 19 individuals with vascular parkinsonism).

The researchers reported are no significant differences between control cases and individuals with idiopathic Parkinson’s in terms of blood pressure or heart rate (before or after each scan).

But…

…when the researchers looks at the rates of flow in the meningeal lymphatic vessels, they found that individuals with idiopathic Parkinson’s displayed a significant reduction in various areas (when compared to other cases).

Slower flow of lymph in the meningeal lymphatic vessels?!? In idiopathic Parkinson’s?!?

Yes.

And notably, there was no significant difference in the physical size of meningeal lymphatic vessels between any of the groups analysed in the study, so this change in flow was not due to a shrinkage or increase in the physical tubes.

To gain a better mechanistic understanding of this phenomenon, the researchers turned to mouse models of Parkinson’s. Specifically, they injected preformed alpha synuclein fibrils into the brains of some mice and then looked at their meningeal lymphatic system over time.

What are preformed alpha synuclein fibrils?

We discuss alpha synuclein a lot on this website.

Alpha synuclein is one of the most common proteins in the brain (making up about 1% of the protein in neurons). The exact function of alpha synuclein is not well understood, but research suggests that it plays a role in multiple cellular functions – including being involved in neurotransmitter release.

But in Parkinson’s, something changes.

For some reason, in many cases of Parkinson’s alpha synuclein protein starts to cluster and clump together. And this “aggregated” form of alpha synuclein is believed to become toxic.

The aggregation of alpha synuclein is also thought to lead to the appearance of Lewy bodies.

What are Lewy bodies?

Lewy bodies are dense circular clusters of alpha synuclein protein (and other proteins) that are found in specific regions of the brain in people with Parkinson’s (Click here for more on Lewy bodies).

A cartoon of a neuron, with the Lewy body indicated within the cell body. Source: Alzheimer’s news

The aggregated alpha synuclein protein, however, is not limited to just the Lewy bodies. In the affected areas of the Parkinsonian brain, aggregated alpha synuclein can be seen in the branches (or neurites; see black arrow in the image below) of cells – see the image below where alpha synuclein has been stained brown on a section of brain from a person with Parkinson’s.

Examples of Lewy neurites (stained in brown; indicated by arrows). Source: Wikimedia

Why does alpha synuclein protein aggregate like this?

In truth, we do not know.

But it may partly have something to do with the nature of the protein. When alpha synuclein protein is produced by a cell, it normally referred as a ‘natively unfolded protein’, in that is does not really have a defined structure. Alone, it will look like this:

Alpha synuclein. Source: Wikipedia

By itself, alpha synuclein is considered a monomer, or a single molecule that can bind to other molecules. When it does bind to other alpha synuclein proteins, they form an oligomer (a collection of a certain number of monomers in a specific structure). In Parkinson’s, alpha synuclein also binds (or aggregates) to form what are called ‘fibrils’.

Microscopic images of Monomers, oligomers and fibrils. Source: Brain

And it is believed that the oligomer and fibril forms of alpha synuclein protein give rise to the aggregations of protein that we refer to as Lewy bodies:

Parkinson’s associated alpha synuclein. Source: Nature

It also believed that the oligomer and fibril forms of alpha synuclein protein may be being passed from cell to cell, and ‘seeding’ protein aggregation in new cells. And this is how the condition may be slowly progressing.

Researchers have developed methods of making alpha synuclein fibrils in the laboratory. These “preformed alpha synuclein fibrils” can then be used in cell culture or animals to model the pathology of Parkinson’s.

Ok, so the researchers made some of these preformed alpha synuclein fibrils and injected them into the brains of mice to model Parkinson’s. Then what happened?

Over a period of 6 months, as the mice developed some of the motor and pathological features of Parkinson’s, the researchers assessed meningeal lymphatic drainage function in them at the same time (using brain imaging).

The investigators reported that the rate of flow in the meningeal lymphatic system decreased over time and there was an increase in markers of inflammation of the meninges.

In addition, the researchers found that if they artificially slowed the rate of flow in the meningeal lymphatic system, the mice would display significantly more aggregated alpha synuclein protein pathology, which worsened their physical and cognitive features (as measured by behavioural tests).

The researchers concluded their study by suggesting that meningeal lymphatic drainage issues may aggravate alpha synuclein pathology and could be contributing to the progression of Parkinson’s. They also question whether “improvement of meningeal lymphatic drainage might be a promising therapeutic target for delaying or even preventing the progression of idiopathic Parkinson’s”

# # RECAP #2: New research reports that people with idiopathic Parkinson’s have a reduced rate of flow in their meningeal lymphatic system. The reduction is not due to any change in size of the tubes. Mouse models of Parkinson’s replicated this effect, and the investigators found that artificially reducing lymphatic flow resulted in enhanced alpha synuclein pathology in these mice. # #

Is this the first time that this has been reported?

Actually, for the mouse model research: no.

In 2019, the another research group published this report:

Title: Blocking meningeal lymphatic drainage aggravates Parkinson’s disease-like pathology in mice overexpressing mutated α-synuclein.
Authors: Zou W, Pu T, Feng W, Lu M, Zheng Y, Du R, Xiao M, Hu G.
Journal: Transl Neurodegener. 2019 Mar 1;8:7.
PMID: 30867902               (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers artificially reduced meningeal lymphatic drainage in genetically engineered mice that produce the human form of alpha synuclein with the Parkinson’s-associated A53T genetic mutation.

Six weeks later, when the investigators examined the mice, they found more severe accumulation of alpha synuclein in the brain, higher levels of inflammation, greater loss of dopamine neurons and more apparent motor issues. It is interesting to note that without the artificial reduction in meningeal lymphatic drainage, the A53T mice were no different to normal mice on most of the measures examined.

Here too, the researchers concluded their study by suggesting that brain lymphatic clearance could be “an aggravating factor in Parkinson’s pathology“.

Is this effect specific to Parkinson’s?

So having been dormant for 200 years, the meningeal lymphatic system is suddenly a VERY hot area of research. And other areas of aging and neurodegenerative research have been diving in to investigate the potential roles of this system.

In 2018, this research report was published:

Title: Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease.
Authors: Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, Contarino C, Onengut-Gumuscu S, Farber E, Raper D, Viar KE, Powell RD, Baker W, Dabhi N, Bai R, Cao R, Hu S, Rich SS, Munson JM, Lopes MB, Overall CC, Acton ST, Kipnis J.
Journal: Nature. 2018 Aug;560(7717):185-191.
PMID: 30046111                  (This report is OPEN ACCESS if you would like to read it)

This study was one of the first to show that meningeal lymphatic vessels are draining molecules and fluid from the brain into the lymph nodes. The investigators also showed that artificially blocking that flow caused cognitive impairment in mice. In addition, reducing meningeal lymphatic flow in a mouse model of Alzheimer’s increased pathology in the brain and worsened memory issues.

Interestingly, when the investigators treated aged mice with a protein called vascular endothelial growth factor C (or VEGF-C), it enhanced meningeal lymphatic drainage from the brain, AND improved performance on learning and memory tests.

And here again, the researchers asked whether “meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer’s pathology and in age-associated cognitive decline“. They also suggested that “augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases“.

Are there any clinical trial efforts focused on improving lymphatic flow?

Not that I am aware of (and I am happy to be corrected on this).

But there is a biotech company called PureTech Health that is exploring this area.

PureTech have been developing a drug called deupirfenidone (previously known as LYT-100), which has anti-inflammatory, antioxidant and antifibrotic properties, but it is being targeted towards disorders of lymphatic flow (specifically lymphedema). It is also being targeted at Long COVID (Source).

The company is also exploring ways of delivering therapeutics via the lymphatic system. They are developing an agent, LYT-300, which is an oral form of FDA-approved allopregnanolone (a natural neurosteroid) for a range of neurological conditions. It is looking to harness “the role of the lymphatic system in the absorption of dietary lipids to orally administer and traffic therapeutics via the lymphatic system” (Source).

PureTech Health exclusively licensed the relevant intellectual property surrounding the Alzheimer’s research – described above – in 2018 (Source), so hopefully we will be seeing signs of clinical translation in the not too distant future. I will be curious to see if the new Parkinson’s research (reviewed in this post) adds additional an indication to those efforts.

So what does it all mean?

New research has found that the flow of the meningeal lymphatic system – a network of tubes that allows fluids and waste to drain from the brain – could be reduced in individuals with idiopathic Parkinson’s. Additional experiments indicate that reducing this flow in mouse models of Parkinson’s increases the pathology associated with the condition.

The brain imaging data appears to be rather lymphatic… excuse me, emphatic given the large number of cases were involved (371 controls and 375 cases of idiopathic Parkinson’s). The result will still need to be independently replicated and expanded on in order for us to have a better understanding of the finding. It is also curious that many of the other Parkinson’s-like conditions (MSA, PSP, etc) were less affected by this lymphatic deficit.

I do like the idea that enhancing meningeal lymphatic flow could help to slow the progression of Parkinson’s – by allowing better clearance of waste. And given that biotech firms are already working on therapeutics to boost lymphatic flow, it will hopefully not be too long before this hypothesis (improving meningeal lymphatic flow can slow progression) can be tested.

It certainly seems like a smarter idea than standing ankle deep in a rain storm with a metal rod raised high in the air.

 

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