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Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Wed Jun 03, 2015 5:50 am
by Cece
http://europepmc.org/articles/pmc3880190
Sleep Drives Metabolite Clearance from the Adult Brain

Lulu Xie,1,* Hongyi Kang,1,* Qiwu Xu,1 Michael J. Chen,1 Yonghong Liao,1 Meenakshisundaram Thiyagarajan,1 John O’Donnell,1 Daniel J. Christensen,1 Charles Nicholson,2 Jeffrey J. Iliff,1 Takahiro Takano,1 Rashid Deane,1 and Maiken Nedergaard1,†


Abstract
The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.
I would like to see a researcher use "real-time assessments of tetramethylammonium diffusion and two-photon imaging" in humans, as this study was done in mice, and comparing healthy subjects with CCSVI subjects. This is a way to test the theory that CCSVI impairs CSF flow and thereby impairs cleansing of the brain.

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Fri Jun 05, 2015 6:57 am
by cheerleader
Dr. Nedegaard (the discoverer of the glymphatic system) is putting together a proposal to study this in relation to MS. I visited her lab in April, spent a few hours touring the facility, and having lunch while she and her associates presented a power point to me on their research and the connection between glymphatics and MS. I brought CCSVI research and the ISNVD info to her lab.. She had not heard of it, and was incredibly excited--her team has put together a research proposal to learn more about how venous flow impacts this system.

Here's the write up on my blog:
http://ccsviinms.blogspot.com/2015/04/g ... gaard.html

exciting times!
cheer

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Fri Jun 05, 2015 8:33 am
by Cece
Feels like progress. With a real-world end result that there will be better, more effective, less damaging treatment for this disease. After five years of paradigm shift to see MS in terms of CCSVI, it is very easy to fit this new information into the CCSVI paradigm. Kudos to Cheer for your continued activism.

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Sat Jun 06, 2015 10:48 am
by cheerleader
Kudos to all of us hanging in there and looking for answers, Cece--

I found an interesting article that discusses the history of finding the immune and cleansing pathways of the brain---
great reading http://www.the-scientist.com/?articles. ... ain-Drain/
“These structures are bona fide vessels—they express all the same markers as lymphatic vessels in every other tissue, and they drain the CSF, the cerebrospinal fluid, from the brain and the spinal cord into the deep cervical lymph nodes,” said Jonathan Kipnis of the University of Virginia School of Medicine, who led the work. “So there’s a direct connection between the CSF and the draining lymph nodes.”

The relationship between the brain and the immune system has long puzzled researchers. For some time, scientists thought that immune cells only showed up in the brain during an infection. The brain is considered “immune privileged,” such that when exposed to foreign material, it takes longer to mount an immune response than does the rest of the body. Furthermore, to date, traditional lymphatic vessels had not been found there.

In 2012, Maiken Nedergaard of the University of Rochester Medical Center in New York and her colleagues reported that the circulation of CSF and ISF in the brain was facilitated by water channels in the glial cells that abut the brain vasculature, and coined the term “glymphatic system.”

The Kipnis team’s latest finding represents an additional lymphatic pathway for the brain. Working in mice, Kipnis and his colleagues found that vessels expressing markers of lymphatic vessels elsewhere in the body ran along the dural sinuses, drainage lines in the brain that collect outgoing blood and CSF, emptying these fluids into the jugular vein. They also found that the vessels contained immune cells.
I'm thankful for these researchers who are breaking down walls of dogma.
Now, we need them to work with Dr. Zamboni and the ISNVD. That's what I'm working towards.
cheer

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Sun Jun 07, 2015 2:02 pm
by 1eye
This is exactly what those mouse researchers were filming in Jeff Iliff's TED talk at https://www.ted.com/talks/jeff_iliff_on ... anguage=en (you can get a transcript too). It sounds to me like a fundamental mammalian process, that all of us milk-drinkers have in common, when we sleep. Don't let the mouse/man/mighty-mouse controversies throw you off. We share a lot of function, DNA, and evolution, with humble mighty. The only big difference between us and they, in this instance, might be that they are nocturnal, sleeping during the day. I hate what we do to these little beggars, but keep mice awake all day, and they might have Alzheimer-like problems too. Or MS?

CCSVI interferes with circulation of CSF, which is created and excreted via venous blood. Where does amyloid-beta go when it leaves the brain? It may be that part of that excretion of brain metabolites is a key function of our solid-waste excretory system. Which might connect it to the gut, the health of microbes, and to biotin.

You might try giving some biotin to those sleepless mice.

The fact that the best mouse-model of MS involves MS following inter-species transfer of human CSF from sufferers to mice, seems very relevant. There must be some MS in that thar fluid.

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Sun Jun 07, 2015 4:22 pm
by Rogan
Cece wrote:http://europepmc.org/articles/pmc3880190
Sleep Drives Metabolite Clearance from the Adult Brain

Lulu Xie,1,* Hongyi Kang,1,* Qiwu Xu,1 Michael J. Chen,1 Yonghong Liao,1 Meenakshisundaram Thiyagarajan,1 John O’Donnell,1 Daniel J. Christensen,1 Charles Nicholson,2 Jeffrey J. Iliff,1 Takahiro Takano,1 Rashid Deane,1 and Maiken Nedergaard1,†


Abstract
Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep.
I would like to see a researcher use "real-time assessments of tetramethylammonium diffusion and two-photon imaging" in humans

Me too.

I have never heard of this concept before or the ability to measure it.

Is the expansion of interstitial space important in other diseases? Is it important in arthritis? Is it important in Alzheimer's?

My question is this…if interstitial space grows 60% during sleep, at the expense of what? What shrinks when you sleep? Also what is convective exchange?

Thanks in advance….and thanks for CeCe for posting this quote….

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Sun Jun 07, 2015 7:48 pm
by cheerleader
Rogan wrote:
I have never heard of this concept before or the ability to measure it.
Is the expansion of interstitial space important in other diseases? Is it important in arthritis? Is it important in Alzheimer's?
My question is this…if interstitial space grows 60% during sleep, at the expense of what? What shrinks when you sleep? Also what is convective exchange?
Thanks in advance….and thanks for CeCe for posting this quote….
I spent over 4 hours with Dr. Nedergaard in her lab, discussing her research, looking at slides, powerpoints and seeing the actual mice being studied. You could actually see the whooshing through the brain of the fluid, which was turned green from tracer dye...and the pathways only opened up during sleep.
The space for interstitial fluid is created during sleep by the resting state of our neurons. The awake brain does not have the ability to cleanse metabolites, proteins and plasmic particles. This cleansing process only happens during the sleep state.
“Sleep changes the cellular structure of the brain. It appears to be a completely different state,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the Center for Translational Neuromedicine at the University of Rochester Medical Center in New York, and a leader of the study.Their results, published in Science, show that during sleep a plumbing system called the glymphatic system may open, letting fluid flow rapidly through the brain. Dr. Nedergaard’s lab recently discovered the glymphatic system helps control the flow of cerebrospinal fluid (CSF), a clear liquid surrounding the brain and spinal cord. http://www.nih.gov/news/health/oct2013/ninds-17.htm
Here's more about my visit to the lab:
http://ccsviinms.blogspot.com/2015/04/g ... gaard.html

And yes, Rogan--it's hugely important in Alzheimer's. Removing beta amyloid protein build up is done by this newly discovered glymphatic system. It's also important traumatic brain injury patients (think about it, common wisdom is to keep concussion patients awake. What Dr. Nedergaard says TBI patients need most is sleep, to allow inflammatory cells an exit.)

Sleep problems in people with MS are well-known.
Yet healing and cleansing of the brain requires deep sleep.
How can we help wMS get good sleep?
UV ray therapy, exercise, stress reduction and melatonin can help reset the circadian rhythm.
http://www.ucdmc.ucdavis.edu/publish/news/newsroom/9230

Interestingly, some sleep meds and anesthesias inhibit this glymphatic clearance...more studies are needed, but Dr. Nedergaard stressed that until then, natural sleep is best.

hope this info helps--
cheer

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Mon Jun 08, 2015 2:05 pm
by 1eye
Just because I suspect sleep has something to do with it, tonight I will try changing my biotin dose to morning from last thing before bed. It may be related to why I can't get to sleep at night. We'll see.

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Tue Jun 09, 2015 10:26 am
by cheerleader
1eye wrote:Just because I suspect sleep has something to do with it, tonight I will try changing my biotin dose to morning from last thing before bed. It may be related to why I can't get to sleep at night. We'll see.
1eye--
suggestions from Dr. Nedergaard on restful sleep.
UV rays on body and eyes during day to set circadian rhythm, melatonin in evening and vitamin D and magnesium supplementation.
No bright screens in bedroom. Daily exercise. Meditation.
Not sure how biotin would affect all of this, but maybe morning is better. I actually read a few blogs of people using biotin as a sleep aid. Dunno...

Dr. Needergaard commented to me that many sleep medications and anesthesia actually impair the glymphatic pathway, which is why she thinks natural might be better. She had a female lab technician who was really good at holding and calming the mice and getting them into a deep sleep--and that's when the glymphatic pathway really showed up. The mice who were sleep induced by medications or anesthesia didn't have as robust a clearance. More research is coming from her lab, but until then, hope this is helpful.

cheer

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Wed Jun 10, 2015 5:13 am
by Cece
Rogan wrote:
Cece wrote:I would like to see a researcher use "real-time assessments of tetramethylammonium diffusion and two-photon imaging" in humans

Me too.

I have never heard of this concept before or the ability to measure it.

Is the expansion of interstitial space important in other diseases? Is it important in arthritis? Is it important in Alzheimer's?

My question is this…if interstitial space grows 60% during sleep, at the expense of what? What shrinks when you sleep? Also what is convective exchange?

Thanks in advance….and thanks for CeCe for posting this quote….
maybe the interstitial space can't grow 60% if there are pressure abnormalities or edema or other poor venous drainage-related issues, or if the interstitial space did grow it would be too compressing on the brain itself?

I don't know what convective exchange means but I think of a convective oven and I think it might mean exchanging by mixing throughout possibly with currents such as the fan in a convective oven ... yeah this is a poor definition attempt when google is available

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Wed Jun 10, 2015 5:24 am
by Cece
This research is essential in understanding MS disease etiology! I was so excited to hear Dr. Nedergaard present her proposal to continue this research into MS and the glymphatic system. She was quite energized to see the connections, and is making a proposal for more research specific to MS, and thanked me for bringing in the vascular research of MS to her attention. I hope to aid her lab in securing funding for this very important work, and will be asking for funding ideas and assistance once her research proposal has been formalized. Establishing the basic science and foundation necessary to understand how brain diseases develop will only aid progress. And of course, I introduced her to the International Society of Neurovascular Disease! http://www.isnvd.org
Right here, kudos, this is very exciting, and it's boots-on-the-ground making connections and bringing research to researchers, not to mention addressing the need for funding

I am wondering what size these lymphatic vessels are. Do they have valves? Do the vessels have abnormal collagen in people with MS just as the jugulars have abnormal collagen? Could a dilated jugular compress the lymphatic vessel as Dr. Zamboni suggested? What is the process of angiogenesis for lympatic vessels, can they reroute or replace themselves if they are abnormal or blocked? Can slow draining of the lympatic vessels be measured? What is the best way to image them? So many questions without answers! Are we and the neurologist community on the same side in wanting research into this lympatic system? Having a tail wind instead of a head wind in that regard would be nice!

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Wed Jun 10, 2015 11:58 am
by cheerleader
Cece wrote:
I am wondering what size these lymphatic vessels are. Do they have valves? Do the vessels have abnormal collagen in people with MS just as the jugulars have abnormal collagen? Could a dilated jugular compress the lymphatic vessel as Dr. Zamboni suggested? What is the process of angiogenesis for lympatic vessels, can they reroute or replace themselves if they are abnormal or blocked? Can slow draining of the lympatic vessels be measured? What is the best way to image them? So many questions without answers! Are we and the neurologist community on the same side in wanting research into this lympatic system? Having a tail wind instead of a head wind in that regard would be nice!

So many things to explore, huh? Now we have to learn lymph vessels, too :) They're kind of like veins, so most of the language will be familiar.
http://biology.about.com/od/anatomy/ss/ ... essels.htm

I first starting reading abut them when I was looking into information on the endothelium, since lymph vessels are lined with endothelial cells, and can suffer from endothelial dysfunction.
Lymphatic vessels DO have valves...pretty amazing. They are larger than blood vessels, but they contain clear liquid, which is why they've been hiding in plain site. The way to image them has just been discovered by Dr. Nedergaard...it was using a newly designed flouresent tracers they used to inject into living mice. But her lab didn't see vessels, they just saw lymphatic flow.
Our team made its initial discovery by injecting fluorescent tracers into the brains of living mice, and then imaging the movement of those tracers, in real time, using two-photon microscopy. These techniques allowed us to visualize the path of different sized molecules as they traversed the cortical layers of the brain, in addition to quantifying the clearance rate. Following the tracers revealed a distinctive pathway: once injected into the subarachnoid cerebrospinal fluid (CSF), the tracers readily flowed into the brain along the outside of the penetrating blood vessels
https://www.urmc.rochester.edu/labs/ned ... tic_system

The University of Virginia was replicating this research and looking for lymphatic pathways, using the same dye, when they quite accidentally found what looked to be like vessel-like patterns in the immune cells.
The vessels were detected after Louveau developed a method to mount a mouse’s meninges – the membranes covering the brain – on a single slide so that they could be examined as a whole.
http://news.virginia.edu/content/resear ... une-system

Game-changer!!

What Dr. Zamboni is suggesting is that the reflux and pressure from stenotic jugular veins is causing the dural sinus to have more pressure and collapse, thus squishing these lymphatic vessels and not allowing for drainage.
I'm not sure whether they can re-route, like collateral veins, Cece...need to learn more about that.
But in other parts of the body, like the legs, blocked or slowed lymphatcis can lead to nasty things, like venous ulcers, which are caused by immune activation. And that's what Dr. Zamboni has been saying all along...the brain is like the rest of the body, and needs good venous flow.

cheer

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Wed Jun 10, 2015 1:15 pm
by Cece
cheerleader wrote:What Dr. Zamboni is suggesting is that the reflux and pressure from stenotic jugular veins is causing the dural sinus to have more pressure and collapse, thus squishing these lymphatic vessels and not allowing for drainage.
Got it.
Do you know if this discovery affects the explanation of drugs such as Tysabri's mechanism of action? Tysabri strengthens the blood-brain-barrier, right? But is there a blood-brain barrier if there is this glymphatic system in place? So confused.

Could a stent in the dural sinuses physically block a lymph vessel?
These lymphatic channels combine as they travel towards the neck, eventually forming one large channel called the thoracic duct. The thoracic duct rejoins the systemic venous system at the lymphovenous junction, near the confluence of the left internal jugular and subclavian veins. http://www.google.com/patents/WO2010080717A1?cl=en
That's a familiar area: the base of the left jugular, near where it joins the subclavian, right where the left jugular valve can be found and where CCSVI blockages are very commonly found.

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Wed Jun 10, 2015 1:53 pm
by Cece
Rogan wrote:
Cece wrote:I would like to see a researcher use "real-time assessments of tetramethylammonium diffusion and two-photon imaging" in humans

Me too.

I have never heard of this concept before or the ability to measure it.

Is the expansion of interstitial space important in other diseases? Is it important in arthritis? Is it important in Alzheimer's?

My question is this…if interstitial space grows 60% during sleep, at the expense of what? What shrinks when you sleep? Also what is convective exchange?

Thanks in advance….and thanks for CeCe for posting this quote….
I agree with these questions but don't have the answers -- an additional question, though, is if sleep drives metabolite clearance from the brain, then does metabolite build-up drive the need for sleep? Could MS fatigue be at least partially caused by this build-up and could there be a treatment?

Re: Sleep Drives Metabolite Clearance from the Adult Brain

Posted: Wed Jun 10, 2015 3:29 pm
by cheerleader
Cece wrote:
Do you know if this discovery affects the explanation of drugs such as Tysabri's mechanism of action? Tysabri strengthens the blood-brain-barrier, right? But is there a blood-brain barrier if there is this glymphatic system in place? So confused.
Tysabri doesn't really strenghten the blood brain barrier---it binds to lymphocytes, and keeps them from gaining entry into brain tissue.
What Dr. Michal Schwartz/Weizmann Institute has been saying for a couple decades is that it is the endothelial layer of cells which educate the immune cells, and gives them entry across the blood brain barrier when and if they are needed. She never believed the idea of an immune-privileged CNS. I blogged about her yesterday. http://ccsviinms.blogspot.com/2015/06/d ... right.html
The newly discovered lymphatic vessels are outside brain tissue with the blood vessels, still separated by the BBB--they are in the meningeal layer.
Cece wrote: Could a stent in the dural sinuses physically block a lymph vessel?
These lymphatic channels combine as they travel towards the neck, eventually forming one large channel called the thoracic duct. The thoracic duct rejoins the systemic venous system at the lymphovenous junction, near the confluence of the left internal jugular and subclavian veins. http://www.google.com/patents/WO2010080717A1?cl=en
That's a familiar area: the base of the left jugular, near where it joins the subclavian, right where the left jugular valve can be found and where CCSVI blockages are very commonly found.
I hope a stent wouldn't block a lymph vessel...I think what Dr. Zamboni was saying was that a lack of flow creates hypertension, which would inhibit lymphocyte drainage and crush the vessels--but I honestly don't know.
cheer