Better drainage of brain debris improves Alzheimer's disease therapies(padiracinnovation.org)
padiracinnovation.org
Better drainage of brain debris improves Alzheimer's disease therapies
https://padiracinnovation.org/News/2021/04/better-drainage-of-brain-debris-improves-alzheimers-disease-therapies
56 comments
In mice. Still, it's nice that it's working (in mice).
I think I'm gonna get a pet mouse.
We really have a lot of excellent therapies to keep mice healthy.
We really have a lot of excellent therapies to keep mice healthy.
You may also need to buy that mouse from a specific lab for the therapies to have reproducible effects. [1]
[1] - https://www.youtube.com/watch?v=ve4q-1D_Ajo
[1] - https://www.youtube.com/watch?v=ve4q-1D_Ajo
>In mice..
In this case I think they could check old pandas (lifespan to 30+ years) if shaking that debris did help them to remove it:
Rolling Is A Specialty For Pandas: https://www.youtube.com/watch?v=F6JIXr4-4Tw (3:27), shorter: https://www.youtube.com/watch?v=KnCuGoxMWas (0:15)
This kind of treatment looks safe even for children (early prevention, ongoing trial since 2014): https://www.youtube.com/watch?v=Q5uCbfxF4w8 (2:51), more advanced later treatment is possible too: https://www.youtube.com/watch?v=UrB1xitSQRI (0:17) (there is more..).
Shaking brain when dancing is not always the safest option (acceleration control problem), better results will be obtained safer by rolling - think: aerotrim with the 'exercise' and laughing - btw check the AirTrack https://www.youtube.com/watch?v=PBWJQ8dAnWg (3:37) or home edition ;)
In this case I think they could check old pandas (lifespan to 30+ years) if shaking that debris did help them to remove it:
Rolling Is A Specialty For Pandas: https://www.youtube.com/watch?v=F6JIXr4-4Tw (3:27), shorter: https://www.youtube.com/watch?v=KnCuGoxMWas (0:15)
This kind of treatment looks safe even for children (early prevention, ongoing trial since 2014): https://www.youtube.com/watch?v=Q5uCbfxF4w8 (2:51), more advanced later treatment is possible too: https://www.youtube.com/watch?v=UrB1xitSQRI (0:17) (there is more..).
Shaking brain when dancing is not always the safest option (acceleration control problem), better results will be obtained safer by rolling - think: aerotrim with the 'exercise' and laughing - btw check the AirTrack https://www.youtube.com/watch?v=PBWJQ8dAnWg (3:37) or home edition ;)
Rolling sounds good for proprioception. My toddler enjoys being rolled around, and I remember rolling as a kid, and having to adjust to keep going in a straight line. Thanks, I’ll do it again.
Also thanks to this thread for the nudge back into morning exercise. “The Five Tibetan Rites”[0] is a dynamic set that can be committed to memory easy enough, as one example. Jogging around the field with an aging-but-still-faster dog for the morning perimeter check/mark also helps.
[0] https://www.wikipedia.org/wiki/Five_Tibetan_Rites
Also thanks to this thread for the nudge back into morning exercise. “The Five Tibetan Rites”[0] is a dynamic set that can be committed to memory easy enough, as one example. Jogging around the field with an aging-but-still-faster dog for the morning perimeter check/mark also helps.
[0] https://www.wikipedia.org/wiki/Five_Tibetan_Rites
This is fascinating... could Alzheimers be a result of a lymphatic analogue of arteriosclerosis or artery blockage?
If so then maybe similar treatments might work.
If so then maybe similar treatments might work.
Perhaps this is why physical exercise appears to reduce the risk of Alzheimer’s disease[1]. Our lymphatic system relies on muscle contractions to move lymph. So, increasing exercise results in increased lymph flow, which might then clear more amyloid-beta from our brain.
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113559/
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113559/
Fascinating! As someone not familiar with how the lymph system operates, do you care to explain how muscle contractions outside the brain cause the lymph system in the brain to expel waste? I understood the blood-brain barrier sort of insulated the brain from a lot of this kind of thing.
Lymph is fascinating. It is your other circulatory system.
Capillaries are are so narrow they can only allow a single erythrocyte through at the same time. The pressure from your heart causes fluid leakage from the thin vessels. Lymph ducts/nodes help get this fluid back into your blood. Since the heart doesn't pump lymph, that helps move it through your body is actually your musculoskeletal system. That is to a certain degree true from your venous / return flow in your "normal" circulatory system, too. It's why your feet can swell if you're sitting down too much. I'd speculate that lymphatic flow efficiency has local and systemic elements that contribute to it (and so your leg muscles moving lymph help your overall lymphatic system health).
Capillaries are are so narrow they can only allow a single erythrocyte through at the same time. The pressure from your heart causes fluid leakage from the thin vessels. Lymph ducts/nodes help get this fluid back into your blood. Since the heart doesn't pump lymph, that helps move it through your body is actually your musculoskeletal system. That is to a certain degree true from your venous / return flow in your "normal" circulatory system, too. It's why your feet can swell if you're sitting down too much. I'd speculate that lymphatic flow efficiency has local and systemic elements that contribute to it (and so your leg muscles moving lymph help your overall lymphatic system health).
Is it just about muscular contraction, or does any kind of motion have positive effect on the lymph system? Say a rollercoaster or jumping on trampoline.
This didn't answer the question, like at all!
"I'd speculate that lymphatic flow efficiency has local and systemic elements that contribute to it (and so your leg muscles moving lymph help your overall lymphatic system health)."
Lymph system helps clear waste / ISF from the brain. Overall lymphatic circulation improvement from increased activity would intuitively improve lymphatic clearance from the brain. That would be true if there was direct lymphatic clearance or some indirectly / osmotic gradient driven process (I don't know which, or neither, is the case).
Lymph system helps clear waste / ISF from the brain. Overall lymphatic circulation improvement from increased activity would intuitively improve lymphatic clearance from the brain. That would be true if there was direct lymphatic clearance or some indirectly / osmotic gradient driven process (I don't know which, or neither, is the case).
I'm no expert, but if the lymphatic system's flow is driven by the motion in its surroundings because the muscles and skeleton are in motion, maybe drainage just happens via gravity if motion continually alters momentum and gravity vectors? Genuinely curious too...
Am I remembering it incorrectly or did someone recently discover a mechanism for lymph to move through connective tissues (in particular, ligaments)?
I'm not sure anyone knows the answer to that in specific. In my experience, exercise is often followed by a nap and my inference is that clearing lymph from other tissues somehow encourages the body to also clear lymph from the brain, but I haven't actually found an explanation for how that works.
You might find this general overview of the body's lymphatic system interesting:
https://news.ycombinator.com/item?id=25427090
You might find this general overview of the body's lymphatic system interesting:
https://news.ycombinator.com/item?id=25427090
As noted by the article, it was only recently discovered that the central nervous system had lymphatic drainage (see [1]). I’m simply connecting the results of this mouse study with what we know about the lymphatic system, skeletal muscle, and the apparent benefit of exercise on Alzheimer’s disease risk, to form a hypothesis. I strongly suspect it’s true, but I cannot represent it as fact.
Edit: Here is a more direct answer to your question:
1) Increased localized pressure from contracting muscle pushes lymph away through a vessel.
2) Reduced localized pressure from relaxing muscle allows new lymph to refill the evacuated vessel portion.
3) Lymphatic vessels have valves that keep all this flow moving in the same direction.
4) Given that the lymphatic system is connected to the central nervous system, increased muscular contraction could increase drainage of the brain.
[1] https://www.nature.com/articles/nature14432
Edit: Here is a more direct answer to your question:
1) Increased localized pressure from contracting muscle pushes lymph away through a vessel.
2) Reduced localized pressure from relaxing muscle allows new lymph to refill the evacuated vessel portion.
3) Lymphatic vessels have valves that keep all this flow moving in the same direction.
4) Given that the lymphatic system is connected to the central nervous system, increased muscular contraction could increase drainage of the brain.
[1] https://www.nature.com/articles/nature14432
I was actually wondering today if hot/cold cycling the head could increase lymphatic drainage and increase cerebrospinal fluid cycling.
Cold shower, hot shower, cold shower etc on the head... Will I become mega mind?
Cold shower, hot shower, cold shower etc on the head... Will I become mega mind?
It is pretty common to jump into a cold bath after spending time in a sauna
Regardless of actual health effects, it feels fantastic!
Regardless of actual health effects, it feels fantastic!
Yes it does but not sure if recommended for people with heart problems. But yes, hot cold cycles reset the nervous system and yes, it feels great afterwards. The worst I find is the initial moment before plunging in cold water and the more I hesitatie the harder it gets
The main psychological benefit of taking only cold showers over the last five months is practice with starting an action I don’t want to do, because oooh there have been times when I was already cold and despite knowing I’d feel great afterwards, the present moment was scary.
I’ve been wondering the same. I think of inducing heat/cold similar to turning a rusty spigot. The first few turns are difficult but the more you do it the easier it gets.
But do spigots in other parts of your body get turned that are also rusty, so to speak?
I notice cold/hot showers help my body regulate my temperature better, generally.
But do spigots in other parts of your body get turned that are also rusty, so to speak?
I notice cold/hot showers help my body regulate my temperature better, generally.
It’s funny, as someone who suffers bouts of Insomnia, I still exercise everyday, often kettle bell training with heavy bells which is pretty good cardio too.
What I’ve noticed is that I almost feel like I’ve had a full nights sleep after a workout. Before it, I feel groggy.
It’d anecdotal but it doesn’t just seem like it’s me who experiences this. I wonder if it’s the result of some type of “drainage”.
What I’ve noticed is that I almost feel like I’ve had a full nights sleep after a workout. Before it, I feel groggy.
It’d anecdotal but it doesn’t just seem like it’s me who experiences this. I wonder if it’s the result of some type of “drainage”.
I have the same experience. I got four hours last night, but I worked out this morning. I feel almost normal.
You're definitely instilling a state on your body that's more normal. Being sleepy does make someone more prone to errors and injuries, though, so I wouldn't count on it as a substitute long term. Anecdote: I've also had a walk around the block help me sleep. Particularly if the house or bed is too hot to sleep.
I started searching for things that would stimulate lymphatic system (supliments/drugs) after reading this but just found the same old unsurprising advice. Eat lite unprocessed foods, avoid sugar, exercise and drink plenty of water. Prevention.
Can I just stick a vibrator against the back of my skull for a few minutes daily?
Perhaps a very tiny one:
https://medicalxpress.com/news/2020-04-evidence-ultrasound-a...
https://medicalxpress.com/news/2020-04-evidence-ultrasound-a...
Neuro PhD here. Here's the experiment they actually did: create a transgenic mouse that overexpesses beta-amyloid. They're all messed up, not just their memory, but we think beta-amyloid causes Alzheimer's, so this is our mouse model of Alzheimer's. Then further screw with the mouse by blocking its CSF drainage. Anti-amyloid drugs help the standard transgenic mice, but don't help the blocked ones. Then unblock the blocked mice, and Voila! you've fixed them. A cure for Alzheimer's is right around the corner, right?
Except, this doesn't necessarily have anything to do with Alzheimer's in humans. You're assuming it's caused by beta-amyloid, but there have been a dozen giant Phase 3 trials testing amyloid-removal drugs and they've all failed. Fundamentally, all you've done is mess with mice in two different ways, then when you undo the ways you've screwed with them, they're more or less back to normal.
This all tells you virtually nothing about how Alzheimer's actually happens in humans, much less how to cure it.
Except, this doesn't necessarily have anything to do with Alzheimer's in humans. You're assuming it's caused by beta-amyloid, but there have been a dozen giant Phase 3 trials testing amyloid-removal drugs and they've all failed. Fundamentally, all you've done is mess with mice in two different ways, then when you undo the ways you've screwed with them, they're more or less back to normal.
This all tells you virtually nothing about how Alzheimer's actually happens in humans, much less how to cure it.
> This all tells you virtually nothing about...
This seems like a somewhat common trend in medical research...or something along the lines of findings being meaningless due to "causal vs correlated" questions. After reading these types of research issues, I always think that there's gotta be a better way to go about it by utilizing wisdom of crowds across industries.
For example, there's a chance electrical battery engineers needed to figure out a way to drain electrons in a special way to increase the life of the batteries. And say for example that same underlying logic is the solution to curing alzheimer's...there's no current way (that I'm aware of) to compare underlying processes that are parts of complex systems. The internal parts can be complex systems themselves, but if we can distill complex systems down to their core components, separate them into separate "repositories" that include the detailed processes and/or components necessary to make that given repository "work", we could essentially create "templates" of core knowledge....almost like a github for knowledge.
My main point is the individual pieces required to solve these types of complex issues may already be solved...would be cool to create a platform to manage those pieces.
This seems like a somewhat common trend in medical research...or something along the lines of findings being meaningless due to "causal vs correlated" questions. After reading these types of research issues, I always think that there's gotta be a better way to go about it by utilizing wisdom of crowds across industries.
For example, there's a chance electrical battery engineers needed to figure out a way to drain electrons in a special way to increase the life of the batteries. And say for example that same underlying logic is the solution to curing alzheimer's...there's no current way (that I'm aware of) to compare underlying processes that are parts of complex systems. The internal parts can be complex systems themselves, but if we can distill complex systems down to their core components, separate them into separate "repositories" that include the detailed processes and/or components necessary to make that given repository "work", we could essentially create "templates" of core knowledge....almost like a github for knowledge.
My main point is the individual pieces required to solve these types of complex issues may already be solved...would be cool to create a platform to manage those pieces.
How far off do you think we are from simulating an entire human on a protein level in accelerated time?
Imagine a world where a drug concept could be simulated on an entire human model in parallel cradle to grave 1000x faster than normal. What level of compute is necessary to pull that off?
Imagine a world where a drug concept could be simulated on an entire human model in parallel cradle to grave 1000x faster than normal. What level of compute is necessary to pull that off?
Very, very far. There are 10^27 atoms in a human body. Even if you go down to individual proteins, that saves you maybe 4-5 orders of magnitude. That's about a zettabyte of data just to describe initial conditions.
Decades at least, we don't even have close to a complete list of the proteins in our bodies which would be needed to start thinking avout simulating them.
We're still struggling to accurately simulate a C. elegans. We're a little way off simulating 50+ kg of conscious organism.
Not to mention the ethical implications. If we're happy to run "cradle to the grave" tests on a human simulated to that level of accuracy, why not just run them on actual humans bred for research? We can do that right now, far cheaper.
...of course, maybe that just means that we're the disease model...
Not to mention the ethical implications. If we're happy to run "cradle to the grave" tests on a human simulated to that level of accuracy, why not just run them on actual humans bred for research? We can do that right now, far cheaper.
...of course, maybe that just means that we're the disease model...
Ethics aside, if we could simulate a whole brain, then we could simulate billions of brains and try all sorts of things, something we wouldn't be able to do with physical humans. At least not without being labelled as mass murderers and turning into a bird.
OK this is still bugging me a day later... I'm missing the reference with the bird bit. What's that from?
This made me laugh. If you put ethics aside, couldn't you just do all those things on physical humans?
I have a hard time believing we'd find it ethical (at least in the long term) to experiment on a simulated brain. If it were accurate enough, might it be considered a person?
I have a hard time believing we'd find it ethical (at least in the long term) to experiment on a simulated brain. If it were accurate enough, might it be considered a person?
Why wouldn't an accurately simulated brain be considered a person?
> Why wouldn't an accurately simulated brain be considered a person?
Ah, and here we come to the crux of the matter! What makes a person a person? Is it merely electrochemical activity in a certain type of tissue?
It's important to recognize that this question comes to the border that marks the end of the territory of biology and the beginning of the territory of philosophy. It's possible to charge right through this border (as Stephen Hawking did in his book The Grand Design) but there is a peril in doing so.
https://www.theguardian.com/commentisfree/2013/may/27/physic...
> The attempt to fit consciousness into the material world, > usually by identifying it with activity in the brain, has failed dismally, > if only because there is no way of accounting for the fact that certain nerve impulses > are supposed to be conscious (of themselves or of the world) > while the overwhelming majority (physically essentially the same) are not.
Ah, and here we come to the crux of the matter! What makes a person a person? Is it merely electrochemical activity in a certain type of tissue?
It's important to recognize that this question comes to the border that marks the end of the territory of biology and the beginning of the territory of philosophy. It's possible to charge right through this border (as Stephen Hawking did in his book The Grand Design) but there is a peril in doing so.
https://www.theguardian.com/commentisfree/2013/may/27/physic...
> The attempt to fit consciousness into the material world, > usually by identifying it with activity in the brain, has failed dismally, > if only because there is no way of accounting for the fact that certain nerve impulses > are supposed to be conscious (of themselves or of the world) > while the overwhelming majority (physically essentially the same) are not.
Is he charging through the border, or gently rebuking the concept of a border?
If you are willing to bend some ethics, brain organoids and other similar organ-on-chip solutions are quite promising. Though it is important to note that scaled down brains may not necessarily express the same behavior vis-a-vis a full sized human cortex.
Well, if they did, you could never power them down...
I did say if you are willing to bend some ethics.
500+ years? Last I looked into what some major players in computational neuroscience were doing simulating highly accurate neurons they were doing on the order of maybe thousands of neurons. It’s been a few years so maybe they can simulate 100k today. The human brain has 100billion neurons. And that’s just part of a system. I don’t know how many other cells you’d need to simulate to model just the space between your ears. And I don’t think we’re even talking at the protein level yet of simulations. Proteins are notoriously difficult to simulate. If bitcoin had managed to use protein folding as it’s proof of work I’m not sure we’d even be able to fill the current demand for research let alone simulating an entire human. I don’t think I can fathom the amount of compute we’re talking about to simulate a human at the drug interaction level to any real degree of accuracy.
That seems overly pessimistic to me, in the last hundred years we've gone from basically no understanding on a molecular level of the human body to a decent understanding of much of the chemistry of the body, it seems like the next hundred years could conceivably advance to the level where we have a good understanding of even the smallest interactions.
we can’t simulate a single protein long enough to determine how it folds, even with a supercomputer. we’re so many orders of magnitude away from such a thing it’s basically unthinkable.
So is the issue that beta-amyloid is the smoke, rather than the fire? Or rather that mice aren't humans?
It's that transgenic beta-amyloid mice are not humans with Alzheimer's.
BUT!
As another neuro PhD: this is still an important finding for our understanding of protein (dis)aggregation in the brain. The opposite finding was totally possible. The protein disaggregation could have been independent of CSF flow. The typical HN hot-take is "not so fast, this translational research actually underdelivers," but I prefer, "this fundamental neurosci research has the added bonus of being preformed on a clinically relevant model."
BUT!
As another neuro PhD: this is still an important finding for our understanding of protein (dis)aggregation in the brain. The opposite finding was totally possible. The protein disaggregation could have been independent of CSF flow. The typical HN hot-take is "not so fast, this translational research actually underdelivers," but I prefer, "this fundamental neurosci research has the added bonus of being preformed on a clinically relevant model."
I would disagree that transgenic A-beta mice are a clinically relevant model. I mean, I understand why we started there -- at first glance Alzheimer's is amyloidosis in the brain. But after all this time, it's pretty clear that removing amyloid doesn't cure AD, and consequently that overexpressing amyloid in a mouse is not a good animal model of AD.
It could be that amyloid is the smoke. It could also be residue from the body's fire extinguishers. That is, something breaks, and amyloid accumulation is a consequence of whatever the body does to try to fix it. Maybe it makes it worse. The point is, we don't know, and 30 years of presuming that we do has led us to a giant dead end.
I'm not a doctor. I haven't worked in a wet lab. All this is from second hand conversations and anecdotes.
Mice aren't human.
There's lots of ways to cure cancer in mice. it's practically a joke. Mice can tell you a bit about danger - if your treatment kills the mouse, think pretty hard about that treatment on a human. It might kill the human too, but maybe not. Might be ok for the mouse but not the human, like maybe thalidomide.
The impression I get is, if it's ok for mice it _might_ be ok for humans, so it helps avoid a large swath of super dangerous stuff. But doesn't tell you a whole lot about what happens in humans. I'm sure there are things that kill mice that are effective treatments for humans, but both of those edges are outlier-ish. If it kills the mouse it's probably not worth continuing without a good understanding of why it might work in humans.
Mice aren't human.
There's lots of ways to cure cancer in mice. it's practically a joke. Mice can tell you a bit about danger - if your treatment kills the mouse, think pretty hard about that treatment on a human. It might kill the human too, but maybe not. Might be ok for the mouse but not the human, like maybe thalidomide.
The impression I get is, if it's ok for mice it _might_ be ok for humans, so it helps avoid a large swath of super dangerous stuff. But doesn't tell you a whole lot about what happens in humans. I'm sure there are things that kill mice that are effective treatments for humans, but both of those edges are outlier-ish. If it kills the mouse it's probably not worth continuing without a good understanding of why it might work in humans.
Drainage of brain is how I'd describe what I feel in my head when meditating: as if there are pipes on the brain that get clogged during day and locking up on a static thought flushes those pipes down. That's a weirdly pleasant feeling.