Jarred Younger on Neuroinflammation in ME/CFS and Fibromyalgia
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" I am guessing that LDN and rituximab provide two different paths to reaching the same goal: stopping neuroinflammation"
Interpret it as you wish.. His hypophesis is that overactivated microglia is the culprit, so if both rtx and LDN will stop the overactivation, he would expect same symptom relief?
Interpret it as you wish.. His hypophesis is that overactivated microglia is the culprit, so if both rtx and LDN will stop the overactivation, he would expect same symptom relief?
The question is what causes the microglia to be overactive. As I understand it LDN may help reduce activation and hence give quick symptom relief where as the hope is Rituximab may help get at the cause (perhaps antibodies) and stop the problem earlier in the cycle.
I think it's important to distinguish between effect size (how much people improve) vs response rate (how many people improve) - I think he's talking about response rate, and that's going to depend on the threshold the two sets of investigators set for a response (and you have to take into account the response rate in the control group, too).
If there are overactivated microglia then there is a process that is either causing there activation or stopping them deactivate.
If we take the first possibility there may be a drug which would help break the activation cycle or maybe just reduce the cycle.
Equally there could be a drug that will help deactivate some of the active microglia.
You wouldn't expect the same symptom relief from both. but if active microglia are a problem within a common subset you might expect common numbers affected (but not equal symptom relief).
Of course there could be many different mechanisms for activation and something like Rituximab may only affect some. Or something like LDN may only affect certain forms of activation. So I wouldn't really conclude much from the 60% figures.
If we take the first possibility there may be a drug which would help break the activation cycle or maybe just reduce the cycle.
Equally there could be a drug that will help deactivate some of the active microglia.
You wouldn't expect the same symptom relief from both. but if active microglia are a problem within a common subset you might expect common numbers affected (but not equal symptom relief).
Of course there could be many different mechanisms for activation and something like Rituximab may only affect some. Or something like LDN may only affect certain forms of activation. So I wouldn't really conclude much from the 60% figures.
I'm open to many possibilities, re the underlying nature of ME, and it's good to see researchers exploring various hypotheses. A hypothesis is just a starting point and can be built upon or knocked down. A misguided hypothesis can lead to unexpected serendipitous insights, and the process of disproving a hypothesis gives us useful information. So if a hypothesis eventually proves to be misguided, it's all a healthy part of the scientific process. (Not that I think Younger's research interests are misguided - far from it.)
Younger actually compares the response rate seen with rituximab in ME patients with the response rate seen with LDN in fibromyalgia patients. Then he hypothesizes that the response rate is similar in each patient group for similar reasons, but via a different mode of action for each drug. He does make it clear that it's just a hypothesis, but it seems to me that it's quite a stretch to make such a direct link between the two very different situations. Not least because he's equating ME with fibromyalgia. I'm very sympathetic to the idea that ME and fibro have the same (or a very similar) underlying cause, in many cases, but I'm not sure if there is any evidence to demonstrate that they are the same illness but with different symptoms.
I'm not aware of the nature of the LDN research and I wonder if there have been any double blind trials with LDN that have demonstrated such a high response rate seen with rituximab in a double blind trial? (The first phase II trial for rituximab was double blind.) If it's only open-label trials that have seen a two-thirds response rate for LDN, then this might not translate to such a high figure in blind trials. I assume that LDN research has only been carried out in very small preliminary open label trials, otherwise I would have taken more notice. In which case, it's sensible not to read too much into the research at this stage.
I think there could be a multitude of potential reasons why LDN is helpful. But it seems fairly likely/certain that rituximab works by reducing antibodies because of the time lag between administration and effect. So I'm not sure how this fits with Younger's hypothesis.
In the above quote, Younger doesn't mention leptin or the vagus nerve which are two other hypotheses that he's interested in. I hope he continues to pursue an academic interest in all his lines of interest. I'm interested in all of them for various reasons.
Younger actually compares the response rate seen with rituximab in ME patients with the response rate seen with LDN in fibromyalgia patients. Then he hypothesizes that the response rate is similar in each patient group for similar reasons, but via a different mode of action for each drug. He does make it clear that it's just a hypothesis, but it seems to me that it's quite a stretch to make such a direct link between the two very different situations. Not least because he's equating ME with fibromyalgia. I'm very sympathetic to the idea that ME and fibro have the same (or a very similar) underlying cause, in many cases, but I'm not sure if there is any evidence to demonstrate that they are the same illness but with different symptoms.
I'm not aware of the nature of the LDN research and I wonder if there have been any double blind trials with LDN that have demonstrated such a high response rate seen with rituximab in a double blind trial? (The first phase II trial for rituximab was double blind.) If it's only open-label trials that have seen a two-thirds response rate for LDN, then this might not translate to such a high figure in blind trials. I assume that LDN research has only been carried out in very small preliminary open label trials, otherwise I would have taken more notice. In which case, it's sensible not to read too much into the research at this stage.
I think there could be a multitude of potential reasons why LDN is helpful. But it seems fairly likely/certain that rituximab works by reducing antibodies because of the time lag between administration and effect. So I'm not sure how this fits with Younger's hypothesis.
In the above quote, Younger doesn't mention leptin or the vagus nerve which are two other hypotheses that he's interested in. I hope he continues to pursue an academic interest in all his lines of interest. I'm interested in all of them for various reasons.
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A lot of good things have been said on this thread... I think we should be a bit critical of Dr. Younger as I don't think his hypotheses are well thought out and as others have said I think he is suffering a bit from "not invented here" syndrome, especially since he's built his entire lab to focus on studying these hypotheses and not for example autoimmunity or infectious causes.
There are so many diseases that cause neuroinflammation as part of the disease process but it certainly isn't the root cause and they aren't treated as such. Most if not all autoimmune diseases cause neuroinflammation as a side effect and we've discussed this countless times on PR.
So many of us have taken combinations of drugs and supplements that are known to potently inhibit microglial activation etc. but they just don't work in a big enough way to be considered treatment. If ME/CFS was a putative neuroinflammatory disease then many of us would be gone into remission or significant recovery by now and for all you taking such drugs I know you feel like I do, they possibly have some effect on some symptoms but they aren't disease modifying at all.
I for one have been taking 8 drugs and multiple supplements that are known to inhibit microglia (http://forums.phoenixrising.me/inde...t-a-putative-neuroinflammatory-disease.37812/) and all together they aren't disease modifying.
There are so many diseases that cause neuroinflammation as part of the disease process but it certainly isn't the root cause and they aren't treated as such. Most if not all autoimmune diseases cause neuroinflammation as a side effect and we've discussed this countless times on PR.
So many of us have taken combinations of drugs and supplements that are known to potently inhibit microglial activation etc. but they just don't work in a big enough way to be considered treatment. If ME/CFS was a putative neuroinflammatory disease then many of us would be gone into remission or significant recovery by now and for all you taking such drugs I know you feel like I do, they possibly have some effect on some symptoms but they aren't disease modifying at all.
I for one have been taking 8 drugs and multiple supplements that are known to inhibit microglia (http://forums.phoenixrising.me/inde...t-a-putative-neuroinflammatory-disease.37812/) and all together they aren't disease modifying.
You might equally find that labs or researchers studying autoimmunity only focus on that area; but that itself is not any reason to criticize the autoimmune hypothesis of ME/CFS. Science by its nature if often divided into specialties.
In the case of diseases with significant mental or cognitive symptoms such ME/CFS, depression, schizophrenia or bipolar, I believe their association with neuroinflammation is a relatively recent one, so the fact that these diseases are not treated by anti-inflammatory protocols may just be because this knowledge is so new.
You may be taking microglial activation inhibitors, but unfortunately I don't think there is any evidence in any given patient that these drugs or supplements are indeed inhibiting microglia.
Even if they were, is inhibiting microglia the right approach to tackling brain inflammation? There are many things going on within brain inflammation, including changes to astrocyte function. Some researchers speculate it is extracellular glutamate build-up from brain inflammation that is the problem, and this involves microglia which release glutamate as well as astrocytes which help clear it.
Some ME/CFS patients experienced dramatic reductions in symptoms when taking a drug which increased glutamate clearance from the brain (see this thread).
I myself had a lot of success in eliminating my severe generalized anxiety disorder using supplements that targeted brain inflammation (see this thread). And when I began regularly taking these supplements, I noticed my ME/CFS symptom slowly but significantly improved, as this may have been a result of their anti-neuroinflammation effect.
Note also it is not just microglial activation that is the issue, it is what phenotype microglia become activated into that counts. There are two main types of microglial activation:
Classical microglial activation which is neurodestructive (and involves COX-2, iNOS, IL-6, and TNF-alpha).
Alternative microglial activation which is neuroprotective (and involves FIZZ-1, YM-1, Arginase-1, and IL-4).
Classical microglial activation is the "kill" mode which destroys pathogens in the brain; alternative microglial activation is the repair mode which heals the brain. When we talk about "microglial activation" and is destructive effects, we are tacitly referring to classical microglial activation.
It may be that what we need to do in ME/CFS is not stop microglial activation, but rather change the phenotype of microglial activation from the neurodestructive classical activation phenotype, to the healing and neuroprotective alternative activation phenotype. Supplements that can do this are given at the bottom of this long post.
In the case of diseases with significant mental or cognitive symptoms such ME/CFS, depression, schizophrenia or bipolar, I believe their association with neuroinflammation is a relatively recent one, so the fact that these diseases are not treated by anti-inflammatory protocols may just be because this knowledge is so new.
You may be taking microglial activation inhibitors, but unfortunately I don't think there is any evidence in any given patient that these drugs or supplements are indeed inhibiting microglia.
Even if they were, is inhibiting microglia the right approach to tackling brain inflammation? There are many things going on within brain inflammation, including changes to astrocyte function. Some researchers speculate it is extracellular glutamate build-up from brain inflammation that is the problem, and this involves microglia which release glutamate as well as astrocytes which help clear it.
Some ME/CFS patients experienced dramatic reductions in symptoms when taking a drug which increased glutamate clearance from the brain (see this thread).
I myself had a lot of success in eliminating my severe generalized anxiety disorder using supplements that targeted brain inflammation (see this thread). And when I began regularly taking these supplements, I noticed my ME/CFS symptom slowly but significantly improved, as this may have been a result of their anti-neuroinflammation effect.
Note also it is not just microglial activation that is the issue, it is what phenotype microglia become activated into that counts. There are two main types of microglial activation:
Classical microglial activation which is neurodestructive (and involves COX-2, iNOS, IL-6, and TNF-alpha).
Alternative microglial activation which is neuroprotective (and involves FIZZ-1, YM-1, Arginase-1, and IL-4).
Classical microglial activation is the "kill" mode which destroys pathogens in the brain; alternative microglial activation is the repair mode which heals the brain. When we talk about "microglial activation" and is destructive effects, we are tacitly referring to classical microglial activation.
It may be that what we need to do in ME/CFS is not stop microglial activation, but rather change the phenotype of microglial activation from the neurodestructive classical activation phenotype, to the healing and neuroprotective alternative activation phenotype. Supplements that can do this are given at the bottom of this long post.
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Indeed. I would like to see more brain autopsies to determine how many ME/CFS patients' brains have low level enterovirus infections which could be driving brain inflammation. A few ME/CFS brain autopsies have shown the presence of enterovirus in brain tissues.
I actually came up with a tentative theory in this post which combined the enterovirus brain autopsy research with the microglial priming hypothesis of ME/CFS to explain how chronic brain inflammation in ME/CFS might arise.
In my tentative theory, the first thing to note is that TLR2, TLR3 and TLR4 are involved in microglial priming (see this paper).
The second thing to note is that TLR3 is the cell's detector of viral dsRNA, and TLR3 is triggered by the presence of viral dsRNA inside the cell.
Now noncytolytic enteroviruses, which are found inside the cells of ME/CFS patients, comprise both dsRNA and ssRNA, so if we have a chronic noncytolytic enterovirus infection of the brain, the virus inside the cells may be constantly triggering TLR3, and in this way, may be priming the microglia.
Thus although the enterovirus infections in the brains of ME/CFS patients may be relatively minor, if this infection is priming the microglia via a TLR3 mechanism, then the inflammatory response from the microglia will much stronger than you would normally expect, and this stronger than normal response may be causing ME/CFS symptoms.
The only problem with this idea is that, as far as we know, enteroviruses don't infect microglial cells; studies have shown that enteroviruses can infect astrocyte cells in the brain, and can infect neural progenitor cells in the brain (brain stem cells), but I have not seen any studies indicating that enteroviruses can infect microglia.
However, an non-cytolytic enterovirus infection inside astrocyte cells may lead to the astrocytes being primed by a TLR3 mechanism (astrocytes as well as microglia can be primed). These infected and primed astrocytes will then produce an exaggerated inflammatory response, and again this stronger than normal inflammatory response may be the cause of ME/CFS symptoms.
The only problem with this astrocyte idea, though, is that the paper I cited said that TLR3 is not involved with astrocyte priming, only microglial priming. Sigh!
I actually came up with a tentative theory in this post which combined the enterovirus brain autopsy research with the microglial priming hypothesis of ME/CFS to explain how chronic brain inflammation in ME/CFS might arise.
In my tentative theory, the first thing to note is that TLR2, TLR3 and TLR4 are involved in microglial priming (see this paper).
The second thing to note is that TLR3 is the cell's detector of viral dsRNA, and TLR3 is triggered by the presence of viral dsRNA inside the cell.
Now noncytolytic enteroviruses, which are found inside the cells of ME/CFS patients, comprise both dsRNA and ssRNA, so if we have a chronic noncytolytic enterovirus infection of the brain, the virus inside the cells may be constantly triggering TLR3, and in this way, may be priming the microglia.
Thus although the enterovirus infections in the brains of ME/CFS patients may be relatively minor, if this infection is priming the microglia via a TLR3 mechanism, then the inflammatory response from the microglia will much stronger than you would normally expect, and this stronger than normal response may be causing ME/CFS symptoms.
The only problem with this idea is that, as far as we know, enteroviruses don't infect microglial cells; studies have shown that enteroviruses can infect astrocyte cells in the brain, and can infect neural progenitor cells in the brain (brain stem cells), but I have not seen any studies indicating that enteroviruses can infect microglia.
However, an non-cytolytic enterovirus infection inside astrocyte cells may lead to the astrocytes being primed by a TLR3 mechanism (astrocytes as well as microglia can be primed). These infected and primed astrocytes will then produce an exaggerated inflammatory response, and again this stronger than normal inflammatory response may be the cause of ME/CFS symptoms.
The only problem with this astrocyte idea, though, is that the paper I cited said that TLR3 is not involved with astrocyte priming, only microglial priming. Sigh!