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Neurodegeneration in MS
I have been reading about this topic recently and find it fascinating (although I think I’d like it more if it weren’t happening to me). Anyway, since I don’t think this has been discussed much on the forum, I thought I’d summarize some of what I’ve read below in case anyone else is interested. I should also say to take this with a large grain of salt as I read some what erratically and only on the topics that interest me and I do not have a scientific or medical background.
I’m sure most of you know this, but I just want to mention at the beginning that axons are long fibers that come off of the cell body of neurons and send signals to other neurons. They are like wires that conduct electricity. Many axons are normally covered with myelin. Myelin, like insulation on a wire, improves conduction and is, as we all know, attacked in MS.
There seem to be two major things that go on in MS:
1. Inflammation. This is thought to be caused by an autoimmune attack on the myelin surrounding the axons in the central nervous system. Acute inflammatory demyelination is what causes relapses where you get suddenly worse. Many of the symptoms of relapses can resolve over time as the attack abates, inflammation goes down, and the body attempts to repair itself and remyelinate the axons. In fact, some inflammation during an attack appears to be good in that it triggers the body’s self-repair mechanisms so it may not be ideal to completely suppress the immune system in MS.
2. Neurodegeneration. This is thought to cause the slow, insidious progression in MS and to be caused by permanent damage to axons. Although neurodegeneration starts early in MS, it usually takes a while to show noticeable effects because the brain is very good at compensating and can work around the damage for some time (yay for neuroplasticity).
**How do axons get damaged in MS?
Axons can be damaged by inflammation in active lesions, due to various substances associated with inflammation that can injure them, and this can be reversible. They are also damaged by transection (which means to cut transversely, which sounds pretty irreversible to me. You can see a picture of transection in the rotating picture, second from top, at http://www.msalliance.com/aboutMS/index.asp?m=1&f=5&s=1&t=3&c=123). It was not clear to me what causes the transection, but it is apparently associated with the level of inflammation in active lesions.
In chronic lesions, the likely cause of damage is lack of trophic support. (I looked this up and it seems to mean something like “nutritive”; basically it has to do with the things in the surrounding environment that support the growth and health of axons, such as myelin, oligodendrocytes, and glia). In addition, axons probably become less able to recover over time.
There is also known to be axonal damage in normal-appearing areas of the brain.
Wilkins and Scolding list some possibilities for mechanisms of axonal loss in later stages of MS:
(1) previous inflammatory damage to axons
(2) low grade inflammation occurring causing damage to already vulnerable demyelinated axons
(3) loss of trophic environment for axons to survive
(4) alterations in energy requirements of demyelinated axons
(5) as part of a completely independent neurodegenerative process
They conclude that “in all likelihood, the axonopathy of MS is multi-factorial.”
**How do we know there are damaged axons in MS?
One way is though a newer type of imaging called MRS (magnetic resonance spectroscopy), which can measure something called NAA (N-acetylaspartate) which is a marker of axonal density. Loss of axons can be seen in brain biopsies and at autopsy. Axonal loss is also associated with brain atrophy.
**What can be done about neurodegeneration?
Right now, it sounds like not much of anything, but trying to find ways to protect axons from damage is a hot area in MS research. Wilkins and Scolding list three potential strategies: (1) neuroprotective drugs; (2) growth factors; (3) stem-cell based therapies.
At least a couple drugs that are in currently in clinical trials are thought to potentially have neuroprotective effects. One is FTY720 or fingolimod (which I am in a trial for and there’s also a new trial for PPMS) and another is MBP8298, which is being tested in secondary progressive MS.
**What is the relationship between inflammation and neurodegeneration?
Until fairly recently, MS was thought to be the “archetypal inflammatory demyelinating disease of the central nervous system” (Wilkins and Scolding) in which the repeated ravages of inflammation and resultant demyelination caused progression and neurodegeneration. This is now thought to be more complicated.
Epidemiological and natural history studies suggest that, when looking at large groups of people (there’s still a lot of individual variation), progression in MS is related to age and that after a certain point progression occurs at more or less the same rate for all people with MS regardless of prior history of relapses. That is, after a certain point the relapses have no significant influence on quickly you progress. This break point usually seems to be given as a sustained score of 4 on the EDSS (Expanded Disability Status Scale). EDSS 4 is defined as “Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite relatively severe disability consisting of one FS grade 4 (others 0 or 1), or combination of lesser grades exceeding limits of previous steps; able to walk without aid or rest some 500 meters.” (My EDSS always seems to work out to 3 or 3.5, which I find uncomfortably close to 4). Some have argued that primary progressive MS is just secondary progressive MS with the relapsing-remitting phase cut off. Trapp and Nave conclude that “much of the recent epidemiological data can be interpreted as indicating that all MS patients have a similar rate of primary neurodegeneration with variable secondary inflammatory demyelination.” These studies suggest that inflammation might not be the cause of neurodegeneration.
Peterson and Fujinami list five possible relationships between inflammation and neurodegeneration (which are not mutually exclusive):
(1) inflammation induces neurodegeneration
(2) neurodegeneration causes inflammation
(3) other factors contribute to the development of inflammation and/or neurodegeneration
(4) inflammation and neurodegeneration participate in a cycle or a cascade in which they augment one another
(5) inflammation can protect against neurodegeneration
Wilkins and Scolding say that it would be hard to show whether inflammation or neurodegeneration is primary, but one approach might be to see whether progression is prevented when intense immunosuppression is used very early in MS.
**References:
Frohman, E. F. et. al. (2005).“Characterizing the mechanisms of progress in multiple sclerosis.” Archives of Neurology, 62 (9), 1345-1356.
Peterson, L. K., & R. S. Fujinami. (2007). “Inflammation, demyelination, neurodegeneration, and neuroprotection in the pathogenesis of multiple sclerosis.” Journal of Neuroimmunology, 184 (1-2), 37-44.
Trapp, B.D., & K.-A. Nave. (2008). “Multiple sclerosis: An immune or neurodegenerative disorder?” Annual Review of Neuroscience, 31, 247-269.
Wilkins, A., & N. Scolding. (2008). “Protecting axons in multiple sclerosis.” Multiple Sclerosis, 14, 1013-1025.
I’m sure most of you know this, but I just want to mention at the beginning that axons are long fibers that come off of the cell body of neurons and send signals to other neurons. They are like wires that conduct electricity. Many axons are normally covered with myelin. Myelin, like insulation on a wire, improves conduction and is, as we all know, attacked in MS.
There seem to be two major things that go on in MS:
1. Inflammation. This is thought to be caused by an autoimmune attack on the myelin surrounding the axons in the central nervous system. Acute inflammatory demyelination is what causes relapses where you get suddenly worse. Many of the symptoms of relapses can resolve over time as the attack abates, inflammation goes down, and the body attempts to repair itself and remyelinate the axons. In fact, some inflammation during an attack appears to be good in that it triggers the body’s self-repair mechanisms so it may not be ideal to completely suppress the immune system in MS.
2. Neurodegeneration. This is thought to cause the slow, insidious progression in MS and to be caused by permanent damage to axons. Although neurodegeneration starts early in MS, it usually takes a while to show noticeable effects because the brain is very good at compensating and can work around the damage for some time (yay for neuroplasticity).
**How do axons get damaged in MS?
Axons can be damaged by inflammation in active lesions, due to various substances associated with inflammation that can injure them, and this can be reversible. They are also damaged by transection (which means to cut transversely, which sounds pretty irreversible to me. You can see a picture of transection in the rotating picture, second from top, at http://www.msalliance.com/aboutMS/index.asp?m=1&f=5&s=1&t=3&c=123). It was not clear to me what causes the transection, but it is apparently associated with the level of inflammation in active lesions.
In chronic lesions, the likely cause of damage is lack of trophic support. (I looked this up and it seems to mean something like “nutritive”; basically it has to do with the things in the surrounding environment that support the growth and health of axons, such as myelin, oligodendrocytes, and glia). In addition, axons probably become less able to recover over time.
There is also known to be axonal damage in normal-appearing areas of the brain.
Wilkins and Scolding list some possibilities for mechanisms of axonal loss in later stages of MS:
(1) previous inflammatory damage to axons
(2) low grade inflammation occurring causing damage to already vulnerable demyelinated axons
(3) loss of trophic environment for axons to survive
(4) alterations in energy requirements of demyelinated axons
(5) as part of a completely independent neurodegenerative process
They conclude that “in all likelihood, the axonopathy of MS is multi-factorial.”
**How do we know there are damaged axons in MS?
One way is though a newer type of imaging called MRS (magnetic resonance spectroscopy), which can measure something called NAA (N-acetylaspartate) which is a marker of axonal density. Loss of axons can be seen in brain biopsies and at autopsy. Axonal loss is also associated with brain atrophy.
**What can be done about neurodegeneration?
Right now, it sounds like not much of anything, but trying to find ways to protect axons from damage is a hot area in MS research. Wilkins and Scolding list three potential strategies: (1) neuroprotective drugs; (2) growth factors; (3) stem-cell based therapies.
At least a couple drugs that are in currently in clinical trials are thought to potentially have neuroprotective effects. One is FTY720 or fingolimod (which I am in a trial for and there’s also a new trial for PPMS) and another is MBP8298, which is being tested in secondary progressive MS.
**What is the relationship between inflammation and neurodegeneration?
Until fairly recently, MS was thought to be the “archetypal inflammatory demyelinating disease of the central nervous system” (Wilkins and Scolding) in which the repeated ravages of inflammation and resultant demyelination caused progression and neurodegeneration. This is now thought to be more complicated.
Epidemiological and natural history studies suggest that, when looking at large groups of people (there’s still a lot of individual variation), progression in MS is related to age and that after a certain point progression occurs at more or less the same rate for all people with MS regardless of prior history of relapses. That is, after a certain point the relapses have no significant influence on quickly you progress. This break point usually seems to be given as a sustained score of 4 on the EDSS (Expanded Disability Status Scale). EDSS 4 is defined as “Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite relatively severe disability consisting of one FS grade 4 (others 0 or 1), or combination of lesser grades exceeding limits of previous steps; able to walk without aid or rest some 500 meters.” (My EDSS always seems to work out to 3 or 3.5, which I find uncomfortably close to 4). Some have argued that primary progressive MS is just secondary progressive MS with the relapsing-remitting phase cut off. Trapp and Nave conclude that “much of the recent epidemiological data can be interpreted as indicating that all MS patients have a similar rate of primary neurodegeneration with variable secondary inflammatory demyelination.” These studies suggest that inflammation might not be the cause of neurodegeneration.
Peterson and Fujinami list five possible relationships between inflammation and neurodegeneration (which are not mutually exclusive):
(1) inflammation induces neurodegeneration
(2) neurodegeneration causes inflammation
(3) other factors contribute to the development of inflammation and/or neurodegeneration
(4) inflammation and neurodegeneration participate in a cycle or a cascade in which they augment one another
(5) inflammation can protect against neurodegeneration
Wilkins and Scolding say that it would be hard to show whether inflammation or neurodegeneration is primary, but one approach might be to see whether progression is prevented when intense immunosuppression is used very early in MS.
**References:
Frohman, E. F. et. al. (2005).“Characterizing the mechanisms of progress in multiple sclerosis.” Archives of Neurology, 62 (9), 1345-1356.
Peterson, L. K., & R. S. Fujinami. (2007). “Inflammation, demyelination, neurodegeneration, and neuroprotection in the pathogenesis of multiple sclerosis.” Journal of Neuroimmunology, 184 (1-2), 37-44.
Trapp, B.D., & K.-A. Nave. (2008). “Multiple sclerosis: An immune or neurodegenerative disorder?” Annual Review of Neuroscience, 31, 247-269.
Wilkins, A., & N. Scolding. (2008). “Protecting axons in multiple sclerosis.” Multiple Sclerosis, 14, 1013-1025.
Okay, I did put this up as a health page, pretty much as is. I will try to incorporate some of the stuff from the "It's not the amount of lesions..." post later.
sho
sho
Thanks, guys, for the nice words.
Tracy: I certainly didn't read all that at once :-)
Quix: I agree this is important, but I feel a little bit over my head here. I suppose, though, if I put it up with my disclaimer, it would be all right.
Jen: I'll look at that old post and see if I can work some of it in. Or maybe it needs it's own health page.
What I understood about the inflammation is that some parts of it are damaging and some parts are helpful because they signal the repair mechanism to kick into gear. I think what they want to find are selective immunosuppressants that just go after the bad parts (probably easier said than done).
sho (who is behind on everything at the moment, but will get back to this)
Tracy: I certainly didn't read all that at once :-)
Quix: I agree this is important, but I feel a little bit over my head here. I suppose, though, if I put it up with my disclaimer, it would be all right.
Jen: I'll look at that old post and see if I can work some of it in. Or maybe it needs it's own health page.
What I understood about the inflammation is that some parts of it are damaging and some parts are helpful because they signal the repair mechanism to kick into gear. I think what they want to find are selective immunosuppressants that just go after the bad parts (probably easier said than done).
sho (who is behind on everything at the moment, but will get back to this)
I've often wondered if the inflammation of the brain to whatever disease activity is going on is actually an immune response that's attempting to stop the axons being severed... and we're doing our bodies a disservice by stopping the relapse. Rather like putting up with a low-grade fever, because it's actually killing the virus in our bodies.
There's no question that I'm progressing, even though I haven't had a real relapse in three months. I have new symptoms all the time!
shoshin, I'd love to see some of Heather's old 'It's not the lesions' post in this health page as well.
http://www.medhelp.org/posts/show/354591
Evidently this neuro that she's seeing is up to date on the current research.
There's no question that I'm progressing, even though I haven't had a real relapse in three months. I have new symptoms all the time!
shoshin, I'd love to see some of Heather's old 'It's not the lesions' post in this health page as well.
http://www.medhelp.org/posts/show/354591
Evidently this neuro that she's seeing is up to date on the current research.
Wow.
This will (read that WILL) become a Health Page as is. Yes? Feel free to load it immediately. This is such important information. I recommend that everyone read this and ask questions about anything they don't understand. We can answer and make sure that we all are on the same page.
Quix
This will (read that WILL) become a Health Page as is. Yes? Feel free to load it immediately. This is such important information. I recommend that everyone read this and ask questions about anything they don't understand. We can answer and make sure that we all are on the same page.
Quix
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