Inflammation vs. neurodegeneration

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Postby gwa » Tue Apr 03, 2007 9:35 am

I believe that the new MRI type machine mentioned several weeks ago will be a tremendous help to doctors who are trying to decipher if DMD's are really working.

Too much emphasis has always been placed on the number of lesions seen on MRI's. Unfortunately, a lot of the damage is ongoing and unseen to the current MRI techniques.

The new machine is about 4 years away, according to the article, but it should really help with diagnosis, treatments and research.

At least people are now realizing that the lesions are just part of the picture. There are companies out there that are working on neurogeneration, which is where the real treatments are going to be found, in my opinion.


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Postby TonyJegs » Wed Apr 04, 2007 1:18 pm

-dignan

Quote-
These studies have consistently shown the presence of diffuse normal-appearing WM damage, marked gray matter involvement and significant cortical functional reorganization, as well as the occurrence of the neurodegenerative component of MS from the earliest clinical stages of the disease with only a partial relation to MRI markers of inflammatory demyelination. - end

WM in MS suffer not only around lesions, but also from certain degree of brain edema, this is visible on sensitive MRI.
Marked gray matter involvement depends on severity of tissue damage in lesions, definitely some degree of axons damage exists and therefore it could lead to death of originated neurons.
Significant cortical reorganization is a part of neuroplasticity in gray matter after partial elimination of neurons by death of some of them (via damaged axons).

Quote-
The present review argues that MS can no longer be viewed as a "two-stage" disease, which suggests that the two pathological components are dissociated in time, but rather as a "simultaneous two-component" disease, where the relative contributions of the various pathological processes of the disease to the development of "fixed" disability, their relationship and their evolution over time need to be clarified. - end

Neurogenerative disorders (of any kind) never have been considered as “two-stage” disorders, they are always complex, all structures and all cells are involved simultaneously in certain degree.

Quote –
This new view of MS should inform the development of future research protocols to define its actual physiopathology and prompt the institution of early treatment which should ideally target not only inflammatory demyelination, but also the neurodegenerative aspects of the disease, as well as promote neuroprotection and enhance reparative mechanisms and adaptive functional reorganization of the cortex. –end

Aseptic (without infectious agent) inflammation is secondary to tissue damage, not primary. Let’s don’t mix genuine inflammation during infections and secondary as a response to brain tissue damage.

-finn
Quote-
If I got it right you're claiming that axonal injury (or dysfunction) can't cause only lesions in any circumstances? – end

It is physiologically impossible to have a myelinated axon, say 7 inches long, and have isolated local demyelination of it, say between 3,5 and 4 inches, only. Any axonal damage causes the demyelination distantly of the site of damage as well as proximally later.

In case of MS we have a situation when several hundreds of axons of different length, different size, different thickness of myelin, from neurons of different location in gray matter, met somewhere in the middle of the brain in local (bordered) lesion, but axons are not the cause here. They are victims :)

I was trying to explain that when talking about cutting wound and describing cutting muscles there, keep in mind that for having muscle cut you need to have skin cut first.

Kind regards,
Tony
"All truth passes through three stages.
First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
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Postby finn » Wed Apr 04, 2007 2:54 pm

dignan,

thanks for sharing another interesting study (and bumping this thread back up ;-)

Tony,

TonyJegs wrote:Neurogenerative disorders (of any kind) never have been considered as “two-stage” disorders, they are always complex, all structures and all cells are involved simultaneously in certain degree.
Was this another rhetorical comment? If it wasn't, I'd have to correct you. During the past years several MS researchers have stated that MS could be a two-stage disease, where inflammatory phase (RRMS) is often followed by degenerative phase (SPMS, PPMS). Naturally I haven't bought it ;-)

TonyJegs wrote:It is physiologically impossible to have a myelinated axon, say 7 inches long, and have isolated local demyelination of it, say between 3,5 and 4 inches, only. Any axonal damage causes the demyelination distantly of the site of damage as well as proximally later.

In case of MS we have a situation when several hundreds of axons of different length, different size, different thickness of myelin, from neurons of different location in gray matter, met somewhere in the middle of the brain in local (bordered) lesion, but axons are not the cause here. They are victims :)
I hear you. In other words you're stating that demyelination in lesions has to come before axonal injury, not vice versa in any circumstances, right? And it would be impossible for any kind of axonal dysfunction to cause local demyelination seen as lesions?

What can a layman like me comment at this point, except hopefully you're right. It might be easier to find ways to prevent axonal degeneration caused by demyelination than demyelination caused by axonal injury/dysfunction.

Be well.

-finn
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
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Postby TonyJegs » Wed Apr 04, 2007 4:07 pm

-finn

1. It was definitely not my intention to write rhetoric comments here; I consider it waste of time. But if it looks that way, well, I apologize.

When I learned from you that several MS researchers have stated that MS could be two-stage disease I felt myself uneasy. Science is very complicated issue today, commercialization is on the rise, and if someone states such ideas he does it for certain reason, take your guess. Why, because it is completely against common rules of pathology, physiology, etc, against Laws of Nature if you wish.
Someone can deny the law of gravity but apples still falling down from the trees and it can’t happen in opposite way, and this is absolutely unrelated to whatever you say.

2. You got me right about axonal injury in WM, myelin damage comes first.

Clinically it gives you a great possibility to influent changes in WM way before lesion formation (months); right before lesion formation, when first “blinking”, or “on-off”, symptoms appear (few days); during acute stage of the lesion formation (2 days); and finally – repairing the damage (few months) and following rehabilitation (years).

Kind regards,
Tony
"All truth passes through three stages.
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Second it is violently opposed.
Third it is accepted as being self-evident."
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Axon Damage in MS

Postby Shayk » Wed Apr 04, 2007 7:18 pm

Tony

Another lay person here trying to understand the basics. :)

You wrote:
2. You got me right about axonal injury in WM, myelin damage comes first.

My basic question: Does the myelin damage cause and/or contribute to the "chronic metabolic dysfunction in axon pathology" noted in the title of the following abstract or might it be caused by something else? If it's something else, do you have any ideas about what it might be, or, can the "chronic metabolic dysfunction" they reference only occur because the myelin is damaged first ?

Discordant white matter N-acetylasparate and diffusion MRI measures suggest that chronic metabolic dysfunction contributes to axonal pathology in multiple sclerosis

Thanks! I look forward to your answer, appreciate your posts and your willingness to share your time and expertise with us.

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Postby TonyJegs » Thu Apr 05, 2007 11:05 am

Thanks to administration of this forum for possibility to share opinions in an unobstructed way.

Damaged brain tissue will never be the same; this is a price of highest level of differentiation. Therefore, whatever happens with brain, every single component of it will suffer, more or less, and, of course, in its own specific way.

Axons, which went through the site of damage (MS lesion), reacted to this ‘catastrophe’ differently. First of all, the severity of total axonal damage depends mostly on volume of the lesion, the greater volume of the lesion - the greater degree of following inflammation we have. Then, the morphological differences among axons will be in play: thicker axons (and therefore more myelinated) will survive at bigger rate. The location of axons in the lesion is also important, more marginally located axons will be less damaged.

To answer your question -
Chronic metabolic dysfunction in WM is non-specific and secondary to lesions.

Kind regards,
Tony
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First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
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Postby Lyon » Thu Apr 05, 2007 12:31 pm

Hi Tony,

This is not in the least intended to be hostile because in your time here much of what you've said seems very sensible and it seems you have a direct knowledge of neurological functions. On the other hand, some things you mention directly contradict what we're used to hearing.

I'm in the search of truth so I have nothing against....and in fact I look forward to strong evidence which contradicts conventional knowledge, but in order to give it any weight I need more to go on.

I apologise that it's rude of me to ask, although I don't ask for specifics, but could I ask that you give whatever background on yourself that you feel comfortable giving?

Thanks,
Bob
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Postby TonyJegs » Thu Apr 05, 2007 5:16 pm

Lyon wrote:This is not in the least intended to be hostile because in your time here much of what you've said seems very sensible and it seems you have a direct knowledge of neurological functions. On the other hand, some things you mention directly contradict what we're used to hearing.

I'm in the search of truth so I have nothing against....and in fact I look forward to strong evidence which contradicts conventional knowledge, but in order to give it any weight I need more to go on.


All right, let’s put it this way – you can ask me anything, and I mean it, on neurobiology, neuropathology and neurology.

About modern science. I've told that it is a complicated issue now, and sometimes it serves commercial interests instead of truth.

Kind regards,
Tony
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Second it is violently opposed.
Third it is accepted as being self-evident."
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Postby Shayk » Thu Apr 05, 2007 7:17 pm

Tony wrote:
Thanks to administration of this forum for possibility to share opinions in an unobstructed way

Yes, I share that sentiment too.

And, thank you very much for answering my question and for the other information you shared.

My knowledge of myelin thickness was limited to the assumed differences between the genders (based on the mice studies--men have thicker myelin than women I think ??) and I didn't realize there was so much general variation in myelin thickness that was itself dependent on the thickness of the axon. Did I understand that correctly? It's always possible I didn't.

The information raised another question though and I'm so glad you're open to our questions. You wrote:
Axons, which went through the site of damage (MS lesion), reacted to this ‘catastrophe’ differently.

What do you think this 'catastrophe' is (I'm assuming you didn't mean it's the lesion itself)? What in your opinion initiates the 'catastrophe' (damage to the myelin)? Or, is that something that's still an unknown?

Again, thank you, both for your time and your expertise.

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Postby TonyJegs » Thu Apr 05, 2007 11:13 pm

Shayk wrote:
My knowledge of myelin thickness was limited to the assumed differences between the genders (based on the mice studies--men have thicker myelin than women I think ??) and I didn't realize there was so much general variation in myelin thickness that was itself dependent on the thickness of the axon. Did I understand that correctly? It's always possible I didn't.

What do you think this 'catastrophe' is (I'm assuming you didn't mean it's the lesion itself)? What in your opinion initiates the 'catastrophe' (damage to the myelin)? Or, is that something that's still an unknown?


The difference in myelin thickness in men and women is not only in number of layers, degree of ‘softness’ is more important. . As everywhere in the brain, in MS lesion difference in axon diameters depends on its function, how many intermediate connections it has (gaps are the place where the new synapses can be formed, part of neuroplasticity) and velocity of impulse transferred. The point of previous discussion was to show nonconformity of axonal damage.

Main difference in two genders, as everybody knows, lies in sex hormones and they are the partial reason why women have MS more often than men.
There was a question in one post about menopause and MS. After menopause the number of relapses reduced remarkably, say ‘stormy weather’ calms down. Most important task for women with MS must be how to reach this period with less disability.

‘Catastrophe’ is the term often used for unusual rapid changes in brain, like stroke, trauma, etc. The formation of acute MS lesion is rapid, full demyelination cycle lasts up to 48 hours max.

Well, I have a dispute recently with one architect, friend of mine, about ‘mysteries of brain’. I personally don’t think that we have ‘mysteries’ in brain, just sometimes the disease (or function or whatever else) is not, say, ‘unveiled’ properly.
Why, well, it is a market place out there, main driving force of everything. I’m not against market, God forbid, but that’s why the road to right explanation (and following exploitation) is not strait, it has a lot of everything, as curves, stops, bumps, etc. All major research labs are private, the funding (of reasonable size) of projects is mostly private (mean, not governmental). Have a patience and wait, it will come sooner or later.

Happy Easter everyone,

Kind regards,
Tony
"All truth passes through three stages.
First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
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Postby Loriyas » Fri Apr 06, 2007 1:35 pm

"After menopause the number of relapses reduced remarkably, say ‘stormy weather’ calms down. Most important task for women with MS must be how to reach this period with less disability. "


Tony-what did you mean by this? I am really interested in this. Are you saying that relapses would most likely decrease after menopause? Why would that be? I would think this would be significant.

Thank you
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Postby CureOrBust » Fri Apr 06, 2007 5:42 pm

I think it would be a "subset" of MS patients that one would be dealing with, as:
1. The "normal" age to get MS is between 25-35
2. I am guessing the normal age for menapause is >45 (ie much greater than 10 years after "getting" MS)
3. 50% or something of people convert from RR to SP after 10 years.

So, if someone is still RR (which they would have to be to see a reduction in relapses) by the time they hit menapause, and they contracted MS at the "normal" age range, they would seem to me to be the exception, rather than the rule. ie either they 1. Contracted MS later than most, 2. stay at RR longer than most, or 3. Hit menapause very early. Or am I missing something here?
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Postby gwa » Fri Apr 06, 2007 6:23 pm

Tony,

What is "it"?

"Have a patience and wait, it will come sooner or later."

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Postby TonyJegs » Sat Apr 07, 2007 8:05 am

-Lori, -CureOrBust, -gwa

It is a part of natural course of MS. If you interested in numbers browse for such study about 20-30 years ago range, I believe that it was German or Swedish study.
If it is far from your reach, take any recent article on pregnancy and MS. Why women are protected from MS relapses during pregnancy? The level of estrogens goes down as protection from abortion (biological common sense). Esp. 3 last months of pregnancy are beneficial for MS patients, clinically they usually blossom up, the progesterone is on the rise.
After labor, the rate of MS relapses increase, and that's why it was not recommended for MS patients get kids in old days practice, say, prohibited. Why we got MS activity back? Estrogens slowly come back, and regain the ‘old’ level within several months completely.
In menopause, women have decreased level of estrogens, and this works at the same way as during pregnancy. Of course, there is a lack of other components, but it is better anyway.
Practical outcome from this: - MS female patients must not use estrogen based therapy for menopause “flushes” treatment, use something else.

Mainly when talking on MS we will discuss R-R as more common form, if we’ll talk about other it will be mentioned separately.

Having patience is the best common advice for everyone; don’t get desperate when you couldn’t change the circumstances around you.

Kind regards,
Tony
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Second it is violently opposed.
Third it is accepted as being self-evident."
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Estrogen: Detrimental or Beneficial in MS ?

Postby Shayk » Sat Apr 07, 2007 8:25 pm

Tony

I’m surprised and confused by several things you said.
Why women are protected from MS relapses during pregnancy? The level of estrogens goes down as protection from abortion (biological common sense)

Did you really mean to say the level of estrogens goes down or was that a mistake maybe? The information I’ve read about the Phase I estriol trial was that the dose (8 mg) was based on estriol levels during the last 3 months of pregnancy, so I definitely thought estriol levels were at their highest level during the last trimester of pregnancy when disease activity “lessens”.

The Phase I estriol trial, albeit a very small one, did significantly decrease the number and size of inflammatory brain lesions, improve cognitive test scores, and decreased “black holes”, i.e. “areas of myelin damage identified during the study did not evolve into severe black holes” in women with RRMS. Here’s one of the original news releases about it.

Pregnancy Hormone Estriol Shows Promise As Multiple Sclerosis Treatment In First Human Trials

and this is a more recent one--

Could Estriol Be The Elixir For Multiple Sclerosis?

Of course progesterone and Vitamin D3 levels are also higher during the third trimester and drop rather dramatically post delivery as well.

Could it be that the drop in estriol (a form of estrogen), progesterone and Vitamin D3 levels in the 3 months post partum contribute to the increased MS disease activity and “relapses” during that time period? Or, maybe it's something that we don't even know about yet?

The articles also indicate estriol is used for menopausal symptoms in Europe, so I’m curious as to why you’re so opposed to it for that purpose.

As to it's possible role in MS, I think

--the rationale for the estriol trial and the trial itself, combined with

--recent epidemiological research that found that oral contraceptives (which contain both estrogen and progesterone) may delay a diagnosis of MS, i.e., the incidence of MS was 40% lower in women who had used oral contraceptives in the previous three years;

--a recent clinical trial that found the EDSS score was about 25% lower in oral contraceptive users prior to treatment than never-users, and,

--the pre-clinical neuroprotective properties of estrogen

all seem to support the idea that estrogen has the potential to be beneficial rather than detrimental to people with MS. Much more research is needed of course.

More importantly though, at least to me, than a focus on relapses, is that the natural history of the disease is more or less as Cure O indicated and you agreed (I think) and that is that the vast majority of people with RRMS transition to a SPMS course and increasing disability, without relapses, after some period of time.

What I think may be a factor that’s been overlooked is that several hormones, including estrogen, all of which display significant neuroprotective properties (at least in pre-clinical research), also are on the decline during the period of time that people transition from RRMS to SPMS.

Menopause itself is just a point in time. DHEA, testosterone, progesterone and estrogen levels all decline, some rather significantly, well before menopause. DHEA for example declines most significantly between the ages of 20-40 when most people are diagnosed. I think progesterone levels also start to decline before there’s a significant drop in estrogen.

So, it seems to me the gradual decline of several hormones with “neuroprotective” properties, which occurs during the aging process, very roughly coincides with and parallels the transition to SPMS and increased disability. Thus, the question becomes, does the loss of this neuroprotection with aging as a result of declining hormones levels, make everyone more vulnerable to neurodegeneration and neurodegenerative insults, and for people with MS, increasing disability over time? There was this recent research:

Progression in multiple sclerosis: Further evidence of an age dependent process
Our data give further support to the notion that progression in MS is an age dependent process independent of relapses.


Taking it out of the realm of sex steroids, here’s some recent research that I think illustrates the point. This research is on Vitamin D, which also declines with age. Head’s up Legs and Finn :wink: (it’s from Finland ).

Neurosteroid hormone vitamin D and its utility in clinical nutrition
In both animals and humans, vitamin D serves as an important endogenous and/or exogenous regulator of neuroprotection, antiepileptic and anticalcification effects, neuro-immunomodulation, interplay with neurotransmitters and hormones, modulation of behaviors, brain ageing, and some other, less-explored, brain processes. SUMMARY: Vitamin D emerges as an important neurosteroid hormone in the brain, with a strong potential for age-specific applications…..


Long post I know. You all know I couldn't let it "rest". I remain ever optimistic about the potential of hormones to help manage MS. Tony, I think it's clear I really don’t understand your total opposition to estrogen and would certainly welcome more information about that.

Take care all.

Sharon
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