Inflammation vs. neurodegeneration

[TonyJegs]

Quotes:

• "Unexpectedly, after adjusting for sex, age and duration of disease, correlations between total plaque load and axonal loss in both the corticospinal tract and sensory tracts were weak or absent at each level investigated. Since there was little correlation between plaque load and axonal loss, the possibility that demyelination is not the primary determinant of spinal cord axonal loss warrants consideration."
  
  "The degree of atrophy varied in different parts of the cord. Individual lesions played a minor role in local atrophy. Our findings suggest that axonal degeneration, possibly caused by the cumulative number of lesions in the brain and cord, or an alternative atrophic process, is responsible for spinal cord atrophy in multiple sclerosis, rather than tissue loss within individual lesions."

-finn

1. In this case we a talking about spinal cord lesions. They differ from WM lesions of brain. From one side, in spinal cord the majority of axons are pretty thick and long, they are myelinated heavier (motor ones more, sensory less, that why patients feel sensory disturbances first during relapse ). More important, the volume of spinal cord WM significantly less compare to brain WM. From other side, they more vulnerable to pressure that always appear during lesion formation, say, very tight quarters. Therefore the degree of axonal loss in spinal cord will depend less on the “plaque load”, it will depend more on localization.
2. It is good to have such imagination, I use knowledge instead.
3. In this forum I will never say directly – use this drug, don’t use that drug. It is not my goal first, second it will depend on your physician and guidelines of MS treatment existed in your country of residence. As I understand people there want to learn more about MS, that’s all, I share. Follow my posts and you find it out.

Kind regards,
Tony

[bromley]

Tony,

I'll say this as politely as I can. I can't work out if you know what you are talking about or are completely bonkers. Can you give us some background on yourself - are you someone with MS?

Ian

[finn]

Tony,

I'm sure I'm not the only one who appreciates your posts and your presence on this board.

Besides, we seem to agree at least on one thing: Inflammation is not the primary pathological process in MS. Only the future will tell whether the primary process in MS could be axonal degeneration, and whether it could trigger local demyelination. Anyway, it might be a good idea to check the upcoming work of researchers like Tsunoda and Fujinami.

Be well.

-finn

Btw, I suppose no intelligent reader would take a medical advice given by an anonymous writer on a discussion board for granted. Like Ian already wrote, so far you've been just another nickname in the cyberspace. Don't get me wrong, that's fine by me becouse you seem to know the stuff you're writing about.

[bromley]

Finn,

This should keep you busy.

http://www.acceleratedcure.org:8080/node/2585

The interesting bit was:

suggesting that different disease mechanisms are occurring in white vs. gray matter

Although the disease mechanisms may be different, they must be linked / related as they are both a product of the disease called MS. Which one comes first / what causes it are still to be resolved. We must all agree that this is one bastard disease!

Have a good Easter - I'm taking a well deserved break on a tropical island and will not be thinking about inflammation v neurodegeneration as I lay on the beach.



Ian

[TwistedHelix]

Axonal degeneration always cause demyelination in mammals, and there in no other way around. It was known from 19th century. Axon can exist without myelin, myelin can not. Myelin sheaths wrap around the axon on demand only

Tony:
I think I must be misunderstanding you: it seems to me that the paragraph quoted above directly contradicts your assertion that myelin damage is the primary event in MS. You're right to say that myelin wraps around the axon "on demand": oligodendrocytes must receive the correct signals from a live, competent and fully active axon; if the signal is missing or weak the myelin will degrade and fail.
You also said earlier that messing about with one neurotransmitter is not a good idea in such a complicated system. That would be true if everything was as finely balanced as it should be, but if there is too much glutamate, or the receptors are hyperactive, that would not be the case.

Can you imagine the mechanism which can produce a local area of demyelination distantly by some kind of coordinated signals from the axons of different length, different diameter and different origin?

... Well, yes I can, actually: supposing a single axon dies, for whatever reason, even if something happens down at your big toe. Because it is no longer signalling, its myelin sheath begins to fail. In the brain, this triggers the "mopping-up operation" which you've already described as being damaging to myelin. This would seem to be enough to create a lesion, but the dead axon would also trigger the glutamate cascade, with all its consequences.

gwa: I didn't realise someone could have such extreme reactions to these substances: ever thought of volunteering to become a guinea pig? I have always been impressed by Bob's posts about intestinal parasites and the hygiene hypothesis, and a thought suddenly occurred to me: "modernisation" brings improved sanitation, but also something else -- processed foods with their attendant neurotoxins.
Glutamate and aspartate are the major excitatory substances in the brain, and if they increase when body chemistry has been altered after parasites have disappeared , well, that would be a real double-whammy.

Manchester: those were great links, (although the first one didn't seem to work for me). I'm glad researchers are looking at different mechanisms.

Bromley another holiday? Who are you married to... Judith Chalmers? (joke for UK consumption only).

Dom

[Lyon]

"modernisation" brings improved sanitation, but also something else -- processed foods with their attendant neurotoxins.
Glutamate and aspartate are the major excitatory substances in the brain, and if they increase when body chemistry has been altered after parasites have disappeared , well, that would be a real double-whammy.

Dom, that is a good point and one that I personally had never considered. It's also of the kind speculating I like in that it seems pretty obvious and just needed to be pointed out.

Yes, I'm among those who sometimes has to have the obvious explained!

Bob

[TwistedHelix]

Thanks Bob,

Obviously, in a "developing" society processed foods containing MSG and aspartame would come much later than the elimination of parasites, but auto-immune diseases fall into the category of "diseases of modern living", so I think these two could at least be classed as joint suspects.
Glutamate occurs naturally in many foods, and is stabilised with ordinary salt to become MSG . It can be obtained from Kombu seaweed, shrimp, and fermented soy and is therefore prominent in Asian diets. The incidence of MS is very low in these countries, so the link is probably not direct -- it's more likely to be just one part the tangled web,

Dom.

[Lyon]

-- it's more likely to be just one part the tangled web,

Hi Dom,
Tangled web is a good way of putting it. If a disease has one instigating factor driving incidence, it's hard enough to identify it. When two are involved identification becomes more difficult in multiples. There might be several factors driving MS incidence but things aren't quite so bad because there is no doubt that genetics are involved.

One thing that makes me certain that there aren't too many factors involved is the fact that we can notice the genetic involvement. If there was more than a big genetic factor and subsequent environmental trigger or more than a big environmental factor and genetic trigger the odds would be so highly against seeing familial clustering that it wouldn't have been noticeable to us.

I honestly can't see the search for MS as anything other than our having dismally flunked the first grade but being progressively promoted to the subsequent higher grades and now we find ourselves in advanced college biochemical classes.....able to do the necessary lab work but not having any idea of what MS is or how any of what we do relates to it, but we keep doing progressively harder and more complicated experiments hoping that at one point it will all come together and we'll understand it all.

It's not going to happen until we go back and take a second look at some of what we've glossed over as unimportant in the past.. We have accumulated knowledge along the way and I'm confident that the wisdom we've gained along the way is going to benefit us if we reinspect the earlier years of our education again.

Even if a person finds no merit in the loss of human parasites being an instigating factor in the increase in MS, it's impossible to overlook the significance of the researchers overlooking such an obvious "possible" factor. These things had been a part of human system and suddenly became absent, yet that wasn't considered? What other things overlooked along the way?
Bob

[HarryZ]

Bob,

Even if a person finds no merit in the loss of human parasites being an instigating factor in the increase in MS, it's impossible to overlook the significance of the researchers overlooking such an obvious "possible" factor. These things had been a part of human system and suddenly became absent, yet that wasn't considered? What other things overlooked along the way?
Bob

An excellent comment!

One example I can give is the immense amount of work that Dr. Hinton Jonez did with histamine back in the late 40's and early 50's before he died suddenly. He had huge successes with treating the symptoms of thousands of MS patients back then but when he died, so did all of his research. The MS docs at the time appeared to ensure that his work got buried...and that they did very well.

Jonez's work didn't answer the cause of MS but it sure helped a lot of patients in their daily misery in fighting the disease. It could be another piece in a very complicated puzzle.

Harry

[Lyon]

I think Ian was right Harry, you really are a nice guy!

I've got one foot out the door to head for an 18 hour drive to Florida, so it's probably not wise to leave for a week on this note....but:

When I read all the highly technical abstracts, although it's not known if any of it is specific to MS, I feel like a guy hanging on for dear life to a pack of hounds who are hell bent on the scent of a rabbit.

In the midst of the chaos I look a few feet to the left and see the rabbit sitting there taking it easy. Obviously the rabbit has done a five mile loop and circled around to his original trail but there is no obvious way to stop the hounds. All I can do is follow the dogs on the time consuming full tilt run back to the beginning, which is where we have to return in order to find any real progress.

Bob

[finn]

Ian,

Finn,

This should keep you busy.

http://www.acceleratedcure.org:8080/node/2585

Thanks! You're absolutely right, I think it was an interesting finding. Believe me or not, reading that kind of stuff doesn't make me cheer, either. I'm just pleased they seem to have found another piece to the puzzle.

We must all agree that this is one bastard disease!

Yes, most definitely. I wouldn't even mind being proven wrong, if somebody could come up with a valid autoimmune theory and a cure to this disease.

Anyway, good easter to you, too. Enjoy your holiday!

Be well.

-finn

[HarryZ]

Bob,

I think Ian was right Harry, you really are a nice guy!

Don't believe everything Ian says....that could land you into trouble I hope you have a safe, good drive to Florida.

In the midst of the chaos I look a few feet to the left and see the rabbit sitting there taking it easy. Obviously the rabbit has done a five mile loop and circled around to his original trail but there is no obvious way to stop the hounds. All I can do is follow the dogs on the time consuming full tilt run back to the beginning, which is where we have to return in order to find any real progress.

If you are right, then we are still many years away from any real progress

Harry

[TonyJegs]

I honestly can't see the search for MS as anything other than our having dismally flunked the first grade but being progressively promoted to the subsequent higher grades and now we find ourselves in advanced college biochemical classes.....able to do the necessary lab work but not having any idea of what MS is or how any of what we do relates to it, but we keep doing progressively harder and more complicated experiments hoping that at one point it will all come together and we'll understand it all.
Bob

Prefect saying, not much to add.

Concerning your link to Italian study of gray matter.
It is not a new fact, it was know for a century at least. Main reason for slight cortical atrophy in MS lies in elevated CSF level, with or without elevated intracranial pressure. Of course you got more involvement at the areas which correspond to certain function.

- finn

Axonal degeneration after its damage or neuron death goes with demyelination of whole length, not partially or locally.

Kind regards,
Tony

[finn]

Harry, Bob, Dom,

(some ;-) your comments make sense to me. Even if MS wasn't an immune mediated disease, changes in enviromental factors (industrialization, improved hygiene, increased amount of processed food, etc.) may have had an impact on its incidence.

Actually, here in Finland they have studied the frequency of diabetes in a small area on both sides of the Russian border. It's much higher in Finland, and according to the study one reason for it might be the "hygiene hypothesis". Quote:

• "Karelian Republic of Russia shares ground border with Finland. Our populations live close to each other and Finns-Karelians also live in Russian Karelia. However, standard of living is totally different in our countries. We live in areas different in ecologic situations, crowding, hygiene, consumption of such products as milk, meat, fruits etc. So it is very interesting for us to know how these differences and genetic factors could influence on people’s health, especially on such severe human diseases like type 1 diabetes and other autoimmune diseases.
  
  At the moment, we have got very interesting and important results: type 1 diabetes is six times lower in Karelian children than in children living in Finland. We then analysed serum samples of healthy schoolchildren, newborns and pregnant women from both countries for risk markers for type 1 diabetes, particularly HLA genes, microbes and autoimmune markers for the disease. We found that microbial infections are more frequent in Russian Karelia while genetic risk markers do not differ significantly between two populations. So we consider that yet unknown environmental factors (probably, virus, microbe infections, parasites, dietary factors etc) could contribute to low incidence of type 1 diabetes in Russian Karelia. We found also that the same trend exists also in other autoimmune diseases such as celiac disease and thyroid gland diseases."

Maybe improved hygiene has made our immune system weaker and our body more susceptible to new and/or previously harmless pathogens. That's how it goes with PML, a common JC-virus can cause PML only if the immune system is suppressed too much.

Tony,

Axonal degeneration after its damage or neuron death goes with demyelination of whole length, not partially or locally.

Allright. If I got it right you're claiming that axonal injury (or dysfunction) can't cause only lesions in any circumstances?

Be well.

-finn


[edit: added the part for Tony]

[dignan]

Some researchers are trying to answer the questions raised in this discussion...and I just wasn't ready to let this thread die...



Inflammatory demyelination and neurodegeneration in early multiple sclerosis.

J Neurol Sci. 2007 Mar 28;
Charil A, Filippi M.
Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy.

A number of recent magnetic resonance imaging studies have challenged the classical view of multiple sclerosis (MS) as a "two-stage" disease where an early inflammatory demyelinating phase with focal macroscopic lesions formed in the white matter (WM) of the central nervous system is followed by a late neurodegenerative phase, which is believed to be a mere consequence of repeated inflammatory insults and irreversible demyelination.

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.

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.

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.

Pubmed URL