Inflammation vs. neurodegeneration

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

Postby finn » Wed Jul 18, 2007 7:53 am

Bob,
Lyon wrote:I suppose since the researchers disclose their financial interests we shouldn't doubt the findings of the studies, but I'm afraid it always makes me wonder. Considering the situation, I think, researchers should be required to post conflict of interest information at the end of their abstract.

Maybe this quote from a review of Marcia Angell's book supports the way you see it: "A quarter of academic scientists now have financial ties to industry: Companies woo them with invitations to sit on scientific advisory committees (for a salary, of course), lucrative consulting contracts, and stock options potentially worth millions of dollars." Maybe instead of just disclosing financial ties, reserchers should also be made to tell the importance of them (e.g. how much money they have received from a drug company during the past five(?) years, the amount of drug company stocks and/or stock options owned by the researcher, etc). It might help us to evaluate if authors of a study really have had bias or not.

Lyon wrote:I don't consider it to injure your argument that the body of the Lucchinetti article actually only mentions that it's currently contentious as to whether inflammation or neurodegeneration is first and actually doesn't specifically address that particular aspect much.

True. The article was quite thorough and unbiased summary of the current situation in MS-research. Naturally I have just concentrated on picking up quotes that support my point of view. In any case, I'd say this is the most important quote: "It is hotly debated whether a primary neuronal or axonal process could lead to WM demyelination as opposed to WM demyelination leading to secondary axonal and neuronal damage."

I suppose the debate will continue...

-finn
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
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Postby Lyon » Wed Jul 18, 2007 12:36 pm

finn wrote: I suppose the debate will continue...
Hi finn,
Of course I lean towards inflammation first and it might be seen as riding the fence but when something conclusive comes around it wouldn't surprise me too much to see it go either way.

Although I do have my convictions, NOTHING about MS could surprise me a heck of a lot.

Bob
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Where does PPMS fit in the inflamm vs degen debate?

Postby Smilingface » Wed Jul 18, 2007 5:41 pm

Hi Finn and Lyon,
You guys are way ahead of me on understanding this stuff but I wanted to throw out an idea. What do you think of the possibility that in PPMS the inflammatory episodes are so quick, they are not detectable? I tried the theory on my neuro the other day right in the middle of my examination. I'm sure he just loves it when the patient tries to come with an explanation. I have to confess, I sometimes lie awake at night trying to figure out how PPMS fits in the picture......
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Postby Lyon » Wed Jul 18, 2007 6:27 pm

Hi Smilingface,
If we're way ahead of you in anything it's in understanding the "speculation" of researchers....which I'm not sure amounts to much :oops:

I couldn't hazard a guess as to the likelihood of what you mention but I personally feel that researchers have used faulty information to arrive at their conclusions regarding SPMS and PPMS, so your theory may be closer than theirs.
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Postby finn » Sun Jul 22, 2007 2:38 am

jackD wrote:I believe in the BOTH theory.

http://home.ix.netcom.com/~jdalton/ms-two-stages.pdf

I'm sorry, but I just have to question Dr. Steinman's theory. Having a disease process firts driven by inflammation and then by neurodegeneration just doesn't make much sense to me, but I suppose the autoimmune camp can easily explain what happens to the autoimmune reaction at the later stage of the disease. Where (and why) does it disappear? And what about PPMS?

The main reason for this post was an article published in the may issue of Neurology which was just sent to me by a dear friend of mine. In it Dr. Robert Lisak writes about neurodegeneration and the importance of neuroprotection, but he also comments the idea of MS being a "two stage disease". Here are few (very carefully selected) quotes from the article:
  • "Although some investigators now consider MS to have two distinctly separate phases that reflect distinct pathogenetic mechanisms, inflammatory and noninflammatory, such an absolute division of phases is now also being challenged."
  • "Significant CNS atrophy begins during the earliest stages of disease, and there is a strong association between brain atrophy and disability."
  • "Disability accumulating in the absence of relapses, or during treatments that reduce relapse rate, challenges the division of the disease into distinct, mutually exclusive relapsing–remitting and progressive phases. For example, interferon beta causes a 30% decrease in relapse rate and a >50% reduction in MRI activity, but the effect of this drug on disability and brain atrophy is minimal."
  • "Support for an ongoing accumulation of subclinical neuron damage in the background of intermittent inflammation-related relapses stems from the recognition of the age-dependence of clinical phenotypes, regardless of whether the disease presents as RRMS or primary-progressive MS (PPMS). According to this view, disability milestones that reflect irreversible neuron damage are reached on a predictable schedule that is not influenced by relapses."
On the other hand, the truth is still out there. In the same issue of Neurology Dr. Bruce Trapp states that "because most patients with RRMS ultimately convert to SPMS, there is increasing speculation that these disease courses are not etiologically distinct but may actually represent stages of a single biphasic disease."

So, we'll just have to wait and see who is proven to be (more) right.

-finn
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
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Postby Lyon » Sun Jul 22, 2007 10:05 am

Not to disagree finn but in my view to possibly expand on what you are saying, this abstract from the August Journal Of The Neurological Sciences seems interestingly pertinent....Bob
Abstract
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.
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Postby jackD » Sun Jul 22, 2007 11:28 am

I guess it all depend on what one calls "significant". It seems obvious that disease progression can continue AFTER inflammation has stopped but can it occur WITHOUT myelin being destroyed first? I do not have the answer to that. Can myelin be destroyed without inflammation? I do not have answer to that either.

My personal approach is to lower MMP-9s and cap the activity of the other players so my Avonex can do its job.

jackD

1: Mult Scler. 2007 May;13(4):490-501. Epub 2007 Feb 9. Links
Interferon beta-1a slows progression of brain atrophy in relapsing-remitting multiple sclerosis predominantly by reducing gray matter atrophy.Zivadinov R, Locatelli L, Cookfair D, Srinivasaraghavan B, Bertolotto A, Ukmar M, Bratina A, Maggiore C, Bosco A, Grop A, Catalan M, Zorzon M.

Department of Neurology, Buffalo Neuroimaging Analysis Center, The Jacobs Neurological Institute, University at Buffalo, State University of New York, Buffalo, NY, USA. rzivadinov@thejni.org

BACKGROUND: Brain atrophy, as assessed by magnetic resonance imaging (MRI), has been correlated with disability in patients with multiple sclerosis (MS). Recent evidence indicates that both white matter (WM) and gray matter (GM) are subject to atrophy in patients with MS. Although neurological deficiencies in MS are primarily due to loss of WM, the clinical significance of GM atrophy has not been fully explored in MS.

METHODS: We have undertaken a three-year, open-label study, comparing 26 patients who elected to receive intramuscular interferon beta-1a (IFN beta-1a) therapy, with 28 patients who elected not to receive therapy. Both groups had quantitative cranial MRI scans at study entry and after three years, and standardized clinical assessments every six months. Brain parenchymal fraction (BPF), GM fraction (GMF), and WM fraction (WMF) percent changes were calculated, and T2- and T1-lesion volumes (LVs) assessed.

RESULTS: After three years, mean percent (%) change in BPF favored the IFN beta-1a treatment group (IFN beta-1a -1.3% versus the control group -2.5%, P=0.009), as did the mean percent change in GMF (+0.2 versus -1.4%, P=0.014), and the mean percent change in T1-LV (-9.3 versus +91.6%, P=0.011). At the end of the study, there was a significant within-patient decrease in BPF for both groups (P=0.02 for the IFN beta-1a treatment group, and P<0.001 for the control group), a significant within-patient decrease in WMF for the IFN beta-1a treatment group (P=0.01), and a significant decrease in GMF for the control group (P=0.013) when compared with baseline.

:D CONCLUSION: Over a three-year period, treatment with IFN beta-1a significantly slowed the progression of whole-brain and GM atrophy, and of T1-hypointense LV accumulation, when compared with the control group.

PMID: 17463072 [PubMed - in process]
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Postby Lyon » Sun Jul 22, 2007 11:45 am

Not to disagree jack, because definitive proof either way isn't available, but it's becoming more obvious that it isn't easy or accurate to determine existance of or degree of inflammation with mri.

What seems to be coming to light is that past conclusions drawn from lack of inflammation based on mri might not be reflective of fact, which doesn't seem to prove or disprove anything but throws a lot of past assumptions into a higher degree of uncertainty.
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Postby finn » Sun Jul 22, 2007 11:47 am

Bob,

Lyon wrote:Not to disagree finn but in my view to possibly expand on what you are saying...

thanks for giving me the opportunity to quote myself. I have always dreamed about it.

finn wrote:There are several (more or less likely) ways to see the pathological process:
  • Inflammation causes demyelination, and eventually demyelination leads to axonal degeneration (traditional hypothesis).
  • MS starts as an inflammatory disease with a neurodegenerative component, but can change into a primary neurodegenerative disease (two stage model)
  • Neurodegeneration is the primary process from the onset of the disease, and inflammation is a reaction to it (my favourite theory).
  • Inflammation and neurodegeneration are seperate and independent processes.
  • etc?

-finn
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Postby Lyon » Sun Jul 22, 2007 11:56 am

finn wrote: thanks for giving me the opportunity to quote myself. I have always dreamed about it.
Hi finn,
Not that your comment was in the least bit offensive but that was the PERFECT opportunity to use a smiley face.

You only get so many opportunities in life :lol:

So.....you are going to add another diamond and
“simultaneous two-component”
to your list?

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Perhaps a dual phase disease?

Postby Smilingface » Sun Jul 22, 2007 5:59 pm

My favorite way to think of the pathological process is two concentric overlapping circles, one labeled inflammatory, the other degenerative, the overlapped area being a transitional phase. I think the literature clearly shows axonal and neuronal injury occurs early in MS and gets greater as more time is spent in the degenerative process. I guess that is why I came up with maybe in PPMS the time spent in the inflammatory phase is just really short bursts of inflammation then followed by a more obvious degenerative phase. This model would fit the disease process in me anyway ...I don't know about the rest of you!
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Postby Lyon » Sun Jul 22, 2007 7:56 pm

Hi Smilingface,
Seems like as good a way as any of viewing it when considering that researchers and laypeople alike are just giving it our best guesses!

I think plasticity isn't given nearly enough credit in explaining the relapsing/remitting phase, "silent" lesions and why, upon initial diagnosis, gm, wm damage and atrophy seems to already be present.

I submit the possibility that the symptoms leading to the diagnosis of MS is invariably synonymous with reaching the limits of plasticity to continue masking the underlying damage, either due to accrued damage reaching a point beyond the ability of plasticity or rate of disability out pacing the ability of plasticity to mask.

If we can finally determine ONE THING with certainty about MS, the rest is a lot more likely to become sensible and I think closer scrutiny of plasticity is the most likely vehicle to get us there.
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Plasticity?

Postby Smilingface » Mon Jul 23, 2007 5:57 pm

Lyon, the more I think about it the more I like your plasticity concept. I think the concept works for PPMS very well. My diagnosis goes back six months, my neurological symptoms go back 5 years, my unususal sensitivity to heat and stiff walking goes back even farther. I was once told by an neurologist that my symptoms were too slow for MS and I had age related cervical radiculopathy. I think his thinking was flawed in more than one way! :)
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Re: Where does PPMS fit in the inflamm vs degen debate?

Postby Lyon » Mon Jul 23, 2007 8:22 pm

Smilingface wrote:but I wanted to throw out an idea. What do you think of the possibility that in PPMS the inflammatory episodes are so quick, they are not detectable?
Hi Smilingface,
At this point I want to go back to one of your recent posts because a similar situation, my wife's, is what caused me to so seriously consider the role of plasticity.

Consider that the different phases of MS (RRMS, SPMS, PPMS, PRMS, Benign and CIS) are man-made definitions and the reason for originally coining those phases was so that researchers have names to refer to situations they've noticed. We put too much emphasis on those definitions of the MS "phases". These phases don't really even exist except by human definition. The course of your disease is going to do whatever it feels like despite the phase that your neuro feels that it seems to fit.

What do you think of the possibility that in PPMS the inflammatory episodes are so quick, they are not detectable?
Alternatively, maybe exacerbations appeared at a rate plasticity is able to match and mask so that you went through the entire RRMS phase without even knowing it, until plasticity reached one of it's limits (in what really should be considered the SPMS "phase") causing you to notice symptoms, or odd things you'd noticed earlier got to the point that you sought diagnosis?

By definition, PPMS is nothing more than SPMS which isn't preceded by RRMS. Is it possible, maybe even likely, that PPMS is nothing more than people who've experienced a "silent" RRMS phase?

I also think there is good reason to believe that, CIS and PRMS are so rare and are so similar to RRMS and SPMS that they should also be explained away as quirky cases of either RRMS or SPMS.

Smilingface wrote:I have to confess, I sometimes lie awake at night trying to figure out how PPMS fits in the picture......
I'm sorry to hear that someone else has to endure this lost sleep obsession but I'm glad to be in such good company :lol: Keep up the interesting thought processes!

Bob
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Postby finn » Tue Jul 24, 2007 7:50 am

Bob,

Lyon wrote:Now to inject some logic to the situation...85% of people with MS are diagnosed with RRMS. 85% is such a high percentage that it's most logical to think of RRMS is the epitome of MS and what we consider the other phases are actually variants of RRMS.

Well, maybe it's time for me to do some quoting again. Dr. Giovannoni has stated that "RRMS and PPMS are the same disease" and "inflammation defines the clinical course of MS". Dr. Behan wrote in his well known paper five years ago that "PPMS is the prototype disease".

I'd suggest that our disease could always be called "progressive MS", a slowly progressive neurodegenerative process followed by demyelination. When there is inflammation present in our CNS, the progression of neurodegeneration (and permanent disability) is slower, and the disease can be called RRMS (or SPMS).

Lyon wrote:So.....you are going to add another diamond and “simultaneous two-component” to your list?

Most likely there is an unknown relationship between the two of them, but I'd say the option is more or less covered when stated that "Inflammation and neurodegeneration are seperate and independent processes".

-finn

Btw, I have decided to quit using smileys and give people an opportunity to interpret my posts just the way they want. I'd like to serve my humour dry.
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