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 » Sun Jul 15, 2007 12:37 am

Bob,
Lyon wrote:One of my wife's uncle's was a finn and one of the nicest guys I've ever known, so I'm confident that all Finns aren't asses.
I really don't understand what you're trying to say. You wrote that COB frustrates you. Well, sometimes I can definitely say the same about you.
Lyon wrote:Lighten up! This is a discussion board where things are questioned and challenged and at that point I wasn't doing either, I was trying to understand exactly what you meant.
Of course I should have realized by now that we probably have a complitely different sense of irony, but I won't start using more smileys just because of you.
Lyon wrote:the simplest and most likely scenario is that the myelin is attacked first and therein lies my opinion.
Then I suppose you're willing and able to explain why researchers have found axonal loss inside healthy myelin?

COB,
thanks for putting this thread back on its tracks.

-finn
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
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Postby CureOrBust » Sun Jul 15, 2007 12:56 am

Finn, glad to help, especially if its while I stumble..

Lyon, ok already...

Lyon, ok already...
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Postby bromley » Sun Jul 15, 2007 1:27 am

Finn,

I've got my sensible hat on this morning. The first two links are to summaries of presentations at an MS conference in June. The second suggests that a protein on axons might be the target of the immune response.

The third link is to Dr Coles. Campath 1-H is very good at dampening down inflammation. For those at the RR stage - there has also been a reduction in disability. Dr Coles speculates that this might be because of an increase in neurotrophins. I know that they have take blood from people who have received Campath 1-H and poured it on rat neurons and the neurons have grown.

Inflammation in MS has been viewed as a double-edged sword - destroying invaders (and sometimes our own tissue becomes collateral damage) and promoting repair (signalling to myelin making cells where to come to in the CNS). I'm assuming that although Campath knocks down the T and B cells, the inflammation which encourages repair is not totally irradicated.

Ian


http://www.mssociety.org.uk/go.rm?id=20354

http://www.mssociety.org.uk/go.rm?id=20355

http://www.neuroscience.cam.ac.uk/direc ... php?Alcool
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Postby finn » Sun Jul 15, 2007 2:13 am

Ian,

if EAE and MS were similar diseases we would have been cured already. Quotes from your links:

"Prof Perry used disease models to look at some of the factors which may be involved in tissue damage and subsequent disease progression during the relapsing remitting phase of the disease."

"Prof Linington’s studies show that the neurofascin on the axon is a primary target of the immune attack in disease models of MS and that these proteins accelerate disease progression and increase its severity. If this process is mimicked in humans, therapies which removed the antibodies which attack neurofascin could offer protection from disease progression."


And what comes to Campath, we'll just have to wait and see how well it works. I'm still far from changing my opinion, but I'm ready to eat my words anytime if it really stops this disease and we can focus on enjoying our lives instead of posting here.

-finn

btw, please, learn how to use shorter links ("hotlinks" or TinyURLs)
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
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Postby bromley » Sun Jul 15, 2007 3:50 am

Finn,

I only post what I see - unfortunately, many researchers still use animal models. You have also posted extracts based on animal models:

Some time ago Sharon posted an abstract of a study by Tsunoda and Fujinami where they showed in an animal model that axonal degeneration can trigger demyelination (the link is already in this thread somewhere).


At least with therapies such as Campath, the researchers are looking at human guinea pigs. They take lots of blood from me and I've had lots of MRIs.

I will also be interested in the results of the Lamotrigine trials as this therapy will hopefully provide some benefit if MS is (i) an inflammatory disease which is then followed by neuro-degeneration or (ii) a neuro-degenerative disease which is followed by inflammation or (ii) both at the same time!

I'm still attracted to the notion of MS being caused by a virus (perhaps EBV). This might explain (i) the so called outbreaks of MS (ii) the age at which may are diagnosed with MS. Whether a virus causes stress on the neurones / axons which leads to degeneration or the immune system gets involved because it recognises there is a virus in the CNS is a matter for debate. I'm hoping that Prof Giovononni may be able to answer this in the near future.

Ian
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Postby Lyon » Sun Jul 15, 2007 4:18 am

finn wrote:I really don't understand what you're trying to say. You wrote that COB frustrates you. Well, sometimes I can definitely say the same about you.
Geez, talk about being misinterpreted. I was simply saying that I've always been fond of Finns because, statistically, the percentage who are asses is very low.
finn wrote:Then I suppose you're willing and able to explain why researchers have found axonal loss inside healthy myelin?
I suppose it's about time I read Harry's Z's favorite bedtime story, Prineas and Barnett's "Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion". Are you aware of any other research on the face of the earth which seems to confirm "axonal loss inside healthy myelin"?
finn wrote:Lyon,
thanks for putting this thread back on its tracks.
If you'll scroll about halfway down the past page you'll notice that I put the thread back on its tracks. I'm glad to see that we're on good terms again, and you're more than welcome :lol:
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Postby finn » Sun Jul 15, 2007 4:43 am

Ian,
bromley wrote:I only post what I see - unfortunately, many researchers still use animal models. You have also posted extracts based on animal models:

Some time ago Sharon posted an abstract of a study by Tsunoda and Fujinami where they showed in an animal model that axonal degeneration can trigger demyelination (the link is already in this thread somewhere).
you didn't disappoint me, I thought you might refer to that study. I'm afraid you can't really compare it to standard EAE-studies. With a virus induced CNS dysfunction Tsunoda and Fujinami just showed that axonal degeneration can trigger demyelination. I believe you understand that the outcome was far from EAE, which is an inflammatory demyelinating animal model.

Btw, I use Firefox and the long link in your previous post really messes up the page layout and makes it quite difficult to read. It would be nice if you could make the link shorter.

Bob,
Lyon wrote:Are you aware of any other research on the face of the earth which seems to confirm "axonal loss inside healthy myelin"?
yes, I am. And after all that time spent on this board you should be, too.

-finn
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Postby Lyon » Sun Jul 15, 2007 4:49 am

finn wrote:Bob,
Lyon wrote:Are you aware of any other research on the face of the earth which seems to confirm "axonal loss inside healthy myelin"?
yes, I am. And after all that time spent on this board you should be, too. :lol:

-finn
Yes, a smiley face, much better! I guess my first, second, third,etc.... impression of you was wrong!

Admittedly I haven't read the article yet but just now finished downloading it and comments but Prineas and Barnett's reply to Professor Pender's comment seemed worthy of note
As noted by Professor Pender, however, our
results do not rule out antibody or other humoral factors as
effectors of oligodendrocyte apoptosis in early MS lesions.
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Postby bromley » Sun Jul 15, 2007 5:11 am

Finn,

You're getting grumpy in your old age - moaning about the length of my links!

The following should keep you off the Vodka for a couple of months. ECTRIMS is taking place in October 2007. Two presentations which may interest you are:

Friday 12 October 2007. MS - a neuronal disease? F. Zipp.

Sunday 12 October 2007. Charcot Award Lecture (MSIF):
“A peculiar lesion in the cord with atrophy” – Is multiple sclerosis an inflammatory or neurodegenerative disease? A. Compston (Cambridge, UK)

I'm off to enjoy the rest of a very bad (wet) summer in the UK. I'll return in the autumn after ECTRIMS.

Glad you and Lyon are getting on again.

Ian
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Postby Lyon » Sun Jul 15, 2007 7:19 am

Hi finn,
As I suppose you would expect, after reading "Relapsing and Remitting Multiple Sclerosis:Pathology
of the Newly Forming Lesion" I tend to agree with the subsequent responses by Lucchinetti
et al and Pender.

I am glad to have finally read the holy grail of the "non-autoimmune", "primary axon attack,
secondary myelin attack" crowd.

With it in mind that Prineas and Barnett's study was based on 12 subjects, I include the Lucchinetti
et al's response.
Bob


Evidence for Pathogenic Heterogeneity in Multiple
Sclerosis
Claudia F. Lucchinetti, MD,1 Wolfgang Bruck, MD,2
and Hans Lassmann, MD3
Barnett and Prineas recently described extensive oligodendrocyte
apoptosis in the absence of inflammation in a pediatric
multiple sclerosis (MS) case, who died 9 months after disease
onset and 17 hours after presenting with acute pulmonary
edema.1 To what extent perimotem hypoxia may in part
have contributed to the pathological observations in this case
is uncertain. The authors confirm our published reports on
aspects of pattern III MS pathology in a subset of MS patients,
2 however, indicate that the coexistence of remyelinating
lesions and complement activation in other lesions from
this and six other patients suggest that all MS lesions begin
with this type of pathology.
In our experience of 201 immunopathologically classified
MS cases to date,2,3 pattern III MS demonstrates inflammatory
lesions with a preferential loss of myelin associated glycoprotein
(MAG), apoptotic oligodendrocytes, limited remyelination,
and ill-defined inflammatory lesion borders. When
analyzing multiple active lesions in pattern III autopsy cases,
we have not found evidence of complement activation by
using the monoclonal antibody against C9neo antigen. Although
apoptosis is occasionally found in pattern II cases,
this is not associated with MAG loss. In addition, the authors
have not stained their cases for MAG. Furthermore, a
subset of pattern III cases in our series also had Balo-type
concentric lesions, with ongoing remyelination, which is
consistent with the presence of remyelination as described by
Barnett and Prineas.
Detailed clinical follow-up of our early MS cohort (n 
99 patients) fails to show any correlation between time of
symptom onset, date of biopsy, and pathological pattern,
thus arguing against all MS lesions beginning with pattern
III pathology.4 In addition, we have observed a striking correlation
between therapeutic response to plasma exchange in
MS patients with evidence for antibody and complement activation
(pattern II pathology, n  10) on biopsy, versus no
response in pattern I (n  3) or pattern III (n  6) cases.5
The sharp border at the active plaque edge with accumulating
macrophages in pattern I and II MS lesions is highly
associated with the presence of ring enhancement on Gd-
MRI, and hypointense T2 rims, whereas these imaging features
are not found in pattern III lesions ( p  0.001; 54
cases examined). Furthermore, on follow-up MRI, we have
not observed ring enhancing lesions in any pattern III case
(n  11).6
Our pathological and clinical observations on a large series
of MS cases continue to support pathogenic heterogeneity in
immune effector mechanisms involved in MS lesion formation,
which persist over a period of time, rather than a single
mechanism dominating the formation of all lesions as suggested
by the authors.
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Postby finn » Sun Jul 15, 2007 7:54 am

Ian,
I visited PubMed just to see what school of thoughts Zipp and Compston represent. After seeing the studies they've done I wouldn't be surprised if they both would argue that "MS is a inlammatory demyelinating disease with a neurodegenerative component".

Anyway, enough of this now. Enjoy the rest of the summer!

Btw, if you'd give it try, you might be amazed how easy it is to make the link shorter.


Bob,
Lyon wrote:Admittedly I haven't read the article yet but just now finished downloading it and comments but Prineas and Barnett's reply to Professor Pender's comment seemed worthy of note

I haven't read the whole article, either. Actually, to me one of the authors makes more difference than the text itself. John Prineas has been a respected figure in the "autoimmune camp", and his controversial paper finally opened the door to new and more innovative thinking amongst some other researchers, too.

Lyon wrote:...I tend to agree with the subsequent responses by Lucchinetti et al and Pender.

Well, more recently Lucchinetti has been a cowriter in a study where you can find these quotes:
  • "a primarily gray matter related process may be the earliest manifestation of MS"
  • "Gray matter involvement is associated with physical disability, fatigue, and cognitive impairment in MS"
  • "Gray matter disease might help explain the observed dissociation between markers of inflammatory demyelination (relapses, white matter gadolinium enhancement, white matter lesion burden) and disease progression."
  • "Early cortical involvement seen on imaging studies raises the intriguing possibility that the GM may represent the primary and initial target of the disease process, leading to axonal degeneration and subsequent demyelination (the “inside-out” model of MS)."
  • "One of the most important questions regarding GM involvement is whether it is a consequence of WM demyelination with secondary axonal damage leading to neuronal loss in GM structures or whether the GM, in particular neurons, are a direct target of the disease process."
  • "Emerging histopathologic and neuroimaging studies support the concept that GM pathology occurs in part independently of WM lesions and may precede WM pathology."
  • "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."

-finn
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Postby Lyon » Sun Jul 15, 2007 8:17 am

Hi finn,

I may disagree with your interpretation sometimes but there isn't much room to doubt your knowledge and awareness.

Thanks for the link. I won't have time to read that article today but I look forward to reading it soon.

I'm not sure how to force this thread into the next page.

Bob
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Postby dignan » Sun Jul 15, 2007 9:52 am

Finn,

That's interesting stuff on gray matter from Lucchinetti et al.
I just noticed this related abstract (which was posted by Raven over 2 years ago, yet was just published 2 months ago).
Interferons aren't great MS treatments, but maybe their impacts on gray matter degeneration are significant.

I'll try to space this out to move us to a new page...




Interferon beta-1a slows progression of brain atrophy in
relapsing-remitting multiple sclerosis predominantly by reducing gray matter atrophy


R. Zivadinov - 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

L. Locatelli - Department of Clinical Medicine and Neurology, University of
Trieste, Trieste, Italy

D. Cookfair - Department of Neurology, Buffalo Neuroimaging Analysis
Center, The Jacobs Neurological Institute, University at Buffalo, State
University of New York, Buffalo, NY, USA

B. Srinivasaraghavan - Department of Neurology, Buffalo Neuroimaging
Analysis Center, The Jacobs Neurological Institute, University at Buffalo,
State University of New York, Buffalo, NY, USA

A. Bertolotto - Centro Riferimento Regionale Sclerosi Multipla (CReSM)
and Laboratori di Neurobiologia Clinica, Ospedale Universitario San Luigi,
Orbassano, Italy

M. Ukmar - Department of Clinical, Morphological and Technological
Sciences, University of Trieste, Trieste, Italy

A. Bratina - Department of Clinical Medicine and Neurology, University of
Trieste, Trieste, Italy

C. Maggiore - Department of Clinical Medicine and Neurology, University
of Trieste, Trieste, Italy

A. Bosco - Department of Clinical Medicine and Neurology, University of
Trieste, Trieste, Italy

A. Grop - Department of Neurology, Buffalo Neuroimaging Analysis
Center, The Jacobs Neurological Institute, University at Buffalo, State
University of New York, Buffalo, NY, USA

M. Catalan - Department of Clinical Medicine and Neurology, University of
Trieste, Trieste, Italy

M. Zorzon - Department of Clinical Medicine and Neurology, University of
Trieste, Trieste, Italy

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
ß-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 ß-1a
treatment group (IFN ß-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 ß-1a treatment group,
and P<0.001 for the control group), a significant within-patient decrease
in WMF for the IFN ß-1a treatment group (P=0.01), and a significant
decrease in GMF for the control group (P=0.013) when compared with
baseline.

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

http://msj.sagepub.com/cgi/content/abstract/13/4/490
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Postby finn » Tue Jul 17, 2007 5:17 am

Bob, Dignan,
I appreciate your efforts, but I assume it's the number, not the length of posts that will take us to the next page. Luckily the link in Ian's post is shorter now, and this page looks good on Firefox again.

Dignan,
thanks for sharing another interesting study. According to it there might be a weak correlation between T1-lesion volumes (T1-LVs) and gray matter fraction (GMF). Between treatment and control group there was a 100.9% difference in the mean percent change in T1-LV (-9.3 versus +91.6%) and 1.6% difference in the mean percent change in GMF (+0.2 versus -1.4%).

-finn
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Postby Lyon » Tue Jul 17, 2007 5:44 am

Not to discredit the article dignan supplied because I do think it was interesting. Not at all specific to this article it's often discouraging to read the financial disclosures at the end. 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.

We acknowledge the support of Pietro Iraci of
Dompe´ Biotec SpA, Italy, for logistic help in testing
for neutralizing antibodies in patients treated with
IFN b-1a IM (Avonex†). We thank Sabrina Maurer,
PharmD, of Thomson Scientific Connexions, Newtown,
PA, USA, for her technical support in thepreparation of this manuscript. Conflict of interest:
This investigator-initiated study was performed
without specific funding support. Dr Zivadinov
received personal compensation from Biogen Idec,
Teva Neuroscience, Pfizer, and Dompe´ Biotec for
speaking fees. Dr Zivadinov received financial support
for research activities from Biogen Idec, Teva
Neuroscience, Pfizer, Serono, Aspreva, National
Science Foundation, National Multiple Sclerosis
Society, National Institute of Health, Physicians
Imaging Center, Kaleida Health, Oishei Foundation,
and Jog for the Jake Foundation. Dr Bertolotto
received personal compensation from Teva Aventis,
Serono, Biogen Idec, and Dompe´ Biotec for speaking
fees. Dr Bertolotto received financial support
for research activities from Serono, Teva Aventis,
Serono, Biogen Idec, and Dompe´ Biotec. Drs Zorzon,
Bosco, Ukmar, Locatelli, Bratina, Maggiore,
Catalan, as well as Mr Grop and Ms Srinivasaraghavan
have nothing to disclose.



Thanks for the link to that other Lucchinetti you provided finn. It was very interesting and one of the most disheartening articles I've read recently, in that it seems that MS damage might be quite a bit more extensive upon diagnosis and affect far more aspects of the brain than I was formerly aware of.

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.
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