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 » Mon May 12, 2008 9:00 am

dignan,
thanks for sharing the abstract with the rest of us. I found its subject very interesting. By coincidence, a dear friend of mine sent me the full article of the same study few days ago, and thus gave me a good reason to visit this thread again.
dignan wrote:I think this abstract sounds interesting, although it would be more interesting if we could read the whole article...
Well, basicly the abstract says it all. According to the researchers metabolic dysfunction in oligodendrocytes might be able to cause both axonal degeneration and focal inflammation. If that was the case, oligodendrocyte apoptosis and axonal degeneration would be the primary processes in MS, and inflammation would cause only "collateral damage".

Anyway, here's a short quote from the article:
    Conclusion
    Recent findings have initiated a possible shift of paradigms, with inflammatory demyelination not only being caused by ‘primary’ immune defects, which is of obvious relevance to MS. Investigating the driving force behind inflammatory changes in the white matter, making use of novel mouse models with a primary defect in glial cell function and metabolism, will be a necessary next step. It is possible that an entire spectrum of inflammatory demyelinating diseases exist, in which multifocal white matter lesions (including classical MS lesions) reveal a final common pathway in brain pathology and the intrinsic susceptibility of oligodendrocytes to stimulate a local immune response. Alterations of lipid metabolism may play a key role.
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 dignan » Mon May 12, 2008 9:12 am

Finn, thanks for the update. It feels like these researchers could be on to something. It just seems more likely that something is actually causing inflamation and not that the inflamatory mechanisms are malfunctioning. That's just my uninformed opinion though.
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Postby bromley » Mon May 12, 2008 10:04 am

Finn,

The UK MS Society website has an article by Professor Alan Thompson about the last 10 years and MS (you can listen to Prof Thompson or read the transcript). One of the interesting bits from the article was:

"We have begun to understand how axons (nerve fibres) may be
damaged in MS, which is very important because disability and
progression in MS are thought to be associated with the loss of
axons. Scientists have been able to appreciate the extent of ‘diffuse’
or more generalised damage to nerve fibres in the central nervous
system in people who have MS. This is damage that extends beyond
the MS scars or lesions to areas of the brain that had appeared
unaffected."


So there is now a recognition that the focal inflammation (the inflammatory lesions that can be seen by MRI) is only part of the puzzle. The same website also includes some interviews with the researchers who presented at the MS Life conference. One of the interviews is with Dr Coles who, at the end of his interview, says that oligodendrocytes must be protected (in addition to stopping the immune attack and having neuro-protective agents). I suppose the next step is for the researchers to work out what is happening to the oligodendrocytes in MS brains and what is causing it.

Ian
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MS: Immune or Neurodegenerative Disease?

Postby Shayk » Thu Jun 19, 2008 7:04 pm

Hi Finn (and all)

I've been remiss in posting info that probably belongs in this thread but the simple title of this one definitely belongs here.

Yet another noted MS researcher, Bruce Trapp from the Cleveland Clinic, is at least asking the question you asked several years ago Finn.

Multiple sclerosis: an immune or neurodegenerative disorder?
We question whether inflammatory demyelination is primary or secondary in the disease process

The other author, Nave, was an author of the abstract/article mentioned earlier in the thread hypothesizing that dysfunctions in oligodendrocytes might trigger the inflammatory response.

One of these days we just might know what kind of disease MS actually is. 8)

Sharon
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Postby dignan » Thu Jun 19, 2008 9:18 pm

Sharon, that's uncanny, I was just looking at that abstract and thinking about this thread too! I was hoping I could dig up the actual article, but it's not freely available. Perhaps somebody with access can give us the low-down...
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Postby jimmylegs » Fri Jun 20, 2008 6:36 am

i have the pdf, but no time to read it right now. will report if no-one else has by the time i get back! or pm me.
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Postby dignan » Sat Oct 04, 2008 10:09 am

I don't think the authors are saying much that's new, but I find their explanation to be accessible.


Multiple sclerosis: a degenerative disease?
Article in French

Bull Acad Natl Med. 2008 Mar;192(3)
Confavreux C, Vukusic S.
Service de Neurologie A et Centre de Coordination EDMUS sur la sclérose en plaques, INSERM Unité 842, Hospices Civils de Lyon, Université Lyon 1, Hôpital Neurologique Pierre Wertheimer, 59 boulevard Pinel, 69677 Lyon-Bron. christian.confavreux@chu-lyon.fr

Multiple sclerosis (MS) is an organ-specific autoimmune disease targeting central nervous system myelin. The clinical course results from an interplay between relapses and progression. Relapses are the clinical counterpart of acute focal inflammation of the central nervous system, whereas progression is due to chronic diffuse neurodegeneration. According to the autoimmune theory, successive clinical and especially subclinical relapses eventually lead to irreversible disability, while the accumulation of focal lesions explains the diffuse neurodegeneration.

Things are not that simple, however. Relapses are not the main contributor to irreversible disability, as shown both in individual patients and at the population level. Likewise, MRI studies show that focal lesions are not entirely responsible for the diffuse neurodegeneration. Relapse prevention with disease-modifying drugs does not markedly influence the onset of irreversible disability or the progression of cerebral atrophy. In fact, acute inflammatory focal lesions and relapses may be the "tree that hides the forest".

Indeed, clinical progression and chronic diffuse neurodegeneration both play a key role, developing independently of relapses and focal lesions. Should MS therefore be considered a primary degenerative disorder rather than a primary autoimmune disease?

Not yet: recent pathological studies clearly demonstrate the presence of disseminated activated microglial-like inflammatory cells in the central nervous system. These could lead to a deleterious inflammatory process, even if not specifically autoimmune, unlike the inflammation occurring in acute lesions. If this pathogenetic picture of the disease is correct, then it has implications for therapeutic strategies. Indeed, treating the acute focal inflammation, as we successfully do nowadays, will not be enough. It will also be necessary to extinguish the slow-burning diffuse inflammation nested in the central nervous system behind the blood-brain barrier. This is the new therapeutic challenge in MS.

Pubmed link
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Postby Lyon » Sat Oct 04, 2008 7:11 pm

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Last edited by Lyon on Sun Nov 27, 2011 12:29 pm, edited 1 time in total.
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Postby dignan » Sun Mar 15, 2009 8:39 am

I refuse to let this thread die. To me, the case study below is a head scratcher: allogenic stem cell transplant, 100% of circulating leukocytes from the donor, but MS disease activity was still there.


Continued disease activity in a patient with multiple sclerosis after allogeneic hematopoietic cell transplantation.

Arch Neurol. 2009 Jan;66(1):116-20.
Lu JQ, Storek J, Metz L, Yong VW, Stevens AM, Nash RA, Joseph JT.
Department of Pathology, Foothills Medical Centre, University of Calgary, 1403 29th St NW, Calgary, Alberta T2N 2T9, Canada.

OBJECTIVE: To examine the effect of allogeneic hematopoietic cell transplantation (HCT) on disease activity in a patient with multiple sclerosis (MS).

DESIGN: Case report, prospective study, and autopsy.

SETTING: Departments of Clinical Neurosciences, Internal Medicine, and Pathology at the University of Calgary, Alberta, Canada.

PATIENT: A 39-year-old woman with chronic myelogenous leukemia and concurrent mild MS.

INTERVENTIONS: Hematopoietic cell transplantation from a healthy unrelated donor.

RESULTS: After HCT the patient developed graft-vs-host disease and experienced worsening, but not new, neurological symptoms. Her circulating leukocytes were 100% of donor origin. Magnetic resonance imaging showed increased lesion burden. She died of adenovirus hepatitis 20 weeks after HCT. An autopsy revealed demyelinating-inflammatory activity in active lesions and chronic active lesions.

CONCLUSION: Despite high-dose, cytotoxic, immunosuppressive therapy and exchange of a presumed autoreactive immune system with a healthy immune system, MS in this patient continued to be active.

http://www.ncbi.nlm.nih.gov/pubmed/19139309
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Postby Lyon » Sun Mar 15, 2009 9:52 am

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Last edited by Lyon on Sat Nov 26, 2011 2:57 pm, edited 1 time in total.
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Postby cheerleader » Sun Mar 15, 2009 9:55 am

CONCLUSION: Despite high-dose, cytotoxic, immunosuppressive therapy and exchange of a presumed autoreactive immune system with a healthy immune system, MS in this patient continued to be active.


thanks, dignan.
1.for not letting this thread die. (Finn, many of us agree with you!!!)
2.for being such a tireless researcher.
One way to view this might be that stenoses in various venous pathways persisted in this poor woman, despite receiving an entire new immune system. Possibly, venous reflux continued, inflammation continued, her MS progressed. (For further info on this paradigm, read the CCVI thread)

I am now looking into the connection between hepatic venous disease and MS, and will have more to come. I've always been curious as to why specifically liver transplants seem to help patients with MS. It has been posited that it was immune ablation. But not here. Her MS progressed, and she died from a virus. More to come-
No research is "valueless"- anecdotal, OK-
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dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby Hub » Sun Mar 15, 2009 10:49 am

finn wrote:Well, basicly the abstract says it all. According to the researchers metabolic dysfunction in oligodendrocytes might be able to cause both axonal degeneration and focal inflammation. If that was the case, oligodendrocyte apoptosis and axonal degeneration would be the primary processes in MS, and inflammation would cause only "collateral damage".


It seems that the issue of metabolic dysfunction in oligodendrocytes is still a hot one. Here's a blurp on Google's search engine from a March 25, 2008 article in Neurology titled "Myelin, mitochondria, and autoimmunity: What's the connection?":

Thus, there is good evidence that a metabolic injury to oligodendrocytes and myelin turnover may depend on mitochondrial dysfunction


Unfortunately, there's no abstract available.

For those interested in the possible connection between mitochondrial dysfunction and MS, I recommend watching the following presentation by Dr. Terry Wahls:


http://www.int-med.uiowa.edu/Media/Wahls10-6-08/Wahls10-6-08.html

Also, Ashton Embry is incorporating Dr. Wahl's protocol into his BBD recommendations:

http://www.msrc.co.uk/index.cfm?fuseaction=show&pageid=2471
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Postby jimmylegs » Sun Mar 15, 2009 11:09 am

all kinds of important things happen in a healthy liver, including d3 hydroxylation to 25(OH)d3, and conversion of ammonia (from amino acid breakdown) to uric acid (which requires adequate zinc).
here's a bunch of stuff. with tie in for LC. i think i also posted some relevant trace element links to venous insufficiency on the ccvi thread.

To investigate the effect of trace element concentrations in liver disorders, we conducted tests comparing the concentrations of trace elements among patients at various stages of chronic liver disease, and found a significant correlation between trace element metabolism and disease presence and progression. There is also a correlation between serum trace element concentrations and metalloprotein concentrations in the body, imbalances in which play a role in chronic liver disease. Excess or deficiency can be rectified for improvement of chronic liver disease. Because trace element concentrations are markers of oxidative stress levels in the liver, analysis of the concentrations can also be used for diagnosis of liver disease as well as indicating the effectiveness of antioxidant therapy.

The association between liver cirrhosis and variations of glucose tolerance has been extensively documented and discussed. Zinc is an essential trace element necessary for normal protein metabolism, for the function of more than 200 zinc metalloenzymes, and for a host of physiologic functions. A poor zinc status is common in both liver cirrhosis and diabetes mellitus. Many of the clinical features of liver cirrhosis and diabetes mellitus have been linked to zinc deficiency. Zinc supplementation improved in patients with liver cirrhosis and hepatic encephalopathy with and without diabetes mellitus neurological symptoms and signs of malnutrition. Furthermore, zinc supplementation increased glucose disposal.
Summarising these facts, we hypothesise that zinc deficiency is a link between liver cirrhosis and the “liver” diabetes mellitus.

Organisms that cannot easily and quickly remove ammonia usually have to convert it to some other substance, like urea or uric acid, which are much less toxic. Insufficiency of the urea cycle occurs in some genetic disorders (inborn errors of metabolism), and in liver failure. The result of liver failure is accumulation of nitrogenous waste, mainly ammonia, which leads to hepatic encephalopathy.

In North America, suboptimal zinc status is more common than once realized. ...marginal zinc deficiency increased the susceptibility to LPS-induced liver injury in rats. These results indicate that patients with sepsis who have suboptimal zinc nutrition status may be at higher risk of developing greater liver damage.

The total soluble ammonia level in a healthy adult with 5 L of circulating blood is only 150 mcg, in contrast to approximately 1000 mg of urea nitrogen present. Because urea is the end product of ammonia metabolism, the disparity in blood quantities of the substrate and product illustrates the following 2 principles:
* The CNS is protected from the toxic effects of free ammonia.
* The metabolic conversion system that leads to production of urea is highly efficient.

The serum zinc levels were inversely correlated with blood ammonia in the fasting state.

Zinc deficiency is common in patients with end-stage liver disease but its prevalence and resolution in liver transplant recipients has not been reported. We hypothesized that with normalization of liver function after transplant, zinc levels should rapidly return to normal, obviating the need for oral supplementation... Thirty-two of the 34 patients (94%) had a zinc level in the subnormal range. There were no differences in zinc levels between patients with alcoholic and non-alcoholic liver failure, males versus females, UNOS status (low = status 1 and 2, high = 3 and 4), pre-transplant use of TIPS nor correlation between age and zinc level. All 22 patients who had a post-transplant zinc level demonstrated an increase from 40.1±9.7 μg/dl to 68.5±14.1 μg/dl (p≤0.0001, paired t-test). Our findings indicate that zinc deficiency, generally profound, should be assumed to be present in every patient with end-stage liver disease awaiting transplant... Following transplantation, zinc levels rapidly recover, obviating the need for checking levels and oral supplementation.
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Postby cheerleader » Sun Mar 15, 2009 12:10 pm

Here's a recent study with immune ablation, autologous stem cell, and yet continued lymphocyte activation (related to inflammation)...8 patients
http://www.ncbi.nlm.nih.gov/pubmed/18223013

Bone-marrow transplantation fails to halt intrathecal lymphocyte activation in multiple sclerosis.

Mondria T, Lamers CH, te Boekhorst PA, Gratama JW, Hintzen RQ.
Department of Neurology, Erasmus University Medical School, Erasmus MC, 3000 CA Rotterdam, The Netherlands.
BACKGROUND: Given the presumed key role for autoreactive lymphocytes in multiple sclerosis (MS), treatment strategies have been developed to ablate lymphocyte activity. Intrathecal lymphocyte activation can be measured by CSF-soluble(s)CD27. OBJECTIVE: To determine the effect of maximum whole-body immune ablation on two different markers that detect lymphocyte activation in CSF-oligoclonal IgG bands and levels of CSF-sCD27. Design, setting and PATIENTS: The study quantified sCD27 levels and assessed the presence of oligoclonal IgG bands in CSF samples of secondary progressive patients with MS treated by autologous bone-marrow transplantation. In eight individuals, CSF was taken before and 6-9 months after conditioning. CSF-sCD27 levels were compared with other MS and non-inflammatory neurological disease controls. Regarding the effect of stem-cell transplantation on CSF oligoclonal bands, the study analysed pooled data of this and four other international studies on stem-cell transplantation in MS. RESULTS: CSF-sCD27 was significantly lower after the extremely immunoablative protocol. However, levels remained elevated compared with non-inflammatory controls and stayed within the range observed in other MS controls. The joint analysis of CSF oligoclonal bands demonstrated persistence of this immune abnormality in 88% of the reported cases (n = 34). CONCLUSIONS: The persistence of CSF lymphocyte activation markers sCD27 and intrathecal oligoclonal IgG bands after maximum immunoablative treatment indicates that complete eradication of activated lymphocytes from the CNS has not been established. This is paralleled by disease progression observed in several studies on the effect of stem-cell transplantation in MS.


Jimmy-thanks so much for the liver info...let's start up a new thread in general real soon, OK?
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Postby jimmylegs » Sun Mar 15, 2009 12:53 pm

it's a date cheer.
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