PPMS can be passed to mice by CSF. IS PPMS DIFFERENT?

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PPMS can be passed to mice by CSF. IS PPMS DIFFERENT?

Postby frodo » Sat Dec 27, 2014 5:23 pm

What do you think about this article? Is PPMS a different disease that RRMS/SPMS? Does it have an immune or chemical origin?

If this article is confirmed, I think we are in front of the major discovery in MS since CCSVI. The authors took CSF from PPMS patients and injected it into mice. They developed lesions while the CSF from RRMS patients had mostly no effect.

Progressive multiple sclerosis cerebrospinal fluid induces inflammatory demyelination, axonal loss, and astrogliosis in mice.

http://www.ncbi.nlm.nih.gov/pubmed/25111532

Abstract

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination and neurodegeneration throughout the CNS, which lead over time to a condition of irreversible functional decline known as progressive MS. Currently, there are no satisfactory treatments for this condition because the mechanisms that underlie disease progression are not well understood. This is partly due to the lack of a specific animal model that represents progressive MS.

We investigated the effects of intracerebroventricular injections of cerebrospinal fluid (CSF) derived from untreated primary progressive (PPMS), secondary progressive (SPMS), and relapsing/remitting (RRMS) MS patients into mice. We found discrete inflammatory demyelinating lesions containing macrophages, B cell and T cell infiltrates in the brains of animals injected with CSF from patients with progressive MS. These lesions were rarely found in animals injected with RRMS-CSF and never in those treated with control-CSF. Animals that developed brain lesions also presented extensive inflammation in their spinal cord. However, discrete spinal cord lesions were rare and only seen in animals injected with PPMS-CSF.

Axonal loss and astrogliosis were seen within the lesions following the initial demyelination. In addition, Th17 cell activity was enhanced in the CNS and in lymph nodes of progressive MS-CSF injected animals compared to controls. Furthermore, CSF derived from MS patients who were clinically stable following therapy had greatly diminished capacity to induce CNS lesions in mice. Finally, we provided evidence suggesting that differential expression of pro-inflammatory cytokines present in the progressive MS CSF might be involved in the observed mouse pathology. Our data suggests that the agent(s) responsible for the demyelination and neurodegeneration characteristic of progressive MS is present in patient CSF and is amenable to further characterization in experimental models of the disease.

Note: I have edited the title. I didn't like the first one.
Last edited by frodo on Tue Dec 30, 2014 7:59 am, edited 2 times in total.
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Re: WHAT DO YOU THINK ABOUT THIS ARTICLE? IS PPMS DIFFERENT?

Postby Brainteaser » Sat Dec 27, 2014 7:57 pm

So if this is true, they should be able to do drug/other testing on mice infected with PPMS-CSF to help solve the PPMS dilemma?
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Re: WHAT DO YOU THINK ABOUT THIS ARTICLE? IS PPMS DIFFERENT?

Postby 1eye » Sun Dec 28, 2014 1:17 pm

The question in my mind is: what happens when you stop? Does it take normal CSF, time, or will the animals ever get back losses?

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Re: WHAT DO YOU THINK ABOUT THIS ARTICLE? IS PPMS DIFFERENT?

Postby frodo » Tue Dec 30, 2014 6:18 am

Brainteaser wrote:So if this is true, they should be able to do drug/other testing on mice infected with PPMS-CSF to help solve the PPMS dilemma?


For sure it will be a much better model that the current EAE, which is not even similar to MS.

Anyway, the most important consequence for me is that maybe this subtype of MS can explain the CCSVI discrepancies between the clinical trials.
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Re: PPMS can be passed to mice by CSF. IS PPMS DIFFERENT?

Postby CarpeDiem2015 » Tue Dec 30, 2014 4:51 pm

The below paper appears to be related - same researchers at Tisch.

Cerebrospinal fluid derived from progressive multiple sclerosis patients induces demyelinating lesions in the mouse CNS

http://tischms.org/research/published/c ... ts-induces

"Finally, treating MS patients with disease modifying therapies appeared to eliminate from their CSF the power to induce CNS lesions in mice."

both were presented in November, 2013. I wonder what they have found out since then.
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Re: PPMS can be passed to mice by CSF. IS PPMS DIFFERENT?

Postby CarpeDiem2015 » Tue Dec 30, 2014 5:01 pm

PDF of the first paper noted by frodo.

Progressive multiple sclerosis cerebrospinal fluid induces inflammatory demyelination, axonal loss, and astrogliosis in mice.

http://multiplesclerosis.elsevierresour ... 5/main.pdf
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Re: PPMS can be passed to mice by CSF. IS PPMS DIFFERENT?

Postby 1eye » Thu Jan 01, 2015 2:45 am

I guess this is how it's going to be. People claiming to have licked the thing at least in mice, other people claiming to have found a cause in mice with interleukin 1-beta and p53. Lots of mouse models, lots of bad guys, but no silver bullets. No treatments in my lifetime. Well, it's officially shorter by a year, as of yesterday, anyway. I didn't expect to be any better at this age.
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Re: PPMS can be passed to mice by CSF. IS PPMS DIFFERENT?

Postby frodo » Fri Jan 02, 2015 11:53 am

1eye wrote:I guess this is how it's going to be. People claiming to have licked the thing at least in mice, other people claiming to have found a cause in mice with interleukin 1-beta and p53. Lots of mouse models, lots of bad guys, but no silver bullets. No treatments in my lifetime. Well, it's officially shorter by a year, as of yesterday, anyway. I didn't expect to be any better at this age.


In this case it seems that this research started around 2000!!! These are some previous related articles:

* Alcázar A1, Regidor I, Masjuan J, Salinas M, Alvarez-Cermeño JC. Axonal damage induced by cerebrospinal fluid from patients with relapsing-remitting multiple sclerosis, J Neuroimmunol. 2000 Apr 3;104(1):58-67.

* Alvarez-Cermeño JC1, Cid C, Regidor I, Masjuan J, Salinas-Aracil M, Alcázar-González A. The effect of cerebrospinal fluid on neurone culture: implications in the pathogenesis of multiple sclerosis. Rev Neurol. 2002 Nov 16-30;35(10):994-7.

* Cid C1, Alvarez-Cermeño JC, Camafeita E, Salinas M, Alcázar A. Antibodies reactive to heat shock protein 90 induce oligodendrocyte precursor cell death in culture. Implications for demyelination in multiple sclerosis FASEB J. 2004 Feb;18(2):409-11. Epub 2003 Dec 19.

* Tiwari-Woodruff SK1, Myers LW, Bronstein JM. Cerebrospinal fluid immunoglobulin G promotes oligodendrocyte progenitor cell migration. J Neurosci Res. 2004 Aug 1;77(3):363-6.

* Cristofanilli M1, Cymring B, Lu A, Rosenthal H, Sadiq SA. Cerebrospinal fluid derived from progressive multiple sclerosis patients promotes neuronal and oligodendroglial differentiation of human neural precursor cells in vitro, Neuroscience. 2013 Oct 10;250:614-21. doi: 10.1016/j.neuroscience.2013.07.022. Epub 2013 Jul 19.

*Oscar G. Vidaurre, Cerebrospinal fluid ceramides from patients with multiple sclerosis impair neuronal bioenergetics , DOI: http://dx.doi.org/10.1093/brain/awu139 First published online: 3 June 2014
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Re: PPMS can be passed to mice by CSF. IS PPMS DIFFERENT?

Postby David1949 » Fri Jan 02, 2015 9:43 pm

With regard to the question is PPMS a different disease than RRMS; In my opinion it is. I base this conclusion on the following differences between them.
1) The course of the two diseases is different.
2) The age of onset for RRMS is typically early 30's. For PPMS it is early 40's.
3) The distribution between the sexes is different. RRMS is 2-3 times more common in women than in men. But PPMS is as common in men as in women.

Now the results of this study demonstrate a 4th difference.
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Re: PPMS can be passed to mice by CSF. IS PPMS DIFFERENT?

Postby 1eye » Sat Jan 03, 2015 9:28 am

Ah, but is the course and onset of mouse-model-MS more prevalent in male mice than it is in female mice? Or less? Or About The Same (TM)?
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Re: PPMS can be passed to mice by CSF. IS PPMS DIFFERENT?

Postby frodo » Mon Jan 12, 2015 12:16 pm

More about CSF and possible autoantibodies or toxic agents:

SPAG16: an autoantibody target in CSF and plasma of MS patients

http://www.researchgate.net/profile/Lau ... 53956e.pdf

Ceramides C16:0 and C24:0

http://www.ncbi.nlm.nih.gov/pubmed/24893707

And some pictures of the CSF acting over a culture of neurons and producing apoptosis

http://www.ncbi.nlm.nih.gov/pmc/article ... re/d35e78/
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Re: PPMS can be passed to mice by CSF. IS PPMS DIFFERENT?

Postby 1eye » Fri Apr 10, 2015 2:06 pm

OK I'll stop being facetious. This seems to be a very significant discovery indeed. It should make the use of EAE (the MS mouse model) unnecessary, for the most part, and cause drug research to stop using it. Do spinal taps of MS patients to have great value after all?

The cause of MS should be within our grasp. Once the cause is known, a cure (if it exists) can be found.

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination and neurodegeneration throughout the CNS, which lead over time to a condition of irreversible functional decline known as progressive MS. Currently, there are no satisfactory treatments for this condition because the mechanisms that underlie
disease progression are not well understood. This is partly due to the lack of a specific animal model that represents
progressive MS
. We investigated the effects of intracerebroventricular injections of cerebrospinal fluid (CSF)
derived from untreated primary progressive (PPMS), secondary progressive (SPMS), and relapsing/remitting
(RRMS) MS patients into mice. We found discrete inflammatory demyelinating lesions containing macrophages,
B cell and T cell infiltrates in the brains of animals injected with CSF from patients with progressive MS. These
lesions were rarely found in animals injected with RRMS-CSF and never in those treated with control-CSF
. Animals
that developed brain lesions also presented extensive inflammation in their spinal cord. However, discrete spinal
cord lesions were rare and only seen in animals injected with PPMS-CSF
. Axonal loss and astrogliosis were seen
within the lesions following the initial demyelination. In addition, Th17 cell activity was enhanced in the CNS
and in lymph nodes of progressive MS-CSF injected animals compared to controls.
Furthermore, CSF derived
from MS patients who were clinically stable following therapy had greatly diminished capacity to induce CNS
lesions in mice
. Finally,we provided evidence suggesting that differential expression of pro-inflammatory cytokines
present in the progressive MS CSF might be involved
in the observed mouse pathology. Our data suggests that the
agent(s) responsible for the demyelination and neurodegeneration characteristic of progressive MS is present in
patient CSF and is amenable to further characterization in experimental models of the disease.


From the paper,
Demyelination precedes axonal loss and glial scar formation.


Progressive MS-CSF treatments altered the expression of immune-system
related genes in the mouse CNS
.


Progressive MS-CSF treatments enhanced Th17 cell activity in the mouse
CNS and in its periphery
.

CSF-induced brain lesions are drastically reduced by clinical treatment and
correlate with patient CSF levels of pro-inflammatory cytokines
.

Something got into the human CSF that caused MS in the mice. Not model MS. Real MS. MS is not contagious to mice, that we know of, though do we really know? It suggests to me an environmental cause.

MS seems to follow the CSF. Progression seems to be related to spinal lesions. MS seems to migrate from brain to spine. Spinal lesions are usually, but not always, found in progressive MS.

These results look to me like they suggest serious genetic involvement, which we already knew. But do genes only cause susceptibility, or are they the direct cause? Compare plain mouse DNA to MS-mouse DNA before and after? Compare MS-mouse DNA to MS-human DNA?

Something takes a while to migrate out of the brain, except in "PPMS" it's immediate. It seems to stop most remissions once it's out.

Do we have to keep using the term "irreversible"? Or are we just quitters?

Cross-posting this to the general discussion forum. There are a number of topics on this paper on TiMS. Perhaps they should be combined and moved there?
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Re: PPMS can be passed to mice by CSF. IS PPMS DIFFERENT?

Postby Cece » Sat Apr 11, 2015 6:24 am

I wonder if they could isolate it so that they used CSF from RRMS when people are not on DMDs and in active relapse -- would that be akin to the effect seen all the time with the CSF from PPMS?

Can this be used as a mouse model??? That alone would be an enormous breakthrough.
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Re: PPMS can be passed to mice by CSF. IS PPMS DIFFERENT?

Postby David1949 » Tue Apr 14, 2015 11:07 am

There is something else here that might be muddying up their results. From table 1 of the PDF file
http://multiplesclerosis.elsevierresource.com/system/files/articles/assets/S0014488614002489/505/main.pdf
you can see that the RR patients had an average disease duration of only 2.5 years. That is much less than the 13.83 years for the PPMS patients and the 21.7 years for SPMS patients. Further, the average EDSS score for the RRMS patients was only 0.88 vs 6.6 and 7.5 for the PPMS and SPMS groups respectively. So the RRMS group had the disease for much less time and had suffered much less disability. That may also be a factor in the results they obtained.
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Re: PPMS can be passed to mice by CSF. IS PPMS DIFFERENT?

Postby 1eye » Wed Apr 15, 2015 7:46 am

David1949 wrote:There is something else here that might be muddying up their results. From table 1 of the PDF file
http://multiplesclerosis.elsevierresource.com/system/files/articles/assets/S0014488614002489/505/main.pdf
you can see that the RR patients had an average disease duration of only 2.5 years. That is much less than the 13.83 years for the PPMS patients and the 21.7 years for SPMS patients. Further, the average EDSS score for the RRMS patients was only 0.88 vs 6.6 and 7.5 for the PPMS and SPMS groups respectively. So the RRMS group had the disease for much less time and had suffered much less disability. That may also be a factor in the results they obtained.


There are fundamental flaws in current thinking about MS. One is that there is any difference in the cause of MS, that has anything to do with these artificial actuarial distinctions, doctors have agreed to use, to group pwMS into RR, PP, SP, CIS, RMS, etc., etc. Divide and conquer. If we continue to believe in these made-up distinctions, we will never agree on a cause, and the disease will be with us forever. The divide-and-conquer strategy goes on: some people have "Benign MS". Some people have "Relapsing MS" with for some reason no "remissions". Some people have "Marburg MS". etc., etc. Yes, sometimes it progresses faster. That does not mean the disease is different. If I am honest, I have never had a "remission", though I was once treated for "relapsing-remitting". The "remissions" have never been complete, though sometimes I have been able to adapt so well that that I seemed symptom-free. Sometimes the symptoms have been so bad that they never reached that state. The brain, I believe, is capable, especially when you are young, of covering up losses by using native plasticity to retrain itself to use different neurons instead of the ones it used before, This is not remission, though it is called that. We have to stop renaming the disease to make it seem less intimidating. It is a trap. Some people just never adapt well enough to be called "remitting".

The other fundamental flaw is reinforcing the first mistake (that of thinking these different names we use means there are different causes) means that age is irrelevant. I am 61. I was diagnosed 18 years ago. It does not feel as if it is a different disease. Yet I have, through progression (new symptoms, not much real worsening) had the neurologists throw up their hands and stop treating me. They think that has no effect? And I can't walk, but I have used my recumbent tricycle for 11 years.

I don't expect to stop tricycling, but then I never expected to stop bicycling.

Time since diagnosis depends heavily on how long it takes for a person to complain about new symptoms. It also depends heavily on how long it takes to diagnose. If I had been diagnosed sooner I would been an "MS"er not for 18 years, but for 20. If I had been correctly diagnosed after the first complaint I made, I would have "had MS" not for 18 years, but for 33! It has not been a different disease for any of that time. Same disease all of that time. Especially if you consider that remissions are just plastic adaptations. All that has happened is that I have aged.

If there is a live pathogen, or a causative agent in my environment, changes in my symptoms, either worsening or improving, could be due to changes in my environment, or changes in my lifestyle, or both, without any change in the cause of my disease. Or all the changes could be the inevitable result of the passage of time, without any change in the cause of my disease.

I do agree this mouse experiment might have been different if disease duration and EDSS score had been taken into account. And I am not surprised, if CSF had any effect at all, that it would have been different depending on those things in the CSF donors. I agree that "relapse" activity (or not) could be very revealing.

"DMD"s could also make a measureable difference. But we will remain ignorant if we continue to treat this as more than one disease.
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