PPMS spinal fluid induces MS in mice

[CureOrBust]

I may of read a quick mention of this result, but this is the actual study! I did a search on TIMS, and could not find a mention of the study, even though its from back in 2014.

http://www.tischms.org/library/progress ... ion-axonal
And the actual publication: http://www.sciencedirect.com/science/ar ... 8614002489

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

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.

The BIG news for me is that they could have a mouse model for progressive multiple sclerosis, which I would expect to help immensely with finding treatments. Anyone know why it hasn't been used? Even by the authors themselves? I followed the links for studies that reference this one, and found nothing along these lines.

[1eye]

Thanks for tracking this down. It seems it is being ignored, because most of the money in DMDs is being made in relapsing-remitting MS. I have been denied any DMD prescriptions for 10 years. They seem not to have noticed my big remission when I had my CCSVI procedure. The local powers that be have me where they want me.

They seem to be ignoring atrophy too.

[frodo]

The thing is that I found it first !!!! Just joking. I found it and I put it in the CCSVI subforum. Not a very good place but at that time I was reading only that.

http://www.thisisms.com/forum/chronic-c ... 25769.html

[1eye]

The thing is that I found it first !!!! Just joking. I found it and I put it in the CCSVI subforum. Not a very good place but at that time I was reading only that.

http://www.thisisms.com/forum/chronic-c ... 25769.html

In fact isn't it a good idea to have a (sub)forum for that? Changing the TiMS structure to combine the two would be so hard and might affect so many other things (like any url to any TiMS page) that it would be a big data loss. It just means some things take more of your energy than others. As long as intelligent people are reading both forums, QED.

Goodness knows I don't think anybody should feel ignored in either place.

How exactly the lesions come about is directly accessible if you are looking at the MS patient's spinal fluid. Why does nobody publish any more on that? Why would anybody use any other mouse model to research MS? Come on, doctors!

[frodo]

Related to the previous article two more publications. Something is changing.

Quantified CSF antibody reactivity against myelin in multiple sclerosis

http://onlinelibrary.wiley.com/doi/10.1 ... 3.264/full

Effect of the Sera of Patients with Multiple Sclerosis on Apoptosis and Nitric Oxide Production of Endothelial Cells

http://eprints.kmu.ac.ir/24228/

(apoptosis and nitric oxide (NO) production of endothelial cells treated with serum of patients with MS)

[1eye]

Related to the previous article two more publications. Something is changing.

Quantified CSF antibody reactivity against myelin in multiple sclerosis

http://onlinelibrary.wiley.com/doi/10.1 ... 3.264/full

Effect of the Sera of Patients with Multiple Sclerosis on Apoptosis and Nitric Oxide Production of Endothelial Cells

http://eprints.kmu.ac.ir/24228/

(apoptosis and nitric oxide (NO) production of endothelial cells treated with serum of patients with MS)

Now we're getting somewhere. Where, I couldn't say. Interesting that the mechanism for beta-1b interferon has to do with both NO production by, and apoptosis of endothelial cells. These both have more to do with plumbing than electricity, as it were. Hmmm.

The other study shows pretty unequivocally that MS follows CSF, and develops a very accurate test for MS that uses ELISA, I think, and not MRI. I would think it also does not require time-and-space (two MRIs) verifications. People with questioned diagnoses should get loud.

[1eye]

It's about time the medical community started recognizing, treating, and disseminating information, about the very real problems that very real people all over the world have, with blood flow, blood brain transit time, nitric oxide production and epithelial apoptosis in MS. These things result in known symptoms like heat sensitivity and lack of balance. We may not know the cause of MS, or exactly how to treat it, but we would know how to survive it a lot better with these key pieces of knowledge about its effects. The MS Society needs to broadcast this information to MS sufferers and caregivers everywhere. Not to do so is dangerous and negligent in the extreme. I am tired of telling people there is really something wrong with their circulation that has very real effects on their lives, merely because a few die-hard xenophobes and irrational neurologists don't like Dr. Zamboni. NASA listens to him -- why can't they? If doctors won't do it, maybe caregivers, personal support workers, nurses and nurse practitioners will. It is vital.

[CureOrBust]

Anyone know why it hasn't been used? Even by the authors themselves? I followed the links for studies that reference this one, and found nothing along these lines.

I will be asking one of my neurologist directly about this topic. He has numerous publications (Barnnett), and I was recently referred to him by another Neurologist (Pollard) (in the hope to get Lemtrada) who is also very well published and renowned around the world. But I don't see him till march. Maybe others could ask their neurologists and report the answer back here?

[frodo]

Anyone know why it hasn't been used? Even by the authors themselves? I followed the links for studies that reference this one, and found nothing along these lines.

I will be asking one of my neurologist directly about this topic. He has numerous publications (Barnnett), and I was recently referred to him by another Neurologist (Pollard) (in the hope to get Lemtrada) who is also very well published and renowned around the world. But I don't see him till march. Maybe others could ask their neurologists and report the answer back here?

Great idea!!! I will wait eagerly for your news.

[1eye]

How Google works is along the same lines: weighting things according to how many people reference them... It could be a conspiracy of silence, or it could be nobody believes it. Or it could be that there are no scientists working along those lines right now, because the EAE model is a proven source of grant income. Wonder which it is...

[CureOrBust]

Neurologists would not be using Google for research (at least not admit to it...) The title of this Journal, without actually knowing any better, I think gives an indication as to why it may not have been noticed by a greater numbers of neurologist. "Experimental Neurology". Also, it is not a publication of the AAN (American Academy of Neurology), which I know at least one of my neurologists uses almost as a filter of what he would consider "respected research", and hence, research that should be given merit. Not my belief, his.

[CureOrBust]

I was searching high and low to see if I could find a little more info on the paper, and possibly more of the actual paper, and i came across this "poster". I have not read it yet, just found it, but it does include more info on methods and results and pretty pictures.

http://tischms.org/sites/default/files/ ... N-2012.pdf

I found it off the following pages (with some repeat info).
http://tischms.org/staff/massimiliano-cristofanilli-phd
http://tischms.org/research/published/c ... s-promotes
http://tischms.org/library/progressive- ... ion-axonal

Actually, one of his other papers invludes the following.
http://tischms.org/library/cerebrospina ... uronal-and

Cerebrospinal fluid derived from progressive multiple sclerosis patients promotes neuronal and oligodendroglial differentiation of human neural precursor cells in vitro
...
Here, we investigate the effect of cerebrospinal fluid derived from primary progressive (PPMS) and secondary progressive (SPMS) MS patients (CSF-MS) on the survival, proliferation, and differentiation of commercially available human embryonic-derived NPCs named ENStem-A. We found that PPMS derived CSF markedly reduced the proliferation of ENStem-A and increased their differentiation toward neuronal and oligodendroglial cells, compared to control CSF. Similar but less striking results were seen when ENstem-A were treated with SPMS derived CSF. Our findings suggest that in both SPMS and PPMS the CNS milieu, as determined by extrapolation from CSF findings, may stimulate the endogenous pool of NPCs to differentiate into neurons and oligodendrocytes.

[1eye]

See the other thread on the epilepsy drug... it looks like they're saving it for the meeting in Hawaii. Nice place for a conference.

[1eye]

New test claims to predict disability progression (26/01/16)
By noting the presence of certain markers in a commonly performed diagnostic test, researchers at the Mayo Clinic say they can predict whether multiple sclerosis patients will suffer a faster onset of disability and counsel them to help ease anxiety.

The research is to be presented at the American Academy of Neurology meeting in Honolulu, Hawaii.

“In this study, we found in patients who developed the progressive form of MS that had preceding relapses, the presence of greater production of immunoglobulin G predicted a faster onset of disability,” explains Orhun Kantarci, M.D., a Mayo Clinic neurologist and the study’s lead author.

The study looked at cerebrospinal fluid (CSF) test results from a sample of 281 progressive MS patients seen at Mayo Clinic from 2002 to 2007. In general, CSF test results help medical staff when the diagnosis is uncertain. For this study, researchers analysed CSF test results and noticed a relationship between a faster disability rate and abnormally high levels of two proteins — oligoclonal band and immunoglobulin-G molecule. If patients had the progressive form of MS with proceeding relapses, and their CSF results showed an elevated protein, researchers concluded they will have a faster rate of disability.

The study is a significant step forward in predicting disability outcomes, says researcher Junger Tang, M.D., a neurology fellow at Mayo Clinic. The next step is further research to confirm the results, he says.

Source: Health Got Mojo (26/01/16)

There is also an MS-UK story which I could not find in the archives, but which said:

PPMS CSF induces inflammatory demyelination....

Postby MSUK » Fri Aug 15, 2014 6:46 am
Progressive multiple sclerosis CSF induces inflammatory demyelination, axonal loss, and astrogliosis in mice

Cristofanilli M, Rosenthal H, Cymring B, Gratch D, Pagano B, Xie B, Sadiq SA.

The abstract is at http://www.ncbi.nlm.nih.gov/pubmed/25111532

Probably the neurology cartel will publish in Hawaii.

I think it is clear that the cause of MS and of MS disability resides in the CSF. That's why the mouse model with MS patient's CSF works. That's why the ELISA array is so completely specific in testing for MS. Now if they would just start using all those existing MRIs to track atrophy. What are they afraid of? That we might start learning too much about MS, and perhaps endanger the existing $15B drug industry?