Dr. Dake on the new animal models of CCSVI

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Postby 1eye » Thu May 26, 2011 5:43 pm

Risk factors are things that can be causes. Like smoking is a risk factor and can cause heart disease. I don't think marmalade can cause CCSVI, but I'd bet CCSVI, the risk factor (not the movie of the same name), can be a cause of symptoms (and lesions) lumped together and labeled 'MS'. Especially the kind diagnosed by a lot of folks around these parts.
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Postby Cece » Thu May 26, 2011 6:33 pm

Risk factors are things that can be causes. Like smoking is a risk factor and can cause heart disease.

Ok, that's a really good point.
Is cause just a step higher than 'risk factor'?
With lung cancer, even if smoking caused it, stopping smoking does not stop the lung cancer. There is a possibility that CCSVI starts the process of MS but that treating CCSVI cannot stop the process.

But CCSVI explains very elegantly why the immune system is involved with no need for an autoimmune boogedyboo.

Maybe marmalade causes ccsvi in marmosets? ;)

I think for myself it's fairly obvious that my 80% and 100% blocked jugulars reduced cerebral outflow, causing a lot of the cerebral symptoms that have lifted since I had my procedure. I think my CCSVI caused my MS and that some of what was mislabelled as MS was really CCSVI, particularly the cogfog.
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Postby 1eye » Thu May 26, 2011 7:27 pm

no, no, that would be marmolade, a Very Different Confiture
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Postby se1956 » Fri May 27, 2011 2:43 am

If you prepare 100 mice with an "average CCSVI" condition and one will get clear MS symptoms the conclusion may be:

CCSVI is a high risk factor for getting MS because mice nearly never get MS.

Many discussions about CCSVI are a waste of time because everyone uses different definitions or has a misconception of slow chronic diseases.

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Postby 1eye » Fri May 27, 2011 6:00 am

se1956 wrote:If you prepare 100 mice with an "average CCSVI" condition and one will get clear MS symptoms the conclusion may be:

CCSVI is a high risk factor for getting MS because mice nearly never get MS.

Many discussions about CCSVI are a waste of time because everyone uses different definitions or has a misconception of slow chronic diseases.

R.


I think these discussions are confused and misleading because, although "average" may be well enough understood, there may be many definitions of "risky", "high risk", and "near", and none, some, or all of them may be quantitative. Throw in "slow" and "MS", and the confusion is complete. If you want to be very precise, don't even use probabilities. Use only certainties. With certainty, 2 + 2 = 4, 100 % of the time.

In a working animal model of CCSVI I think you are much more likely to find that the animals get lesions 100% of the time. It may be that there is a threshold of reflux or slowed perfusion or both that will achieve this.
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Postby Cece » Fri May 27, 2011 7:14 am

se1956 wrote:If you prepare 100 mice with an "average CCSVI" condition and one will get clear MS symptoms the conclusion may be:

CCSVI is a high risk factor for getting MS because mice nearly never get MS.

Many discussions about CCSVI are a waste of time because everyone uses different definitions or has a misconception of slow chronic diseases.

R.

This is helpful.
To say CCSVI is a 'cause' of MS, would it be necessary for all 100 of the mice to get MS? A 'cause' leads directly to the result 100% of the time?

All the talk about specificity and sensitivity in Dr. Zivadinov's latest paper was along these lines.
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Postby cheerleader » Fri May 27, 2011 7:37 am

I think there's a bit of confusion about animal models.
These are merely ways to view how certain outside effects work on a mammal...they are not meant to be complete replications. Obviously, an animal model is incomplete.

The current model of MS is EAE and it is very convoluted. Dr. Dake explains that in his lecture....

"There's an animal model, but it's not really, unfortunately, like most animal models, it's not really a human model. Basically, you take like a mish of ground up spinal cord and brain from some other species, you mix it with some oily substance, some TB bacilli, and some bordadella pertussis, some whooping cough toxin, and inject into peridium, and what you get is this whopping inflammatory response, and that's good because you get the accelerated disease process, but obviously in humans, it's a much more chronic and progressive thing.


The reason to use a marmoset, an animal that shares many characteristics with the human animal (upright, mammal, jugular and vertebral veins) is to simply study how reduced venous flow affects the brain and spine. That's it...nothing more, nothing less. IF the marmoset shows lesions, paraplesia, fatigue, depression, hippocampal atrophy, etc....we can make the connection to slowed venous drainage in MS. The current model says that occluded jugulars are no big deal, the vertebrals take over, no worries. But if there are MS-like changes in the brain and spine of marmosets after partial ligation, the case continues to build. It doesn't have to happen in 100% of marmosets 100% of the time...they will probably be ligating one jugular, both jugulars, and changing location of ligation (high, low) to see how this changes the effects on brain and spine.

We're dealing with competing with a 60 year old animal model--this is going to take time and patience and rigorous science. Which is why I'm glad it's happening at Stanford,
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Postby Cece » Fri May 27, 2011 7:53 am

I was wondering about the marmoset venous system! So they do have jugulars and vertebral veins, do these function much as humans do (jugulars when supine, vertebrals when upright)? If marmosets have azygous veins, will these be involved too? It's possible that the worst physical disability comes when the azygous is blocked, since it drains the spine.
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Postby 1eye » Fri May 27, 2011 9:49 am

It may be that the model only works after some elapsed time, and that the posture dependency is part of what makes it happen more slowly in humans. It may also be that the changes themselves which happen as a result of our lying down for a big part of each day and being up for the rest, are the thing that is required to be modeled. That would complicate things a lot, I would think. I am thinking of an analog of metal fatigue from repeated flexing.

I was also thinking, I wonder if changes in our (meaning the human race's) proportion of upright-time versus prone-time due to the advent of low-cost artificial light have had anything to do with it? I would think for most of our evolution we have been pretty regular about it. I have a reproduction of instructions to servants circa 1840 that reads "To get up in Summer by half paft five & in Winter by day light or forfeit two pence to the Box for each offence...every Man belonging to the Hall to go to bed by ten in winter & half paft ten in Summer..." Until comparatively very recently, only richer people could afford either many candles, night-time entertainment, or unemployment.

I would think something being reproducible would be a big enough clue without any 100% of anything as well. I am just very optimistic.

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Postby ozarkcanoer » Fri May 27, 2011 4:29 pm

This is the most exciting basic research going on. I hope there are other independent labs also trying to make animal models. Dr Zivadinov in his recent presentation also emphasized the importance of an animal model of CCSVI. Using an "upright" and larger model is a great idea.

Boy the flash of imagination that went through my brain when I imagined a little bitty mouse in an MRI :) And this made me wonder if MRI has ever been used on such a small beastie !!

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Re: Dr. Dake on the new animal models of CCSVI

Postby Cece » Thu Feb 13, 2014 7:21 am

http://www.ncbi.nlm.nih.gov/pubmed/23773983
Mult Scler. 2014 Jan;20(1):64-71. doi: 10.1177/1352458513492244. Epub 2013 Jun 17.

Perivenular brain lesions in a primate multiple sclerosis model at 7-tesla magnetic resonance imaging.

Gaitán MI, Maggi P, Wohler J, Leibovitch E, Sati P, Calandri IL, Merkle H, Massacesi L, Silva AC, Jacobson S, Reich DS.

Abstract

BACKGROUND Magnetic resonance imaging (MRI) can provide in vivo assessment of tissue damage, allowing evaluation of multiple sclerosis (MS) lesion evolution over time--a perspective not obtainable with postmortem histopathology. Relapsing-remitting experimental autoimmune encephalomyelitis (EAE) is an experimental model of MS that can be induced in the common marmoset, a small new world primate, and that causes perivenular white matter (WM) lesions similar to those observed in MS.

METHODS Brain lesion development and evolution were studied in vivo and postmortem in four marmosets with EAE through serial T2- and T2*-weighted scans at 7-tesla. Supratentorial WM lesions were identified and characterized.

RESULTS Of 97 lesions observed, 86 (88%) were clearly perivenular, and 62 (72%) developed around veins that were visible even prior to EAE induction. The perivenular configuration was confirmed by postmortem histopathology. Most affected veins, and their related perivascular Virchow-Robin spaces, passed into the subarachnoid space rather than the ventricles.

CONCLUSION As in human MS, the intimate association between small veins and EAE lesions in the marmoset can be studied with serial in vivo MRI. This further strengthens the usefulness of this model for understanding the process of perivenular lesion development and accompanying tissue destruction in MS.

I googled but there is internet silence on any progress of any CCSVI-in-marmosets trials anywhere.
I found this, though. I wonder what a trial would show if you gave EAE and CCSVI to the poor marmosets at the same time. In EAE, the brain lesions are showing up in perivenular areas. If CCSVI worsens the venous health or affects the hemodynamics, then it might exacerbate the EAE. If EAE+CCSVI leads to worse disease than EAE alone, then that might provide justification for treatment of CCSVI.
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Re: Dr. Dake on the new animal models of CCSVI

Postby cheerleader » Fri Feb 14, 2014 5:27 pm

Dr. Dake mentioned at ISNVD that the CCSVI marmoset study was being done in China--not sure when publication might be. Will get back to you, Cece. Dr. Haacke has been bringing in imaging labs from all over the world---it might be thru him. I'll see if I can get more info.
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