iron deposition is independent of inflammation

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

iron deposition is independent of inflammation

Postby Cece » Thu Aug 25, 2011 12:44 pm

www.biomedcentral.com/content/pdf/1471-2202-12-59.pdf
Iron deposition is independent of cellular inflammation in a cerebral model of multiple sclerosis

Rachel Williams1, Aaron M Rohr1, Wen-Tung Wang2, In-Young Choi1,2,4, Phil Lee1,2, Nancy EJ Berman3, Sharon G Lynch4 and Steven M LeVine1*

Abstract

Background: Perivenular inflammation is a common early pathological feature in multiple sclerosis (MS). A recent hypothesis stated that CNS inflammation is induced by perivenular iron deposits that occur in response to altered blood flow in MS subjects. In order to evaluate this hypothesis, an animal model was developed, called cerebral experimental autoimmune encephalomyelitis (cEAE), which presents with CNS perivascular iron deposits. This model was used to investigate the relationship of iron deposition to inflammation.

Methods: In order to generate cEAE, mice were given an encephalitogen injection followed by a stereotactic intracerebral injection of TNF-a and IFN-g. Control animals received encephalitogen followed by an intracerebral injection of saline, or no encephalitogen plus an intracerebral injection of saline or cytokines. Laser Doppler was used to measure cerebral blood flow. MRI and iron histochemistry were used to localize iron deposits. Additional histological procedures were used to localize inflammatory cell infiltrates, microgliosis and astrogliosis.

Results: Doppler analysis revealed that cEAE mice had a reduction in cerebral blood flow compared to controls. MRI revealed T2 hypointense areas in cEAE animals that spatially correlated with iron deposition around vessels and at some sites of inflammation as detected by iron histochemistry. Vessels with associated iron deposits were distributed across both hemispheres. Mice with cEAE had more iron-labeled vessels compared to controls, but these vessels were not commonly associated with inflammatory cell infiltrates. Some iron-laden vessels had associated microgliosis that was above the background microglial response, and iron deposits were observed within reactive microglia. Vessels with associated astrogliosis were more commonly observed without colocalization of iron deposits.

Conclusion: The findings indicate that iron deposition around vessels can occur independently of inflammation providing evidence against the hypothesis that iron deposits account for inflammatory cell infiltrates observed in MS.
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Postby 1eye » Fri Aug 26, 2011 5:10 pm

I don't know if I agree with their conclusions: something other than a mouse can determine whether iron causes inflammation. Do you know how small a mouse-brain is? Did they use nano-MRV? But what they did find, was that whatever they did to those poor animals caused significant iron deposition.

Some iron-laden vessels had associated microgliosis that was above the background microglial response, and iron deposits were observed within reactive microglia.


and...
Doppler analysis revealed that cEAE mice had a reduction in cerebral blood flow compared to controls. MRI revealed T2 hypointense areas in cEAE animals that spatially correlated with iron deposition around vessels and at some sites of inflammation as detected by iron histochemistry. Vessels with associated iron deposits were distributed across both hemispheres.


Sounds to me like they caused EAE, and the EAE caused iron deposition and CCSVI!

Wow! Laser Doppler!
Last edited by 1eye on Sat Aug 27, 2011 4:17 am, edited 1 time in total.
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Postby cheerleader » Fri Aug 26, 2011 5:34 pm

I'd seen this study, so has Dr. Zivadinov, and his response is below....looks like the researchers are trying to prove that CCSVI is not the primary mechanism for iron deposition---that an immune reaction does the same thing.

But the animal model used is not relapsing remitting...it's another ADEM model, or that of encephalitis, which is not MS.

Here is Dr. Zivadinov on this paper:

Whether iron deposition is an epiphenomenon of the multiple sclerosis (MS) disease process or may play a primary role in triggering inflammation and disease development remains unclear at this time, and should be studied at the early stages of disease pathogenesis. However, it is difficult to study the relationship between iron deposition and inflammation in early MS due to the delay between the onset of symptoms and diagnosis, and the poor availability of tissue specimens. In a recent article published in BMC Neuroscience, Williams et al. investigated the relationship between inflammation and iron deposition using an original animal model labeled as "cerebral experimental autoimmune encephalomyelitis", which develops CNS perivascular iron deposits. However, the relative contribution of iron deposition vs. inflammation in the pathogenesis and progression of MS remains unknown. Further studies should establish the association between inflammation, reduced blood flow, iron deposition, microglia activation and neurodegeneration. Creating a representative animal model that can study independently such relationship will be the key factor in this endeavor.


This animal model just isn't MS.

A potential critique of the model [2] is that focally increased concentrations of TNF-α and IFN-γ in the brain occurring at the same time as the development of an autoimmune myelin epitope response may not plausibly occur spontaneously; however, the modification of the immune response clearly has led to a model of focal iron deposition in the brain in the context of inflammation.


Here's the full Zivadinov response:
http://www.biomedcentral.com/1471-2202/12/60

Let's see how those Stanford marmoset brains look after losing their jugular veins for awhile....

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dx dual jugular vein stenosis (CCSVI) 4/09
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Postby Cece » Fri Aug 26, 2011 6:05 pm

Thanks, Cheer, for that response. I read this paper as being slightly negative toward CCSVI but not much to worry about.
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Postby MSBOB » Sat Aug 27, 2011 3:26 am

I didn't really know how to take this study.

I was under the assumption that the iron deposits caused oxidative damage to glial cells and stunted the brain from remyelinating its nerves. I never knew that iron was suspected of causing inflammation, or had any association to inflammation - except as iron deposited from dying cells and lack of a good cleanout mechanism.

The only reason this study was probably done was to try to disprove an early claim from ccsvi theorists, that iron deposits were causing inflammation. I don't know if that was the exact claim or not. I am working from memory.

Really, the study didn't prove or disprove anything we didn't already know or have assumed for a long time. Iron is really interesting though.
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EAE is not MS

Postby MarkW » Sat Aug 27, 2011 10:56 am

EAE is a model for MS which does not replicate MS progression and only applies to mice, not pwMS. I agree with Cheer, just ignore this paper. Unless you are an MS expert, ignore all papers on EAE. If you claim to be an MS expert and accept EAE reasearch fully, you need to read the challenges to this model.

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Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Postby 1eye » Sat Aug 27, 2011 7:00 pm

here we show the accumulation of endogenous iron
deposits are colocalized to T2 hypointense areas.


Aren't hypointense areas black holes? I thought that iron, like gadolinium, would be hyper-intense, and light up the MRI. What do I know?

Colocalized with hypointensities. Didn't we already know that MS lesions are at places where the BBB is leaky? These don't look much like my lesions. I think you might need to be a radiologist to make head or tail of these mouse MRIs.
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