Iron and neurodegeneration in the multiple sclerosis brain

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Iron and neurodegeneration in the multiple sclerosis brain

Postby MSUK » Thu Aug 01, 2013 1:34 am

This study looked at the distribution of non-heme iron as well as the expression of the iron-related proteins ferritin, hephaestin and ceruloplasmin as regards the oxidative damage in the brain tissue of 33 people with MS and 30 controls.

The researchers found an age related increase of iron in the white matter of controls and in people with MS with a short disease duration. They found a significant decrease of iron in normal appearing white matter (NAWM) in people with chronic MS........ Read More -
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Re: Iron and neurodegeneration in the multiple sclerosis bra

Postby bifrostlake » Fri Aug 02, 2013 7:28 am

Well, so much for that theory.
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Re: Iron and neurodegeneration in the multiple sclerosis bra

Postby CureOrBust » Sun Aug 04, 2013 3:36 am

bifrostlake wrote:Well, so much for that theory.

Not so fast...
Results: We found an age-related increase of iron in the white matter of controls as well as in patients with short disease duration. In chronic MS, however, there was a significant decrease of iron in the normal appearing white matter (NAWM) with disease duration, when corrected for age. This decrease of iron in oligodendrocytes and myelin was associated with an up-regulation of iron-exporting ferroxidases. In active MS lesions, iron was apparently released from dying oligodendrocytes, resulting in extracellular accumulation of iron and uptake into microglia and macrophages. Iron-containing microglia showed signs of cell degeneration. At lesion edges and within centers of lesions, iron accumulated in astrocytes and axons.

Interpretation: Iron decreases in the NAWM of MS patients with increasing disease duration. Cellular degeneration in MS lesions leads to waves of iron liberation, which may propagate neurodegeneration together with inflammatory oxidative burst.

I have no medical training, but my reading of this passage is that in NORMAL appearing white matter there was lower iron. However, the degeneration leads to the release of Iron and they found Iron accumulation in astrocytes and axons at the CENTER of lesions.

In very simple terms (please feel free to correct me on this understanding), we have less iron in the healthy bits, and higher iron in the lesions (ie the "sick bits").
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Re: Iron and neurodegeneration in the multiple sclerosis bra

Postby cheerleader » Sun Aug 04, 2013 7:03 pm

Hi Cure--
yes, your simple term explanation is right--the damaged part of brain shows higher iron accumulation. And you're also right that it's a bit soon to proclaim Zamboni's theory is over.

Most of the SWI scans (Haacke, Ge, etc) in MS have been looking at ALL sources of iron in all of the MS brain. And they have very different findings.

Neurologists seem intent on proving that Zamboni's theory has no merit---and are explaining the iron deposition in terms of purely a secondary result of myelin degradation. While this may be true in white matter--that explanation does not explain the deep gray matter issue. It's not just about white matter lesions.

Here's a new BNAC study that used SWI MRI to look at gray matter atrophy and iron deposition in CIS

Patients with CIS showed significantly increased content and volume of iron, as determined by abnormal SWI-phase measurements, in the various sub-cortical deep gray matter structure, suggesting that iron depostion may precede structure-specific atrophy. ... 0.full.pdf

And here's a paper from Haacke, the inventor of SWI technology-

Brain iron accumulation has been shown histologically in MS and recently, an iron increase from 24% to 39.5% was reported in the deep gray matter in MS patients compared to control subjects (25,26).

The source of iron deposition may be myelin/oligodendrocyte debris (17), concentrated iron in the macrophages (that phagocytize the destructed myelin/oligodendrocyte), or the product of hemorrhages from damaged brain vessels.

The amount of iron deposition could reflect the extent of tissue damage, thus iron could be used as a biomarker to predict clinical outcome. This is a reasonable hypothesis given recent findings (27), which show very clear iron deposition encircling dilated veins in MS. The source of this iron is still unclear, but it could result from microhemorrhaging and hemosiderin buildup

And here's another study, looking at pediatric MS patients with significantly increased iron content and atrophy in the SDGM--
Pediatric MS patients, at an early stage of the disease, showed significantly increased iron content and atrophy in the SDGM compared to HC, with regional predilection for the pulvinar nucleus of the thalamus. ... ts/S50.006

It makes no sense to just look at white matter lesions, and not consider gray matter- but of course, that's the problem with 90% of MS research.
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Re: Iron and neurodegeneration in the multiple sclerosis bra

Postby cervocuit » Mon Aug 05, 2013 1:06 am

Zamboni’s theory is that iron deposition is caused by CCSVI, right ? So if pediatric MS patients have iron deposition, why CCSVI is not found in pediatric MS patients ?
There are two recent studies proving this:

No association between chronic cerebrospinal venous insufficiency and pediatric-onset multiple sclerosis. ... tric+ccsvi
OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) was hypothesized to play a causative role in multiple sclerosis (MS). The assessment of pediatric-onset MS (POMS) may provide a unique window of opportunity to study hypothesized risk factors in close temporal association with the onset of the disease.
METHODS: Internal jugular veins, vertebral veins and intracranial veins were evaluated with extracranial and intracranial ultrasound in 15 POMS and 16 healthy controls. Assessor's blinding was maintained during the study. We considered subjects positive to CCSVI when at least two criteria were fulfilled.
RESULTS: CCSVI frequency was comparable between POMS and controls (p > 0.05). Clinical features were not significantly different between CCSVI-positive and CCSVI-negative patients.
CONCLUSIONS: Our findings add to previous data pointing against a causative role of CCSVI in MS.

No Evidence for Impairment of Venous Hemodynamics in Children or Young Adults with Pediatric-Onset Multiple Sclerosis.
BACKGROUND AND PURPOSE:Chronic cerebrospinal venous insufficiency is a postulated etiologic factor for multiple sclerosis, but the higher frequency with longer disease duration and progressive disability suggests that chronic cerebrospinal venous insufficiency is secondary to chronic disease. We evaluated the presence of chronic cerebrospinal venous insufficiency in pediatric-onset MS.
MATERIALS AND METHODS:Twenty-six pediatric patients with MS (18 years of age or younger), 26 age-matched healthy controls, and 13 young adults with pediatric-onset MS underwent sonography of the internal jugular, vertebral, and deep cerebral veins. Five venous hemodynamic criteria were assessed, with 2 criteria required for chronic cerebrospinal venous insufficiency. MR imaging studies, performed in the pediatric patients with MS and healthy control groups, included intracranial 2D time-of-flight MR venography and velocity-sensitive phase-contrast sequences. Contrast-enhanced brain MR images were obtained in pediatric patients with MS to further evaluate venous patency. We used paired t tests, Wilcoxon matched pairs, McNemar tests, and exact conditional logistic regression to estimate the association of chronic cerebrospinal venous insufficiency with MS.
RESULTS:Fifty participants (73.5%) had normal ultrasound findings, 15 (23.1%) met 1 venous hemodynamic criterion, and 2 pediatric patients with MS and 1 young adult with pediatric-onset MS met chronic cerebrospinal venous insufficiency criteria. Chronic cerebrospinal venous insufficiency was not associated with MS (odds ratio, 2.41; 95% CI, 0.19-infinity). Demographic and disease characteristics did not differ between the patients with MS meeting chronic cerebrospinal venous insufficiency criteria (n = 3) and those who did not (n = 36; all, P > .05). The mean (SD) MR imaging measures of intracerebral flow did not differ between the 2 pediatric patients with MS meeting chronic cerebrospinal venous insufficiency criteria (0.85 ± 0.11) and healthy controls (0.87 ± 0.16, P = .50); no child demonstrated venous obstruction.
CONCLUSIONS:Chronic cerebrospinal venous insufficiency is rarely observed in children or young adults with pediatric-onset MS. Venous anatomy and flow rates indicate that venous outflow is intact in pediatric patients with MS. Our findings argue against chronic cerebrospinal venous insufficiency as a component of MS etiology.
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Re: Iron and neurodegeneration in the multiple sclerosis bra

Postby DrGeoff » Mon Aug 05, 2013 3:07 am

An interesting study, but the conclusions do make one say "So What"

There are bits about age related, and short disease duration, but what does the study really offer someone like me?
Age 69 at onset, rapid progression - EDSS 1.5 just two years ago, and now EDSS 6.5.

Is this something that can inform lifestyle, diet, medication, use of supplements, etc? Never mind the arguments over CCSVI, there are just two things that matter from my viewpoint:
What causes anyone to get MS?
What can be done to moderate it?

Yes, there is some expensive medication out there, and a lot of wild theories which have not been properly explored, but most of us need help now.

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Re: Iron and neurodegeneration in the multiple sclerosis bra

Postby HappyPoet » Mon Aug 05, 2013 9:01 am

DrGeoff wrote:What causes anyone to get MS?
What can be done to moderate it?

Hello and welcome, DrGeoff.

In partial answer to both your questions, uninhibited venous, arterial, CSF, and lymph flows are extremely important. Proper AO (atlas orthogonal) X-rays will show a misalgined C1 vertebra which can GREATLY impede flows and impinge the Vagus nerve. A misaligned C1 can be easily, quickly, and painlessly fixed by a qualified, experienced AO chiro.

cheerleader, TiMS' CCSVI Leader Emeritus, founder of CCSVI Alliance, and manager of the "CCSVI in Multiple Sclerosis" Facebook page (Joan Beal), was initially skeptical about AO Chiro; however, thanks to Dr. Flanagan (uprightdoc) and his thread, "CCSVI and CCVBP," on the CCSVI subforum, cheer read about groundbreaking studies being conducted by Dr. Rosa who was using Upright MRI to look at what was really happening with flows around a misaligned C1, and his results are astonishing.

Hopefully, cheer or Sharon Richardson, president of CCSVI Alliance, will expand on what Sharon saw when she visited Dr. Rosa during his study of MS patients (2012). Disclosure: I was one of several MS patients in his first Upright MRI AO study that enrolled mostly non-MS patients (2011). Also, cheer, herself, went to an AO chiro because of neck pain, and found out her C1 was misaligned. After her adjustment, her neck pain resolved (cheer does not have MS; her husband, Jeff Beal, does).

In summary, to answer your questions, get checked by a qualified, experienced AO chiro because a misaligned C1 is something that might contribute to causing and/or worsening MS.
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Re: Iron and neurodegeneration in the multiple sclerosis bra

Postby cheerleader » Mon Aug 05, 2013 9:26 am

Dr. Geoff--Welcome. I'm sorry your MS has progressed so quickly. What causes MS? That's still unknown. But these studies are really important, because it appears that gray matter health is a better indicator of MS disease progression than simply studying white matter lesions.

Like you, I was frustrated by the lack of understanding, and went back to the history books to look at how MS research has developed over time. I found a correlation in my husband's first MS flare to blood flow, and created a program to help him. He's six years with no MS progression, and his gray matter now looks normal on MRI--he has no atrophy at all. Whether this is due to his venoplasty, or his new diet and lifestyle or simply good fortune, is anyone's guess. But I feel committed to sticking around and trying to help people learn about their own particular MS disease process. As Happy Poet mentions, the spine and cerebrospinal fluid play a large part--mechanics are important. Here's what I put together for Jeff ... ial-health
keep learning, and I hope you find your answers.

The studies you posted did not utilize the full Zamboni criteria. BNAC took the time to work with Dr. Zamboni, the researcher who discovered CCSVI and created a specific protocol to determine venous reflux and insufficiency, and they found the level of venous hemodynamic parameters, CCSVI, and iron deposition were directly related. Iron deposition was also related to age and EDSS, so that may be a factor in the pediatric studies. Certainly, this needs more investigation---utilizing the correct protocol.

Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular phenomenon recently described in multiple sclerosis (MS) that is characterized by stenoses affecting the main extracranial venous outflow pathways and by a high rate of cerebral venous reflux that may lead to increased iron deposition in the brain. Aim of this study was to investigate the relationship between CCSVI and iron deposition in the brain of MS patients by correlating venous hemodynamic (VH) parameters and iron concentration in deep-gray matter structures and lesions, as measured by susceptibility-weighted imaging (SWI), and to preliminarily define the relationship between iron measures and clinical and other magnetic resonance imaging (MRI) outcomes.
Sixteen (16) consecutive relapsing-remitting MS patients and 8 age- and sex-matched healthy controls (HC) were scanned on a GE 3T scanner, using SWI.
All 16 MS patients fulfilled the diagnosis of CCSVI (median VH=4), compared to none of the HC. In MS patients, the higher iron concentration in the pulvinar nucleus of the thalamus, thalamus, globus pallidus, and hippocampus was related to a higher number of VH criteria (P<0.05). There was also a significant association between a higher number of VH criteria and higher iron concentration of overlapping T2 (r=-0.64, P=0.007) and T1 (r=-0.56, P=0.023) phase lesions. Iron concentration measures were related to longer disease duration and increased disability as measured by EDSS and MSFC, and to increased MRI lesion burden and decreased brain volume.
The findings from this pilot study suggest that CCSVI may be an important mechanism related to iron deposition in the brain parenchyma of MS patients. In turn, iron deposition, as measured by SWI, is a modest-to-strong predictor of disability progression, lesion volume accumulation and atrophy development in patients with MS.

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