7T MRI shows MS vascular connection

High powered MRI is allowing us to see the vascular connection to MS.  A recently published study used 7T MRI to compare the lesions of people with MS and those with Neuromyelitis Optica (NMO).  link

21 patients with MS and 21 patients with NMO were imaged.  There was one important difference between the two groups.  Only the patients with MS showed signs of "iron laden lesions" which contained a central vein.  None of the people with NMO showed this.

NMO is a truly autoimmune disease, in which immune cells attack the optic nerve and spine.   In contrast to MS,  NMO has a known antigen, called Aquaporin 4.  In NMO, the immune cells attack this antigen and cause demyelination.  However, there has never been a specific antigen discovered for MS.  In fact, MS lesions are very different from NMO lesions, as high powered MRI is showing us that inside MS lesions, there is a central vein which is allowing blood products, like iron, into brain tissue.

Here is how the researchers describe the difference:

Distinguishing MS from NMO lesions. 
Axial T2-weighted image from a representative patient with MS demonstrating a hyperintense lesion (black arrow) traversed by an ill-defined central venule adjacent to the inferior horn of the lateral ventricles. The lesion appears hypointense on a corresponding T1-weighted MPRAGE image. The lesion shows a hypointense peripheral rim and an iso- to hypointense central core traversed by a well-defined venule on GRE-T2*-weighted image. This lesion is hyperintense on QSM. Hypointense signal intensity within the lesion on GRE-T2*-weighted image and hyperintensity on QSM suggest iron accumulation (upper row). An axial T2-weighted image from a representative NMO lesion reveals 2 round hyperintense lesions (white arrows) in the subcortical WM region. The lesions appear hypointense on T1-weighted and hyperintense on GRE-T2*-weighted images. However, these lesions are isointense and therefore inconspicuous on QSM (lower row). The scale bar is for the QSM image with units of parts per billion.

Looking at the images, we can see the arrows pointing to the MS and NMO lesions.  All the images (on the top for MS and bottom for NMO) are of the same area of brain tissue.   It is the GRE-T2 image which clearly shows the MS lesion has a very small, yet well-defined vein (venule) going through the center.  The NMO lesion does not.  The QSM image shows that around this vein, in the MS patient, there is iron.  The researchers do not say that this is from blood leaking into tissue.  But this is the very obvious inference.  Blood, or heme, contains iron.  Microbleeds into brain tissue have been documented in MS. link   And here, once again, we have more proof.

For those of us who know our history, we remember that Rindfleisch saw the EXACT SAME THING through his microscope in 1863.

If one looks carefully at freshly altered parts of the white matter ...one perceives already with the naked eye a red point or line in the middle of each individual focus,.. the lumen of a small vessel engorged with blood...All this leads us to search for the primary cause of the disease in an alteration of individual vessels and their ramifications; All vessels running inside the foci, but also those which traverse the immediately surrounding but still intact parenchyma are in a state characteristic of chronic inflammation. 

Rindfleisch E. - "Histologisches detail zu der grauen degeneration von gehirn und ruckenmark". Archives of Pathological Anatomy and Physiology. 1863;26:474–483.

link

CW Adams published on damaged cerebral veins and the deposition of iron from blood in MS brains in 1988.
Yet, even after all the historical evidence, when Dr. Zamboni published on the link between venous disease, iron deposition into tissue, inflammation and MS lesions in his "Big Idea" paper in 2008---he was resoundingly ignored (or worse, mocked) by MS researchers. Here's the history of this research into the central vein sign, iron deposition and MS lesions-- link

Once again, we see the evidence of the vascular connection, in clear, high-powered MRI images. Iron deposited into brain tissue, creating inflammatory lesions, all around a small, central vein.

At a certain point, you simply have to say---
WAKE UP!

My family reached that point almost a decade ago, and because of this, my husband remains healthy. The evidence continues. There is a vascular connection to MS.
Whether or not MS specialists and immunologists will ever acknowledge this fact and help patients is moot. It is up to all of us to educate, inform, encourage, and move the research forward.


Be well,
Joan

From cells to space stations--vascular research continues

While astronaut Samantha Cristoforetti works high above our planet on the International Space Station---studying venous return in microgravity and utilizing Dr. Paolo Zamboni's technologies----cellular biologists are looking at the MS brain. The macrocosm and the microcosm of MS vascular research is happening right now!

New technologies are allowing researchers to view the MS brain at a cellular level, before formation of lesions.  I wanted to share three of these new papers, all published in the last month.

Please note that the researchers are cellular biologists---they are looking at the MS brain on the most basic level, and they all see the vascular links to the disease.  They are not studying MS to find out how immune modulating drugs work, they are trying to solve the mystery of what causes MS.  And they are all seeing a connection to blood flow and the blood brain barrier.

When neurologists tell you CCSVI research is over, please point them to the continuing, confirming research which is further elucidating the vascular connection to MS. 

If NASA can work directly with Dr. Paolo Zamboni, why won't neurologists?
NASA wants to understand why 20% of their astronauts are coming back to earth with neurological and visual issues, and how it's related to blood flow.  So, they went to the expert.
http://www.nasa.gov/mission_pages/station/research/experiments/1278.html

Here are the brand new papers, all finding a link to MS and blood flow.

1.  The Role of Angiogenesis in the Pathology of MS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253611/

Cell biologists from the University of Irvine have noted how the loss of endothelial tight junctions in the blood brain barrier contributes to inflammation and angiogenesis (the growth of new blood vessels) in the MS brain,  and how this process is initiated by hypoxia.  This low oxygen state and resultant angiogenesis occurs prior to formation of demyelinating lesions.

This cellular research is further defining the hypothesis of cellular biologist Dr. Bernhard Juurlink, made in the 1990s.
http://ccsviinms.blogspot.com/2010/08/blood-flow-and-white-matter-lesions.html

It also fits in with my hypothesis of MS as a disease of hypoperfusion/reperfusion injury.
 http://ccsviinms.blogspot.com/2013/09/multiple-sclerosis-hypoperfusionreperfu.html


2. In vitro study of the direct effect of extracellular hemoglobin on myelin components.
http://www.ncbi.nlm.nih.gov/pubmed/25463632

The cellular biologists from the University of Guelph are looking at how blood particles damage myelin.  They are seeing microscopic deposits of hemoglobin in the MS brain, around the veins.  This blood contains iron, which when deposited into delicate brain tissue, begins a process of oxidative stress.

"This study provides new insight into the mechanism by which hemoglobin exerts its pathological oxidative activity towards myelin components. This work supports further research into the vascular pathology in MS, to gain insight into the origin and role of iron deposits in disease pathogenesis, or in stimulation of different comorbidities such as cardiovascular disease."

This work confirms the theory of Dr. Zamboni from 2006, called his "Big Idea" theory, which saw the similarities of venous disease to MS, by noting how blood particles caused damage to tissue via the iron found in our red blood cells.   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633548/

3.  Focal disturbances in the blood brain barrier are associated with formation of neuroinflammatory lesions

http://www.ncbi.nlm.nih.gov/pubmed/25448765

Neurobiologists from the University of Montreal are seeing changes to the blood brain barrier which happen before immune cells enter the MS brain. There are changes to the tight junctions of endothelial cells. 

 Our findings suggest that BBB breach occurs before significant immune cell infiltration and demyelination.

I wanted to briefly highlight these new studies, and encourage all readers to pursue cardiovascular and endothelial health in 2015.  

The discoveries of endothelial dysfunction and the link to the breakdown of the blood brain barrier in MS are being made.  While we wait for the venoplasty and pharmaceutical solutions, there is much that can be accomplished with lifestyle changes.
http://ccsvi.org/index.php/helping-myself/endothelial-health

Happiest of holidays to all.  Here's to a healthy 2015.

Joan

Here is Samantha's view                                               Here is a microbiologist's view

Iron and gray matter - What do we know?

January 3, 2012 at 8:52am

As more and more MS reseachers come forward and explain how MS appears to be a disease of the gray matter first---before white matter lesions appear---it is vital that we look at gray matter structures in the MS brain, to see what is different in the MS brain when compared to normal brains.

This post will be long, but I believe it's important to understand MS research as it stands today, the beginning of 2012.

Last month, University of Texas researchers published in the Journal of Neuroscience--reporting that the thalamus, the deep gray matter of the brain, is smaller and atrophied in people with MS when compared to normal brains, and that this loss of deep gray matter tissue happens at the beginning of the disease, early on and before any white matter lesions are detected.

http://health.usnews.com/health-news/family-health/brain-and-behavior/articles/2011/12/30/multiple-sclerosis-may-cause-changes-in-thalamus-study

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A recent paper from Hubbard, Haacke, et al shows how stenotic veins creates slowed jugular return of blood in pwMS.  Blood flow thru the brains of pwMS is much less than those with non-stenotic veins.  This may be an indication of hypoperfusion and decreased oxygenation, and we'll be hearing more about that from the Hubbard Foundation later this year.

Dr. E. Haacke has also noted an early change in the gray matter of MS brains--abnormally high iron content.

Dr. E. Mark Haacke has been looking at the gray matter in MS brains for almost a decade.  He is one of the inventors of SWI technology, an imagery system that can visualize iron deposed into brain tissue.

This is from his new paper is published in the American Journal of Neuroradiology--

Fifty-two patients with MS were recruited to assess abnormal iron content in their basal ganglia and thalamas (THA) structures. One hundred twenty-two healthy subjects were recruited to establish a baseline of normal iron content in deep gray matter (GM) structures.

RESULTS: A clear separation between iron content in healthy subjects versus patients with MS was seen. For healthy subjects 13% and for patients with MS 65% showed an iron-weighting factor.

The results for those patients younger than 40 years are even more impressive. In these cases, only 1% of healthy subjects and 67% of patients with RRMS showed abnormally high iron content.

Currently, there is an increased interest in studying how GM is affected and particularly deep GM involvement in MS when iron deposition has been observed.  

Brain iron accumulation in neurodegenerative diseases, including MS, is not new and has been shown histologically in the past.  In MS, its source is likely due to myelin or oligodendrocyte debris, concentrated iron in the macrophages, or as a product of local microhemorrhages following venule wall damage.  As the wall breaks down, free iron may escape outside the vessel. This process has typically been seen in the basal ganglia, neurons, oligodendrocytes, macrophages, and microglia.6 Generally, free iron is known to lead to the formation of highly reactive hydroxyl radicals that can trigger cell membrane dysfunction and chronic microglial activation. Thus, iron from any of the above-mentioned sources could lead to inflammation and a further buildup of iron, causing the system to be self-sustainable.  

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What Dr. Haacke is explaining is that we've known about iron in gray matter tissue in MS brains and other neurodegenerative diseases for awhile.   This is not new information.   Dr. Haacke explains that there are three possible causes of this iron in the MS brain.  The iron could come from one, two, or all three of these sources.

Harvard professor visits Dr. Zamboni in Italy-- The More Iron, The More Severe the Disease

September 28, 2010 at 7:30am

From the Italian press---Professor Rohit Bakshi of Harvard University came to Ferrara University to discuss how his decade long study of iron deposition in MS brains has now intertwined with Dr. Zamboni's research:

Here is a Google translation of the press release:

Too much iron, more severe disease

New Ferrara - September 24, 2010 page 19 Section: Commentary

"It 's another piece of the puzzle that is made," says the researcher Paolo Zamboni.To place a new tile on the mosaic of research on multiple sclerosis was yesterday Professor Rohit Bakshi, Harvard University, came to Ferrara to explain the outcome of a decade of study during which he analyzed the role of iron as a contributory cause of the disease. His line of research was independent from that beaten by Ferrara Zamboni, but its conclusions have been come to intertwine with the results of tests carried out by the researcher and neurologist Bologna Ferrara Fabrizio Salvi on Ccsvi, which have established a hypothetical link between stenosis of the venous vessels in the brain iron accumulation and the onset of multiple sclerosis.

"The current therapies - said the scientist in the main hall of the university - are not effective in stopping the neurodegeneration. Bakshi was able, with a common magnetic resonance imaging to measure the actual concentration of iron in the brain, an operation in the past only run during the autopsy. Plaques and iron stores were associated, but especially "the greater the presence of iron - Bakshi said - the more you exacerbate the effects of the disease." Studies have revealed that the abnormal presence of iron affects the white matter and gray and tends to cause atrophy of certain areas of the brain.

http://ricerca.gelocal.it/lanuovaferrara/archivio/lanuovaferrara/2010/09/24/UCNPO_UCN06.html?ref=search

http://lanuovaferrara.gelocal.it/cronaca/2010/09/23/news/sclerosi-multipla-oggi-la-lezione-di-bakshi-2406157

Please note that Dr. Bakshi is confirming that current pharmaceuticals DO NOT stop the neurodegeneration of the MS disease process.

Here is an article on Dr. Bakshi's studies of MS and iron deposition from 2003:

http://www.webmd.com/multiple-sclerosis/news/20031022/multiple-sclerosis-tied-to-iron-in-brain

Let's talk about iron....

January 1, 2010 at 5:41pm

Now, let's talk about the iron issue. This has been Dr. Zamboni's "smoking gun." He wrote a paper on iron called "The Big Idea: Iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis"- in which he explicitly outlines the parallels between chronic venous insufficiency in the legs and iron deposition and what we see in MS brains. If you haven't read it yet, it's a must read-

http://jrsm.rsmjournals.com/cgi/content/full/99/11/589?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=zamboni&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT

So, how long have doctors known about this connection of iron and the MS brain? 

Here is a paper from 1988- yes, that is over 20 years ago- discussing the cerebral vein walls and iron deposition in multiple sclerosis-

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1031540/pdf/jnnpsyc00537-0096.pdf

"C W M ADAMS
From the Division of Histopathology, United Medical and Dental Schools of Guy's and St Thomas's Hospitals, University of London, UK

SUMMARY Evidence of damage to cerebral vein walls was sought in 70 cases of multiple sclerosis. Seventy control cases were also examined. The multiple sclerosis cases showed venous intramural fibrinoid deposition (7 %), recent haemorrhages (17%), old haemorrhages revealed by haemosiderin deposition (30%), thrombosis (6%) and thickened veins (19%). In all, 41% of all multiple sclerosis cases showed some evidence of vein damage. Occasional control cases showed haemosiderin deposition in the brain but, unlike the multiple sclerosis cases, these were diffuse and almost entirely related to coexistent cardiovascular or cerebrovascular disease. Haemosiderin deposition was common in the substantia nigra and other pigmented nuclei in all cases. It is concluded that the cerebral vein wall in multiple sclerosis is subject to chronic inflammatory damage, which promotes haemorrhage and increased permeability, and constitutes a form of vasculitis."

Here we have a study in 1988 showing vein damage in almost half of the MS patients- and the researchers note hemorrhage, hemosiderin (iron storage) deposition, thickened vein walls and call it a form of "vasculitis."

"The results reported here reinforce the view that damage to the vein wall is an important aspect of the pathology of the multiple sclerosis plaque. The vasculitis caused is different from and of a more modest nature than that, for example, in systemic lupus or polyarteritis nodosa but is, nevertheless, enough to cause haemorrhage, and structural and permeability changes in the vessel wall. The term proposed by Lendrum for a wide range of vasculitic disorders is plasmatic vasculosis, and the damage to the vein wall in multiple sclerosis could be regarded as causing a minor degree of such plasmatic vasculosis. Inflammatory and reparative changes in the vein wall might be exacerbated by pulsations or surges in intracranial venous pressure and may result in increased permeability of the multiple sclerosis plaque, as shown at necropsy, by immunohistochemistry and by brain scan."

So, the researchers note that this is different than vasculitis- it's really about damage to the VEIN wall. They even posit that this damage may be caused by PULSATIONS or SURGES of intracranial venous pressure (like from venous reflux, perhaps?)
Let's just move ahead 20 years, thru the vast miasma of autoimmune research-

Here is Dr. Haacke's paper from earlier this year. This is research completed BEFORE he read Dr. Zamboni's research. After attending the first CCSVI symposium in Bologna in 2009, Dr. Haacke has since became so convinced that Dr. Zamboni's research provided the missing link, he is now covering the globe, opening research centers to diagnose venous stenosis and reflux.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650739/

Iron deposition in the MS brain is real, and we need to understand how it gets there, and what we can do to stop this injurious process.

Joan