An ischemic stroke treatment--to be trialled for MS

Add a new medication to the ever-growing list of MS drug trials that address cerebral blood flow -not the immune system--3K3A-APC
With the growth of research into the connection of MS to cerebral blood flow,  we've seen an interest in exploring new ways to address hypoperfusion (slowed blood flow), endothelial dysfunction (damaged blood vessels) and brain atrophy (loss of brain tissue).

Why is this?  Because MS specialists, neurologists and advocacy groups are much more comfortable designing, testing and recommending a drug for MS, rather than encouraging healthy lifestyles and treating venous malformations.  It's almost impossible to have a placebo-controlled clinical trial for lifestyle.  

http://ccsviinms.blogspot.com/2013/08/medications-for-ms-addressing-blood.html


3K3A-APC is a modified form of human protein C.  Human protein C is an anti-inflammatory which protects the endothelial barrier.  3K3A-APC was created to strengthen the endothelial barrier--to prevent reperfusion injury and microbleeds in the brain after stroke.
http://www.zzbiotech.com/zz/About_the_Company.html
http://www.scripps.edu/newsandviews/e_20120820/griffin.html

3K3A-APC was created by Dr. Berislav Zlokovic.  Dr. Zlokovic was the keynote speaker at the ISNVD two years ago.  He is an endothelial researcher I contacted in 2008 regarding the potential connection to MS.  I reached out to him while he was at my alma mater, and he kindly replied.   Dr. Zlokovic is now at the University of Southern California, where he has continued his research on the blood brain barrier, stroke and neurodegenerative disease.  

Zlokovic is the scientific founder of ZZ Biotech, a Houston-based biotechnology company he co-founded with USC benefactor Selim Zilkha to develop biological treatments for stroke and other neurological ailments.

ZZ Biotech’s 3K3A-APC is a genetically engineered variant of the naturally occurring activated protein C (APC), which plays a role in the regulation of blood clotting and inflammation. 3K3A-APC has been shown to have a protective effect on the lining of blood vessels in rodent brains, which appears to help prevent bleeding caused by tPA.  http://news.usc.edu/56646/experimental-drug-reduces-brain-damage-in-rodents-afflicted-by-stroke/

Dr. Zlokovic's team has reached phase II this week, and they have just received and $8 million dollar grant from the NIH to test this drug in those who have had ischemic stroke.  I truly hope it can help these patients.  Dr. Zlokovic is a brilliant researcher, and this new drug has the potential to save brains.   http://www.acrpnet.org/MainMenuCategory/Resources/News/ACRP-Wire/CampusConnections.aspx

But the story does not end here....
ZZ Biotech's 3K3A-APC will also be tested for MS by USC's Neurology Dept.  

This is from the Erase MS website, where they discuss research they are funding.

The fourth research study is Dr. Weiner’s at USC. He plans to test a drug that works on multiple disease processes that are observed in MS, including inflammation, changes in blood vessel functions and neurodegeneration. This drug is known as human 3K3A-APC, and is modified from a protein called activated protein C (APC). 
http://www.erasems.org/current-research-update/

Here is what Dr. Weiner says about the drug...

Although anti-inflammatory drugs are clearly beneficial, there is a great need to develop treatments that can also protect brain cells from injury or death and subsequently, prevent neurodegeneration and disease progression.

To this end, and with the help of the Race to Erase MS, we have begun to test the possibility that a new neuroprotective drug can be developed for the treatment of MS. The drug, named 3K3A-activated protein C (3K3A-APC), provides potent protection for brain cells against injury and death in models of stroke and Alzheimer’s disease. 
http://www.erasems.org/media/uploads/News_2013_R2E.pdf

Why does Dr. Weiner not even mention the fact that this drug's method of action is on the vascular endothelium?  That it is made to strengthen the blood brain barrier?   Why does he skirt around the fact that the anti-inflammatory/immune-modulating DMDs are NOT preventing neurodegeneration and disease progression?  Calling 3K3A-APC "neuroprotective" is not the whole story.  Dr. Weiner has spoken out against CCSVI research, calling those who have been successfully treated with venoplasty as benefiting from placebo affect.  But why did my husband's gray matter atrophy reverse?  Why no more progression?  Isn't adequate blood flow to the brain also "neuroprotective?"

Once more, 3K3A-APC was created to strengthen the endothelial barrier--to prevent reperfusion injury and microbleeds in the brain after an hypoxic event.

Is this further tacit proof of the connection of MS to cerebral blood flow?
I believe so.
Joan

(For those who enjoy hypotheses and research--here's my hypoperfusion/reperfusion injury theory of MS.  I still believe this is what we are seeing in the disease.  I believe this is MS.  If so, this medicine may be very helpful.)
http://ccsviinms.blogspot.com/2013/09/multiple-sclerosis-hypoperfusionreperfu.html

Blood Matters

Seven years ago, when Jeff was diagnosed with MS, I asked his neurologist why his blood was hypercoagulated.  Why were his fibrinogen, c reactive protein, pro-thrombin and SED rates so high?  Why did he have all those tiny blood spots on his legs?  She replied that she didn't know, since it "had nothing to do with his MS."

But seven year later, we know that wasn't true for him, and it's apparently not true for other people with MS.

Blood matters.

After Jeff's diagnosis I went to the library and read medical journals online. I read Dr. Roy Swank's research, and saw he noted this blood vessel breakdown, as evidenced by what he called, "capillary fragility" on the limbs of his MS patients during their relapses, manifesting as blood spots called petechiae.  (see pic below.)   He saw hypercoagulation in their serum, too.    Dr. Swank knew it mattered.  In 1958, he saw what I was seeing on Jeff's legs in 2007.

Additional evidence that blood vessel fragility may be an important aspect of MS derives from Swank's study in which he concluded that MS is not confined primarily in or localized to the CNS: He observed small cutaneous hemorrhages in 77.4% of female patients observed repeatedly over a 5-9 year period. In 66.7% of these patients, the hemorrhages were spontaneous. `Biopsies of 5 spontaneous hemorrhages, where trauma could be confidently ruled out, revealed extravasated red blood cells infiltrating the deeper layers of the derma and the subcutaneous fat.' Swank goes on to state that `a number of patients have described petechial hemorrhages in large numbers after having their blood pressure taken both under and distal to the cuff.' He notes that the petechial hemorrhages are similar to sub- cutaneous hemorrhages seen in capillary resistance studies.   
Swank RL. Subcutaneous hemorrhages in multiple sclerosis. Neurology. 1958; 8: 497-498.

Jeff's hypercoagulation and petechiae were related to his MS.  Dr. Swank did not have the science of nitric oxide as EDRF in his time, but modern researchers have since connected hypercoagulation and clotting proteins as evidence of endothelial dysfunction and a break down of the blood brain barrier, and activation of the coagulation cascade.  This research comes decades after Dr. Swank's discoveries, but confirms what he saw as "blood vessel fragility."  We now know that endothelial dysfunction and a break in the BBB will affect the blood through out the body.  Once the coagulation cascade is activated, it is systemic.  And these extravasated red blood cells will leak and appear throughout the body.  Just like Jeff's petechiae--and the break in his blood brain barrier.

The disruption of integrity of the walls of brain blood microvessels rapidly activates the coagulation cascade. 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268209/

The coagulation cascade plays a major role in the development of an inflammatory response in MS.
http://circres.ahajournals.org/content/110/9/1157.extract#

Other researchers have noted hypercoagulation and high fibrin levels in the blood of pwMS for decades.  But these markers have been largely ignored.  Until recently.
Here's more on this research from the Gladstone Institute.

A protein involved in blood clotting may be a new indicator to help detect multiple sclerosis (MS) lesions before symptoms arise. The presence of the clotting protein, thrombin, signals an early stage of the disease when the blood-brain barrier is breached and the brain’s immune response is set into motion. The research was presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health. 

The researchers found that thrombin, usually a beneficial protein involved in blood clotting, builds up in the central nervous system as MS progresses. Thrombin enters in the brain together with fibrinogen, another clotting protein when the protective barrier between the blood and brain becomes leaky. Thrombin converts the fibrinogen to fibrin which activates brain’s immune cells that break down the protective myelin sheath that surrounds neurons in the central nervous system. Because thrombin levels increase as the disease progresses, the researchers conclude that it could be used as an early detector of the disease. 
http://www.bioquicknews.com/node/1420

More researchers are noting this break in the endothelium, and detecting these microscopic bleeds in the MS brain.  At the ISNVD conference, Dr. Yulin Ge recently discussed how 7T MRI technology is allowing us to see tiny hemorrhages in the MS brain which occur before demyelination.  This further elucidates the microvascular connection to MS.
From his abstract at the ISNVD:

Being the most common demyelinating disease of the central nervous system, multiple sclerosis (MS) MS has a significant microvascular pathological component as a consequence of the perivascular inflammation. The role of vascular pathology in MS was suggested long ago. Now there is accumulating evidence of a primary vascular pathogenesis in MS. In vivo studies of vascular and hemodynamic impairment in MS may provide insights into the etiology and pathophysiology of MS and offer the potential metrics for assessment of outcome of the disease. 

Canadian microbiologists have recently published a paper on the iron around MS lesions, and link it to the vasculature and "chronic extravasation of hemoglobin", or microbleeds causing oxidative stress in the brain. 
http://www.ncbi.nlm.nih.gov/pubmed/24504127

Dr. Zamboni saw the parallels of venous disease of the legs and MS, and wrote about iron deposition and the inflammatory response in his 2006 publication,
The Big Idea: Iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633548/

These researchers would tell you that blood matters.  When red blood cells enter brain tissue, there are serious repercussions--including oxidative stress, inflammation, iron deposition and an upregulation of clotting proteins.   Why does the blood brain barrier become leaky, and allow plasmic particles access into brain tissue? The exact mechnism is not known, but it appears to be related to endothelial dysfunction.  It may be venous hypertension, lack of shear stress, and hypoxic injury created by CCSVI which is compounded by environmental factors like diet, exercise, stress, UV rays, viral and bacterial infections and smoking.  We need more research.

MS researchers ignore this connection at the peril of their patients' brains---and lives.
I'll keep writing about it, until the day when neurologists understand the connection of the red blood spots I saw on Jeff's legs, the lesions in his brain and spine, and his MS diagnosis.
Joan

Fibrinogen---found In ALL neurodegenerative diseases, not just MS

December 4, 2012 at 9:29am

The "news" this week was that fibrinogen, an essential clotting protein, crosses over the blood brain barrier in the mouse model of MS and initiates the disease process by destroying nerve cells.  

Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation

http://www.nature.com/ncomms/journal/v3/n11/full/ncomms2230.html

But this isn't news.  Researchers have been studying this process in neurodegenerative disease for a decade.  Because this process happens when the blood brain barrier breaks down.

The overall findings from study of Alzheimer's Disease brain tissue and in vivo in Abeta(1-42) and Abeta(1-42) plus fibrinogen stimulated rat hippocampus suggest microglial responses to promote increased extravasation of blood protein as a critical component in amplifying inflammatory reactivity and causing neuronal damage in inflamed AD brain.

http://www.ncbi.nlm.nih.gov/pubmed/18657226

Fibrinogen is a pleiotropic blood protein that regulates coagulation, inflammation and tissue repair. Fibrinogen extravasates in the nervous system after injury or disease associated with vascular damage or blood-brain barrier (BBB) disruption. Fibrinogen is not merely a marker of BBB disruption, but plays a causative role in neurologic disease as a potent inducer of inflammation and an inhibitor of neurite outgrowth. Fibrinogen mediates functions in the nervous system as a ligand for cell-specific receptors. In microglia, fibrinogen mediates activation of Akt and Rho via the CD11b/CD18 integrin receptor, while in neurons fibrinogen induces phosphorylation of epidermal growth factor (EGF) receptor via the alphavbeta3 integrin. Pharmacologic targeting of the interactions of fibrinogen with its nervous system receptors could provide novel strategies for therapeutic intervention in neuroinflammatory and neurodegenerative diseases.

http://www.ncbi.nlm.nih.gov/pubmed/19630789

Why the race for researchers to understand fibrinogen?

Because pharma wants to monetize a way to block it.

That's right....researchers are not studying WHY fibrinogen is breaking through the blood brain barrier.  No one is looking at causation.

Everyone is studying this to find a pharmacological means of stopping fibrinogen.

But, what if there is an underlying mechanism which begins fibrinogen activation in all neurodegenerative disease?

Wouldn't that be something to study?  Wouldn't that be causation, and lead to potential answers in disease aetiology?

Here's a paper I researched and wrote up for CCSVI Alliance on the discovery of CCSVI in other neurological disease.  It proposes the mechanism found in common with CCSVI in neurodegenerative disease.  Slowed cerebral bloodflow.

http://www.ccsvi.org/index.php/the-basics/ccsvi-in-other-neurological-diseases

HYPOPERFUSION.   A mechanism found in all neurodegenerative disease, which starts fibrin deposition in the brain. This is being studied by stroke researchers.  A decline in cerebral bloodflow initiates fibrin deposition in the brain immediately.

One of the most surprising findings of the present study is that the decline of cerebral blood flow (CBF) in conjunction with hypoxia is sufficient to induce rapid microvascular thrombosis and fibrin deposition within the brain (Figure 9). By analyzing challenged fibrinogen-null mice we have established that fibrin(ogen) plays an important role the reperfusion deficits and brain infarction (Figure 10). These results suggest that if cerebral ischemia is accompanied with hypoxia, this combination can precipitate local coagulation and impede reperfusion after ischemia, similar to the previously described no-reflow phenomenon after cerebral ischemia5 and cardiac arrest.56 It seems likely that fibrin stabilization of platelet thrombi is a major determinant of brain tissue damage. If so, we would predict that a similar, if not more impressive, protection from tissue damage could be realized in mice with a profound defect in platelet function. It is also conceivable that fibrin-mediated inflammatory processes drive secondary tissue damage in the brain. Thus, the modified Levine/Vannucci model described here may be useful for testing new therapies to restore postischemic reperfusion in the face of thrombolytic agents and other approaches to reopened large vessels.

Regarding the mechanism of ischemia/hypoxia-induced thrombosis, it seems likely that hypoxia alters the balance between anti- and procoagulation properties of the endothelial cells in cerebral blood vessels. Although focal ischemia can trigger platelet accumulation and fibrin deposition, these events typically show a late-onset after a transient hyperemia phase.49,53 In contrast, the present study shows that the combination of ischemia and hypoxia precipitates these events almost immediately. 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1780162/

Please encourage and support the researchers of the International Society for Neurovascular Disease.  

http://www.isnvd.org

There are only a few groups looking at disease aetiology, or what is causing the disease process.

Blocking fibrinogen won't cure MS.  

Understanding why there is fibrinogen in brain tissue may.

Joan

What's blood got to do with it?

Nov. 27, 2012  10:17 AM

NIH researchers find that fibrinogen appears to be "the trigger" which begins neurodegeneration in MS.

http://www.nih.gov/news/health/nov2012/ninds-27.htm

Researchers are honing in on fibrinogen as a mediator in vascular disease, and they are also finding a link in MS.

Fibrinogen is always present in the blood.  The normal range is 200 - 400 milligrams per deciliter (mg/dL).

Fibrinogen is a protein which is made in our livers.  It's the signaling protein for fibrin, which allows our blood to clot.  When people develop venous ulcers on their legs, due to chronic venous insufficiency, it's fibrinogen that leaks from the veins and creates a build up of fibrin, depleting the tissue of oxygen and allowing those hallmark ulcers to form.  This is called a "fibrin cuff."  It's fibrinogen which initiates the coagulation cascade and causes our blood to thicken, as a response to low oxygen levels.

Dr. Zamboni was the first to suggest that MS lesions looked a lot like venous ulcers because of the fibrin cuffs found in both sites of injury.  

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633548/

And researchers have noted that fibin deposition comes FIRST, before demyelination.

Here is some recent research on this connection:

Compromised vasculature in the nervous tissue is a pathogenic manifestation apparent in traumatic injuries, such as spinal cord, optic nerve, and sciatic nerve injury, as well as in central nervous system (CNS) diseases with autoimmune characteristics, such as multiple sclerosis (MS) (7). 

Blood-brain barrier (BBB) disruption precedes clinical symptoms in MS patients (8), and fibrin is deposited in the lesions (9, 10), apparently before cerebral tissue injury and demyelination (11). Fibrin deposition also coincides with areas of demyelination (12), as well as with areas of axonal damage.

http://www.pnas.org/content/101/17/6698.full

From Dr. Putnam to Astrocytes--MS as a Vascular Disease

June 22, 2012 at 12:04pm

For those who haven't had a chance to read about the history of the beginnings of the MS Society and the founding neurologist, Dr. Tracy J Putnam---here's a bit of background on the vascular history of MS.
http://ccsviinms.blogspot.com/2012/06/dr.html

The very latest research into multiple sclerosis is discovering what Dr. Putnam hypothesized. MS is created by a response from the vascular system to injury. 

New research, published this month, continues Putnam's thesis, at the cellular level.

Something is signaling the vascular cells in the brain.

Here's how it works.

Astrocytes are beautiful, star-shaped cells that live in the central nervous system. ( I love the fact that our smallest cells look like the largest bodies in our solar system.  There's wonderful symmetry in creation.)

Astrocytes are the most abundant cell in the human brain.  One of the most important things astrocytes do is support the endothelial cells in our brain, and maintain the very important blood brain barrier. The blood brain barrier should have tight junctions, that don't allow blood particles into brain or spinal tissue.  (For those new to the idea of the endothelium, please check out the Endothelial Health program I made for Jeff.  It will explain how MS and our blood supply are connected.)

http://www.ccsvi.org/index.php/helping-myself/endothelial-health

Researchers have recently noted that when the brain is subject to hypoxia, or low levels of oxygen, the blood brain barrier becomes open, or "permeable."  This allows infiltration of blood cells and the immune system, which create damage to the brain.  Please notice that if the blood brain barrier was not open, T and B cells would not have entry.  The immune system isn't just going into the brain, uninvited and without cause.  The gate is wide open.

Blood brain barrier (BBB) permeability is an early and prominent feature of inflammatory CNS conditions, including MS (13), viral encephalitis (14), and traumatic and hypoxic/ischemic injury (15). BBB disruption correlates with neurologic exacerbation, and MS patients with contrast-enhancing plaques are more likely to have irreversible pathology (13, 16). BBB breakdown leads to edema, metabolic imbalance, excitotoxicity, and ingress of factors that potentiate inflammation and inhibit repair (17–20) and facilitates infiltration of T and B lymphocytes, macrophages, and neutrophils (21). In diseases such as MS, current options to restrict relapse severity are limited, and patients may benefit from more selective agents (22).

What is going on?  What signals the astrocytes to open the gate?  Researchers are looking specifically at VEGF--vascular endothelial growth factor.

Studies have identified astrocytes as regulators of BBB induction and maintenance (9–11) and have implicated astrogliosis, particularly induced by IL-1, as a driver of both BBB breakdown and repair (10, 12, 48). The mediators producing the effects of reactive astrocytes are incompletely characterized, and our data revealed VEGF-A as an important astrocyte-derived inducer of BBB disruption and pathology in vivo. Although VEGF-A–induced vascular permeability has previously been implicated in pathogenesis of disorders, including myocardial infarction, CNS hypoxia/reperfusion injury, and tumor growth and metastasis (49), and we and others have previously speculated on its role in BBB breakdown (12, 26), this study is the first to our knowledge to show the significance of astrocyte-derived VEGF-A in lesion pathogenesis and generation of clinical deficit in models of CNS inflammatory disease.

http://www.jci.org/articles/view/60842

This is the first study that has noted the importance of astrocyte derived VEGF in the formation of lesions and brain damage in a model of MS.

Please note the other diseases that have VEGF created "vascular permeability"--hypoxia and myocardial infarction--are vascular diseases.  VEGF-a is activated in situations where there is low oxygen, and the organ begins to suffer the effects of low O2.

So, what is VEGF and why does it matter in MS?  

Vascular endothelial growth factor (VEGF) is a chemical signal produced by cells that stimulates the growth of new blood vessels, called "angiogenesis."  This is part of a system which restores the oxygen supply to tissues when blood circulation is inadequate.

VEGF's normal function is to create new blood vessels during embryonic development, new blood vessels after injury, and new vessels (collateral circulation) to bypass blocked vessels.

Here is a rather pejorative look at the vascular connection, written in a condescending tone by a group of German Neurologists-- 

Vascular pathology in multiple sclerosis: mind boosting or myth busting?

The idea of MS being a vascular disease is not new. In the 1930s T.J. Putnam proposed venous obstruction as the primary alteration in MS [7]. Given the venotopic localization of MS plaques, this hypothesis has been discussed on and off ever since. In 2007 an Italian group headed by P. Zamboni added new fuel to the fire by demonstrating that venous blood flow alterations can be found at a high frequency in MS patients [5]. 

While the concept of CCSVI has gained much attention in the field of MS research and in particular among MS patients, there is increasing evidence that the relation of venous changes to the pathophysiology of MS may not be as simple as initially described. Most importantly, new MR imaging techniques add to the notion of vascular changes in MS, yet again raise doubts whether these alterations are cause or rather consequence of the disease process.

(At the end of the article, the authors state they have nothing to disclose, yet all of them have participated in many MS drug trials. Drugs which are based on the EAE immune model of MS-  Dr. Linker has received personal compensation for activities with Bayer Health Care, BiogenIdec, Merck Serono, Novartis and TEVA Pharma. Dr. Linker has received research support from BiogenIdec, Novartis and TEVA Pharma.)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156723/?tool=pubmed

Why is it only neurologists who believe some "mystery mechanism" disease process is behind VEGF activation, blood brain barrier disruption and inflammation---when we have other models of vascular disease in vivo, such as stroke, which illustrate how hypoxic injury creates this scenario? 

If MS specialists want to continue to pretend there is no vascular involvement in MS, and that MS is a disease of a mysterious and crazed immune system,  they can keep saying it-- and creating, testing and selling the drugs.  But the truth is, all of the research continues to point to the importance of the endothelium and the vascular response of the body to injury of the brain.  

What's causing the injury?  Slowed flow through the brain, hypoperfusion, low O2 and glucose levels from collateral venous return?   Makes sense to me.   More to come.

Joan

CCSVI and the blood brain barrier--new research

February 2, 2012 at 8:56am

New research is showing us how the blood brain barrier functions.  Our understanding of what this barrier is and how it works has changed.

We may not see this happening in our neurologists' offices, or in the press, but it is important to understand that independent researchers (those with no connection to pharma) are looking at how CCSVI impacts the blood brain barrier.  I want to share this as encouragement. 

This is from an article written by K.K. Jain, MD on Medlink.  It was originally released in 1998, but Dr. Jain updates this article, as new research emerges.  The last update was in 2011.  

And now it includes CCSVI.  

Professor Jain is a nanotechnology and neurological expert, and serves as associate editor of Medlink Corporations online encyclopedia of neurology.

For over a century it has been recognized that the entry of certain substances into the brain is restricted. The old concept of the blood-brain barrier as a passive, impermeable barrier that segregates blood and brain interstitial fluid is giving way to the idea that the blood-brain barrier is a dynamic conduit for transport between blood and brain of those nutrients, peptides, proteins, or immune cells that have access to certain transport systems localized within the blood-brain barrier membranes.

When the BBB was first described in the 1800s, it was thought to be an impassible wall between blood, cerebrospinal fluid and brain tissue.  But we now understand:

 Key points

  • The blood-brain barrier is an important conduit of nutrients and cells from the blood to the brain.

  • It also has an important function in protecting the brain from the entry of harmful substances.

  • Knowledge of impairment of permeability of the blood-brain barrier in various neurologic disorders is important in understanding the pathomechanisms and devising strategies for management.

  • Permeability of the blood-brain barrier is manipulated for drug delivery to the brain.

Contrast-enhanced MRI in patients with multiple sclerosis show that increased permeability of the blood-brain barrier commonly occurs with this disease. Lymphocyte recruitment into the brain across endothelial cells of the blood-brain barrier, which is otherwise restricted and well regulated, represents a critical event in pathogenesis of multiple sclerosis (Correale and Villa 2007). The changes in capillary permeability often precede T2-weighted MRI evidence of tissue damage. Increased gelatinase B (a type of matrix metalloproteinase) is associated with an open blood-brain barrier on MRI. Steroids may improve capillary function by reducing activity of gelatinase B.

  Various inflammatory factors produced by perivascular cells in multiple sclerosis affect the permeability of the blood-brain barrier. One of these, the intercellular adhesion molecule-1, binds to its leukocyte ligands and allows activated leukocytes entry into the central nervous system. According to 1 hypothesis, pathological reflux of venous flow in the cerebral and spinal veins increases the expression of intercellular adhesion molecule-1 by the cerebrovascular endothelium, which, in turn, could lead to increased permeability of the blood-brain barrier (Simka 2009).

Specialists of the blood brain barrier and cerebral endothelium understand CCSVI.

Dr. Philip James on CCSVI

June 23, 2011 at 9:20am

Dr. Philip James has been studying MS for the past 30 years in Dundee, Scotland.  He has long been speaking out about the vascular connection to MS, and the importance of oxygenation of the central nervous system.  Here is a recent quote on his interpretation of where MS research "went wrong."

 "The recent publicity given to the work of Professor Paolo Zamboni has highlighted a growing disaffection with the concept of ‘auto’ immunity which has dominated MS research and treatment for more than half a century. Zamboni trained as a vascular surgeon specializing on problems of leg veins, which often leak as we age, allowing red blood cells into the surrounding tissues. When the red cells break down they liberate iron which causes damage to the walls of veins and the surrounding cells. Similar damage was found in the veins in the centre of the typical ‘plaques’ of multiple sclerosis as long ago as 1863.

However, the use of an animal model for MS research after WW2 led to the concept of auto immunity where, it is claimed, the immune system attacks normal tissue. Despite sixty years of research there is no evidence of this and it remains just a theory. What is certain is the damage in MS involves veins and inflammation and Professor Zamboni has focused on these proven observations. He noticed, when using ultrasound scanning of the neck in a Multiple Sclerosis patient, that blood flowed the wrong way in a vein and also that the vein appeared to be constricted.

After more investigations he has used the same procedure used to stretch arteries in the heart to relieve the vein constrictions. Several patients have found the procedure beneficial, greatly reducing their symptoms although stretching the veins will not affect existing scarring. There has been no indication of why the veins constrict, although increased ‘reactivity’ of blood vessels has been reported before in MS patients.

Professor Zamboni’s work has highlighted the importance of the blood-brain barrier. Oxygen is responsible for the genetic control of inflammation and lack of oxygen has been shown in affected areas in MS patients by brain imaging. Neurologists are likely to remain sceptical of vein stretching until a ‘controlled’ study is done in which a sham procedure is used and compared to a group of matched patients who have the real procedure undertaken."

- Philip B James MB ChB DIH PhD FFOM

Emeritus Professor of Medicine University of Dundee

Honorary Medical Adviser MS Therapy Centres.

Zonulin and gluten: the link to the blood brain barrier

May 18, 2011 at 2:49pm

Dr. David Hubbard discussed research into zonulin in his presentation at the Hubbard Foundation conference.  As many of you know, the Hubbard Foundation recommends a gluten-free diet to maintain endothelial integrity and a healthy blood brain barrier.

http://www.hubbardfoundation.org/nutrition

Another neurologist named David--Dr. David Perlmutter-- also recommends a gluten free diet.  Here is his newly published book, Grain Brain  http://drperlmutter.com/about/grain-brain-by-david-perlmutter/

So, what is gluten? Gluten is a special type of protein that is commonly found in rye, wheat, and barley. Therefore, it is found in most types of cereals and in many types of bread. Not all foods from the grain family, however, contain gluten. Examples of grains and seeds that do not have gluten include wild rice, corn, buckwheat, millet, amaranth, quinoa, teff, oats, soybeans, and sunflower seeds.

If you're like me, you've probably wondered, "What the heck does gluten have to do with the brain?"

Well, there is a very interesting connection, and it's based on research being done at the University of Maryland on a protein called zonulin.