Welcome! This blog contains research & information on lifestyle, nutrition and health for those with MS, as well as continuing information on the understanding of CCSVI and cerebral hypoperfusion. This blog is informative only--all medical decisions should be discussed with your own physicians.

The posts are searchable---simply type in your topic of interest in the search box at the top left.

Almost all of MS research is initiated and funded by pharmaceutical companies. This maintains the EAE mouse model and the immune paradigm of MS, and continues the 20 billion dollar a year MS treatment industry. But as we learn more about slowed blood flow, gray matter atrophy, and environmental links to MS progression and disability--all things the current drugs do not address--we're discovering more about how to help those with MS.

To learn how this journey began, read my first post from August, 2009. Be well! Joan

Monday, February 24, 2014

KIR4.1 antibodies and the big picture


The American Academy of Neurology will be meeting in Philadelphia from April 26-May 3.  In advance of this meeting, some press releases are being sent out.  Apparently, the BIG NEWS in MS research is KIR4.1 antibodies are present in about half of the plasma samples from patients with a pre-clinical diagnosis of MS patients, and this could be a diagnostic and treatment target.  According to research by the Technical University in Munich-

The researchers found that KIR4.1 antibody titers were significantly higher for pre-clinical MS patients than healthy controls (P = 0.0185). Seven of the pre-clinical patients were considered KIR4.1 antibody positive, while two had borderline activity and seven were found to be negative. All healthy controls were also KIR4.1 antibody negative. In the longitudinal analysis, pre-clinical MS patients had KIR4.1 antibodies several years prior to the first clinical attack. In individual pre-clinical MS patients, antibody titers varied at different time points. There was no significant difference in titers before and after disease onset


But research into KIR4.1 antibodies is not new....nor is it exclusive to MS.  
We see the same immune reaction to KIR4.1 in hydrocephalus and cerebral edema.

A paper published in the New England Journal of Medicine in 2012 was the first research to identify the immune reaction to KIR4.1 in MS.

Researchers tested the IgG levels in the blood of people with MS and found a very specific reaction to the protein KIR4.1. 

And the researchers found there was an antibody, or immune system, response to KIR4.1

KIR4.1 is a potassium channel protein which is vitally important to myelination, neuronal plasticity and the inflammatory response.  KIR4.1 is a good guy.  

Let's get an understanding of what the researchers found.  IgG stands for Immunoglobin G, which is the main antibody found in our blood.  Antibodies are major componants of the immune system.  When something is presented in the body that is seen as foreign, like a virus or bacteria,  the immune system goes after the invader, and the white blood cells produce an antibody. This antibody is like a footprint marker leading back to the "invader"---it can tell us what the body sees as foreign.  This can also happen if a protein or plasmic particle ends up on the wrong side of the blood brain barrier.  It doesn't mean the body is having an "autoimmune reaction."  In this case, the body sees the good guy, KIR4.1, as an invader.

We screened serum IgG from persons with multiple sclerosis to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane proteins, we identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of the IgG antibodies. We used a multifaceted validation strategy to confirm KIR4.1 as a target of the autoantibody response in multiple sclerosis and to show its potential pathogenicity in vivo. 

When KIR4.1 serum IgG was injected into cisternae magnae of mice, there was an alteration of glial fibrillary acidic protein and loss of KIR4.1 expression, suggesting that "multiple sclerosis-specific anti-KIR4.1 serum IgG can recognize its target antigen in the CNS and induce structural damage to glial cells," Hemmer et al say.

In a related editorial, Anne Cross (Washington University, St Louis, Missouri, USA) and Emmanuelle Waubant (University of California, San Francisco, USA) describe KIR4.1 as "an unexpected but plausible antigenic target."
They note that while autoantibodies do not play a primary role in MS pathology, they may perpetuate the breakdown of the CNS, which is a hallmark of the disease.

So, my question is---Where else do we see this happen??
What is going on?  Why is this happening?  How did KIR4.1 become identified as a bad guy?

And by using pub med, I find out that this reaction towards KIR4.1 occurs in brains with hydrocephalus and edema.  
KIR4.1 is a protein which is involved in "water flux" or water transport.
If it shows up where it isn't supposed to, the immune system becomes activated.

In this research, in cytotoxic edema, KIR4.1 becomes "mislocalized."  It goes where it should't go.   Perhaps it is the involvement of this protein in the break of the blood brain barrier which creates the immune reaction for some in MS, when KIR4.1 appears in brain tissue??

In this paper, KIR4.1 is upregulated in edema.
In normal brain tissue, AQP4 and Kir4.1 were detected around the microvessels. In pathological brain tissue, AQP4 was upregulated in astrocytes in oedematous regions and Kir4.1 was upregulated in astrocytes in damaged brain. 

In this research, there is immunoreactivity to KIR4.1 in the swollen astrocytes surrounding brain tumors
In normal brain, Kir4.1 was seen around microvessels (fig 1B1B),), in the glia limitans/pia (fig 1E1E),), and in occasional neurones in cortical layers I and II (fig 1E1E insert). In brain contusion (fig 2B2B)) and brain surrounding carcinoma and oligodendroglioma, Kir4.1 expression was also seen around microvessels. Kir4.1 was upregulated in astrocytes in bacterial meningitis (fig 2E2E),), contusion (fig 2B2B),), and in carcinoma (fig 2H2H),), oligodendroglioma (fig 2K2K),), and glioblastoma cells (fig 22N).N). Gemistocytes in glioblastoma showed pronounced Kir4.1 immunoreactivity (fig 2N2N insert).
And in this study in rats with hydrocephalus, there is an immune reaction to KIR4.1

Hydrocephalus is characterized by impaired cerebrospinal fluid (CSF) flow with enlargement of the ventricular cavities of the brain and progressive damage to surrounding tissue. Bulk water movement is altered in these brains. We hypothesized that increased expression of aquaporins, which are water-permeable channel proteins, would occur in these brains to facilitate water shifts. We used quantitative (real-time) RT-PCR, Western blotting and immunohistochemistry to evaluate the brain expression of aquaporins (AQP) 1, 4, and 9 mRNA and protein in Sprague–Dawley rats rendered hydrocephalic by injection of kaolin into cistern magna. AQP4 mRNA was significantly up-regulated in parietal cerebrum and hippocampus 4 weeks and 9 months after induction of hydrocephalus (P < 0.05). Although Western blot analysis showed no significant change, there was more intense perivascular AQP4 immunoreactivity in cerebrum of hydrocephalic brains at 3–4 weeks after induction. We did not detect mRNA or protein changes in AQP1 (located in choroid plexus) or AQP9 (located in select neuron populations). Kir4.1, a potassium channel protein linked to water flux, exhibited enhanced immunoreactivity in the cerebral cortex of hydrocephalic rats; the perineuronal distribution was entirely different from that of AQP4. These results suggest that brain AQP4 up-regulation might be a compensatory response to maintain water homeostasis in hydrocephalus.

Could it be that CCSVI creates venous congestion--a situation akin to normal pressure hydocephalus--with swelling and an interruption in cerebral spinal fluid causing a break in the blood brain barrier, and this activates the immune reaction to KIR4.1??  

Here is a recent paper looking at the body's reaction to aquaporins and damage to the brain in other neurodegenerative diseases, including NMO and Alzheimer's.

Thus, it is reasonable to predict that changes in potassium channel (Kir 4.1 channels) function may alter brain homeostasis leading to brain impairment. Water movement via the AQP4 water channel localized to astrocyte end-feet maintains osmotic balance and promotes effective potassium siphoning [71]. 

In a recent paper, Wilcock and colleagues [97] studied the effects of amyloid accumulation at cerebral vessels on the NVU, using a transgenic mouse model that show amyloid deposition, tau pathology and neuronal loss. Transgenic mice with high levels of CAA have significant reductions in AQP4 and Kir4.1 positive staining associated with the blood vessels. A potential explanation for the loss of AQP4 and Kir4.1 channels is that they share a common anchoring protein that is affected by vascular amyloid deposition: the Dp71 dystrophin protein, localized on perivascular astrocytes [40]. Dystrophin is associated with dystroglycan, which in turn, associates with syntrophins: genetic deletion of syntrophin has resulted in mislocalization of AQP4 [72] and decreased perivascular Kir4.1 channel expression [25]. Thus, changes in dystrophin levels and function may, in part, explain the loss of AQP4 from the astrocyte end-feet as well as the reduction in levels of Kir4.1 channels in mice that express high levels of CAA. Moreover, in support to this hypothesis, Wilcock and colleagues found that gene expression of Kir4.1, AQP4 and dystrophin were significantly reduced also in human post-mortem diagnosed AD brain with moderate and severe CAA.

Together, these findings show increased expression of water channels in the brain in human and animal prion diseases that may have implications in the regulation of water transport in astrocytes and may account for an imbalance in water and ion homeostasis. Although change in AQPs expression may be a secondary change of TSE pathologies, it may reflect important aspects of astrocytic pathology associated with these diseases.

Which means the immune reaction to KIR4.1 in MS could very well be a secondary reaction, due to changes in the water channels in the MS brain--and not "auto-immune."

The discovery of this antigen does not mean it is a primary reaction.  Nor does it mean that blocking the antigenic response will help people with MS.  The fact that it is not found with 100% specificity in MS means there are more questions about the relevance of this discovery. 

MS researchers--we beg you, ask the big questions, look at the big picture.
If lay people can do this, surely you should be able to, as well.
Joan




Monday, February 10, 2014

Endothelin 1-- More vascular evidence

In the news--- Newly discovered peptide, blocks remyelination!!   Stopping this process repairs MS damage.  
http://www.natureworldnews.com/articles/5951/20140208/study-identifies-protein-inhibits-brain-tissue-repair-ms-patients.htm

What's this "new" peptide we want to block?   
It's called endothelin-1 or ET-1, and it's released by the astrocytes maintaining the endothelial layer of your blood brain barrier.
http://www.cell.com/neuron/abstract/S0896-6273(13)01083-0

We've known about ET-1 for years.  It's not only found in MS.
Endothelin-1 is raised in situations where there is endothelial distress.  When endothelial cells are hurt by ischemia and oxidative stress, and nitric oxide levels are low.  ET-1 creates vasoconstriction,  is pro-inflammatory, pro-fibrotic and slows blood flow.  Which would explain why it inhibits remyelination. Yet not one single press release on this exciting new MS discovery mentioned this important fact, or what causes ET-1 levels to be high in the first place.

As you might expect, plasma ET-1 levels are very high in ischemic stroke.
http://stroke.ahajournals.org/content/23/7/1014.full.pdf

ET-1 released by astrocytes is seen after subarachnoid hemorrhage
http://www.biomedcentral.com/1471-2202/14/131

Serum levels of ET-1 are used as a marker of cerebral ischemia
http://www.intmed.ro/attach/rjim/2010/rjim410/art06.pdf

And Endothelin 1 serum levels are through the roof in people with MS----

The plasma ET-1 levels were, on average, 224% higher in the patients with MS than in the controls (p < 0.005). The mean ET-1 levels (mean +/- standard deviation [SD]) were 3.5 +/- 0.83 pg/mL (min 2.13, max 5.37 pg/mL) in patients with MS and 1.56 +/- 0.3 pg/mL (min 0.9, max 2.13 pg/mL) in healthy volunteers. Neither the different forms nor stages of MS had an influence on the results. The ET-1 level was also not correlated with the duration of the disease.
http://www.ncbi.nlm.nih.gov/pubmed/11315981

In fact, researchers have been looking at ET-1 for many years.
Here are some MS researchers that found that hypoperfusion in MS was related to ET-1 levels.  They used an ET-1 inhibitor called Bosentan, which increased cerebral blood flow.  (Bosentan is a high blood pressure medicine, which can be toxic to the liver.)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619305/

Why are MS researchers reticent to fully explore  the connection of extracranial venous obstruction to hypoxic/ischemic conditions in the brain?   I'm sure I don't need to reiterate this, but this ET-1 "breakthrough" may well be caused by Dr. Zamboni's discovery of restricted venous return.

The truth is, the best way to lower ET-1 levels might be to increase nitric oxide levels yourself.
High ET-1 levels are a sign that your nitric oxide supply is too low.
http://www.ncbi.nlm.nih.gov/pubmed/21368267

While we are waiting for that Breakthrough Drug! ™ 
here are some things you can do for free, on your own, to potentially increase your cerebral perfusion, remyelinate your brain, raise your NO levels and lower your ET-1 levels.



EXERCISE 
The present study suggests that exercise causes an increase in production of NO and a decrease in production of ET-1 in humans, which may produce beneficial effects (i.e., vasodilative and antiatherosclerotic) on the cardiovascular system.
http://www.sciencedirect.com/science/article/pii/S0024320501011924


EAT MORE FLAVONOIDS (fruits and veggies)
Epidemiological evidence demonstrates that diets rich in fruits and vegetables benefit heart and vascular health.() Molecularly, these beneficial effects of fruits and vegetables have been largely ascribed to their content in flavonoids. These compounds are synthesized in many edible plants and remain present when plants are processed to foods. Grapes and wine, cocoa and chocolate, black and green tea, and soy and soy-derived products, are among the most important sources of flavonoids in the human diet.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022066/

Dietary flavonoids, such as quercetin and (-)-epicatechin, can augment nitric oxide status and reduce endothelin-1 concentrations and may thereby improve endothelial function.
http://www.ncbi.nlm.nih.gov/pubmed/18842789


EAT MORE POLYUNSATURATED FATS (from nuts, seeds and fish)
Serum levels of ET-1 were positively correlated with saturated fatty acids (SFAs, r = 0.257; P = 0.025) and negatively correlated with polyunsaturated fatty acids (PUFAs, r = -0.319; P = 0.005). http://www.ncbi.nlm.nih.gov/pubmed/18702940


WATCH YOUR WEIGHT
These results demonstrate that overweight and obesity are associated with enhanced ET-1-mediated vasoconstriction that contributes to endothelial vasodilator dysfunction and may play a role in the increased prevalence of hypertension with increased adiposity.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191085/


Here are some more ideas on how to address endothelial dysfunction.  Always discuss any new health regimen with your own physician.
http://ccsvi.org/index.php/helping-myself/endothelial-health


There are things we can control, and things we can't.
There are ways to boost your nitric oxide levels, lower you ET-1 levels and potentially improve your health.  While researchers continue to look for ways to mediate the vascular connection to MS without mentioning or exploring the vascular connection to MS....
take control.

Joan









Sunday, February 9, 2014

ISNVD 2014--the big picture

Jeff and I are home from the intense sessions at the fourth annual International Society for Neurovascular Disease (ISNVD) conference.  We both commented that it was like being back in college---the amount of information presented was impressive and challenging, and by the end of the day, our brains were quite literally fried.  We are very thankful to Dr. Michael Dake, the current president of this group, for allowing non-medical folks (I call us the "laity") to sit in on the presentations.  It is very informative for those of us with "skin in the game" to hear where the research is going.

I had a chance to sit down with Dr. Paolo Zamboni and discuss the developments of the past five years.  It was September 2009, when we first met and talked about CCSVI research, at the Bologna conference.  Much has changed since that time, yet one fact remains the same---

We know that the extracranial venous system contributes to neurodegenerative disease, and in many cases, venoplasty to relieve CCSVI can improve neurological symptomology, by increasing cerebral perfusion and cerebrospinal fluid flow.

For those waiting for venoplasty treatment, the progress has been painfully slow, full of delays and frustration.  (The FDA approval of the Hubbard Foundation CCSVI registry is one beacon of good news!)  While many of these delays have seemed like simply a waste of time, some of the delays have helped the researchers understand the larger picture of cerebral hemodynamics--and the skeletal, muscular and truncular venous malformations which may contribute to restricted venous return.

We now know that CCSVI can affect those with Parkinson's and other neurodegenerative diseases.  This is not simply a problem in multiple sclerosis.  The diversity of specialties represented by the conference faculty was indicative of this change.  There were specialists in Alzheimer's research, traumatic brain injury, migraine,  panic attacks, stroke, TIA, and other neurovascular conditions.  All spoke of the vascular connection to their research, and the importance of the venous side of blood flow.  The jugular veins got a lot of attention---something that is a new development, thanks to Dr. Zamboni!

Participants heard research presentations on the cellular level of the endothelium in Alzheimer's disease process, where endothelial dysfunction begins prior to amyloid plaque formation.  Endothelial dysfunction is also implicated in the vascular connection to MS, where an increase of iNOS and a break in the blood brain barrier leads to inflammation and neurodegeneration.

There are still debates as to how to treat CCSVI--whether venoplasty is the best or only way.  I had a few opportunities to discuss the importance of lifestyle with Dr. Paula Grammas.  I first reached out to Dr. Grammas after reading her impressive research on endothelial dysfunction in Alzheimer's Disease.  Dr. Grammas considers the beta amyloid plaques, which have become the only focus of Alzheimer's research, to be a potential symptom of a larger problem--the miscommunication of endothelial cells.  I introduced her to the ISNVD, and was so pleased to hear her give the keynote presentation this year.

Dr. Grammas is a warm and thoughtful woman.  She was a pleasure to talk to. We discussed the anti-angiogenesis drugs that she will be looking at in clinical trials.  But we also discussed "the things we can change" today, in our own lives, without needing a prescription.  There are many known cardiovascular factors which increase our risk for dementia--including smoking, obesity, high cholesterol, inactivity, and stress.  And the best thing we can do for ourselves and our brains is maintain a healthy weight, eat a whole food diet, full of phytonutrients, move every day, not smoke, and reduce stress.  We also talked about the fact that healthy living is not about a "cure" for disease, but a means of prevention of disease progression.  The old adage, "an once of prevention is worth a pound of cure", is being proven in labs around the globe.

It was great to reconnect with friends who are patients and advocates.  The efforts of volunteers like Carol Schumacher and Sharon Richardson cannot be praised enough.  The doctors are always happy to see their patients---Dr. Dake was thrilled to see Jeff doing so well, and to hear him playing his trumpet at the ISNVD Gala.  It was a pleasure to see our Canadian friends--including journalists Avis Favaro and Anne Kingston.

I was thankful to have Jeff with me---for him to see the part of my world and work that has consumed much of my free time during the past five years.  As a friend commented, this research isn't "really his thing."  He is thankful for it, but it hasn't preoccupied him in the same way.  However, Jeff was touched and honored to sit with Dr. Zamboni, to hug and visit with other people with CCSVI, and to meet so many of the doctors who are changing the paradigm in neurovascular research.  I am thankful every day for his renewed energy, health, and our ability to travel together.  As I huffed and puffed, climbing those famous San Francisco hills, struggling to keep up with Jeff on our brisk daily walk...I marvelled at his health, and recommitted myself to helping other people with MS find hope and healing.

Joan




Wednesday, February 5, 2014

Newly diagnosed are healthier today than a decade ago


Dr. Lawrence Steinman recently made a very interesting comment in an article on vitamin D levels in MS progression. (Dr. Steinman, MS researcher and inventor of Tysabri, is now behind the upcoming clinical trial of Lisinopril, an inexpensive generic blood pressure medication, as a treatment for MS.)
 http://ccsviinms.blogspot.com/2013/08/medications-for-ms-addressing-blood.html


Dr. Steinman noted that there has been a decrease in relapse rates in the placebo end of MS drug trials over the last decade.


"I might wonder if these data might explain the progressive decrease in relapse rate in the placebo arm of clinical trials of MS over the past decade. Maybe more and more individuals are aware of vitamin D, and that they are taking vitamin D supplements, thus lowering the relapse rate in placebo arms of trials."
http://www.medpagetoday.com/Neurology/MultipleSclerosis/43899

That's right.

People who are diagnosed with MS today are having less relapses than people diagnosed a decade ago---without being on a disease modifying drug.  These patients were in the placebo end of trials, and not getting the real medication.

What does this mean?  I believe it means the self-help, or "alternative" information is getting out there, thanks to the internet.  People with MS are sharing information, and getting healthier.

When Jeff was diagnosed seven years ago,  I asked his neurologist to test his Vitamin D3 levels.  I had been reading research on Dr. Ashton Embry's website, Direct MS, 
http://www.direct-ms.org  and wondered about the correlation.  His neurologist said it didn't matter.  Neither did diet or exercise.  MS was an immune-mediated degenerative disease, and there were no scientifically proven means, aside from disease modifying drugs, to slow disease progression.  Case closed.  Good luck.

We got Jeff's GP to order the test, although we had to pay for it, since our insurance didn't cover vitamin D testing.  Sure enough, his level was very low at 15ng/mL  He began to get more sunshine exposure, and take a D supplement w/magnesium and zinc, and the next time he was tested, six months later, his level was at 70ng/mL.  He felt better, too.


And today, we have research showing that Vitamin D levels really do make a difference.  So important, that it is now part of my insurance's paid complete blood testing.  This is new!

But I would submit that it's not just about Vitamin D.


We also have Dr. Terry Wahls, Dr. David Perlmutter, and Dr. George Jelinek sharing their knowledge about nutrition and the importance of a whole food diet and exercise with their large online communities. T
here are self help groups on websites like This Is MS and Facebook encouraging healthy lifestyles.  Information for newly diagnosed patients now includes nutrition, exercise, Vitamin D, smoking cessation, and stress reduction--and this advice sometimes even comes from the neurologist or the MS Societies.  I hope I've made a small contribution in discussing the endothelium and vascular connection to MS, and by bringing Dr. Zamboni's research to the states and connecting new doctors to the ISNVD.


What a change from only seven years ago!!


When Dr. Roy Swank first noted what he called "capillary fragility" in the 1950s and designed a diet and exercise program to deal with the hypercoagulated blood he found in his MS patients, he was decades ahead of the discovery of nitric oxide and endothelial health.  His patients had fewer relapses and slower MS disease progression in the era before the DMDs.  His contribution to helping MS patients was called "junk science" and he was labled a quack by neurologists.  Yet 60 years later, we see newly diagnosed RRMS patients incorporating whole food diets, vitamin D and exercise--and doing better.


I've said this before, I'll say it again.  Don't wait for your neurologist to tell you that the "science is finally in."  Take your life and health into your own hands today.  Move every day, eat well, get UV rays and supplement D3, laugh and find ways to reduce stress, don't smoke, get a good night's sleep, take care of yourself.


Because in seven years----it may well be a whole new world,
Joan