Some Interesting Connections

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Some Interesting Connections

Postby Annesse » Tue Aug 06, 2013 7:03 pm

I was doing some research and think I may have stumbled on a few interesting connections.

As some of you know, I believe that MS originates with a lack of enzymes called protease and DNase 1. These enzymes digest dietary DNA and proteins. Protease are also essential for the proper metabolism of vitamin B12 and iron. Specifically the "binding and transport" of vitamin B12. Numerous studies show that patients with MS are unable to properly metabolize vitamin B12. Here are a few studies.

Vitamin B12 metabolism in multiple sclerosis.
Reynolds, E.H., T Bottiglieri, M. Laundy, R.F. Crellin, S.G. Kirker. 1992. Arch Neurol.
49(6):649-52.

“…Patients with MS had significantly lower serum vitamin B12 levels…than neurological and normal controls…There is a significant association between MS and disturbed vitamin B12 metabolism… The cause of the vitamin B12 disorder and the nature of the overlap with MS deserve further investigation.”


In the next study the researchers stated they suspect the vitamin B12 deficiency in MS may be due to problems with binding and/or transport. In addition, the researchers concluded that further studies of vitamin B12 metabolism, binding, and transport in MS are indicated, as they feel this may offer clues to the understanding of MS.

Multiple sclerosis associated with vitamin B12 deficiency.
Reynolds, E.H., J.C. Linnell, J.E. Faludy. 1991. Arch Neurol. 48(8):808-11.

“…A vitamin B12 binding and/or transport is suspected. The nature of the association of multiple sclerosis and vitamin B12 deficiency is unclear but is likely to be more than coincidental. Further studies of vitamin B12 metabolism, binding, and transport in multiple sclerosis are indicated, as these cases may offer a clue to the understanding of a still mysterious neurologic disorder.”


So, I was doing some research on dimethyl fumarate (marketed as Tecfidera, formerly known as BG-12).

Vitamin B12 is necessary to produce fumaric acid and its ester dimethyl fumarate. Fumaric acid is generated by the oxidation of succinate. Vitamin B12 is a crucial component in the conversion of odd chain fatty acids into succinate.
http://www.virtualmedstudent.com/links/ ... inB12.html

I thought that was quite interesting, but also, as the following study states, once fumaric acid is generated it is then converted to maleate. Succinic and malic acids are both important chelators of aluminum. Research has found that patients with MS have higher levels of aluminum (up to 40 times more) than those seen in patients without MS.

Fumaric acid and its esters: An emerging treatment for multiple sclerosis.
D Moharregh-Khiabani,1 R.A Linker,2 R Gold,2 and M Stangel1,*

“Fumaric acid is an intermediate product of the citric acid cycle that is a source of intracellular energy in the form of adenosine triphosphate (ATP). It is generated by oxidation of adenylsuccinate by the enzyme succinate dehydrogenase and is then converted to maleate by the enzyme fumarase..."

Here is a study on MS and aluminum.

http://www.ncbi.nlm.nih.gov/pubmed/17086897

I don't believe aluminum is playing a large role in MS pathogenesis, but I think the connection to vitamin B12, Tecifidera, succinic and malic acid ,and aluminum is quite interesting.

What do you guys think?
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Re: Some Interesting Connections

Postby Annesse » Tue Aug 06, 2013 7:08 pm

Here is a study on malic and succinic acids and aluminum.

Hum Toxicol. 1988 May;7(3):259-62.
Comparative effects of several chelating agents on the toxicity, distribution and excretion of aluminum.
Domingo JL, Gómez M, Llobet JM, Corbella J.

The relative efficacy of citric, malic, malonic, oxalic and succinic acids, and deferoxamine mesylate (DFOA) on the toxicity, distribution and excretion in mice exposed to aluminum were compared. Chelating agents were administered intraperitoneally at a dose equal to one-fourth of their respective LD50. To determine the effect of the various chelators on the toxicity of aluminum, various doses of aluminum nitrate (938-3188 mg/kg) were administered intraperitoneally, followed by one of the chelators. Survival was recorded at the end of 14 days. Malic and succinic acids were the most effective…”
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Re: Some Interesting Connections

Postby Annesse » Thu Aug 08, 2013 7:08 am

I also thought this was interesting. Vitamin B12 is involved in the regulation of nerve growth factor and epidermal growth factor. Here is study on the loss of epidermal growth factor regulation by vitamin B12 (cobalamin) in MS. The researchers stated that the decrease in epidermal growth factor may be one factor impeding CNS remyelination in MS.

http://www.ncbi.nlm.nih.gov/pubmed/20347721

Brain Res. 2010 May 28;1333:64-71. doi: 10.1016/j.brainres.2010.03.073. Epub 2010 Mar 27.

Loss of epidermal growth factor regulation by cobalamin in multiple sclerosis.

"...Our results indicate that: (a) the positive Cbl-mediated regulation of myelino- and oligodendrocyte-trophic EGF is lost in the CSF of RR- or SP-MS patients; (b) the decrease in EGF levels in the CSF may be one factor impeding CNS remyelination in MS; and (c) the PP clinical course may have different pathogenetic mechanism(s) also on the basis of the molecules investigated in this study."

Here is an additional study on the association between vitamin B12 and epidermal growth factor.

http://www.ncbi.nlm.nih.gov/pubmed/11722601

Eur J Haematol. 2001 Aug;67(2):123-7.
Human cobalamin deficiency: alterations in serum tumour necrosis factor-alpha and epidermal growth factor.

CONCLUSIONS: In humans, as in rats, cobalamin concentration appears to be correlated with the synthesis and release of TNF-alpha and EGF in a reciprocal manner, because cobalamin deficiency is accompanied by overproduction of TNF-alpha and underproduction of EGF.
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Re: Some Interesting Connections

Postby Annesse » Fri Aug 09, 2013 7:39 am

A vitamin B12 deficiency can also lead to a serious blood disorder called thrombocytopenia. A study from Johns Hopkins found that the prevalence of MS amongst patients with thrombocytopenia was 25 TIMES MORE than the prevalence that would be expected in the general population.


J Thromb Haemost. 2006 Nov;4(11):2377-83. Epub 2006 Jul 27.
Prevalence of immune thrombocytopenia: analyses of administrative data.
Segal JB, Powe NR.
SourceJohns Hopkins University School of Medicine, Baltimore, MD 21205, USA. jsegal@jhmi.edu

" ...A concurrent diagnosis of multiple sclerosis was 25 times more prevalent than anticipated..."



In thrombocytopenia there is an abnormally low amount of platelets. Platelets are parts of the blood that help blood to clot. According to the U.S. Department of Health and Human Services, “Vitamin B12 deficiency has several major manifestations. A very characteristic anemia, in which the red blood cells are larger than normal, may progress to include low numbers of white blood cells and platelets as well.”

Visible symptoms of thrombocytopenia include nosebleeds, bruising, bleeding at the gums, excessive menstrual bleeding, and petechiae. Petechiae are small red or purple spots that appear on the skin as a result of bleeding under the skin.

Serious and possibly fatal complications of thrombocytopenia may include hemorrhage at the back of the eye (retina), bleeding inside the skull or brain, and lower gastrointestinal bleeding or other internal bleeding.
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Re: Some Interesting Connections

Postby want2bike » Fri Aug 09, 2013 9:19 am

Dr. Bergman believes autoimmune disease is the result of toxicity or deficiency. If you are deficient in vitamins necessary for good health you have a potential for disease. Do not think it is necessary one specific vitamin but we need all of them for our health. Our bodies are smart and if we eat the real food the body can pick the vitamins it needs out of the food. The China study shows what it takes to be healthy. Eating a diet consisting of raw fruits and vegetables is where we should start to get our health back. Try juicing the fruits and vegetables so you can run as many of these nutrients through the body is also helpful. Since each of us has a different the history of vitamins and minerals we need could be different. Everything I have read suggest that vitamin D is the most important and is the one vitamin you cannot get sufficient amounts from the food we eat. It is the sunshine vitamin so spending time in the sun is important. I take 5000 IU of vitamin D3 a day.

http://www.youtube.com/watch?v=zGmyUppmt-g

http://www.youtube.com/watch?v=HvA55xj8iMI

http://www.youtube.com/watch?v=4utSo4MH1ds
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Re: Some Interesting Connections

Postby Annesse » Fri Aug 09, 2013 10:39 am

Right- I believe the cause of MS is missing enzymes that digest dietary proteins and DNA. These enzymes do much more than bind and transport vitamin B12. However, vitamin B12 is necessary for every cell in the body. An inability to properly metabolize vitamin B12 would lead to many of the symptoms and explain numerous valid scientific findings in MS. It is just ONE consequence of these missing enzymes however. I too believe in a whole foods diet to restore health. Patients with MS are not able to properly metabolize vitamin B12, so taking more in supplement form would not solve the problem and it may lead to additional health consequences.

I do disagree though with just eating raw fruits and vegetables in an attempt to restore health. Vitamin B12, for instance, is only found in dietary "animal" proteins.

The country with the most vegetarians in the world is India. India also leads the world in heart disease and diabetes.

Research shows this is a direct consequence of their vegetarian diet.

A lack of vitamin B12 will lead directly to elevated levels of homocysteine. Homocysteine has been found to be 40 times more predictive of heart disease than cholesterol. Elevated levels of homocysteine will also lead to insulin resistance. Here is some information from my book on the association to the lack of vitamin B12, homocysteine and heart disease.

"Heart Disease in India and Homocysteine

As we have learned, India is the diabetic capital of the world. Another
surprising fact is that India also leads the world in heart disease. India is
responsible for 60% of the world’s heart disease. Commenting on why
Indians are more at risk for heart disease, Dr. Shashank Shah, author of
a new research report presented at a World Congress event for Obesity
and Metabolic Diseases in Los Angeles, stated, “We found that Indians are
grossly deficient in vitamin B12, which is a crucial cardio-protective factor
in the body. Vitamin B12 is usually found in food that comes from animals,
like fish, meat, poultry, milk and milk products. However, since a lot of
Indians are vegetarians, they do not get adequate amounts of vitamin B12
in their diet. When vitamin B12 levels fall, homocysteine levels increase.
The latter is known to cause atherosclerosis (hardening and narrowing of
the arteries), as well as an increased risk of heart attacks, strokes and blood
clot formation,” noted Dr. Shah in his report (Suryanarayan, 2010).

Dr. Shah is not alone in his findings. The following excerpt came
from The Times of India: “Widespread deficiency of vitamin B12 among
vegetarians is leading to a growing incidence of stroke and heart attacks
among young people, warn doctors. Deficiency of vitamin B12 increases the
concentration of a chemical called homocysteine in the blood, which causes
blocks in arteries and veins. These blocks, in turn, are responsible for heart
attacks and strokes. ‘More and more young people are having heart attacks
and falling prey to strokes. Invariably, it is a vitamin B12 deficiency caused
by a pure vegetarian diet that is leading to this condition,’ said Sudhir
Kothari, neurologist at Poona Hospital” (Polanki, 2004). Rustom S. Wadia,
neurologist at Ruby Hall Clinic, also agrees, saying, “There is no doubt that
it is a huge phenomenon. Nearly 70 percent of vegetarians have vitamin
B12 deficiency. And 70 percent of the cases of strokes that I have come
across are due to this deficiency.”

The following study shows how prevalent both low vitamin B12 and high
homocysteine are in India. Even with an extremely low limit tested for vitamin B12
(150 pg/mL), it was found that 81% of the urban middle class group had
low vitamin B12, and 79% had hyperhomocysteinemia.

Vitamin B12 deficiency and hyperhomocysteinemia in rural and urban Indians.

Yajnik, C.S., S.S. Deshpande, H.G. Lubree, S.S. Naik, D.S. Bhat, B.S. Uradey, J.A.
Deshpande, S.S. Rege, H. Refsum, J.S. Yudkin. 2006. JAPI 54:775-82.

“…Of the urban middle class, 81% had low vitamin B12 concentration and 79% had hyperhomocysteinemia…Low vitamin B12 concentration and hyperhomocysteinemia are common in Indian men, particularly in vegetarians and urban middle class residents…”



For a different reason, MS patients also lack vitamin B12, but the consequences would be the same. A lack of vitamin B12 will lead to elevated levels of homocysteine and an increased risk of cardiovascular disease.

In the following study published in the Journal of Clinical Neuroscience the researchers found high homocysteine and low vitamin B12 in patients with MS and concluded there is a significant relationship between MS and vitamin B12 deficiency.


J Clin Neurosci. 2009 Mar;16(3):399-403. doi: 10.1016/j.jocn.2008.05.015. Epub 2009 Jan 18.
Serum vitamin B12, folate, and homocysteine levels and their association with clinical and electrophysiological parameters in multiple sclerosis.
Kocer B, Engur S, Ak F, Yilmaz M.
“…Homocysteine levels were high in…patients with MS but were within normal limits in the control group…Thus, we found a significant relationship between MS and vitamin B12 deficiency…”



Patients with MS are also at a higher risk of cardiovascular disease. In the following study from the Karolinska Institute in Sweden, the institute that awards the Nobel prizes in medicine, the researchers found that MS patients have more heart attacks, strokes, and heart failure than the rest of the population. In the study of nearly 74,000 people, 7,664 of them people with MS, the research group showed that those with MS, compared with age and sex-matched controls from the general population, had 85% more heart attacks, 71% more strokes, and 97% more heart failure.

Mult Scler. 2013 Jan 30.


High risk of cardiovascular diseases after diagnosis of multiple sclerosis.
Jadidi E, Mohammadi M, Moradi T.
“…Among MS patients, the incidence rate ratio for MI was 1.85 (95% confidence interval (CI) 1.59 to 2.15), for stroke was 1.71 (95% CI 1.46 to 2.00), for HF was 1.97 (95% CI 1.52 to 2.56) and for AF/Flutter was 0.63 (95% CI 0.46 to 0.87), as compared with individuals without MS. The increased risks were particularly prominent for women. These associations remained after stratification by sex, age and country of birth…”



An increased risk of cardiovascular disease is only ONE consequence of elevated homocysteine, there are many more that are associated with the disease process of MS.
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Re: Some Interesting Connections

Postby Annesse » Sat Aug 10, 2013 6:48 am

Here is some additional information on the role elevated homocysteine caused by an inability to properly metabolize vitamin B12 is playing in MS.

In the following study the researchers stated that homocysteine is a marker for a B-vitamin deficiency, and that studies have shown a “dose-dependent” relationship between concentrations of homocysteine and the risk for neurodegenerative diseases. In addition, the researchers stated that a “positive association” has been reported between homocysteine and multiple sclerosis.

Fortschr Neurol Psychiatr. 2007 Sep;75(9):515-27.
Review of the role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric disorders--current evidence and preliminary recommendations.
Herrmann W, Lorenzl S, Obeid R.

“Elevated concentration of total homocysteine (Hcy)…is a risk factor for several diseases of the central nervous system. Epidemiological studies have shown a dose-dependent relationship between concentrations of Hcy and the risk for neurodegenerative diseases. Hcy is a marker for B-vitamin deficiency…Hyperhomocysteinemia (HHcy) causes hypomethylation which is an important mechanism that links Hcy to dementia… a positive association has been reported between HHcy and multiple sclerosis…”

It is no wonder that homocysteine is associated with an increased risk of cardiovascular disease. Researchers in the following concluded that homocysteine kills heart muscle cells (cardiomyocytes).


Biochem Biophys Res Commun. 2007 Aug 3;359(3):445-50. Epub 2007 May 30.
Homocysteine induces cell death in H9C2 cardiomyocytes through the generation of peroxynitrite.
Levrand S, Pacher P, Pesse B, Rolli J, Feihl F, Waeber B, Liaudet L.

“Homocysteine (HCY) is toxic on blood vessels, but a potential direct toxicity of HCY on the heart is unknown…These results provide the first demonstration that HCY kills cardiomyocytes through the generation of peroxynitrite and can activate key signaling cascades in the myocardium…”
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Re: Some Interesting Connections

Postby Annesse » Sun Aug 11, 2013 7:31 am

Elevated homocysteine would clearly explain the increased risk of cardiovascular disease found in patients with MS, but I believe it also explains many other defining components of MS as well. Components such as blood-brain barrier dysfunction, down regulation of tight junction proteins, endothelial cell damage, excess nitric oxide, peroxynitrite, leukocyte extravasation (movement), fibrinogen leakage etc.

For instance, in the following study the researchers stated that blood-brain barrier disruption is one of the hallmarks of MS. The blood-brain barrier is the selectively permeable layer of cells within the capillaries of the central nervous system. When functioning properly, the blood-brain barrier prevents foreign invaders and immune cells from passing out of the bloodstream and into the central nervous system.

Dis Markers. 2006;22(4):235-44.
Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis.
Waubant E.

“Blood-brain barrier (BBB) disruption is one of the hallmarks of multiple sclerosis (MS)…”


In the following study the researchers investigated the "anatomical route" of the blood-brain barrier (BBB) breakdown in MS by examining the expression of the tight junction proteins occludin and ZO-1. The researchers determined that BBB breakdown DUE TO DISRUPTION TO TIGHT JUNCTIONAL PATHOLOGY should be regarded as a significant form of tissue injury in MS, alongside demyelination and axonopathy.

Brain Pathol. 2002 Apr;12(2):154-69.
Abnormal endothelial tight junctions in active lesions and normal-appearing white matter in multiple sclerosis.
Plumb J, McQuaid S, Mirakhur M, Kirk J.

Blood-brain barrier (BBB) breakdown, demonstrable in vivo by enhanced MRI is characteristic of new and expanding inflammatory lesions in relapsing-remitting and chronic progressive multiple sclerosis (MS). Subtle leakage may also occur in primary progressive MS. However, the anatomical route(s) of BBB leakage have not been demonstrated. We investigated the possible involvement of interendothelial tight junctions (TJ) by examining the expression of TJ proteins (occludin and ZO-1 ) in blood vessels in active MS lesions from 8 cases of MS and in normal-appearing white (NAWM) matter from 6 cases. Blood vessels (10-50 per frozen section) were scanned using confocal laser scanning microscopy to acquire datasets for analysis. TJ abnormalities manifested as beading, interruption, absence or diffuse cytoplasmic localization of fluorescence, or separation of junctions (putative opening) were frequent (affecting 40% of vessels) in oil-red-O-positive active plaques but less frequent in NAWM (15%), and in normal (< 2%) and neurological controls (6%). Putatively "open" junctions were seen in vessels in active lesions and in microscopically inflamed vessels in NAWM. Dual fluorescence revealed abnormal TJs in vessels with pre-mortem serum protein leakage. Abnormal or open TJs, associated with inflammation may contribute to BBB leakage in enhancing MRI lesions and may also be involved in subtle leakage in non-enhancing focal and diffuse lesions in NAWM. BBB disruption due to tight junctional pathology should be regarded as a significant form of tissue injury in MS, alongside demyelination and axonopathy.


In the following study the researchers stated that homocysteine "causes" blood brain barrier dysfunction and concluded that homocysteine downregulated the tight junction proteins occludin and ZO-1. The researchers stated, "In conclusion, Hcy-induced oxidative stress leads to BBB dysfunction, in part by, activating TJ proteins."


Homocysteine attenuates blood brain barrier function by inducing oxidative stress and the junctional proteins.
Neetu Tyagi, Munish Kumar, SB Pushpakumar, David Lominadze, Karni S Moshal, Utpal Sen, Thomas Paul Vacek and Suresh C Tyagi

“Hyperhomocysteinmia (HHcy) is associated with neurological disorders and causes blood brain barrier (BBB) dysfunction. However, the mechanism of BBB dysfunction is unclear. We hypothesize that Hcy induces oxidative stress, activates inter-endothelial junctional (TJ) proteins leading to BBB dysfunction. In this study mosue brain microvascular endothelial cells (MBEC) were treated with different doses of homocysteine (Hcy) for 18hrs. Reactive oxygen species (ROS) was detected using DCFH-DA assay. The expression of junctional proteins and activation of mitogen activated protein kinases (MAPK) was analysised by Western-blotting. The interaction of junctional proteins were investigated using co-immunoprecipitation. Our results show that Hcy induces oxidative stress, which causes down regulation of the inter-endothelial junctional proteins ((ZO-1, caludin, occuldin). Furthermore, oxidative stress leads to disruption of the cadherin-beta-catenin complex and an activation of extracellular signal-regulated kinase. In conclusion, Hcy-induced oxidative stress leads to BBB dysfunction, in part by, activating TJ proteins.
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Re: Some Interesting Connections

Postby Annesse » Mon Aug 12, 2013 6:54 am

The blood-brain barrier consists of endothelial cells. In the following study the researchers found elevated endothelial microparticles in MS patients. As the study explains, during activation or apoptosis (cell death), endothelial cells release microparticles. The researchers concluded that endothelial dysfunction is “evident” during exacerbation of MS.

Elevated plasma endothelial microparticles in multiple sclerosis.

http://www.neurology.org/content/56/10/1319
“…Endothelial cells release microparticles…during activation or apoptosis. …Endothelial dysfunction is evident during exacerbation of MS…”



Researchers in the following study concluded that microparticle formation is a physiological response to even "moderate" levels of homocysteine.

Cell Mol Biol Lett. 2011 Mar;16(1):69-78. doi: 10.2478/s11658-010-0040-2. Epub 2010 Dec 15.

Endothelial microparticle formation in moderate concentrations of homocysteine and methionine in vitro.
Sekuła M, Janawa G, Stankiewicz E, Stępień E.

“Microparticles (MPs) are small membrane vesicles released by stimulated or apoptotic cells, including the endothelium. Hyperhomocysteinemia (HHcy) is a blood disorder characterized by an increase in the plasma concentrations of total homocysteine (Hcy)… On average, 24% of the entire MP population was apoptotic…Endothelial function impairment due to HHcy is related to MP shedding, which may involve platelets and other blood and vascular cells. MP shedding is a physiological response to moderate HHcy.”


In the following study the researchers concluded that homocysteine induced programmed cell death (apoptosis) in endothelial cells.

Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response.
Zhang, C, Y. Cai, M.T. Adachi, S. Oshiro, T. Aso, R.J. Kaufman, S. Kitajima. 2001. J Biol
Chem 276(38):35867-74.


“…In this study, homocysteine induced programmed cell death in… endothelial cells…”
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Re: Some Interesting Connections

Postby Annesse » Tue Aug 13, 2013 6:49 am

If the endothelial cells are damaged, leukocytes (white blood cells) from the peripheral circulation can pass through the endothelial layer of the blood-brain barrier into the central nervous system.

In the following study the researchers stated that extravasation (movement) of leukocytes (white blood cells) from the peripheral circulation through the endothelial layer of the blood-brain barrier into the central nervous system (CNS) is the most fundamental step in formation of MS lesions. The researchers stated, “During MS pathogenesis, once the activated leukocytes enter the CNS environment, they propagate a massive wave of destruction which culminates in the loss of both myelin/oligodendrocyte complex and neurodegeneration. Multiple clinical and basic scientific observations support endothelial cell 'stress' and apoptosis as a hallmark characteristic of MS.”

Neurol Res. 2012 Oct;34(8):738-45. doi: 10.1179/1743132812Y.0000000072. Epub 2012 Jul 23.


Emerging roles of endothelial cells in multiple sclerosis pathophysiology and therapy.
Minagar A, Maghzi AH, McGee JC, Alexander JS.

“Although multiple sclerosis (MS) has traditionally been viewed and researched as an immune-mediated demyelinating and neurodegenerative disease of the human central nervous system (CNS), its highly complex pathogenesis clearly includes a significant vascular inflammatory component and many therapeutic approaches achieve benefit by direct or indirect effects on cerebrovascular endothelial cells. Cerebral endothelial cells create and separate the compartments of the peripheral circulation and CNS creating the blood-brain barrier (BBB), a selectively permeable boundary layer between these spaces… Extravasation of activated and committed leukocytes from the peripheral circulation through the endothelial layer of the BBB into the CNS milieu is the most fundamental step in formation of MS lesions. During MS pathogenesis, once the activated leukocytes enter the CNS environment, they propagate a massive wave of destruction which culminates in the loss of both myelin/oligodendrocyte complex and neurodegeneration. Multiple clinical and basic scientific observations support endothelial cell 'stress' and apoptosis as a hallmark characteristic of MS. The manipulation of the endothelial biology aiming to block trans-endothelial migration of activated immune cells into the CNS is a potent form of treatment for MS achieving significant reductions in disease activity and new lesion formation. In particular, endothelial microparticles are now well-recognized as important biomarkers and mediators of this type of stress…”


Homocysteine not only damages the endothelial cells, which leads to blood-brain barrier permeability, it also directly influences leukocyte adhesion and migration. As the previous study stated, “once activated leukocytes enter the CNS environment, they propagate a massive wave of destruction which culminates in the loss of both myelin/oligodendrocyte complex and neurodegeneration.” In the following study the researchers concluded that homocysteine upregulates expression of adhesion molecules on endothelial cells which “recruits leukocytes” and initiates atherosclerosis (vascular disease in which fatty material accumulates on the walls of the blood vessels causing them to become narrow or completely blocked).

Chronic homocysteine exposure upregulates endothelial adhesion molecules and mediates leukocyte: endothelial cell interactions under flow conditions.
Alkhoury, K and Parkin, SM and Homer-Vanniasinkam, S and Graham, AM (2011) EUR J VASC ENDOVASC , 41 (3) 429 - 435. 10.1016/j.ejvs.2010.11.012.

“…Homocysteine upregulates expression of adhesion molecules on endothelial cells which recruits leukocytes and initiates atherosclerosis… homocysteine significantly increased interactions between neutrophils and endothelial cells under flow conditions…”


In the following study researchers found that homocysteine at the lowest concentrations significantly increased surface adhesive molecule expressions on monocytes and neutrophils (types of leucocytes).

Chin Med J (Engl). 2001 Dec;114(12):1235-9.
Homocysteine induces expressions of adhesive molecules on leukocytes in whole blood.
Guo X, Dudman NP.

“…Homocysteine at the lowest concentration…significantly increased surface adhesive molecule expressions…on monocytes and neutrophils in whole blood…Homocysteine alters leukocyte expressions…which may be involved in homocysteine-induced leukocyte adhesion and migration.”



Vascular cell adhesion molecule-1(VCAM-1) is a key player in leukocyte extravasation in MS lesions, as the following study states. Natalizumab (Tysabri), one of the medications used in the treatment of MS, reduces leukocyte extravasation by down-regulating VCAM-1.

J Neuroimmunol. 2010 Oct 8
Natalizumab treatment reduces endothelial activity in MS patients.
Millonig A, Hegen H, Di Pauli F, Ehling R, Gneiss C, Hoelzl M, Künz B, Lutterotti A, Rudzki D, Berger T, Reindl M, Deisenhammer F.

“Vascular cell adhesion molecule-1 a ligand for leukocyte very late activating antigen-4 is a key player in leukocyte extravasation in MS lesions… VCAM-1 and its soluble form are up-regulated during endothelial activation in MS… Our findings indicate that Natalizumab reduces transmigration…by down-regulating VCAM-1.”




In the following study the researchers concluded that homocysteine induced VCAM-1 expression.

Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2344-54. Epub 2007 Jun 22.
Homocysteine induces VCAM-1 gene expression through NF-kappaB and NAD(P)H oxidase activation: protective role of Mediterranean diet polyphenolic antioxidants.
Carluccio MA, Ancora MA, Massaro M, Carluccio M, Scoditti E, Distante A, Storelli C, De Caterina R.

“Hyperhomocysteinemia is a recognized risk factor for vascular disease, but pathogenetic mechanisms involved in its vascular actions are largely unknown…VCAM-1 expression is crucial in monocyte adhesion and early atherogenesis…Hcy-induced VCAM-1 expression and monocytoid cell adhesion to the endothelium. These data indicate that pathophysiologically relevant Hcy concentrations induce VCAM-1 expression…”
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Re: Some Interesting Connections

Postby Annesse » Wed Aug 14, 2013 6:23 am

Homocysteine is also toxic to Purkinje (par-KIN-jee) neurons. Purkinje neurons play a vital role in motor function. In the following study the researchers found a significant decrease in Purkinje neurons in the animal model of MS, experimental autoimmune encephalomyelitis (EAE).

Neuroimage. 2009 Dec;48(4):637-51. doi: 10.1016/j.neuroimage.2009.06.073. Epub 2009 Jul 6.

Purkinje cell loss in experimental autoimmune encephalomyelitis.
MacKenzie-Graham A, Tiwari-Woodruff SK, Sharma G, Aguilar C, Vo KT, Strickland LV, Morales L, Fubara B, Martin M, Jacobs RE, Johnson GA, Toga AW, Voskuhl RR.

“…The pro-apoptotic marker caspase-3 was detected in Purkinje cells and a significant decrease in Purkinje cell number was found in EAE…”


In the previous study the researchers stated that the pro-apopotic marker "caspase-3" was detected in Purkinje cells. Caspase-3 is a protein that plays a central role in the “execution-phase” of cell apoptosis. In the following study the researchers found that homocysteine induced caspase-3 activation.

Biosci Biotechnol Biochem. 2011;75(7):1300-5. Epub 2011 Jul 7.
Homocysteine-induced caspase-3 activation by endoplasmic reticulum stress in endothelial progenitor cells from patients with coronary heart disease and healthy donors.
Li L, Hu BC, Gong SJ, Yan J.

“homocysteine induced endothelial progenitor cell apoptosis and activation of caspase-3...”



In the following study the researchers discovered that homocysteine at ALL concentrations studied caused a significant decrease in Purkinje neurons.

Neurosci Lett. 2007 Feb 8;413(1):52-7. Epub 2006 Dec 6.
Neurotoxic effects of homocysteine on cerebellar Purkinje neurons in vitro.
Oldreive CE, Doherty GH.

“Whilst a plethora of studies that describe the toxicity of homocysteine to CNS neurons have been published, the effects of homocysteine on the Purkinje neurons of the cerebellum that play a vital role in motor function remain wholly unexplored. We have therefore established cultures of embryonic cerebellar Purkinje neurons and exposed them to a range of concentrations of homocysteine and determined its effects on their survival. The experiments revealed that all concentrations of homocysteine studied, from 50 to 500microM, caused a significant decrease in cerebellar Purkinje neuron number. This loss could be counteracted by the pan-caspase inhibitor z-VAD-fmk in the first 24h following homocysteine exposure, revealing that the initial loss was apoptotic. However, z-VAD-fmk could not prevent homocysteine-mediated loss of cerebellar Purkinje neurons in the longer term, after 6 days in vitro. In addition to its effects on Purkinje neuron survival, homocysteine markedly reduced both the overall magnitude and the complexity of the neurite arbor extended by the cerebellar Purkinje neurons, following 6 days incubation with this agent in vitro. Taken together our data reveal that homocysteine is toxic to cerebellar Purkinje neurons in vitro, inhibiting both their survival and the outgrowth of neurites.”
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Re: Some Interesting Connections

Postby Annesse » Thu Aug 15, 2013 5:55 am

Research has found that homocysteine also induces glutamate excitotoxicity. Glutamate is the major excitatory neurotransmitter in the brain. In the following study from Albert Einstein College of Medicine the researchers stated that glutamate excitotoxicity is known not only to damage neurons, but also the myelin-producing cell of the central nervous system, the oigodendrocyte. The researchers concluded that glutamate excitotoxicity appears to be an important mechanism in autoimmune demyelination.

J Neural Transm Suppl. 2000;(60):375-85.
Glutamate excitotoxicity--a mechanism for axonal damage and oligodendrocyte death in multiple sclerosis?
Werner P, Pitt D, Raine CS.

“Glutamate excitotoxicity…is known not only to damage neurons but also the myelin-producing cell of the central nervous system (CNS), the oligodendrocyte. In multiple sclerosis (MS), myelin, oligodendrocytes and axons are lost or damaged as a result of an inflammatory attack on the CNS...glutamate excitotoxicity appears to be an important mechanism in autoimmune demyelination…”

In the following study published in the Journal of Neuroscience Research the study authors found that homocysteine stimulated glutamate excitotoxicity. The researchers concluded that their findings indicate that homocysteine compromises neuronal homeostasis by multiple, divergent routes.

J Neurosci Res. 2002 Dec 1;70(5):694-702.
Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage.
Ho PI, Ortiz D, Rogers E, Shea TB.

“Homocysteine (HC) is a neurotoxic amino acid that accumulates in several neurological disorders including Alzheimer's disease (AD)…Homocysteine-induced calcium influx through NMDA channel activation, which stimulated glutamate excitotoxicity…These findings indicate that HC compromises neuronal homeostasis by multiple, divergent routes.”
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Re: Some Interesting Connections

Postby NHE » Thu Aug 15, 2013 4:20 pm

Homocysteine linked with diminished cognitive function in older men and women
http://www.lef.org/whatshot/2013_08.htm ... -and-women

August 14, 2013. An article published online on August 5, 2013 in the Journal of Affective Disorders 1 reports an association between higher levels of plasma homocysteine and an increased risk of cognitive impairment in older adults.

Researchers from the University of Western Australia and Royal Perth Hospital recruited 358 individuals aged 50 and older with depressive symptoms, among whom 70% met the criteria for major depression. Fasting blood samples were analyzed for total plasma homocysteine, serum vitamin B12 and red blood cell folate levels. Cognitive tests administered included the Mini-mental state examination and tests of verbal fluency, naming, word list immediate recall, word list delayed recall and drawing (visual) recall.

Seventy-one participants had high homocysteine levels, defined in this study as 13 micromoles per liter or more. In subjects with and without major depression, those with higher homocysteine levels had lower median folate and vitamin B12 levels. “The results of this cross-sectional study show that in this sample of older adults, elevated total homocysteine was associated with weaker performance in tests of immediate and delayed memory and global cognitive performance when compared to those with normal total homocysteine,” authors Andrew H. Ford and his colleagues report.

“The finding that high total homocysteine is associated with cognitive inefficiency in later life independent of depressive status has potential public health implications,” they note. “Homocysteine can be reliably lowered by around by daily supplementation with vitamin B12 and folic acid, making it a potential modifiable risk factor for cognitive impairment in depressed older adults.”

“Homocysteine lowering B-vitamin supplementation may offer a potential therapeutic target to try and mitigate the often-disabling impact of cognitive deficits found in this population,” they conclude.

1. http://www.ncbi.nlm.nih.gov/pubmed/23928176
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Re: Some Interesting Connections

Postby Annesse » Fri Aug 16, 2013 7:01 am

Thank you NHE~I have the following similar study in my book.

"Numerous studies have found evidence that low vitamin B12 and high homocysteine
are related to the risk of developing Alzheimer’s disease. In the following study the researchers concluded that homocysteine (tHcy) levels were significantly higher and vitamin B12 levels were lower in patients with Alzheimer’s disease (AD).

Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.
Clarke, R., A.D. Smith, K.A. Jobst, H. Refsum, L. Sutton, P.M. Ueland. 1998. Arch Neurol. 55(11):1449-55.

“…Serum tHcy levels were significantly higher…and vitamin B12 levels were lower in patients …with histologically confirmed AD than in controls…Low blood levels of…vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.”





It is the inability to properly "metabolize" vitamin B12 due to a lack of enzymes, specifically protease and DNase 1, that I believe the evidence shows is the reason for the low vitamin B12 and resulting high homocysteine found in Alzheimer's disease and MS.

In the following study the researchers stated that there is increasing evidence for an association between Alzheimer’s disease and “nutritionally independent” cobalamin (vitamin B12) deficiency. The researchers believe this may be due to a PROTEASE inhibition, a "common factor" in Alzheimer’s disease. The lack of protease results in protein-bound cobalamin malabsorption and disrupted cobalamin metabolism.




Trypsin inhibition: a potential cause of cobalamin deficiency common to the pathogenesis of Alzheimer-type dementia and AIDS dementia complex?
McCaddon, A., B. Regland, C.F. Fear. 1995. Med Hypotheses. 45(2):200-4.

“There is increasing evidence for an association between Alzheimer-type dementia (AD) and nutritionally independent cobalamin deficiency. Furthermore, low serum cobalamin values occur in a kindred with familial Alzheimer's disease (FAD) and histopathological confirmation of AD neuropathology…This paper presents the hypothesis that protease inhibition is a common factor in AD and ADC resulting in protein-bound cobalamin malabsorption and disrupted cobalamin metabolism.”

In addition to low vitamin B12 and elevated homocysteine, there are many more disease ramifications that would result from these missing enzymes. A lack of these enzymes results in other nutrients that are not being properly metabolized as well. The question is, should you take these nutrients in supplement form if your body is unable to properly metabolize them? Is there a possibility you may see an increased risk of disease? I will be providing some more information on this.
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Re: Some Interesting Connections

Postby PointsNorth » Fri Aug 16, 2013 9:26 am

Annesse wrote:

It is the inability to properly "metabolize" vitamin B12 due to a lack of enzymes, specifically protease and DNase 1, that I believe the evidence shows is the reason for the low vitamin B12 and resulting high homocysteine found in Alzheimer's disease and MS.

In the following study the researchers stated that there is increasing evidence for an association between Alzheimer’s disease and “nutritionally independent” cobalamin (vitamin B12) deficiency. The researchers believe this may be due to a PROTEASE inhibition, a "common factor" in Alzheimer’s disease. The lack of protease results in protein-bound cobalamin malabsorption and disrupted cobalamin metabolism.

Trypsin inhibition: a potential cause of cobalamin deficiency common to the pathogenesis of Alzheimer-type dementia and AIDS dementia complex?
McCaddon, A., B. Regland, C.F. Fear. 1995. Med Hypotheses. 45(2):200-4.

“There is increasing evidence for an association between Alzheimer-type dementia (AD) and nutritionally independent cobalamin deficiency. Furthermore, low serum cobalamin values occur in a kindred with familial Alzheimer's disease (FAD) and histopathological confirmation of AD neuropathology…This paper presents the hypothesis that protease inhibition is a common factor in AD and ADC resulting in protein-bound cobalamin malabsorption and disrupted cobalamin metabolism.”

In addition to low vitamin B12 and elevated homocysteine, there are many more disease ramifications that would result from these missing enzymes. A lack of these enzymes results in other nutrients that are not being properly metabolized as well. The question is, should you take these nutrients in supplement form if your body is unable to properly metabolize them? Is there a possibility you may see an increased risk of disease? I will be providing some more information on this.


Hi Annesse,

I've been dependant on B12 for over 20 years now (injections) but more so since MS diagnosis and since SPMS 3 years ago I've had little or no benefit from B12 shots even though I began taking them with increased frequency. Have assumed it was malabsorption of some kind but can't resolve. I used to respond so well - numbness in hands, mobility, quality of sleep etc. - all lost now. Wondering where to go now.

PN
Albany 2010. Brooklyn 2011
Hayes inspired Calcitriol+D3 2013-2014
Coimbra Protocol 2014-
DrG B12 Transdermal Spray 2014-
My Current Regimen http://www.thisisms.com/forum/regimens-f22/topic25634.html
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