White Brain Lesions

[SjoAmy]

Nat, I don't see any mention of MTHFR Deficiency.....

[Nat]

Hi SjoAmy~MTHFR deficiency can lead to elevated homocysteine, but I am sure you already knew that. Homocysteine is elevated in autoimmune disease patients and it plays a very large role in the autoimmune disease process, but in the vast majority of cases it is not due to MTHFR.

Homocysteine is elevated in autoimmune disease due to a lack of vitamin B12. Vitamin B12 is required for the proper metabolism of homocysteine. For instance, 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.


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. 2009. J Clin Neurosci. 16(3):399-403. doi: 10.1016/j.jocn.2008.05.015. Epub 2009 Jan 18.

"?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?"


I noticed you have COPD in your profile.This would be associated with elevated homocysteine.
Here is a section from my book on this.


"Researchers in our next study discovered there was a more than two-fold increased risk of MS in patients with chronic obstructive pulmonary disease (COPD), a progressive lung disease that makes it hard to breathe. In COPD, the small capillaries that run through the walls of the air sacs in the lungs are damaged or completely destroyed.  Symptoms of COPD include coughing that produces large amounts of mucus, wheezing, shortness of breath, and chest tightness.  The researchers concluded their results indicate that COPD and MS have an "inflammatory vulnerability" in common.

Increased prevalence of multiple sclerosis among COPD patients and their first-degree relatives: a population-based study.
Egesten A, Brandt L, Olsson T, Granath F, Inghammar M, L?fdahl CG, Ekbom A. 2008. Lung 186(3):173-8. doi: 10.1007/s00408-008-9081-y. Epub 2008 Mar 20.


"?In the COPD cohort, there was a more than twofold increased risk of MS compared with controls? This study indicates that COPD and MS have an inflammatory vulnerability in common...These diseases may share inflammatory pathways?"

Homocysteine would be the "inflammatory vulnerability" that both COPD and MS patients share. In the following study the researchers found that homocysteine was significantly elevated in COPD patients and was related to serum C-reactive protein (CRP), a common inflammatory marker, and COPD severity.


Plasma homocysteine is elevated in COPD patients and is related to COPD severity.
Seemungal TA, Lun JC, et al. 2007. Int J Chron Obstruct Pulmon Dis 2(3):313-21.

"?Plasma homocysteine is significantly elevated in COPD patients?and is related to serum CRP and COPD severity."


Homocysteine destroys the cells that line the blood vessels. These cells are called "endothelial cells".


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, Cai Y, Adachi MT, Oshiro S, Aso T, Kaufman RJ, Kitajima S. 2001. J Biol Chem. 276(38):35867-74.

"?In this study, homocysteine induced programmed cell death in endothelial cells..."




The researchers from the following study concluded that "endothelium" dependent vasodilation was impaired in primary SS patients, in particular those presenting with Raynaud?s phenomenon??

Endothelial dysfunction in patients with primary Sj?gren?s syndrome.
Pirildar, T., C. Tikiz, S. Ozkaya, S. Tarhan, O. Ut?k, H. Tikiz, U.K. Tezcan. 2005. Rheumatol Int . 25(7):536-9.

"The aim of this study was to determine the endothelial function in patients with primary Sj?gren?s syndrome (SS)? We concluded that endothelium-dependent vasodilation was impaired in primary SS patients, in particular those presenting with Raynaud?s phenomenon, when compared with the healthy controls?"

[SjoAmy]

True....and from what I know by book and personal experience, folic acid and B12 can both lower high homocystiene levels.

There's an inability to metabolize the methylation part of MTHFR and DHFR.  So a true break down doesn't occur.

I agree the COPD can be related to homocystiene......but now I have another pulmonary culprit.....To consider at least....Alpha 1 Anti Trypsin Deficiency.  This deficiency relates back to protease inhibition.  Correct me, if I am wrong......but A 1 A T Deficiency could likely then cause low albumin, an inflammation state, COPD/Bronchitis /Asthma /Emphysema, liver damage, and an inability to assimilate any protein because most proteins are bigger than albumin....and high homocystiene.

It is sad that so many with A1AT Deficiency go unscreened and just left with the COPD label until they get worse. Methotrexate with this combo can end up in end stage liver disease.  I'll post the study.....gotta find it first.  Lol

[SjoAmy]

http://www.ncbi.nlm.nih.gov/m/pubmed/7612033/

A1AT deficency, Methotrexate & end stage liver disease

[Nat]

I think if a disease does originate at a certain point, which I believe the evidence shows with autoimmue disease is with missing digestive enzymes, it will follow a very straightforward pathway. For instance, as the research I posted above shows, due to a lack of vitamin B12, patients with MS have elevated levels of homocysteine. As the research shows, homocysteine is linked to COPD. This would be why patients with MS have a more than two-fold increased risk of developing COPD.

So, you can take this a step further and look at another autoimmune disease, such as RA, to see if a lack of digestive enzymes would follow the same pathway. I have already posted research that shows patients with RA lack these digestive enzymes.

This means we should find low B12, high homocysteine, and an increased risk of developing COPD.


Here is a study that shows patients with RA have elevated homocysteine.

Abnormal homocysteine metabolism in rheumatoid arthritis.
Roubenoff, R., P. Dellaripa, M.R. Nadeau, L.W. Abad, B.A. Muldoon, J. Selhub, I.H. Rosenberg IH. 1997. Arthritis Rheum. 40(4):718-22.

"?Elevated tHcy levels occur commonly in patients with RA, and may explain some of the increased cardiovascular mortality seen in such patients. Studies of the prevalence and mechanism of hyperhomocysteinemia in RA are warranted."


This leads to the same increased risk of developing COPD in RA as it does in MS.  More book info:

"A new study presented at the EULAR (European League Against Rheumatism) 2011 Annual Congress has confirmed a link between rheumatoid arthritis and COPD. An article discussing this study published in News-Medical stated, "Patients with rheumatoid arthritis are two times more likely to have COPD than healthy controls. The study, of 15,766 patients with RA and 15,340 controls, found that the prevalence of COPD was significantly higher in RA patients than healthy controls. Interestingly, the link was still significant after risk factors common in both RA and COPD patients, such as smoking, obesity and socioeconomic status, were controlled for" (News- Medical, 2011).


Taking this one step further...

In the following study from Rome researchers discovered that patients with COPD had low levels of vitamin B12 and, as a consequence, increased homocysteine. The researchers concluded this may contribute to the COPD-related atherothrombotic risk.

Hyperhomocysteinaemia and poor vitamin B status in chronic obstructive pulmonary disease
Fimognari, F.L., L. Loffredo, S. Di Simone, F. Sampietro, R. Pastorelli, M. Monaldo, F. Violi, A. D?Angelo. 2009. Nutr Metab Cardiovasc Dis. 19(9):654-9.

"Patients with chronic obstructive pulmonary disease (COPD) are at increased atherothrombotic risk. Preliminary findings have suggested that COPD patients may have increased plasma total homocysteine (tHcy), a cardiovascular risk factor often caused by a poor B vitamin status?COPD patients have a poor B vitamin status and, as a consequence,increased tHcy. These abnormalities may contribute to the COPD-related atherothrombotic risk."

I have also posted research that shows the white matter lesions in autoimmune disease are caused by the inability to properly metabolize vitamin B12.

The low levels of vitamin B12 found in COPD would also lead to an increased risk of white matter lesions. The following study confirms that COPD is associated with white matter lesions.

Arterial oxygen saturation, COPD, and cerebral small vessel disease.
Van Dijk, E.J., S. Vermeer, J.C. de Groot, J. van de Minkelis, N. Prins, M. Oudkerk, A. Hofman, P. Koudstaal, and M. Breteler. 2004. J Neurol Neurosurg Psychiatry 75(5):
733?736.

"?Participants with COPD had more severe periventricular white matter lesions than those without?Lower SaO2 and COPD are associated with more severe periventricular white matter lesions."

You have to look at the "entire" disease pathway in order to determine where it originates.
I think the evidence is clear that in autoimmune disease, this pathway originates with missing enzymes.

And yes, it is true you may be able to lower the serum (blood) levels of homocysteine through B12 supplementation, but research has confirmed you will not stop the damage being caused by homocysteine on the "cellular" level.

[mistyrain]

So, high homocysteine is one of the elephants in the room - how many of us have had our levels of homocysteine checked - not me.

And what is the connection with women predominantly having sjogren's syndrome.  Could this be it?



Free Radic Biol Med. 2013 Aug 6. pii: S0891-5849(13)00394-8. doi: 10.1016/j.freeradbiomed.2013.07.041. [Epub ahead of print]

"Mass spectrometry evidence for formation of estrogen-homocysteine conjugates: Estrogens can regulate homocysteine levels."

Gaikwad NW.

[Nat]

And just for fun, we can do it again. (mistyrain, I will address your question in the next post).


In the following study the researchers link the peripheral neuropathy found in patients with diabetes with impaired exocrine pancreatic function. The exocrine pancreas is where DNase I and protease originate. The researchers stated that compared to normal controls, ALL diabetics exhibited a significant reduction in both enzyme and bicarbonate secretion to all stimuli.

Impaired exocrine pancreatic function in diabetics with diarrhea and peripheral neuropathy.

El Newihi, H., C.P. Dooley, C. Saad, J. Staples, A. Zeidler, J.E. Valenzuela. 1998. Dig Dis Sci. 33(6):705-10.

"?Compared to normals, all diabetics exhibited a significant reduction in both enzyme and bicarbonate secretion to all stimuli. This reduction was not corrected by administering bethanechol?We conclude that diabetics with diarrhea and peripheral neuropathy exhibit impairment of their exocrine pancreatic secretion?"

So, why would peripheral neuropathy be linked to impairment of the exocrine pancrease? Because the exocrine pancreatic enzymes protease are responsible for the proper metabolism of vitamin B12 and a "clear link" has been established between a lack of vitamin B12 and peripheral neuropathy.

Low B12 would lead to elevated homocysteine in patients with diabetes, as the following study confirms.


Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus.
Soinio, M., J. Marniemi, M. Laakso, S. Lehto, T. R?nnemaa. 2004. Ann Intern Med. 140(2):94-100.

"?In this large cohort of patients with type 2 diabetes, plasma homocysteine level was a strong and independent risk factor for CHD events."



Elevated homocysteine would then lead to the same risk found in all autoimmune disease pateints of developing COPD.

In the following study, researchers found that those with COPD were nearly twice as likely to develop type 2 diabetes as those without COPD. The researchers believe that inflammation may explain this association.

Chronic obstructive pulmonary disease, asthma, and risk of type 2 diabetes in women.
Rana, J.S., M.A. Mittleman, J. Sheikh, F.B. Hu, J.E. Manson, G.A. Colditz, F.E. Speizer, R.G. Barr, C.A. Carnargo, Jr. 2004. Diabetes Care vol. 27 no. 10 2478-2484.

"?Inflammation plays a key role in chronic obstructive pulmonary disease (COPD)? Increasing evidence points toward a role of inflammation in the pathogenesis of type 2 diabetes?Our findings suggest that COPD may be a risk factor for developing type 2 diabetes?"


And then of course, we would expect to find that patients with diabetes have white matter lesions, just like all patients with autoimmune disease. Also, just like all patients with autoimmune disease, patients with diabetes have a loss of brain grey matter, due to the inability to properly metabolize dopamine.

In the following study published in Diabetologia the researchers concluded that type 2 diabetes was associated with a smaller volume of brain grey matter and with larger white matter lesion (WML) volume.

Automated measurement of brain and white matter lesion volume in type 2 diabetes
mellitus.
Jongen, C., J. van der Grond, L.J. Kappelle, G.J. Biessels, M.A. Viergever, J.P. Pluim. Utrecht Diabetic Encephalopathy Study Group. 2007. Diabetologia. 50(7):1509-16. Epub 2007 May 11.

"Type 2 diabetes mellitus has been associated with brain atrophy and cognitive decline, but the association with ischaemic white matter lesions is unclear?Type 2 diabetes was associated with a smaller volume of grey matter? and with larger white matter lesion volume?The combination of atrophy with larger WML volume indicates that type 2 diabetes is associated with mixed pathology in the brain."

[Linda196]

Bearing in mind that almost all studies in this line contain at some point the words "commonly found", "frequently found" or "in some cases"; as much as this sounds like a valid pathway to an eventual control or cure, it only pertains to some of the people with SjS.

Yes, following homocysteine levels can be of value, considering the possibility of predicting or preventing heart and lung disease, but it doesn't always show a complete picture. For example, my levels consistently run between 1 and 3 micromoles/l (>10 micromoles/liter as a normal), so quite low, but I have a history of both heart disease and COPD (restrictive in nature, not classic). I also have consistently normal, mid to high range, B12 levels, and have documented peripheral and autonomic neuropathy.

I might add that my immune mediated diagnosis (sarcoidosis, Sjogrens, dermatomyositis, vasculitis, inflammatory polyarthritis and aseptic tendonitis), have all been diagnosed with positive autoantibodies and/or tissue biopsy, so there is little question that I do have autoimmune diseases.

[Nat]

I think the problem lies at the "cellular" levels, due to a functional deficiency, so serum (blood) levels would not be a reliable indicator. For instance, one of the known associations with Sjogrens  and other autoimmune disease patients is "subacute combined degeneration of the spinal cord" which is caused, according to the National Institutes of Health, by a lack of vitamin B12.




The following study demonstrates that subacute combined degeneration of the spinal cord can occur even with so-called ?normal? levels of vitamin B12 in the blood.

Subacute combined degeneration with high serum vitamin B12 level and abnormal vitamin B12 binding protein New cause of an old syndrome.
Reynolds E.H., T. Bottiglieri, M. Laundy, J. Stern, J. Payan, J. Linnell, J. Faludy 1993. Arch Neurol. Jul;50(7):739-42.

"Subacute combined degeneration of the spinal cord due to vitamin B12 deficiency invariably has been associated with a low serum vitamin B12 level? To our knowledge, this is the first example of neurologic disease associated with high serum vitamin B12 level and provides further evidence that sometimes a serum vitamin B12 level may not be a reliable guide to vitamin B12 deficiency??

The same is true of elevated homocysteine.

For instance, in the following study on CFS and fibromyalgia the researchers found low B12 and high homocysteine in the "cerebrospinal fluid" of patients with CFS and fibro and  stated they believe that the low vitamin B12 levels found in the cerebrospinal fluid may reflect disruption of the "mechanism of transport" across the blood brain barrier. The researchers also stated they believe additional evidence from other studies further support the idea that deficiencies of "enzymatic" pathways involving vitamin B12 and homocysteine underlie a range of neurological disorders. Here is the conclusion of the study I have in my book.


"This study provides convincing preliminary evidence that a high homocysteine level in cerebrospinal fluid is an underlying factor in patients suffering from fibromyalgia and chronic fatigue syndrome. Low vitamin B12 levels in cerebrospinal fluid and possibly low SAMe levels are implicated as contributing factors. Additional evidence from other studies further support the idea that deficiencies in enzymatic pathways in the brain involving vitamin B12, homocysteine, and folic acid underlie a range of neurological disorders. Deficiencies in these essential biochemical pathways in the brain should be considered by health practitioners in the evaluation of successful interventions for reversing symptoms of fibromyalgia, chronic fatigue syndrome, and other neurological conditions (Regland,1997)."

[Nat]

Here are a few more studies that demonstate the inability of autoimmune patients to properly metabolize vitamin B12.

For instance, as the following study states, "Neuropathic features, such as trigeminal neuralgia, peripheral neuropathy, and subacute combined degeneration of the spinal cord as a consequence of vitamin B12 MALABSORPTION  are well recognised in systemic sclerosis." Systemic sclerosis is scleroderma. 

Autonomic neuropathy in systemic sclerosis.
Klimiuk, P.S., L. Taylor, R.D. Baker, and M.I. Jayson. 1988. Ann Rheum Dis. 47(7): 542?545.

??Neuropathic features such as trigeminal neuralgia, peripheral neuropathy, and subacute combined degeneration of the cord as a consequence of vitamin B12 malabsorption are well recognised in systemic sclerosis??


Here is one in MS.

In the following study the researchers stated they suspected 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 EH, Linnell JC, Faludy JE. 1991. Arch Neurol. 48(: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."


Also here is one on vitamin B12 "metabolism" and Crohn's disease  that found elevated homocysteine and concluded it might be due to altered "intracellular" vitamin B12 status.

http://www.ncbi.nlm.nih.gov/pubmed/8689919

[rudytudy]

Finallyadx, I agree with you and have many 'abnormal white foci' located together in the lower center of my brain MRI.  I've had a brain MRI each year for the last three years.  NO MORE for me though.  Unless I have something catostrophic happen I'm done with doctors not being able to fix my cognitive slowing down.  I just adapt to my 'new normal' life.

Neuro says that my brain fog is a symptom of fibro and SJS and says that the white brain matter spots that seem to increase annually are caused from getting older, high blood pressure, headaches, etc.

I had neuropsch. testing that showed 'marked difficulty' with facial recognition, (only with seeing a new face on a flash card and trying to remember if I'd seen it earlier in the test)  cognitive problem solving, etc.

I've completely given up on anyone being able to help me overcome my cognitive challenges.
I sing for a living everyday and sing the same songs for over seven years.   I can't learn any new songs.  Anything new that's complex involving memory is too hard but I do challenge myself daily with other easier things.

Doctors seem to be looking for the big things on MRIs....tumors, brain bleeds, bruising, and large MS type lesions.   I wish you all luck in your search for relief.    Gina   

[trc1962]

I was told my MRI showed white spots called UBO's which are unidentified bright objects-not MS lesions. Saw a neuro and he said 4 or more might be concerning and I have 5, but he said I don't have MS symptoms so not to worry about them. I wonder why I have them though and wonder if any of you have them?

[SjoAmy]

Perhaps calcifications?

[wendyoh]

Hi SjoAmy~

Sorry, I haven't done any research on Alpha 1 Antitripsyin Deficiency.

For a person with autoimmune disease, taking supplemental BCAA's could be harmful.

If you lack the ability to properly metabolize proteins, not only would you be deprived of the amino acids and vitamin B12 found in those proteins, but the components of which those proteins are comprised (amino acids) would enter the bloodstream and trigger an immune response.

Here is a picture of these unbroken down protein particles in a lupus patients bloodstream. (Notice the last paragraph where it states lupus patients lack the enzyme DNase 1)

http://www.sciencedaily.com/releases/2010/05/100503161423.htm

Taking additional amino acids in supplement form would lead to an increased risk of disease. This is evident in the findings from a study entitled ?Intermediary metabolism of phenylalanine and tyrosine in diffuse collagen diseases? (Nishimura, 1959). When lupus patients were given supplements of tyrosine and phenylalanine, the supplements ?unfailingly aggravated both clinical signs and laboratory data of collagen disease.?

I think this is one of the strongest lesions that can be learned about autoimmune disease--you shouldn't take supplemental nutrients into your body that you have lost the ability to properly metabolize-even if you lack them. They will just do as the researchers stated in the lupus study-unfailingly aggravate both clinical signs and laboratory data of the disease. The nutrients that are lacking in patients with autoimmune disease--amino acids, vitamin B12, zinc, iron, calcium, magnesium, and vitamin D are all lacking because the body has lost the ability to properly metabolize them.

I can address your question about the MTHFR deficiency in the next post.

hi the original subject in this thread was brain lesions but I did a search on branched chain amino acids (BCAA) and this thread came up and Nat's info is incredibly helpful to me! I was recommended to take them because am on a limited soft diet right now, dental problems coupled with food reactivity that is getting worse. Unfortunately pretty quickly I realized I feel worse on them, increases pain and fatigue etc and just awful feeling....which has happened to me with other aminos and supplements....Nat has best explanation I have seen backed up with studies he cites to why so many things bother me that I "need" like vitamin D

curious if there are others that have tried BCAA with same bad effect? trying to figure out the anti-dote now....best can come up with is activated charcoal, more water, quercetin, bit of molybdenum and tinch of this one digestive enzyme I can sometimes tolerate.

[Way2dry]

I was glad to find this thread although I don't understand most of it.  I had an MRI with & without contrast in 2016.  My doctor just said it was "normal".

I recently found the report online and read it.  To my dismay it said I had "one focus of T2/FLAIR hyperintensities ... within the subcritical white matter of the right frontal lobe..." ..."In this age group, minimal chronic small vessel ischemic gliosis is a leading consideration."

Is this the same as white brain lesions?  It also sounds like I'm a candidate for a stroke.  ☹️