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Folate, Vitamin B12, and MTHFR

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I participate in the 23andMe Parkinson's study and have seen very interesting and informative forum discussions there on the topics of the MTHFR gene mutations (which I do have), which may cause deficiencies of folate metabolism and Vitamin B12, possibly affecting PD, so this issue is of great interest to me as a person with PD. However, I can't seem to get a clear idea anywhere of exactly how you find out your levels of each, what actually constitutes a deficiency, and what type and how much supplementation to take if deficient. Do you have any information on this that would include clear guidelines of what to do? Many thanks.

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Dear Appala,

You're right to seek more information. For one thing, some people with PD who have used levodopa for an extended period develop elevated serum homocysteine, a substance commonly found in the blood after a meal. It is normally cleared away by B12, B6, and folic acid. If it remains elevated it is associated with risk for stroke, and heart disease. In any case, deficiencies of B12 and folate are of concern for anyone. I will separately post a short article on the importance of these vitamins in PD.


Regarding your levels, a test can be conducted by your primary care physician by drawing a blood sample from your arm. For serum B12, the test is for Methylmalonic Acid. Most labs consider a range of 210 - 911 pg/mL to be within normal limits.


For folate, either serum or red blood cell folate levels may be tested; if either is low, it indicates a deficiency. Normal levels are generally considered to be 2.8 - 40 ng/mL.


If either is elevated, discuss a test for serum homocysteine. Normal levels are usually considered to be 4 - 12 umol/L


If a deficiency is present, your doctor will discuss the best way to supplement, depending upon the degree of deficiency. Usually supplements are sufficient; in rare cases of extreme deficiency, intramuscular injections may be needed.


Check this forum for a message on B vitamins related to PD; I will post it shortly.

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Parkinson's, B6, B12, and Folate - What's the Connection?

Kathrynne Holden, MS

Copyright 2008-2012



In the past decade, there has been increasing interest among

researchers about the effects of three B vitamins - B6, B12, and folate.

We now know that deficiencies occur with greater frequency than ever

suspected previously, particularly in older adults. We also now know

that deficiencies, if not corrected, can result in irreversible damage

in some people. Some health professionals are beginning to suspect that

these three vitamins may be significant factors in Parkinson's disease.


What are B6, B12, and folate, and what do they do?


These are essential nutrients, meaning that they are vital to life.

These three vitamins work both independently and together in many of the

body's systems.


Vitamin B6 assists in making hormones, new proteins, and

neurotransmitters ("messengers" between nerve cells) for the body's use.

It also helps release stored sugar when we need it for fuel. It works

together with B12 and folate to remove homocysteine from the blood.

Homocysteine is a substance increasingly associated with a number of

diseases; more about this later.


Vitamin B12 plays a role in the synthesis of DNA, needed for formation

of new red blood cells. It takes part in the manufacture of the myelin

sheath - the protective coating that surrounds nerve cells. With B6 and

folate it removes homocysteine from the blood.


Folate, also called folacin or folic acid, is a partner with B12 in DNA

synthesis and in removal of homocysteine, and is required in many other

vital processes. Without folate, B12 would be unable to complete many of

its functions, and vice versa. Folate is the form found in foods, folic

acid is the form in dietary supplements.


How much do we need of these vitamins?


Nutrient needs are broken down by gender, age group, pregnancy, and

lactation. New guidelines have also established a Tolerable Upper Intake

Level. So, for example, while the RDA for vitamin B6 for males and

females age 19-30 years is 1.3 mg/day, the Tolerable Upper Intake Level

for both is 100 mg/day, making it easier to provide recommended amounts.



RDA* Tolerable Upper Intake Level ** +


Vitamin B6*** + 1.7 mg/day 100 mg/day (age 19 and older)


Vitamin B12 + 2.4 mcg/day Not Determined


Folate + 400 mcg/day 1000 mcg/day



* Recommended Dietary Allowance

** The Tolerable Upper Intake Level is the maximum level of daily

nutrient intake that is likely to pose no risk of adverse effects, and

represents the total intake from food, water, and supplements.

*** Adults age 51 and older

+ not applicable if pregnant or lactating


Why do deficiencies occur, and what are signs of deficiencies?


Vitamin B6. Mild deficiencies of B6 are fairly common in the U.S.,

mostly because of dietary deficiencies, but sometimes due to use of

certain medications which interfere with B6, including hydralazine,

isoniazid, MAO inhibitors, penicillamine, and theophylline. (Conversely,

large amounts of B6 can interfere with the absorption of levodopa, an

important medication for Parkinson's disease. Current use of the

combinations of carbidopa-levodopa or benserazide-levodopa offset this

interaction for the most part; but use of supplements containing more

than 15 mg of B6 can overwhelm the protective effects of the carbidopa

and benserazide.)


Good food sources of B6 include chicken, fish, eggs, nuts and seeds,

dried beans and peas, soybeans, wheat germ, bananas, avocados, and

brewer's yeast. Also, some foods, including a number of breakfast

cereals, are fortified with B6.


Signs of B6 deficiency include irritability, depression, and confusion;

sore tongue, sores or ulcers of the mouth, and ulcers of the skin at the

corners of the mouth.


Vitamin B12. The human body stores this vitamin so well that it can

take a long time to deplete, sometimes several years. Nevertheless,

there are several reasons why people sometimes do experience deficiency.

Animal foods are the only source of B12, therefore people who eat few or

no animal products (meat, fish, poultry, eggs, milk) are at risk unless

they use vitamin supplements.


Another problem is that B12 in foods cannot be absorbed by the body

until it is freed from the proteins in the food; the stomach produces an

acid that removes this protein. However, with age, we produce less and

less of this stomach acid. Many older adults don't produce enough acid

to allow them to absorb B12. Further, people who have acid reflux often

use medications that reduce stomach acid, which unfortunately also

decreases absorption of B12. Vitamin B12 is one of the few nutrients

that is better absorbed in pill form than from dietary sources.


Signs of B12 deficiency include numbness or a tingling "pins and

needles" sensation, or a burning feeling; a red, sore, or burning

tongue; loss of appetite; gait abnormalities, personality changes, an

Alzheimer-like dementia, psychosis, depression, and agitation,

particularly in older adults. Other signs are megaloblastic anemia, and

elevated serum homocysteine, in people of all ages. Researchers believe

that as many as 42% of people aged 65 and older may have some degree of

B12 deficiency. Many people with PD are age 65 or older, and should be

considered at risk and tested for B12 deficiency.


Folate. Folate is available in many foods: lima beans, brewer's yeast,

orange juice, dried beans, green peas, asparagus, beets, Brussels

sprouts, broccoli, corn, spinach and other dark green leafy vegetables,

soybeans, nuts and seeds. Further, the U.S. government requires that

food manufacturers fortify processed grain products with folic acid.

Yet, deficiencies of folate are not uncommon. This could be in part

because folate is another of the few nutrients in which the synthetic

form is absorbed much better (about 40 percent better) than the natural



Because of the possibility of deficiency, women, including women with

PD, who are pregnant or wish to become pregnant are advised to take

supplements of folic acid; deficiencies can result in neural tube

defects in the unborn child.


Deficiencies of folate are also being increasingly studied for a

possible role in other diseases:


. A low intake of folic acid is associated with risk for colon cancer.

Chronic constipation, experienced by many people with PD, also increases

risk for colon cancer; it is prudent for those with PD to control

constipation and to be sure the diet is adequate in folate.

. A low level of folic acid in the blood is associated with higher

levels of serum homocysteine, a substance in the blood that may

contribute to heart disease, stroke, and dementias.

. Animal studies point to a link between low levels of folic acid and

Alzheimer's disease; and people with Alzheimer's are often found to have

low levels of folic acid. Some people with PD develop an Alzheimer-type

dementia. Again, prudence dictates consumption of adequate folate.

. Another study using mice found that folic acid deficiency led to

increased levels of homocysteine and symptoms of Parkinson's disease.

Researchers speculate that homocysteine may damage DNA in the substantia

nigra, the area of the brain affected in Parkinson's disease.

. There are reports of improvement in restless leg syndrome (RLS) with

use of folate supplements; this has not as yet been studied thoroughly,

so it is too early to say whether there is a definite link. However,

people with PD often complain of RLS, and physicians should rule out the

possibility of folic acid deficiency.

Signs of folic acid deficiency include appetite loss, weight loss,

burning tongue, fatigue, weakness, shortness of breach, memory loss,

irritability, megaloblastic anemia, and increased levels of serum



Should people with PD be concerned about these vitamins?


Although there are concerns, as mentioned above, that deserve further

study, it's too early to say definitely that these three vitamins are of

significance to people with PD. However, if you are over age 50 these

vitamins are of importance independently of PD. Furthermore, studies

have demonstrated that some people who use levodopa, considered the best

medication for PD, develop elevated levels of serum homocysteine, due to

the way in which the medication is metabolized. It is certainly a good

idea to ask your doctor to test levels of serum homocysteine annually,

and to check for signs of B vitamin deficiencies.


Should you take supplements?


There is growing agreement that older adults are at risk for nutrient

deficiency, whether PD is present or not, and that supplements can help.


. One study of older adults found that a multivitamin containing 100% of

the Daily Value improved low levels of several nutrients, including

vitamins B6, B12, and folate.

. A recent study in the United Kingdom suggests that folic acid intake

should be about three times that of the current recommendation for

elderly people.

. Other studies indicate that up to 10% of older adults with low-normal

levels of B12 are actually deficient and could benefit from supplements.

Because folate supplements can mask a B12 deficiency, it becomes extra

important to get enough B12 daily.

. The American Heart Association recommends a folate-rich diet to lower

homocysteine levels, and supplements of 2 mg B6, 400 mcg folic acid, and

6 mcg of B12 if dietary means are not sufficient to lower the



For people with PD who use a medication that contains levodopa (such as

Sinemet, Madopar, Syndopa, Larodopa, etc.), you should be aware that

large amounts of vitamin B6 (more than 15 mg) can affect the absorption

of levodopa, by converting levodopa to dopamine in the stomach and

bloodstream. Dopamine cannot cross the blood-brain barrier, so it is

effectively blocked from its purpose.


Sinemet and Madopar contain either carbidopa or benserazide, which

"protect" the levodopa from B6; so ordinary supplements of B6 should not

be a problem for most people. However, very large amounts of B6, greater

than 15 mg (and in sensitive persons, possibly as low as 10 mg), could

overwhelm the protective effects of the carbidopa or benserazide. Such a

supplement should be taken at bedtime with a light snack, or with meals

at least two hours separately from levodopa.


In summary, older adults are acknowledged to be at increased risk for B

vitamin deficiencies. People with PD who are age 50 and over, therefore,

are at increased risk also. Whether younger people with PD should be

concerned about such deficiencies remains to be seen. A prudent and

rational approach for all those with PD is to:


. Discuss the possibility with their physicians, and to request tests

for B vitamin deficiencies

. Be aware of the signs of B vitamin deficiency

. Take a multivitamin/mineral supplement daily. Unless anemic, choose a

supplement that does not contain iron

. Take a B complex supplement if deficiencies occur; and take the

supplement separately from levodopa by at least two hours, preferably

with meals or a snack.


Knowledge is strength; awareness of dietary needs can prevent illness,

malnutrition, suffering, and hospitalization. If you have questions

about B vitamins or other nutrition or dietary needs, please visit the

National Parkinson Foundation website:

<http://www.parkinson.org and click on "Ask About Nutrition."


The above article may not be reproduced in any form except with

permission from the author.




Giovannucci, E. et al. Alcohol, low-methionine-low-folate diets, and

risk of colon cancer in men. Journal of the National Cancer Institute.

1995; volume 87: pages 265-273.


Kruman II, Kumaravel TS, Lohani A, Pedersen WA, Cutler RG, Kruman Y,

Haughey N, Lee J, Evans M, Mattson MP. Folic Acid deficiency and

homocysteine impair DNA repair in hippocampal neurons and sensitize them

to amyloid toxicity in experimental models of Alzheimer's disease. J

Neurosci 2002 Mar 1;22(5):1752-62.


Lobo A, Naso A, Arheart K, Kruger WD, Abou-Ghazala T, Alsous F, Nahlawi

M, Gupta A, Moustapha A, van Lente F, Jacobsen DW, Robinson K. Reduction

of homocysteine levels in coronary artery disease by low-dose folic acid

combined with vitamins B6 and B12. Am J Cardiol 1999 Mar 15;83(6):821-5.


Malinow, M.R. et al. Homocyst(e)ine, diet, and cardiovascular diseases:

a statement for healthcare professionals from the nutrition committee,

American Heart Association. Circulation. 1999; volume 99: pages 178-182.


Muller T, Werne B, Fowler B, Kuhn W. Nigral endothelial dysfunction,

homocysteine, and Parkinson's disease. Lancet. 1999 Jul



Muller T, Woitalla D, Hauptmann B, Fowler B, Kuhn W. Decrease of

methionine and S-adenosylmethionine and increase of homocysteine in

treated patients with Parkinson's disease.

Neurosci Lett. 2001 Jul 27;308(1):54-6.


Naurath HJ, Joosten E, Riezler R, Stabler SP, Allen RH, Lindenbaum J.

Effects of vitamin B12, folate, and vitamin B6 supplements in elderly

people with normal serum vitamin concentrations. Lancet 1995; 346:85-89.


O'Keeffe ST. Restless legs syndrome. A review. Arch Intern Med.


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Homocysteine, B vitamins, and Parkinson's disease

by Kathrynne Holden, MS, RD

Copyright 2008-2012


What is homocysteine?


Homocysteine is an amino acid found in the bloodstream; it is naturally

produced in small amounts by the human body from its precursor,

methionine. The body also removes homocysteine from the blood, using the B

vitamins folate, B12, and B6. An amount of homocysteine between 5 and 15

micromoles per liter of blood is considered normal; amounts greater than

that are considered "hyperhomocysteinemia" or elevated homocysteine.


Why is elevated homocysteine a problem?


The relationship between homocysteine and diseases is not clearly

understood at this time. However, researchers have discovered that

homocysteine can prevent the formation of nitric oxide, a substance that

keeps blood vessels pliable and prevents formation of atherosclerosis.

Thus, homocysteine could be implicated in cardiovascular disease, strokes,

and heart attacks.


Homocysteine may also be associated with memory impairment. In a study of

elderly individuals, elevated homocysteine was associated with cognitive

impairment (poorer ability to read, learn, remember, and understand) while

high levels of folate and vitamin B12 were associated with improved

cognition. Other researchers studied 1092 people aged 68 to 97, and found

that those whose homocysteine levels were over 14 micromoles per liter had

twice the risk of developing Alzheimer's disease as those with lower



The findings are based on a study of 1,092 people from

68 to 97 who were initially healthy and free of dementia. Their

homocysteine levels were measured and their health was monitored for

eight years. At the end of the study, 111 individuals had dementia,

including 83 with Alzheimer's. People whose homocysteine levels were

higher than 14 micromoles per liter of blood, one- fourth of the

participants, had nearly twice the Alzheimer's risk of those with lower



What about people with Parkinson's disease?


Some scientists found that people with PD who had been using levodopa for

some time had higher levels of homocysteine than newly-diagnosed PD

patients who had not begun treatment with levodopa. In another study,

using mice, researchers found that on a low-folate diet the mice had

increased levels of homocysteine. They speculate that increased

homocysteine can worsen oxidative stress on the neurons that produce

dopamine, and make them more easily damaged by environmental toxins.


Some degree of cognitive impairment, ranging from mild memory loss to

various types of dementias, is common among people with PD, more so than

in the general population. While not all cognitive impairment is related

to nutrient deficiency, some cases may well be, especially as people with

PD often change their eating habits in unsatisfactory ways.


In an article "Homocysteine and Atherosclerotic Heart Disease: A New and

'Unusual Suspect,'" Michelle Taylor-Chinn writes:


..... clinicians are advised to assess fasting homocysteine levels only

in high-risk patients -- including those with arterial occlusive disease,

hypothyroidism, impaired kidney function, systemic lupus erythematosus, or

a significant family history of premature atherosclerosis. Elderly

patients should also be considered for testing, as should patients who

receive certain medications or therapy (eg, theophylline, methotrexate,

levodopa, niacin [vitamin B3], nitrous oxide exposure). [Clinician Reviews

10(10):45-57, 2000. © 2000 Clinicians Publishing Group]


Because many people with PD meet one or more of these risk factors

(i.e., age, use of levodopa, and possibly other conditions), I recommend

that you discuss testing for homocysteine with your physician. Older

people in particular may not absorb vitamin B12 sufficiently from food,

and should be assessed for possible deficiency. I also advise an eating

pattern that includes vegetables, whole-grain and fortified breads and

cereals, fruits, dried beans, peas, and lentils, and fish.


-- Kathrynne Holden, MS, RD



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patients with Parkinson disease: motor, affective, and cognitive

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Muller T, Renger K, Kuhn W. Levodopa-associated increase of homocysteine

levels and sural axonal neurodegeneration. Arch Neurol. 2004



Sachdev P. Homocysteine and neuropsychiatric disorders. Rev Bras

Psiquiatr. 2004 Mar;26(1):50-6


Lokk J. Treatment with levodopa can affect latent vitamin B 12 and folic

acid deficiency. Patients with Parkinson disease runt the risk of elevated

homocysteine levels. Lakartidningen. 2003 Aug 28;100(35):2674-7.


Teunissen CE, Lutjohann D, von Bergmann K, Verhey F, Vreeling F, Wauters

A, Bosmans E, Bosma H, van Boxtel MP, Maes M, Delanghe J, Blom HJ, Verbeek

MM, Rieckmann P, De Bruijn C, Steinbusch HW, de Vente J. Combination of

serum markers related to several mechanisms in Alzheimer's disease.

Neurobiol Aging. 2003 Nov;24(7):893-902.


Miller JW, Selhub J, Nadeau MR, Thomas CA, Feldman RG, Wolf PA. Effect of

L-dopa on plasma homocysteine in PD patients: relationship to B-vitamin

status. Neurology. 2003 Apr 8;60(7):1125-9.


McIlroy SP, Dynan KB, Lawson JT, Patterson CC, Passmore AP. Moderately

elevated plasma homocysteine, methylenetetrahydrofolate reductase

genotype, and risk for stroke, vascular dementia, and Alzheimer disease in

Northern Ireland. Stroke. 2002 Oct;33(10):2351-6.


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degenerative diseases. Clin Lab 2002;48(9-10):471-81.


Kelly PJ, Furie KL. Management and Prevention of Stroke Associated with

Elevated Homocysteine. Curr Treat Options Cardiovasc Med 2002



Kelly PJ, Rosand J, Kistler JP, Shih VE, Silveira S, Plomaritoglou A,

Furie KL. Homocysteine, MTHFR 677C-->T polymorphism, and risk of ischemic

stroke: results of a meta-analysis. Neurology 2002 Aug 27;59(4):529-36.


Cindy J. Warren CJ. Emergent Cardiovascular Risk Factor: Homocysteine.

Prog Cardiovasc Nurs 17(1):35-41, 2002.

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Thank you very much for this excellent information. I will print it out to read & digest more carefully. I recently had testing with these results: Vitamin B12 was 908 pg/mL and Folate RBC was 658 ng/mL. My G.P. doctor says these are fine, but 23andMe forum participants say I may still need supplementation, esp. for folate, due to my MTHFR "compound heterozygous" status. But I'm unclear about type, source, dosage. Shoould I also request homocysteine testing? Thanks again.

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Is your neurologist a movement disorders specialist? Your B12 and folate levels seem very good, and ordinarily I would say not to supplement. But indeed, in view of your genetic susceptibility, supplementation could be warranted. I would discuss this with your neurologist -- and, in fact, you might post the question to Dr. Okun on "Ask the Doctor" as he conducts advanced research in PD and would be an excellent source for information.


Should supplements be advised, I doubt that intramuscular injections would be warranted at this time. I would ask your physician to recommend a type or brand for your particular needs, but it is likely that brands containing activated methylcobalamin and methyl tetrahydrofolatesuch would be good choices. In a recent study, sublingual cyanocobalamin and nutritional yeast both repleted B12 satisfactorily.

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