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SECTION B. MTHFR, folate (B9), folic acid, and LMF (9)
8. What does MTHFR mean?
This an acronym for “methylene terrahydrofolate reductase”. This is an especially important enzyme in vitamin B9 (folate) metabolism. Basically, the MTHFR enzyme has a significant influence on how well the body processes, makes, and utilizes several different forms of folate.
9. What is folate?
Another word for vitamin B9. Both “folate” and “B9” are generic vitamin category terms as they include a variety a different folate forms in the body that have different functions. So they refer to a family of closely related B9 vitamins more than any one B9 form per se.
10. What is the MTHFR enzyme’s main function?
A-MTHFR’s most important job is to make a specialized form of B9 called “L-methyl folate” (AKA “LMF” or “5-MTHF”). As it produces each molecule of LMF, it also helps to keep other less specialized upstream forms of folate from building up in an unhealthy way. When MTHFR functions properly and is able to produce LMF in a consistent way, it also helps to support the normal functioning of other chemical reactions that are critically dependent on LMF, including keeping toxic metabolites in check (homocysteine) and supporting neurotransmitter production (Ex: serotonin and dopamine).
11. What is LMF?
A-It’s a specialized bioactive folate form that the body produces from simpler ingested folate forms. It is also the main natural folate form found in blood. “Bioactive” means that it is a vitamin that can perform one or more key biological functions. From a brain health perspective, LMF is a critically important micronutrient given that it is the only form of folate (B9) that can pass into brain tissue from the bloodstream. All other forms of folate are not able to access brain tissue. This is due to the fact that the brain is normally protected by something called the blood brain barrier (BBB). The BBB is a natural filter that surrounds the brain, creating an nearly impenetrable boundary/barrier between brain tissue and the fluid that surrounds the brain (CSF) vs the blood and other tissues outside of the brain. When it comes to folate, even though there are several versions of folate in the body, only one-LMF-can use specific folate transporters to pass into brain tissue through the blood brain barrier. It’s like having the right key for a lock. After LMF gets into the CSF through the blood brain barrier, it is is then taken up by brain cells and used to help make key neurotransmitters like dopamine, norepinephrine, and serotonin. This unique and specialized brain support function is one of the main reasons that LMF has garnered lots of attention in clinical and brain research settings over the past two decades.
12. What is “folic acid”? Isn’t this also a good way to increase your folate levels?
Folic acid (FA) is a synthetic form of folate (B9) that is a commonly consumed folate source in many industrialized countries including the US. It has also been a regular if not main source of folate for many people in the US after the FDA required that it be added to all enriched grain products in 1998. As the science of how folic acid is processed in the body has rapidly advanced in recent years, updated research suggests that while it still likely has some cost-effective health value as an inexpensive folate source for some groups of people, it’s no longer regarded (particularly in the MTHFR research and medical communities) as an ideal “one-size-fits-all” folate suited source for everybody. It’s main advantages include: a very low cost and the fact that it can be easily added to nearly all commercially-available processed foods, cereals, breads, and most inexpensive supermarket-stocked over-the-counter multivitamins. It is also credited with helping to reduce the overall rate of neural tube defects when taken by pregnant women. While folic acid has several potential advantages, it is still a synthetic form of folate that is not found in nature. So before it can be used by any cells of the body it has to first get metabolized and converted to biologically usable folate forms that the body can recognize and respond to. This set of extra processing steps can create some folic acid drawbacks for many people. One of Folic acid’s main drawbacks is the fact more than 50% of people have an genetic susceptibility that can interfere with their ability to efficiently use folic acid. In fact, published studies report that a significant percentage of the general population (up to 60% in the US) has a genetically-caused impairment (an MTHFR enzyme defect) in folate metabolism that reduces their ability to process and utilize folic acid. This common MTHFR-related metabolic defect has been shown to result in: (a) an unhealthy and potentially toxic accumulation of unmetabolized folic acid (UMFA) in the blood combined with (b) an insufficient production of a bio-active folate form (LMF) that is essential for normal neuronal and vascular tissues. Given these adverse health concerns, folic acid can end up having an unfavorable risk/benefit profile for many people, particularly those who have some underlying genetic defects (MTHFR mutations) and/or who are are on certain medications that impair folic acid metabolism (Ex: Depakote, Lamictal etc). In short, for people who have susceptibilities in their ability to metabolize folic acid, it’s better to avoid or at least greatly minimize the consumption of foods/vitamin products that contain folic acid.
13. Why/how are higher levels of unmetabolized folic acid (UMFA) a health concern?
Higher UMFA levels have been linked to several adverse health outcomes/problems in multiple published scientific studies including: • Impaired immune function through the reduction of both NK cells and NK cell activity • Reduced transport of bioactive folate (LMF) into brain tissue from folic acid binding to and blocking LMF transport receptors • Increased cognitive symptoms in some elderly patients • Increased levels of neurotoxic inflammatory biomarkers (ex: IL8, TNF-alpha) associated with cognitive dysfunction
14. How is LMF important for brain health?
In several ways: (1) LMF is the only known folate form that can pass through an intact blood brain barrier into the cerebral spinal fluid where it is then taken up by neurons. (2) It is a key cofactor for the production of neurotransmitters like Dopamine and Serotonin. (3) It enhances neurotransmitter synthesis by supporting the production of SAMe and BH4. (4) It helps to reduce/regulate levels of homocysteine (Hcy) which is important since increased Hcy is neurotoxic. (5) Clinical studies show that LMF can help to reduce depression and cognitive symptoms.
15. How is Folic acid metabolized in the body? Can Folic acid eventually be converted to a folate form that the brain can use?
The body has several standard enzymatic steps for converting synthetic Folic acid into natural bioactive folate forms and eventually into LMF, the most specialized folate form that is used by brain cells. There are 4 main steps to get from Folic acid to LMF. Those are depicted here in a simple flow chart: FA->->->->LMF Health problems can develop when one or more of these 4 enzymatic steps is slowed or impeded. This metabolic slowing can result in reduced levels of downstream folates like L methyl folate (LMF) and a build-up of upstream folates like Folic acid (AKA “UMFA”).
16. How is Folic acid metabolized in the body? Can Folic acid eventually be converted to a folate form that the brain can use?
While folic acid (FA) is inexpensive and plentiful (it’s in most foods that people in the US consume each day), it’s also not a natural B9 form. It’s synthetic, so it’s not known in nature. Therefore the body’s cells don’t have any pre-existing way to use it directly. They have to first convert it to a natural folate form that the body’s cells can recognize. So, tradeoff is that while Folic acid is very cheap, available in most processed foods, and something that quickly accumulates in the blood, the body can’t immediately utilize this absorbed FA so it has some extra work to do to get it converted to a B9 form that is biologically useful. One could say Folic acid a “high maintenance” form of folate.
17. Why is it important for the body to metabolize folic acid (FA) through all of these extra steps? Why not just use it “as is” after it is absorbed?
While folic acid (FA) is inexpensive and plentiful (it’s in most foods that people in the US consume each day), it’s also not a natural B9 form. It’s synthetic, so it’s not known in nature. Therefore the body’s cells don’t have any pre-existing way to use it directly. They have to first convert it to a natural folate form that the body’s cells can recognize. So, tradeoff is that while Folic acid is very cheap, available in most processed foods, and something that quickly accumulates in the blood, the body can’t immediately utilize this absorbed FA so it has some extra work to do to get it converted to a B9 form that is biologically useful. One could say Folic acid a “high maintenance” form of folate.
Section C. MTHFR mutations, low Bs, elevated homocysteine, and their linkages to psychiatric/medical problems
18. What are MTHFR mutations?
These are common genetic mutations that increase one’s susceptibility for developing: various B vitamin insufficiencies; increased neurotoxic biomarkers such as elevated homocysteine; imbalances in folate (B9) metabolism; cardiovascular disease; and various neuropsychiatric conditions.
19. How common are MTHFR mutations?
An estimated 50-60% of US residents have at least one MTHFR mutation.
20. Are MTHFR mutations more commonly found in people with psychiatric symptoms/conditions?
Yes. In two different psychiatric clinical settings in which we (CS; MKS) screened for MTHFR mutations in all referred patients over a several year period, we observed frequencies of 91% (OBH) and 94% (CCI). Increased rates of MTHFR mutations in persons being treated for psychiatric conditions has also been reported in the literature.
21. Have MTHFR mutations been more commonly found in people with dementia/memory loss?
Yes. In published dementia studies, MTHFR mutations have been observed in 89-93% of subjects.
22. How are MTHFR mutations related to B vitamins levels?
Having MTHFR mutations increase the risk for developing several B vitamin insufficiencies/deficiencies (Ex: B2, B6, B9, B12 especially).
23. How are MTHFR mutations related to increased neurotoxic biomarkers such as elevated homocysteine levels?
Several MTHFR mutation variants appear to increase the risk for having/developing increased homocysteine levels in the blood and brain tissue. Elevated homocysteine is a potentially modifiable neurotoxic marker that increases risk for depression, dementia, increased loss of neurons, injury to the blood brain barrier, and accelerated brain atrophy (shrinkage). Elevated homocysteine levels are also associated with elevations in other potentially neurotoxic biomarkers such as: homocysteic acid (HCA), thiolactone (HTL), and S-adenosyl homocysteine (SAH).
24. Chicken and egg question: what comes first among MTHFR, B vitamins, and elevated homocysteine risk markers?
This risk relationship is well established in 20+ years of published scientific studies: MTHFR mutations lead to lower Bs, which secondarily lead to elevations in homocysteine (HCY).
25. How are low B vitamins and psychiatric problems linked?
Low B vitamin levels have been linked to memory loss, cognitive decline, dementia, Alzheimer’s dementia, and vascular dementia.
26. How are elevated homocysteine and psychiatric problems related?
Elevated homocysteine has been associated with various kinds of psychiatric symptoms/conditions including depression, psychosis, anxiety, ADHD, autism, and bipolar symptoms.
27. How are low B vitamins and cognitive problems related?
Low B vitamins (B9, B12 etc) are associated with reduced levels of neurotransmitters in the brain (in cerebral spinal fluid studies).
28. How do low B vitamin levels impact brain atrophy risk (brain shrinkage)?
Low levels of B12 and B9 have been linked to increased brain atrophy.
29. How do elevated homocysteine levels impact brain atrophy risk (brain shrinkage)?
In prospective brain MRI studies, elevated homocysteine levels have been consistently linked to increased rates of brain atrophy in a graded positive association fashion (the higher homocysteine, the greater the atrophy). The homocysteine level with the lowest atrophy risk was assessed as < 8.
30. Are there different MTHFR mutation variants found in the general population? If so, do they have different observed health risk associations?
Yes. In the 60% of the US population is estimated to have at least one allele of the two most common clinically-significant MTHFR mutations-1298C and/or 677T, these 5 mutation combinations tend to occur 99% of the time: C677T TT (677 homozygote.. means two 677 mutations) C677T+ A1298C (677+1298 double heterozygote.. means one mutation of each) A1298C CC (1298 homozygote.. means two 1298 mutations) C677T T (677 heterozygote…means one 677 mutation) A1298C C (1298 heterozygote…means one 1298 mutation) These 5 MTHFR mutation variants have also been found to confer different relative/predictive risks for developing other associated health conditions (psychiatric, cognitive, cardiovascular etc). It’s too complicated to try to summarize all of the main risks here, but in general the adverse health risk gradient is believed to be the highest for C677T TT and the lowest for A1298C C, following roughly the first (highest risk) to last (lowest risk) sequence of these 5 mutations as listed just above. The relative risk for having lower B vitamins and/or elevated homocysteine appears to more or less follow this same mutation gradient according to available studies and our clinical findings.
Section D. Strategies for improving brain health, cognitive, and psychiatric outcomes in people with B vitamin insufficiencies, elevated homocysteine, and/or MTHFR mutations
31. Is there published research on the use of micronutrient interventions for people with MTHFR mutations, low Bs, and/or elevated homocysteine in relation to the goal of improving brain health outcomes?
Yes. Clinical studies have demonstrated multiple kinds of benefits from B vitamin combinations in terms of several improved brain health outcomes including: reduced depression symptoms, improved cognitive performance, reduced rate of cognitive decline, and reduced brain shrinkage on serial MRI tests.
32. Is it possible to treat elevated homocysteine levels with low-cost B vitamin replenishment approaches?
Yes. Studies indicate that several kinds of B vitamin regimens have been successfully used to reduce elevated homocysteine levels. B vitamin regimens are actually the most common strategy for treating elevated homocysteine. That said, the lack of access to baseline lab screening is often a barrier to using some of these newer evidence-based approaches.
33. Are primary care providers willing to order these kinds of baseline screening labs?
In many cases, yes. However, some primary care providers are less familiar with the published research findings on MTHFR mutations, homocysteine, and B vitamin insufficiencies. Therefore, some providers may be less comfortable ordering these kinds of labs, especially as they relate to risks for cognitive decline, depression, and brain atrophy outcomes. On the other hand, most primary care providers are much more willing to draw a fasting homocysteine, B12, folate, and sometimes also an MTHFR mutation lab, after a stroke, heart attack, blood clot, or new diagnosis of dementia. So access to these labs will often vary depending on the provider and medical risk context.
34. Do any clinical studies show a correlation between reduced homocysteine levels and improved psychiatric outcomes such as reduced depression symptoms?
Yes, including a recent placebo-controlled double-blinded study in subjects who had at least one MTHFR deficiency and clinical evidence for depression at baseline. B vitamins demonstrated efficacy for reducing depression symptoms and homocysteine level by 6 weeks.
35. What about between reduced homocysteine levels and a reduced rate of cognitive decline over time?
Yes. Published studies have shown that B vitamins can be used to reduce the rate of cognitive decline and homocysteine level at the same time.
36. What about between reduced homocysteine levels and improvements in cognitive performance scores?
A-B vitamins have also been used to improve cognitive performance in correlation with reductions in baseline homocysteine level.
37. What about between reduced homocysteine levels and a reduced rate of cognitive decline over time?
A-B vitamins have also been used to reduce both homocysteine levels and the rate of brain atrophy (shrinkage) as assessed by prospective MRI brain scans.
38. What about between improved B vitamin levels and reduced rate of brain shrinkage or atrophy over time? What about just improvements in dietary intake of B vitamin containing foods?
Aa) improving brain health outcomes, (b) reducing neurodegenerative risk, and/or (c) addressing modifiable risk factors for people who have underlying MTHFR mutations, low Bs, and/or elevated homocysteine levels? 38. Yes, there are multiple published micronutrient/B vitamin studies that have looked at several different outcomes in relation to each of these three key brain health goals.