Tag Archives: methylmalonate

Serum levels of vitamin B12 are not accurate for brain health and cognition

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Numerous times over the past couple decades I’ve regrettably had to contradict a colleague when a patient has been told that their serum levels of vitamin B12 are adequate and supplementation is not warranted. A study just published in the journal Neurology offering yet more evidence that serum vitamin B12 levels within the typical normal range can mislead about serious consequences of B12 deficiency in the brain. The authors’ intent was to…

“…investigate the interrelations of serum vitamin B12 markers with brain volumes, cerebral infarcts, and performance in different cognitive domains in a biracial population sample cross-sectionally.”

They examined serum markers of vitamin B12 in relation to neuropsychological tests of 5 cognitive domains and brain MRI studies obtained on average 4.6 years later among 121 older community dwelling adults. The data paint an important picture:

“Concentrations of all vitamin B12–related markers, but not serum vitamin B12 itself, were associated with global cognitive function and with total brain volume. Methylmalonate levels were associated with poorer episodic memory and perceptual speed, and cystathionine and 2-methylcitrate with poorer episodic and semantic memory. Homocysteine concentrations were associated with decreased total brain volume. The homocysteine-global cognition effect was modified and no longer statistically significant with adjustment for white matter volume or cerebral infarcts. The methylmalonate-global cognition effect was modified and no longer significant with adjustment for total brain volume.”

In other words, the decrease in total brain volume due to vitamin B12 insufficiency appeared to the mediating the impact on function of the markers besides homocysteine (also associated with brains infarcts)—and serum B12 did not correlate with the MRI or cognitive testing results. For lay readers, your brain can be shrinking with concomitant loss of cognitive function due to B12 insufficiency and the blood test for B12 can still appear normal. The authors’ conclusion needs to become common knowledge among all practitioners:

“Methylmalonate, a specific marker of B12 deficiency, may affect cognition by reducing total brain volume whereas the effect of homocysteine (nonspecific to vitamin B12 deficiency) on cognitive performance may be mediated through increased white matter hyperintensity and cerebral infarcts. Vitamin B12 status may affect the brain through multiple mechanisms.”

Note: methylmalonate (methylmalonic acid) in urine or serum, while not perfect, are practicable. This study also adds more evidence to the importance of homocysteine and brain health.

DNA methylation—a key factor in breast cancer prognosis and treatment

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Landmark research just published in PLoS Genetics (Public Library of Science) brings to light two important points in breast cancer diagnosis and treatment. First, the authors prove that defects in methylation (addition of a methyl group) a critical process for maintaining DNA health, is a powerful prognostic indicator for breast cancer outcome. The authors first observe:

“Although tumor size and lymph node involvement are the current cornerstones of breast cancer prognosis, they have not been extensively explored in relation to tumor methylation attributes in conjunction with other tumor and patient dietary and hormonal characteristics…We investigated DNA methylation profiles in over 160 well annotated breast tumor samples and found significant relationships with standard and other known predictors of prognosis, as well as established risk factors for disease: alcohol intake and dietary folate.”

They measured the methylation patterns of critical genes primary breast tumors from 162 women. Their findings are compelling:

“Tumor grade, size, estrogen and progesterone receptor status, and triple negative status were significantly associated with altered methylation…”

The second valuable point confirms the role of alcohol intake and folate status, both known to impact methylation capability.

“Using multinomial logistic regression to adjust for potential confounders, patient age and tumor size, as well as known disease risk factors of alcohol intake and total dietary folate, were all significantly associated with methylation class membership.”

The authors’ conclusion indicates the profound importance of assessing and protecting methylation capacity:

“Breast cancer prognostic characteristics and risk-related exposures [alcohol and folate status] appear to be associated with gene-specific tumor methylation, as well as overall methylation patterns.”

I use measurements of urinary methylmalonate and formiminoglutamate, objective indicators of important methylation cofactors. One or both of these is typically abnormal in patients with breast cancer. In my opinion, measuring this and treating methylation abnormalities with physiological interventions should be part of the standard of care for breast cancer.