June 6, 2006
Studies regarding the correlation between unhealthy cardiovascular function and abnormally high blood levels of the amino acid homocysteine have been appearing with increasing regularity. Relatively overlooked among the research articles is a recently published Swedish study, the results of which demonstrate consistently high homocysteine levels and low concentrations of vitamin B12 in the cerebrospinal fluid (CSF) of individuals who report repetitive or continual fatigue at levels that interfere with normal life functioning.
In the Swedish study by Regland M.D., Ph.D., et al., published in the Scandinavian Journal of Rheumatology, twelve female trial subjects that met criteria for repetitive or continuing fatigue that interfered with normal life functioning were studied along with a control group of eighteen healthy women. Subjects were also evaluated using a subset of items from the Comprehensive Psychopathological Rating Scale. The aim of the study was to determine factors present in cerebrospinal fluid related to homocysteine metabolism that correlate with the occurrence of repetitive or prolonged fatigue.
The mean value of cerebrospinal fluid homocysteine in the fatigued trial group was over three times the mean level in the control group, a highly significant difference. Cerebrospinal fluid vitamin B12 levels measured below normal in the majority (7/12) of the fatigued subjects.
On the other hand, blood Serum levels of homocysteine, folate, and vitamin B12 did not significantly deviate from normal ranges in the fatigued subjects. The authors interpret their findings to mean that biochemical events leading to high homocysteine levels in their patient group occur predominantly, if not exclusively, within the brain itself. Low vitamin B12 levels in the cerebrospinal fluid may reflect disruption of the mechanism of transport across the blood brain barrier. Incidentally, according to health practitioners who have used vitamin B12 in complimentary nutritional programs, high doses are often required to achieve measurable effects.
Homocysteine is a sulfur-containing amino acid involved in several important methyl and sulfur transfer reactions. Excessive accumulation of homocysteine in the body fluid compartments is normally prevented by degradation through two enzymatic reactions called transsulfuration and remethylation. Importantly, these enzyme reactions depend on folate, vitamin B 6 (pyridoxal 5- phosphate), and vitamin B12 (cobalamin) as cofactors.
When functioning properly, the enzymatic break-down of homocysteine forms methionine, which can then be converted to S-adenosyl-methionine (SAM). SAM is an important cofactor in the metabolism of central nervous system monoamine neurotransmitters, including dopamine, norepinephrine and serotonin. It has also been used successfully to treat both on-going fatigue and mood balance. Unfortunately, SAM was not measured in the Swedish study.
Another explanation for high cerebrospinal fluid homocysteine levels was considered by the Swedish authors. Nitric oxide, which is an inhibitor of the enzyme that converts homocysteine to methionine, is produced as a result of inflammatory reactions. Most of the fatigued trial subjects in the study, in addition to their on-going fatigue, had accompanying symptoms of viral or bacterial infections. Theoretically, the inflammation caused by these infections increased nitric oxide levels, which in turn increased homocysteine levels.
In conclusion, this study provides convincing preliminary evidence that high homocysteine levels in cerebrospinal fluid is an underlying factor in patients suffering from recurrent or continuing fatigue. Low vitamin B12 levels in cerebrospinal fluid and possibly low SAM 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 function issues. Deficiencies in these essential biochemical pathways in the brain should be considered by health practitioners in the evaluation of successful interventions for nutritional support in overcoming recurrent or continuing fatigue.
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