Novel Biomarkers and Therapeutic Options to Address Neuronal Injury

Novel Biomarkers and Therapeutic Options to Address Neuronal Injury

Orr Sean C
Published: US Neurology - Volume 4 - Issue I
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Studies show that the aging population is at increased risk for folate deficiency, which may contribute to cognitive decline.1 Data reveal that with increasing age, serum and cerebrospinal fluid (CSF) folate may drop below normal levels, while serum homocysteine (Hcy), a sensitive marker of functional folate deficiency, may rise to above normal levels. The association between elevated serum Hcy and Alzheimer’s disease (AD) raises the possibility that vitamin therapy to optimize CSF folate2,3 or lower Hcy levels may decrease the risk for AD or age-related cognitive decline.4

The Significance of One-carbon Metabolism Abnormalities of one-carbon metabolism lead to elevated levels of Hcy. In one-carbon metabolism, methionine condenses to form S-adenosylmethionine (SAM), which is the substrate for many methyltransferase enzymes important in the synthesis of nucleic acids, phospholipids, proteins, neurotransmitters, and other molecules (see Figure 1). The methyltransferase enzymes convert SAM to S-adenosyl-L-homocysteine (SAH), which inhibits methylation reactions when it accumulates. SAH is converted to Hcy, and elevated levels of Hcy favor the accumulation of SAH. Therefore, the rapid removal of Hcy is essential in maintaining physiologically normal levels of SAH and methylation reactions. Homocysteine may accumulate due to defects in re-methylation, the primary pathway for Hcy metabolism. This results in increased SAH and decreased SAM. This primary pathway for Hcy metabolism, re-methylation, regenerates methionine by an enzymatic reaction requiring L-methylfolate and methylcobalamin. Suboptimal levels of either of these two co-factors for re-methylation will increase Hcy levels. Similarly, a genetic polymorphism in the enzyme 5,10 methyltetrahydrofolate reductase (MTHFR) enzyme (see Figure 1a) may compromise the ability to reduce dietary folate or synthetic folic acid to L methylfolate, also increasing Hcy levels.5

A secondary pathway of Hcy metabolism is reduction via transulfuration (see Figure 1b) to form cysteine. Elevated levels of Hcy may increase the use of the transulfuration pathway, which is of concern due to the vascular toxicity of cysteine. In brain tissue, the enzyme necessary for transulfuration, cystathione-beta synthase (CBS), is minimally expressed.5 Due to the low expression of CBS, Hcy metabolism in the CNS is largely dependent on re-methylation (see Figure 1c). There are several acquired and genetic factors that can cause alterations in the metabolic pathways and lead to cognitive decline.

Acquired Factors
Hypomethylation related to hyperhomocysteinemia can result from a complex interaction of acquired and genetic factors. The most important acquired factor is a relative nutritional deficiency of methylfolate and methylcobalamin. Since 1998, the US Food and Drug Administration (FDA) has required that enriched grain products contain at least 140μg of folic acid per 100g. The effect of this low-level fortification on Hcy levels is not fully known.

Epidemiological studies6,7 have found an association between low cobalamin levels and elevated plasma Hcy. Importantly, there was no association between high Hcy and low cobalamin intake, suggesting that, in contrast to folate, failure to absorb cobalamin—rather than inadequate dietary consumption—was the main culprit. Individuals above 60 years of age are of particular concern because of age-related declines in vitamin absorption and extraction of cobalamin from protein, and age-related increases in autoimmunity against intrinsic factor or the gastric parietal cells that produce intrinsic factor.8

Other factors that affect Hcy levels have received less attention. Drugs such as phenytoin, methotrexate, sulphasalazine, metformin, non-steroidal anti-inflammatory drugs (NSAIDS), niacin, and bile acid sequestrates (fenofibrates) cause elevations in Hcy levels by interfering with folate status. Other risk factors associated with decreased folate status and increased Hcy include coffee consumption of four or more cups daily, excessive alcohol intake, poor nutrition, atrophic gastritis, Crohn’s disease, and a 20-year history of smoking.9

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