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Alzheimer’s Disease
Novel Biomarkers and Therapeutic Options to Address Neuronal Injury
a report by
Sean C Orr, MD
Medical Director, Stroke Center, Jacksonville Baptist Medical Center
Studies show that the aging population is at increased risk for folate transulfuration, cystathione-beta synthase (CBS), is minimally expressed.
5
deficiency, which may contribute to cognitive decline.
1
Data reveal that Due to the low expression of CBS, Hcy metabolism in the CNS is
with increasing age, serum and cerebrospinal fluid (CSF) folate may drop largely dependent on re-methylation (see Figure 1c). There are several
below normal levels, while serum homocysteine (Hcy), a sensitive marker acquired and genetic factors that can cause alterations in the metabolic
of functional folate deficiency, may rise to above normal levels. The pathways and lead to cognitive decline.
association between elevated serum Hcy and Alzheimer’s disease (AD)
raises the possibility that vitamin therapy to optimize CSF folate
2,3
or lower Acquired Factors
Hcy levels may decrease the risk for AD or age-related cognitive decline.
4
Hypomethylation related to hyperhomocysteinemia can result from a
complex interaction of acquired and genetic factors. The most important
The Significance of One-carbon Metabolism acquired factor is a relative nutritional deficiency of methylfolate and
Abnormalities of one-carbon metabolism lead to elevated levels of methylcobalamin. Since 1998, the US Food and Drug Administration
Hcy. In one-carbon metabolism, methionine condenses to form (FDA) has required that enriched grain products contain at least 140µg of
S-adenosylmethionine (SAM), which is the substrate for many folic acid per 100g. The effect of this low-level fortification on Hcy levels
methyltransferase enzymes important in the synthesis of nucleic acids, is not fully known.
phospholipids, proteins, neurotransmitters, and other molecules
(see Figure 1). The methyltransferase enzymes convert SAM to S-adenosyl- Epidemiological studies
6,7
have found an association between low
L-homocysteine (SAH), which inhibits methylation reactions when it cobalamin levels and elevated plasma Hcy. Importantly, there was no
accumulates. SAH is converted to Hcy, and elevated levels of Hcy favor the association between high Hcy and low cobalamin intake, suggesting
accumulation of SAH. Therefore, the rapid removal of Hcy is essential in that, in contrast to folate, failure to absorb cobalamin—rather than
maintaining physiologically normal levels of SAH and methylation reactions. inadequate dietary consumption—was the main culprit. Individuals
Homocysteine may accumulate due to defects in re-methylation, the primary above 60 years of age are of particular concern because of age-related
pathway for Hcy metabolism. This results in increased SAH and decreased declines in vitamin absorption and extraction of cobalamin from protein,
SAM. This primary pathway for Hcy metabolism, re-methylation, regenerates and age-related increases in autoimmunity against intrinsic factor or
methionine by an enzymatic reaction requiring L-methylfolate and the gastric parietal cells that produce intrinsic factor.
8
methylcobalamin. Suboptimal levels of either of these two co-factors for
re-methylation will increase Hcy levels. Similarly, a genetic polymorphism in Other factors that affect Hcy levels have received less attention.
the enzyme 5,10 methyltetrahydrofolate reductase (MTHFR) enzyme (see Drugs such as phenytoin, methotrexate, sulphasalazine, metformin,
Figure 1a) may compromise the ability to reduce dietary folate or synthetic non-steroidal anti-inflammatory drugs (NSAIDS), niacin, and bile acid
folic acid to L methylfolate, also increasing Hcy levels.
5
sequestrates (fenofibrates) cause elevations in Hcy levels by interfering
with folate status. Other risk factors associated with decreased folate
A secondary pathway of Hcy metabolism is reduction via transulfuration status and increased Hcy include coffee consumption of four or
(see Figure 1b) to form cysteine. Elevated levels of Hcy may increase more cups daily, excessive alcohol intake, poor nutrition, atrophic
the use of the transulfuration pathway, which is of concern due to the gastritis, Crohn’s disease, and a 20-year history of smoking.
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vascular toxicity of cysteine. In brain tissue, the enzyme necessary for
Genetic Factors
The methylenetetrahydrofolate reductase (MTHFR) 677 C→T genotype
Sean C Orr, MD, is Medical Director at the Stroke Center at Baptist Medical Center in
is a genetic factor controlling Hcy remethylation. This enzyme
Jacksonville, a position he has held since November 2004. His core areas of research focus are
stroke, vascular neurology, critical care neurology, interventional neurology, and neuroimage
reduces 5,10-methylenetetrahydrofolate to L-methylfolate. L-methylfolate is
interpretation. Dr Orr earned his MD from the University Of South Florida College of Medicine needed to convert Hcy to methionine. Individuals with the C/T
in 1995. After graduating, he underwent his residency and was named Neurology Chief
(heterozygous) or T/T (homozygous) polymorphism have higher
Resident. He completed his fellowship under Camilo R Gomez, MD, in vascular and critical care
neurology, interventional neurology, and stroke in 2001.
concentrations of plasma Hcy. This is a common polymorphism, and may be
present in as many of two-thirds of vascular dementia patients: 25.5% (T/T)
E: strokedr@gmail.com
homozygous, 40.6% (C/T) heterozygous.
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The MTHFR mutation produces
modestly elevated plasma Hcy levels and a reduction in CNS L-methylfolate.
26 © TOUCH BRIEFINGS 2008
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