Hermann_subbed.qxp 16/2/09 5:13 pm Page 10
Current Issues
Evaluation of the Current Evidence on
Hyperhomocysteinaemia in Neurological Diseases
a report by
Rima Obeid, Klaus Fassbender and Wolfgang Herrmann
Homocysteine Expert Panel, Homocysteine Round Table Discussion, Annual Meeting of the German Society for Clinical Chemistry, Mannheim
Homocysteine – A Marker for Vitamin Deficiency and a protein phosphatase 2A [PP2A]). Elevated levels of Hcy can therefore
Risk Factor for Neurological Diseases cause damage to several key pathways in the central nervous system,
Homocysteine (Hcy) is the demethylated product of methionine. This toxic either directly or by changing the methylation potential (SAM/SAH).
amino acid can be removed by remethylation to methionine via
methionine synthase, which utilises 5-methyl tetrahydrofolate as a methyl Changes in brain volume and intensity or the presence of small infarcts
donor and methyl cobalamin as a co-factor. An alternative remethylation are early signs of dementia. These conditions can be detected by
pathway for Hcy depends on betaine-Hcy-methyltransferase, which utilises magnetic resonance imaging (MRI) of the brain. Changes in these MRI
betaine as a methyl donor. Another method of Hcy catabolism is via two parameters indicate increased risk of stroke, dementia and Alzheimer’s
vitamin-B
6
-dependent enzymes, cystathionine beta synthase and disease (AD). Numerous studies have found an association between
cystathioninase, to cysteine. The catabolism of Hcy in the brain depends plasma concentrations of Hcy and qualitative or quantitative MRI
mainly on its remethylation to methionine, utilising folate and methyl analyses.
3,4
Additionally, several longitudinal studies have documented
cobalamin. Because B vitamins (folate, vitamin B
12
, vitamin B
6
) are an association between baseline Hcy, folate, vitamin B
12
or vitamin B
6
important co-factors for Hcy catabolism, an elevated concentration of Hcy concentrations and decline in cognitive function with age.
can indicate B-vitamin deficiency.
1
An important role of Hcy-methionine
metabolism is to provide S-adenosylmethionine (SAM), the methyl donor Evidence has suggested that increasing intake of the B vitamins may have
for numerous biological reactions. SAM donates its methyl group to a a protective effect on the central nervous system. This effect can be
methyl acceptor and is transformed to S-adenosylhomocysteine (SAH). related either to lowering Hcy or to a direct effect of the vitamins. An
SAH is hydrolysed to Hcy by SAH-hydrolase. The SAH-hydrolase reaction is improvement in cognitive impairment or delaying its progression by Hcy-
reversible, but favours SAH formation in the presence of increased Hcy. lowering vitamins may support a causal role for hyperhomocysteinemia
Hcy metabolism in the brain is an important source of SAM.
2
This methyl (HHcy) in neurodegenerative diseases. In this article we discuss recent
donor plays important roles in the formation and catabolism of findings from longitudinal, observational and treatment studies on the
neurotransmitters and phospholipids (phosphatidylcholine is the role of Hcy in neurodegeneration.
methylated product of phosphatidylethanolamine), DNA methylation and
activation of several enzymes that have essential roles in the brain (e.g. Homocysteine in Dementia and Cognitive Decline
Dementia and AD are the most common age-associated diseases in western
countries. The pathophysiological mechanisms in dementia involve
Rima Obeid is a Professor in the Department of Clinical
Chemistry and Laboratory Medicine in the University of
degenerative (cellular) or vascular mechanisms, or both. Degenerative
Saarland College of Medicine. She completed her post- dementia constitutes 80% of all dementias in elderly people, whereas
doctoral fellowship in the Department of Clinical Chemistry
approximately 10% are vascular dementias. Sporadic age-associated
and Laboratory Medicine in Homburg, and graduated from
Damascus University in Syria.
dementia is a long-standing disease that extends over several decades and
usually starts as mild cognitive impairment (MCI). MCI is characterised by
E:
rima.obeid@uniklinik-saarland.de
memory impairment and/or only a mild decline in cognitive abilities. Patients
with MCI are at markedly increased risk of developing AD: approximately
Klaus Fassbender is Head of the Department of Neurology at
the University Hospital of Saarland. He was formerly Medical
20% of patients with MCI develop AD or progressive dementia within two
Director and a Professor of Neurology at the University of
years of follow-up.
5
On the one hand, neuronal degeneration and loss in AD
Göttingen. Professor Fassbender studied medicine at the
is reflected by reduced brain volume, hippocampal volume and lobar
University of Padua and chemistry at the University of
Wayne-State, Detroit, and received his PhD at the Johannes volume; on the other hand, the majority of dementia patients show
Gutenberg-University in Mainz.
microvascular and macrovascular injuries that are reflected by the presence
of silent brain infarct and extensive white matter hyperintensity, respectively.
Wolfgang Herrmann is a Professor and Head of the
Department of Clinical Chemistry at the University Hospital of
The association between Hcy and dementia has been shown in several
Saarland in Homburg. Professor Hermann was formerly an longitudinal studies. In the MacArthur Studies of Successful Aging,
6
Associate Professor at the University of Regensburg and
370 subjects 70–79 years of age were followed for a mean of seven
Lecturer in Clinical Chemistry at the Medical Academy of
Erfurt. He graduated from the University of Leipzig in 1972.
years. The mean change in total cognitive scores over seven years was
-4.3 points. Patients who were in the highest quartile of Hcy
(14.4–40µmol/l) lost ≥9 points. Low folate had also significant effect
on cognitive delay in this follow-up study.
10 © TOUCH BRIEFINGS 2008
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