Table Of ContentHomocysteine
Related Vitamins
and Neuropsychiatric Disorders
Springer-Verlag France S.A.R.L
Dr Christina Balander-Gouaille
Dr Teodoro Bottiglieri
Homocysteine
Related Vitamins
and Neuropsychiatric Disorders
Springer
Christina Bolander-Gouaille
Edvin Berlings Gata 32
SE-25258 Helsingborg
Sweden
[email protected]
Teodoro Bottiglieri
Baylor University Medical Center Institute
of Metabolic Disease
3812 Elm Street, Dallas, Texas 75226
ISBN 978-2-287-04393-2 ISBN 978-2-8178-0759-1 (eBook)
DOI 10.1007/978-2-8178-0759-1
© Springer-Verlag France 2003
Originally published by Springer-Verlag France in 2003
Apart from any fair dealing for the purposes of the research or private study, or criticism or review, as permitted under
the Copyright, Designs and Patents Act 1998, this publication may only be reproduced, stored or rransmitted, in any
form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduc
tion in accordance with the terms of licenses issued by the copyright. Enquiry concerning reproduction outside those
terms should be sent to the publishers.
The use of registered names, trademarks, etc, in this publication does not imply, even in the absence of a specific sta
tement, that such names are exempt from the relevant laws and regulations and therefore free for general use.
Product liability: the publisher can give no guarantee for information about drug dosage and application thereof contai
ned in this book. In every individual case, the user must check its accuracy by consulting other pharmaceuticalliterature.
SPIN: 10927168
Maquette de couverture : Nadia Ouddane
Preface
It is not always recognised that we face a silent epidemic of chronic neu
ropsychiatric disease that in many ways has as great an impact world-wide
as the epidemics of acute diseases such as AIDS, tuberculosis and malaria.
The World Health Organisation's Global Burden of Disease study (1997)
found that psychiatric and neurological diseases together were the single
largest contributors to global ill-health, measured as disability-adjusted life
years. In 1990, psychiatric diseases alone accounted for about 10% of total
morbidity but this expected to rise to around 15% in 2020. The burden
of chronic psychiatric disease is not confined to developed countries, but
is the most important factor in all parts of the world except sub-Saharan
Mrica. Indeed, the developing world also faces a growing problem, as life
expectancy increases, due to age-related non-communicable diseases such
as dementia.
The main contributors to global ill-health amongst psychiatric diseases
are unipolar depression and dementia. By 2020, depression will be the
second leading cause of disease burden in the world after ischemic heart
disease. By 2040 dementia, principally Alzheimer's disease, is expected to
affect at least 20 million people in Europe and the North America.
Cognitive impairment in the elderly is a major risk factor for dementia;
right now, every year, about two million people in Europe and North
America develop cognitive impairment. The costs of dementia alone are
some 20% of the health budgets of developed countries.
How can we tackle this challenge of neuropsychiatric disease? First of
all, we must identify risk factors for the different brain diseases that cause
psychiatric illness. One such factor for several brain diseases is homocy
steine. This book is very timely for it introduces the newcomer to this
important new field of research and explores the evidence for a link
between homocysteine and the major neuropsychiatric diseases. The best
evidence so far is for associations between moderately elevated homocy
steine levels and stroke, cognitive impairment and dementia, including
Alzheimer's disease.
6 Homocysteine Related Vitamins and Neuropsychiatric Disorders
Having identified an association between a brain disease and homocy
steine, we then face the challenge of causality. Homocysteine is an esta
blished risk factor for vascular disease. Those studying homocysteine in
relation to psychiatric disease thus have to consider: could the association
be due to the influence of homocysteine on blood vessels in the brain?
Or is it independent of vascular disease? Since any psychiatric disease is
likely to have multiple causal factors, we should also consider whether
homocysteine might be acting both directly on neurons and indirectly
through its effects on the cerebral vasculature. Another important ques
tion is whether the association of a disease with homocysteine is due to
an effect of raised homocysteine levels, or whether homocysteine is just a
marker for an abnormal status of folate and/or vitamin B 12. From a cli
nical perspective, these scientific questions matter less than the answer to
the question: can we prevent the psychiatric disease by lowering the level
of homocysteine by administering folic acid and vitamin B12? Thus the
final stage in the quest for establishing a role for homocysteine in psy
chiatric disease will be to carry out long-term randomised controlled trials.
The evidence we already have for a link between homocysteine and cogni
tive impairment makes these trials an urgent priority for public health.
A. David Smith, DPhil, Professor of Pharmacology and Director of
Oxford Project to Investigate Memory and Ageing, University of Oxford,
Oxford, UK
Irwin H. Rosenberg, MD, Professor and Freidman School of Nutrition
and Policy, Tufts University, Boston, MA, USA
Acknowledgements
We are grateful for the constructive comments, criticism and advice of
many researchers and clinicians. Many thanks also to authors and jour
nals for generously granting permission to reproduce tables and figures.
Contents
Introduction 11
What is Homocysteine? 15
Homocysteine Metabolism 21
The methylation cycle 21
Common enzyme defects 28
How can Homocysteine be Neurotoxic? 35
Oxidative stress 36
Decreased synthesis of tetrahydrobiopterin 45
NMDA receptors and excitotoxcity 47
Impaired methylation 48
Interaction with inflammatory markers 53
Other proposed mechanisms 55
Why do Homocysteine Levels increase? 59
Lifestyle factors 59
Age-related factors 72
Hormonal changes 79
Diseases affecting the homocysteine metabolism 82
Drugs that interact with the homocysteine metabolism 92
10 Homocysteine Related Vitamins and Neuropsychiatric Disorders
Neuropsychiatric Conditions associated
with Hyperhomocysteinemia 109
Cognitive impairment and dementia 110
Depression 126
Schizophrenia 132
Multiple Sclerosis 132
Parkinson's Disease 134
Stroke 134
Other neuropsychiatric disorders 140
Neuropsychiatric complications associated with diabetes, alsoholism
and HIV/A IDS 143
Clinical Impact of Enzyme Defects 151
Cognitive impairment 152
Depression 153
Schizophrenia 154
Parkinson's Disease 154
Epilepsy 155
Down syndrome 155
Stroke 157
Other neurological disorders and complications 158
Interaction with drug treatment 159
When and how to check Homocysteine Levels? 163
When should hyperhomocysteinemia be suspected? 163
Blood sampling 165
Methionine loading 168
How to interpret the Test Result and how to handle
Hyperhomocysteinemia 171
Reference ranges 171
Interpretation 173
Intervention 175
Folic acid food fortification programmes 176
Vitamin supplementation 179
Abbreviations 183
References 185
Introduction
The importance of homocysteine as a risk factor or risk marker is becoming
a familiar concept. Since the early 1990s a constantly increasing number
of studies have been published on homocysteine. It has also been the topic
of three international conferences, in 1995, 1998, and 2001.
Increased plasma or serum levels of homocysteine have been shown to
be an independent risk factor for cardiovascular disease, for neural tube
defects and other birth defects.
Many studies have found a link between impaired homocysteine meta
bolism and neuropsychiatric disorders such as depression and cognitive
impairment in the elderly.
There is also much focus on the association between carcinogenesis and
deficiency of vitamins involved in the homocysteine metabolism, prima
rily folate.
Hyperhomocysteinemia is in most cases associated with low levels of
folate, vitamin B]2 and B6. Successful lowering of elevated homocysteine
levels may, in most cases, be accomplished by a simple vitamin supple
mentation.
Within the next few years, the results of several large homocysteine-low
ering intervention studies will become available. There are strong reasons
to believe that they will confirm the predicted preventive effects of homo
cysteine-lowering treatment not only on cardiovascular disease, but also
on cognitive decline.
Supplementation with folic acid during the peri-conceptional period has
already been shown to substantially decrease the incidence of neural tube
defects. It may also reduce the incidence of other birth defects pregnancy
complications.
Moderate elevations of homocysteine may often be caused by one or
more unhealthy lifestyle factors that influence vitamin status/metabolism,
such as smoking, high alcohol consumption, low nutritional intake of
vitamins, high coffee consumption and lack of physical exercise. A recent
large cross-sectional study indicates that a change in lifestyle factors only,
