Homocysteine. Related Vitamins and Neuropsychiatric Disorders

Transcription

1 Homocysteine Related Vitamins and Neuropsychiatric Disorders

2 Springer Paris Berlin Heidelberg New York Hong Kong London Milan Tokyo

3 Christina Bolander-Gouaille Teodoro Bottiglieri Homocysteine Related Vitamins and Neuropsychiatric Disorders Second edition

4 Christina Bolander-Gouaille Edvin Berlings Gata 32 SE Helsingborg Sweden Teodoro Bottiglieri Baylor University Medical Center Institute of Metabolic Disease 3812 Elm Street, Dallas, Texas ISBN : Paris Berlin Heidelberg New York Springer-Verlag France 2007 Printed in France Springer-Verlag France is a member of Springer Science + Business Media 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 transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction 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 statement, 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 contained in this book. In every individual case, the user must check its accuracy by consulting other pharmaceutical literature. SPIN: Maquette de couverture : Nadia Ouddane

5 Preface It is not always recognised that we face a silent epidemic of chronic neuropsychiatric 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 lifeyears. In 1990, psychiatric diseases alone accounted for about 10% of total morbidity but this expected to rise to around 15% in 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 Africa. Indeed, the developing world also faces a growing problem, as lifeexpectancy 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 homocysteine. 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 homocysteine levels and stroke, cognitive impairment and dementia, including Alzheimer s disease.

6 6 Homocysteine Related Vitamins and Neuropsychiatric Disorders Having identified an association between a brain disease and homocysteine, we then face the challenge of causality. Homocysteine is an established 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 question 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 clinical 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 B 12? Thus the final stage in the quest for establishing a role for homocysteine in psychiatric disease will be to carry out long-term randomised controlled trials. The evidence we already have for a link between homocysteine and cognitive 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, University Professor and Dean, Friedman School of Nutrition and Policy, Tufts University, Boston, MA, USA

7 Acknowledgements We are grateful for the constructive comments, criticism and advice of many researchers and clinicians. Many thanks also to authors and journals for generously granting permission to reproduce tables and figures.

8 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

9 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/AIDS 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