Lifetime Nutritional Influences on Cognition, Behaviour and Psychiatric Illness (Woodhead Publishing Series in Food Science, Technology and Nutrition)

Lifetime nutritional influences on cognition, behaviour and psychiatric illness

© Woodhead Publishing Limited, 2011

Related titles: Performance functional foods (ISBN 978-1-85573-671-9) Some of the newest and most exciting developments in functional foods are products that claim to influence mood and enhance both mental and physical performance. This important collection reviews the range of ingredients used in these ‘performance’ functional foods, their effects and the evidence supporting functional benefits. Functional foods, ageing and degenerative disease (ISBN 978-1-85573-725-9) This important collection reviews the role of functional foods in helping to prevent a number of degenerative conditions, from osteoporosis and obesity to immune system disorders and cancer. Introductory chapters discuss the regulation of functional foods in the EU and the role of diet generally in preventing degenerative disease. Part I examines bone and oral health, the use of diet to control osteoporosis, the use of functional ingredients to improve bone strength, and ways of maintaining dental health. Part II discusses how obesity can be controlled, whilst Part III looks at gut health and maintaining the immune function using functional ingredients. The book concludes by reviewing research on functional foods and cancer with chapters on synbiotics, anti-angiogenic functional foods, glucosinolates, dietary fibre and phytoestrogens. Food for the ageing population (ISBN 978-1-84569-193-6) The world’s ageing population is increasing. Food professionals will have to address the needs of older generations more closely in the future. This unique volume reviews the characteristics of the ageing population as food consumers, the role of nutrition in healthy ageing and the design of food products and services for the elderly. Chapters in Part 1 discuss aspects of the elderly’s relationship with food, such as appetite and ageing and the social significance of meals. The second part reviews the role of nutrition in conditions such as Alzheimer’s and eye-related disorders. Concluding chapters address issues such as food safety and the elderly and nutrition education programmes. Details of these books and a complete list of Woodhead’s titles can be obtained by: • visiting our web site at www.woodheadpublishing.com • contacting Customer Services (e-mail: [email protected]; fax: +44 (0) 1223 832819; tel.: +44 (0) 1223 499140 ext. 130; address: Woodhead Publishing Limited, 80, High Street, Sawston, Cambridge CB22 3HJ, UK) If you would like to receive information on forthcoming titles, please send your address details to: Francis Dodds (address, tel. and fax as above; e-mail: [email protected]). Please confirm which subject areas you are interested in. © Woodhead Publishing Limited, 2011

Woodhead Publishing Series in Food Science, Technology and Nutrition: Number 223

Lifetime nutritional influences on cognition, behaviour and psychiatric illness Edited by David Benton

Oxford

Cambridge

Philadelphia

New Delhi

© Woodhead Publishing Limited, 2011

Published by Woodhead Publishing Limited, 80 High Street, Sawston, Cambridge CB22 3HJ, UK www.woodheadpublishing.com Woodhead Publishing, 1518 Walnut Street, Suite 1100, Philadelphia, PA 19102-3406, USA Woodhead Publishing India Private Limited, G-2, Vardaan House, 7/28 Ansari Road, Daryaganj, New Delhi – 110002, India www.woodheadpublishingindia.com First published 2011, Woodhead Publishing Limited © Woodhead Publishing Limited, 2011 The authors have asserted their moral rights. This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. Reasonable efforts have been made to publish reliable data and information, but the authors and the publishers cannot assume responsibility for the validity of all materials. Neither the authors nor the publishers, nor anyone else associated with this publication, shall be liable for any loss, damage or liability directly or indirectly caused or alleged to be caused by this book. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming and recording, or by any information storage or retrieval system, without permission in writing from Woodhead Publishing Limited. The consent of Woodhead Publishing Limited does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific permission must be obtained in writing from Woodhead Publishing Limited for such copying. Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library. Library of Congress Control Number: 2011932262 ISBN 978-1-84569-752-5 (print) ISBN 978-0-85709-292-2 (online) ISSN 2042-8049 Woodhead Publishing Series in Food Science, Technology and Nutrition (print) ISSN 2042-8057 Woodhead Publishing Series in Food Science,Technology and Nutrition (online) The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp which is processed using acid-free and elemental chlorine-free practices. Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards. Typeset by Toppan Best-set Premedia Limited Printed by TJI Digital, Padstow, Cornwall, UK

© Woodhead Publishing Limited, 2011

Contents

Contributor contact details......................................................................... xiii Woodhead Publishing Series in Food Science, Technology and Nutrition ............................................................................................... xix Introduction ................................................................................................. xxvii

Part I Nutritional influences on brain development ........................... 1

The effects of early diet on cognition and the brain ..................... E. B. Isaacs and A. Lucas, UCL Institute of Child Health, UK 1.1 Introduction ............................................................................ 1.2 Nutrition, cognition and the brain: background considerations ......................................................................... 1.3 Research example – the preterm cohort............................. 1.4 Cognitive outcomes at different ages .................................. 1.5 Imaging studies ....................................................................... 1.6 Issues raised by these studies ............................................... 1.7 Nutrition, cognition and brain relationships: some general considerations ........................................................... 1.8 Suggestions for further research and sources of further information and advice ............................................ 1.9 References ...............................................................................

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Contents Influence of long-chain polyunsaturated fatty acids (LC-PUFAs) on cognitive and visual development ...................... J. P. Schuchardt and A. Hahn, Leibniz University of Hannover, Germany 2.1 Introduction ............................................................................ 2.2 Structure, metabolism and general physiological functions of polyunsaturated fatty acids (PUFAs) ............ 2.3 Placental transfer of PUFA and fetal lipid transport .................................................................................. 2.4 PUFA levels in human milk ................................................. 2.5 Significance of PUFAs in the development and function of brain and retina .................................................. 2.6 Significance of an adequate LC-PUFA supply for neonates and infants on cognitive and visual outcomes .................................................................................. 2.7 Potential consequences of PUFA deficiency or imbalances ............................................................................... 2.8 PUFA intake recommendations and supply situation ................................................................................... 2.9 Implications for the food industry, nutritionists and policy makers .......................................................................... 2.10 Future trends .......................................................................... 2.11 Sources of further information and advice ......................... 2.12 References ............................................................................... 2.13 Appendix: list of abbreviations ............................................

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32 33 35 36 36

41 60 61 63 64 66 66 77

3 Zinc deficiency and cognitive development .................................... M. M. Black, University of Maryland School of Medicine, USA 3.1 Introduction ............................................................................ 3.2 Measurement of zinc status .................................................. 3.3 Implications for the food industry, nutritionists, and policy-makers .......................................................................... 3.4 Future trends .......................................................................... 3.5 Sources of further information and advice ......................... 3.6 References ...............................................................................

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4

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Iron deficiency and cognitive development .................................... S. J. M Osendarp and A. Eilander, Unilever Research and Development, The Netherlands 4.1 Introduction ............................................................................ 4.2 Effects of iron deficiency on cognitive development ............................................................................ 4.3 Implications for the food industry, nutritionists, and policy-makers .................................................................. 4.4 Future trends ..........................................................................

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Contents 4.5 4.6

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Sources of further information and advice ......................... References ...............................................................................

104 105

Iodine and cognitive development ................................................... S. A. Skeaff, University of Otago, New Zealand 5.1 An overview of iodine, thyroid hormones, and the consequences of iodine deficiency ....................................... 5.2 The effect of iodine deficiency on cognition ...................... 5.3 Implications for the food industry, nutritionists and policy-makers .......................................................................... 5.4 Future trends .......................................................................... 5.5 Sources of further information and advice ......................... 5.6 References ...............................................................................

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Part II Diet, mood and cognition ..........................................................

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5

6

7

Macronutrients and cognitive performance.................................... L. Dye, D. Lamport, N. Boyle and A. Hoyland, The University of Leeds, UK 6.1 Introduction ............................................................................ 6.2 The effects of meals on cognitive performance ................. 6.3 Carbohydrate and cognitive performance .......................... 6.4 Macronutrients, stress and cognitive performance ............ 6.5 Implications for the food industry, nutritionists and policy-makers .......................................................................... 6.6 Future trends and opportunities for this research field ........................................................................................... 6.7 Sources of further information and advice ......................... 6.8 References ............................................................................... Carbohydrate consumption, mood and anti-social behaviour ............................................................................................. D. Benton, Swansea University, UK 7.1 Introduction ............................................................................ 7.2 Carbohydrate metabolism and mood .................................. 7.3 The incidence of hypoglycaemia .......................................... 7.4 Serotonin synthesis after the consumption of carbohydrate ........................................................................... 7.5 Anti-social behaviour and refined carbohydrate consumption ............................................................................ 7.6 Chocolate – macronutrients or palatability? ...................... 7.7 Future trends .......................................................................... 7.8 Sources of further information and advice ......................... 7.9 References ...............................................................................

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Contents Hydration and mental performance ................................................ K. E. D’Anci, Tufts University, USA 8.1 Introduction ............................................................................ 8.2 Thirst and water intake regulation ...................................... 8.3 Cognition, mood, and hydration status ............................... 8.4 Implications for the food industry, nutritionists, and policy-makers .......................................................................... 8.5 Future trends .......................................................................... 8.6 Sources of further information and advice ......................... 8.7 References ............................................................................... Vitamin status, cognition and mood in cognitively intact adults ......................................................................................... D. Kennedy, E. Jones and C. Haskell, Northumbria University, UK 9.1 Introduction ............................................................................ 9.2 Vitamin deficiency in developed societies .......................... 9.3 Mechanisms of action of vitamins related to brain function .................................................................................... 9.4 Evidence from epidemiological studies............................... 9.5 Evidence from intervention studies ..................................... 9.6 Conclusions ............................................................................. 9.7 Implications for the food industry, nutritionists and policy-makers .......................................................................... 9.8 Future trends .......................................................................... 9.9 Sources of further information and advice ......................... 9.10 References ............................................................................... Caffeine, mood and cognition........................................................... P. J Rogers and J. E. Smith, University of Bristol, UK 10.1 Introduction ............................................................................ 10.2 Background – caffeine intake and its physiological effects ....................................................................................... 10.3 Caffeine reinforcement.......................................................... 10.4 The alerting and psychomotor effects of caffeine – net benefit or withdrawal reversal? .................................. 10.5 Caffeine and anxiety .............................................................. 10.6 Caffeine (tea and coffee) consumption and risk of cognitive decline ..................................................................... 10.7 Conclusions and future trends: implications for the food industry, nutritionists and policy-makers ................... 10.8 Sources of further information and advice ......................... 10.9 Acknowledgements ................................................................ 10.10 References ...............................................................................

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Neurocognitive effects of herbal extracts ....................................... A. Scholey and C. Stough, Swinburne University, Australia 11.1 Introduction ............................................................................ 11.2 Ginkgo biloba ......................................................................... 11.3 Ginseng .................................................................................... 11.4 Bacopa Monnieri .................................................................... 11.5 Salvia ........................................................................................ 11.6 Melissa officinalis.................................................................... 11.7 Guaraná ................................................................................... 11.8 Flavonoids ............................................................................... 11.9 Conclusions and future trends.............................................. 11.10 References ...............................................................................

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Part III Nutritional influences on behavioural problems, psychiatric illness and cognitive decline associated with ageing .................................................................................

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12

301

13

Malnutrition and externalizing behaviour ...................................... J. Liu and A. Raine, University of Pennsylvania, USA 12.1 Introduction ............................................................................ 12.2 Dietary influences on externalizing behaviour .................. 12.3 Implications for the food industry, nutritionists, and policy-makers .......................................................................... 12.4 Future trends .......................................................................... 12.5 Sources of further information and advice ......................... 12.6 References ............................................................................... The role of nutrition and diet in learning and behaviour of children with symptoms of attention deficit hyperactivity disorder ................................................................................................ N. Sinn, University of South Australia, Australia and J. Rucklidge, University of Canterbury, New Zealand 13.1 Overview of attention deficit/hyperactivity disorder (ADHD) .................................................................................. 13.2 Nutrition and the brain ......................................................... 13.3 Nutrients and ADHD ............................................................ 13.4 Botanicals ................................................................................ 13.5 Multi-ingredient formulations .............................................. 13.6 Food intolerance ..................................................................... 13.7 Conclusions ............................................................................. 13.8 Implications for the food industry, nutritionists and policy-makers ..........................................................................

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Contents 13.9 Future trends .......................................................................... 13.10 Sources of further information and advice ......................... 13.11 References ...............................................................................

347 348 349

Vitamin status and psychiatric disorders......................................... D. Benton, Swansea University, UK 14.1 Introduction ............................................................................ 14.2 Homocysteine ......................................................................... 14.3 Dementia and homocysteine ................................................ 14.4 Vitamin B1 ............................................................................... 14.5 Niacin ....................................................................................... 14.6 Vitamin B6 ............................................................................... 14.7 Vitamin B12 .............................................................................. 14.8 Anti-oxidants, micronutrients and the oxidative stress hypothesis of ageing .................................................... 14.9 Future trends .......................................................................... 14.10 Sources of further information and advice ......................... 14.11 References ...............................................................................

359 359 360 365 367 371 372 374 377 383 384 384

Antioxidants, diet, polyphenols and dementia ............................... J. K. Sahni, INRS-Institut Armand Frappier, Canada and INRS-Énergie, Matériaux et Télécommunications, Canada, L. Letenneur, INSERM, France and Victor Segalen University, France, L. H. Dao, INRS-Énergie, Matériaux et Télécommunications, Canada and C. Ramassamy, INRS-Institut Armand Frappier, Canada and Université Laval, Canada 15.1 Introduction ............................................................................ 15.2 Antioxidants and diet approach for cognitive functioning and dementia ..................................................... 15.3 Brain targets and sources of polyphenols ........................... 15.4 Summary of the classification of polyphenols .................... 15.5 Important polyphenols with neuroprotective potential ................................................................................... 15.6 Conclusions ............................................................................. 15.7 Future trends .......................................................................... 15.8 References ...............................................................................

392

Vitamin D, cognitive function and mental health .......................... E. P. Cherniack and B. R. Troen, University of Miami Miller School of Medicine, Miami VA Health System, USA 16.1 Introduction ............................................................................ 16.2 The epidemic of vitamin D insufficiency – sources of vitamin D intake, epidemiology ...................................... 16.3 Vitamin D action on the brain .............................................

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Contents 16.4 16.5 16.6

Cognition ................................................................................. Vitamin D in dementia and Parkinson’s disease ............... Vitamin D and depression, bipolar illness, and schizophrenia .......................................................................... 16.7 The diagnosis and treatment of vitamin D insufficiency ............................................................................. 16.8 Future trends .......................................................................... 16.9 Sources of further information and advice ......................... 16.10 References ...............................................................................

xi 424 426 426 429 432 432 432

17 Caloric intake, dietary lifestyles, macronutrient composition and dementia ....................................................................................... H. C. Fivecoat and G. M. Pasinetti, Mount Sinai School of Medicine, USA 17.1 Introduction ............................................................................ 17.2 Obesity and the metabolic syndrome in Alzheimer’s disease (AD) ........................................................................... 17.3 Calorie intake and caloric restriction .................................. 17.4 The role of insulin in AD ...................................................... 17.5 Hypertension and AD ........................................................... 17.6 The link between dietary choices and AD ......................... 17.7 Conclusions and future trends.............................................. 17.8 Sources of further information and advice ......................... 17.9 References ...............................................................................

441 442 446 448 450 455 456 456

18

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19

Fatty acids and schizophrenia ........................................................... M. Peet and K. Williamson, Rotherham Early Intervention Service, UK 18.1 Introduction ............................................................................ 18.2 Tissue levels of polyunsaturated fatty acids in patients with schizophrenia.................................................................. 18.3 Treatment studies with omega-3 fatty acids in schizophrenia .......................................................................... 18.4 The importance of diet for physical health in schizophrenia .......................................................................... 18.5 Recommended programme of assessment and intervention ............................................................................. 18.6 Further research ..................................................................... 18.7 References ............................................................................... Fatty acids, depression and suicide .................................................. S. J. Long, Swansea University, UK 19.1 Introduction ............................................................................ 19.2 Essential fatty acids (EFAs) ................................................. 19.3 EFAs and depression .............................................................

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Contents 19.4 19.5 19.6 19.7 19.8 19.9 19.10 19.11

EFAs and post-natal depression (PND) ............................. EFAs and bipolar disorder (BD) ......................................... EFAs and suicide.................................................................... Personality factors associated with suicide ......................... Future trends .......................................................................... Implications for practice ....................................................... Sources of further information and advice ......................... References ...............................................................................

505 507 509 510 512 513 514 515

Fatty acid intake and cognitive decline ........................................... M. Plourde, Université de Sherbrooke, Canada 20.1 Introduction ............................................................................ 20.2 Epidemiological link between dietary fats and cognitive decline ..................................................................... 20.3 Omega-3 fatty acids metabolism and risk of cognitive decline ..................................................................... 20.4 Implications for the food industry, nutritionists and policy-makers .................................................................. 20.5 Future trends for better cognition ....................................... 20.6 Sources of further information and advice ......................... 20.7 References ...............................................................................

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Index .............................................................................................................

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Contributor contact details

(* = main contact)

Chapter 2

Editor and chapters 7 and 14 David Benton Department of Psychology Swansea University Singleton Park Swansea SA2 8PP UK

Dr Jan Philipp Schuchardt* and Professor Dr Andreas Hahn Leibniz University of Hannover Institute of Food Science and Human Nutrition Am Kleinen Felde 30 30167 Hannover Germany

E-mail: [email protected]

E-mail: schuchardt@nutrition. uni-hannover.de; hahn@ nutrition.uni-hannover.de

Chapter 1

Chapter 3

Elizabeth B. Isaacs* and Alan Lucas Childhood Nutrition Research Centre UCL Institute of Child Health 30 Guilford Street London WC1N 1EH UK

Professor Maureen M. Black University of Maryland School of Medicine 737 W. Lombard Street, 161 Baltimore MD 21201 USA E-mail: [email protected]; [email protected]

E-mail: [email protected]

© Woodhead Publishing Limited, 2011

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Contributor contact details

Chapter 4

Chapter 8

Saskia J. M. Osendarp* and Ans Eilander Unilever Research and Development Vlaardingen Olivier van Noortlaan 120 3130 AC Vlaardingen The Netherlands

Dr Kristen E. D’Anci Department of Psychology Tufts University 490 Boston Ave Medford MA 02155 USA E-mail: [email protected]

E-mail: saskia.osendarp@unilever. com Chapter 9 Chapter 5 Dr Sheila A. Skeaff Department of Human Nutrition University of Otago P.O. Box 56 Dunedin 9010 New Zealand

Professor David Kennedy*, Dr Emma Jones and Dr Crystal Haskell Brain, Performance and Nutrition Research Centre Northumbria University Newcastle upon Tyne NE1 8ST UK

E-mail: [email protected]

Chapter 6 Professor Louise Dye*, Dr Daniel Lamport, Neil Boyle and Dr Alexa Hoyland Human Appetite and Research Unit Institute of Psychological Sciences The University of Leeds LS2 9JT UK E-mail: [email protected]

E-mail: david.kennedy@ northumbria.ac.uk; emma2. [email protected]; crystal.haskell@northumbria. ac.uk

Chapter 10 Professor Peter J. Rogers* and Jessica E. Smith School of Experimental Psychology 12a Priory Road University of Bristol Bristol BS8 1TU UK E-mail: [email protected]; [email protected]

© Woodhead Publishing Limited, 2011

Contributor contact details Chapter 11 Professor Andrew Scholey* and Professor Con Stough NICM Centre for the Study of Natural Medicines and Neurocognition Brain Sciences Institute Swinburne University Melbourne VIC 3122 Australia E-mail: [email protected]

Chapter 12 Dr Jianghong Liu* and Adrian Raine University of Pennsylvania 3451 Walnut Street Philadelphia PA 19104 USA E-mail: [email protected]

Chapter 13 Dr Natalie Sinn* School of Health Sciences University of South Australia GPO Box 2471 Adelaide SA 5001 Australia

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Professor Julia Rucklidge Department of Psychology University of Canterbury Private Bag 4800 Christchurch New Zealand E-mail: julia.rucklidge@canterbury. ac.nz

Chapter 15 J. K. Sahni INRS–Institut Armand Frappier 531 Boulevard des Prairies Laval Québec H7V1B7 Canada and INRS-Énergie, Matériaux et Télécommunications 1650 Boulevard Lionel-Boulet Varennes Québec J3X 1S2 Canada L. Letenneur INSERM U 897 Bordeaux France and

E-mail: [email protected] Victor Segalen University 146 rue Léo-Saignat 33076 Bordeaux France

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Contributor contact details

L. H. Dao INRS–Énergie, Matériaux et Télécommunications 1650 Boulevard Lionel-Boulet Varennes Québec J3X 1S2 Canada C. Ramassamy* INRS–Institut Armand Frappier 531 Boulevard des Prairies Laval Québec H7V1B7 Canada E-mail: charles.ramassamy@iaf. inrs.ca and

Chapter 16 Dr E. Paul Cherniack* and Dr Bruce R. Troen Division of Gerontology and Geriatric Medicine University of Miami Miller School of Medicine Geriatric Research Education and Clinical Center Miami Veterans Affairs Health System 1201 NW 16 St Miami FL 33125 USA E-mail: [email protected]; [email protected]

Chapter 17

Faculté de Médecine 2325 Rue de L’Université Université Laval Quebéc GIV 046 Canada

Hayley Cameron Fivecoat and Dr Giulio Maria Pasinetti* Department of Neurology Mount Sinai School of Medicine 1 Gustave L. Levy Place Box 1137 New York NY 10029 USA E-mail: [email protected]

© Woodhead Publishing Limited, 2011

Contributor contact details Chapter 18

Chapter 20

Malcolm Peet* and Kevin Williamson Rotherham Early Intervention Service 144a Aughton Road Swallownest Sheffield S26 4TH UK

Dr Mélanie Plourde Research Center on Aging Université de Sherbrooke 1036 Belvédère sud Sherbrooke Québec J1H 4C4 Canada

E-mail: [email protected]; [email protected]

E-mail: melanie.plourde2@ usherbrooke.ca

Chapter 19 Sara Jayne Long Department of Psychology Swansea University Singleton Park Swansea SA2 8PP UK E-mail: [email protected]

© Woodhead Publishing Limited, 2011

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Introduction D. Benton, Swansea University, UK

Nutrition impacts on brain functioning in various ways: we are what we eat. The brain, like the rest of the body, is made up of building blocks that are supplied by the diet. Energy for the brain, in particular glucose, comes from the diet. The enzymatic processes that allow the architecture of the brain to develop and the release of energy in addition requires minerals and vitamins to allow these functions to proceed. There are constituents of food, for example caffeine, that act in a drug-like manner. Given this context can what we eat influence our mood and the way we think? In fact there has been an explosion of interest in the possibility that, throughout life, aspects of nutrition might influence the functioning of the brain. This interest includes the diet of the pregnant mother and nutrition during the early years while the brain is growing rapidly (Chapters 1–5). Similarly, throughout childhood and adolescence the diet plays an important role in the development of the adult brain. From early adulthood, the brain begins to shrink and diet is likely to have a slow and pervasive influence on cognitive functioning in later life (Chapters 14–17, 20). When adult, many use food and drink to try to keep alert and clear-headed throughout the day (Chapters 7, 8, 10). A suggestion that is attracting attention is that diet can influence a range of behavioural problems including depression (Chapters 14, 16, 19), schizophrenia (Chapters 14, 16, 18), dementia (Chapters 14–17, 20) and Attention Deficit Hyperactivity Disorder (Chapters 12–14). If this widespread potential can be realised, the approach will be of interest to policy-makers, medicine, education, food and ingredient manufacturers as well as the general public. As yet, however, there is more potential in this area than certain conclusions: it is, however, a fast-moving field that is reviewed in a series of chapters written by world experts.

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In fact, many in the population seem to have a ready predisposition to see diet as both the cause of behavioural problems and the means of solving them. Such a view is supported by a visit to the news archive of the British Broadcasting Corporation website where, for example, over the years headlines have repeatedly related the aging of the brain to what we eat. Coffee ‘may reverse Alzheimer’s’; folic acid ‘cuts dementia risk’; a diet rich in oily fish and vegetables can reduce the chances of dementia; wine protects against dementia; vitamins E and C may protect the ageing brain – but only if taken together; curry ‘may slow Alzheimer’s’. Such claims have been amplified in popular books. For example the Wine Diet (Corder, 2009) claims that those who drink wine live longer and are less likely to suffer from dementia, although you can get similar benefits from chocolate. Similarly, there are suggestions in popular books that you can influence your child’s development by manipulating their diet. Titles include Feed Your Kids a better I.Q. (Prince and Prince, 1988) and Boost Your Child’s Brain Power: How to Use Good Nutrition to Ensure Success at School (Roberts, 1988). However, most claims need to be viewed with caution. In the UK, the Advertising Standards Agency (ASA) ruled that a television commercial that advertised milk was misleading and unsubstantiated when it claimed that ‘Recent scientific studies suggest omega-3 may play an important role in enhancing learning and concentration in some children.’ Although this is an area with many extravagant and premature claims it is also an area that is attracting increasing interest from both scientists and food manufacturers who hope to produce functional foods with proven benefits. Therefore, the aim of the book is to review a range of ways in which diet can influence both mood and cognition in both the industrialized and developing world. The suggestion that diet in industrialized societies might influence the psychological functioning of children traditionally has at best generated scepticism in scientists, if it was not totally dismissed. For example, when Benton and Roberts (1988) in a double-blind trial reported that the consumption of a multi-vitamin/mineral supplement increased the non-verbal intelligence of school children, Whitehead (1991), one of the most influential nutritionists in the UK, commented that ‘No physiological explanation exists of how vitamin and mineral supplementation could affect brain function in a well nourished subject’. Yudkin (1988) was even more forthright commenting that ‘The study is ludicrous meaningless nonsense’. However, several years later he added, following a study with which he had been associated, ‘Our studies show, we believe conclusively, that adding vitamins and minerals to the diets of children who have no obvious physical signs of nutrient deficiency can nevertheless produce an increase in their IQ scores’ (Yudkin, 1991). These initial responses reflected the received wisdom of many nutritionists who at the time tended to believe that the diet of children typically supplied adequate levels of micronutrients. If you consumed sufficient calories and sufficient protein, then micronutrient intake was

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likely to be adequate. As the intake of calories and protein is virtually never a concern, then micronutrient intake was not a problem; it was unreasonable to even suggest that the diet of some children was so poor that micronutrient status could influence cognitive functioning. However, when Benton (2001) reviewed the topic ten years later, he found that in ten out of 13 studies a positive response has been reported, in at least a sub-set of children, although he concluded that ‘the topic is at a very early stage and needs the clarification gained from a series of large-scale studies’. Since this time, micronutrient supplementation has been reported to increase verbal learning and memory in Australia and in girls in Indonesia (Osendarp et al., 2007). More recently, it has become more likely that the possibility that diet might influence the behaviour of those in industrialized countries will be entertained, although it is rare to find a body of results sufficient to draw conclusions with confidence. One factor in this change of perspective has been the study of fatty acids and homocysteine, topics that have gained some credibility in recent years. Homocysteine is a sulphur-containing amino acid that, when present in the blood in high levels, is a risk factor for mental retardation, cardiovascular disease, dementia and depression. As the level of homocysteine in the blood can be influenced by folate, vitamin B6 and vitamin B12 status, the influence of diet has generated considerable attention. Homocysteine as such does not come from the diet; rather, it is formed by the demethylation of the dietary amino acid methionine and broken down with the involvement of several B vitamins. The topic is considered in Chapter 14. About 50–60 % of the dry weight of the human brain is lipid of which 35 % are phospholipids of which the polyunsaturated fatty acid docosahexaenoic acid (an omega-3 fatty acid) and arachidonic acid (an omega-6 fatty acid) occur in the highest concentrations. As these are essential fatty acids, that is they cannot be made by the body and must be consumed in the diet, it has been considered whether they play a role in both brain development and mental health. The roles of dietary fatty acids in cognitive development (Chapter 2), schizophrenia (Chapter 18), depression (Chapter 19) and cognitive decline (Chapter 20) are reviewed. In developing countries there is more certainty of an association between nutritional deficiencies and psychological functioning. The big four nutritional deficiencies are often discussed: protein–energy malnutrition (500 million people affected), vitamin A deficiency causing blindness (40 million deficient, 14 million with eye lesions), iodine deficiency (a billion at risk, 20 million mentally retarded) and iron deficiency (2 billion people suffer). In the context of food fortification the World Bank has commented that no other ‘technology available today offers as large an opportunity to improve lives and accelerate development at such low cost and in such a short time.’ It is commonly accepted that iodine deficiency early in development results in severe learning difficulties (Chapter 5). Similarly iron deficiency

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in early life has irreversible adverse consequences, although in later life the affect of a deficiency is reversible (Chapter 4). Both zinc (Chapter 3) and vitamin D (Chapter 11) play important roles in brain development. A deficiency of vitamin B1 results in beriberi with associated problems of mood, concentration and memory. A lack of niacin results in pellagra with symptoms of irritability and mental confusion (Chapter 14). Although malnutrition tends to be studied in the context of cognitive functioning, it also influences anti-social behaviour (Chapters 12, 13). There is, however, also growing interest in the role of diet in the functioning of individuals in industrialized societies going about their everyday lives. For example, when commercial organizations undertake consumer research a common response is the request for foods that increase mental energy, or keep them going throughout the day. One of the most researched topics is the study of the influence of caffeine, that has been repeatedly reported to have alerting properties (Chapter 10). However, the role of macronutrients (Chapter 6), micronutrients (Chapter 9), hydration (Chapter 8) and herbal products (Chapter 11) are also considered. One consequence of an aging population is an increasing incidence of dementia. In those aged 65–69 years, between 1 and 2 % will suffer with dementia, although in those over 85 years the rate is 25 %. Yet dementia is not an inevitable consequence of advanced age and many of those aged more than 100 years do not suffer with dementia. The race is on to establish factors that do and do not lead to cognitive decline. One area of study is the role played by diet. There are several biological theories of the aging of the brain that all have in common that they can be influenced by diet. Oxidative stress and inflammation (Chapter 15), homocysteine (Chapter 14) and fatty acid status (Chapter 20) amongst others. The study of the acute effect of a single nutritional on mood and cognition is relatively straightforward, using methods similar to those familiar to psychopharmacology. Although traditionally the greatest weight has been placed on information from randomized, double-blind, placebo-controlled studies it is obviously not possible to randomly allocate individuals to a dietary pattern that they will follow for a lifetime. When considering nutrition, to date there is a paucity of randomly controlled, double-blind trials. If, however, the entire diet is considered, particularly over a long time period, considerable methodological issues arise. To establish the influence of dietary style over many decades, there is likely to be little alternative to the use of epidemiology. The study of the aging process is not easy as the decline in cognition and the shrinking of the brain begins in your twenties, such that if diet is influential it is potentially important throughout adult life (Benton, 2010). Rather than looking for a rapid change from normal cognition to dementia, changes in brain structure take place slowly over many decades. Although this is a methodologically demanding area, the rewards are potentially great; socially, medically and economically. If we can distinguish

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the important aspects of the diet that influence the functioning of the brain there will be a challenge for the food industry to develop food items that meet these needs. Although it would be unwise to overstate the importance of diet, as it is only one factor amongst many others that modulate behaviour, as part of package the rewards may be large. Better cognitive development and behaviour in children; slower intellectual decline; feeling more alert; being in a better mood. As well as enhanced wellbeing, improved nutrition could help to reduce health care costs and increase economic productivity and safety.

References benton, d (2001) Micro-nutrient supplementation and the intelligence of children. Neuroscience and Biobehavioral Reviews, 25, 297–309. benton d (2010) Neuro-development and neuro-degeneration – are there critical stages for nutritional intervention? Nutrition Reviews, 68(Suppl 1), S6–10. benton d and roberts g (2001) Effect of vitamin and mineral supplementation on the intelligence of a sample of schoolchildren. Lancet, 1, 140–143. corder r (2009) The Wine Diet. London: Little, Brown Book Group. osendarp s j, baghurst k i, bryan j, calvaresi e, hughes d, hussaini m, karyadi s j, van klinken b j, van der knaap h c, lukito w, mikarsa w, transler c, wilson c and nemo study group (2007) Effect of a 12-mo micronutrient intervention on learning and memory in well-nourished and marginally nourished school-aged children: 2 parallel, randomized, placebo-controlled studies in Australia and Indonesia. American Journal of Clinical Nutrition, 86(4), 1082–1093. prince f and prince h (1988) Feed Your Kids a Better I.Q. Slough: W. Foulsham & Company. roberts g (1988) Boost Your Child’s Brain Power. Wellingborough: Thorsens. yudkin j (1988) Daily Telegraph, 22 February. yudkin j (1991) Intelligence of children and vitamin-mineral supplements: the DRF study. Discussion conclusions and consequences. Personality and Individual Differences, 12, 363–365. whitehead r g (1991) Vitamins minerals schoolchildren and IQ. British Medical Journal, 302, 548.

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1 The effects of early diet on cognition and the brain E. B. Isaacs and A. Lucas, UCL Institute of Child Health, UK

Abstract: Animal studies have found effects of early nutrition on both cognition and brain structure. In humans, effects on cognition have been found in observational studies and, more recently, in randomised controlled trials but it was not possible to examine dietary effects on brain structure until the recent advent of neuroimaging. This chapter uses one particular cohort to illustrate both cognitive and brain structure findings and discusses issues arising from these studies as well as more general ones relevant to this emerging field of research. Key words: early infant diet, nutrition and cognition, nutrition and brain structure.

1.1 Introduction Differences in specific nutrients in the diets of infants and children have been shown to have an effect on their cognitive behaviour. Studies have also shown show that diets differing mainly in their total energy/ protein content may affect subsequent cognition (Lucas et al., 1998; Grantham-McGregor and Baker-Henningham, 2005). Although neuroscientists have largely ignored nutrition as an independent variable of interest in cognitive development, the finding should come as no surprise in view of the large animal literature that clearly illustrates the link. Smart (1986), for example, undertook a review of the animal literature to address the question of whether early under-nutrition had effects on later intellectual functioning. One hundred and sixty-five studies in non-human species (85 % in rodents) in which there had been a period of protein–energy malnutrition sometime between conception and early post-weaning, followed

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by at least one month of good quality diet, were reviewed. Learning and memory measures obtained from maze-running tasks were compared between previously undernourished animals and well-nourished controls. Smart concluded that the finding of significantly superior performance by the control groups predominated strongly. These studies, both in animals and humans, illustrate the role that nutrition can play in later cognitive behaviour. Since cognitive behaviour has its basis in the brain, these findings raise the hypothesis that nutrition exerts its effects on cognition by affecting the brain, either in terms of how it is structured (anatomy) or how it functions (physiology) or both. Animal studies have been able to demonstrate this using histological methods (Dauncey and Bicknell, 1999). Studies in humans, although biologically plausible, are limited in scope and number because such methods can only be used post mortem. The few post mortem studies carried out in human infants in relation to nutrition have been informative. Benitez-Bribiesca et al. (1999), for example, reported that the brains of infants severely malnourished in early postnatal life showed pathology related to the spines of dendrites in neurons, important in nerve transmission, and maybe related to future neuropsychological deficits. This accords with the fact that dendritic spines are known to be highly responsive to changes in the environment. The use of electroencephalographic (EEG) methods to study patterns of neural electrical activity has provided some information about brain function in vivo. Hayakawa et al. (2003) compared extremely low birth weight infants in whom enteral feeding was established by three weeks after birth to those in whom it was not, finding a higher incidence of dysmature patterns of background EEG in the group with poor nutrition. Khedr et al. (2004) used evoked potentials, another EEG method, to demonstrate greater maturity of electrophysiological function in infants aged approximately one year who had been breastfed compared to those formula-fed. A large leap forward in our ability to study the important question of whether nutrition can affect the human brain in vivo came about with the advent of neuroimaging (Dauncey, 2009). Although still few in number, studies using this methodology to examine nutrition–brain relationships are now beginning to appear in the literature. The main concern of this chapter is to describe the methods that have become available and the results of some of the first studies to use these in the field of nutrition. To do this, we concentrate on a cohort from a particular randomised controlled trial of early infant feeding that has been studied over time using both psychological assessment and, recently, neuroimaging. After describing the cohort and the design of the randomised controlled trial, we present the cognitive results obtained at different ages and then the results of some of the first studies of the effects of nutrition on the human brain using neuroimaging methods. The issues raised by these studies are discussed along with the implications they have for future research.

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1.2 Nutrition, cognition and the brain: background considerations 1.2.1

Is it biologically plausible that nutrition affects cognition and the brain? From the time of conception, the brain of any organism is subject, first in utero and then after birth, to a large number of environmental influences, one of which is nutrition. Walker (2005) states that nutrition is the environmental variable with the greatest potential for affecting brain development. According to Wachs (2000), there is consistent evidence that the level and quality of dietary intake can affect the development of both the macrostructure and microstructure of the central nervous system (CNS) as well as the level and operation of neurotransmitters. He provides a useful summary of the evidence linking nutritional deficits to the development of behaviour. There are good reasons to expect that differences in nutritional intake might also exert influences on the everyday running of the brain. It is dietary sources, for example, that provide the metabolic resources that are necessary for the maintenance of activity in the CNS. Greenwood and Craig (1987) describe three ways in which food intake can affect neurochemistry: 1. by providing nutrient precursors for neurotransmitter synthesis, 2. by providing vitamins and minerals that are essential cofactors for enzymatic activity in such synthesis, and 3. by the action of some dietary fats in altering nerve cell membrane properties with an impact on neural function. Since the underpinning of cognitive activity is brain processing, nutritional effects on the brain have the potential to affect cognitive performance. Such effects, however, will not be seen if the neural areas affected are not implicated in the cognitive activity being assessed or if the effects are too subtle to be detected by the particular tests being used. It is often assumed that groups that have the same overall cognitive level, as indexed by IQ scores, will show no differences in more specific cognitive functions, but this is not the case and differences may be missed simply because the specific functions are not assessed. It may also be that nutritional effects on the brain exist but that they cannot be detected by our present imaging techniques.

1.2.2 When might nutrition exert influence? Nutrition, in its effects on the maintenance of normal function of the brain, has an influence across the entire lifespan. Some effects are short-term with dietary intake leading to fluctuations in the ongoing function of the brain. The intake of glucose, for example, can affect learning and memory function, particularly in the normal elderly (Gold, 1995). Convit et al. (2003) showed that reduced glucose tolerance in a group of normal adults with a mean age of 68 years was associated with degree of hippocampal atrophy.

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Corresponding changes in brain structure accompanying these minute-tominute changes would not be expected. Long-term effects on structure are more likely to happen at specific times in development. One important period is prenatally when the foetus is dependent on the maternal diet for its nutrient intake and might, in theory, be affected for the duration of pregnancy, although the third trimester seems to be the most important in terms of birth weight (Stein et al., 2004). The second is the period of greatest brain development, often referred to as the ‘brain growth spurt’ that occurs between the start of the third trimester of pregnancy and approximately 18 months of age in humans (Dobbing and Sands, 1973). The CNS appears to be most vulnerable to outside influences when it is developing rapidly, as is particularly true during this period, making diet in the early postnatal years of particular interest. Animal studies show that early malnutrition may have profound effects on various aspects of brain development (Rice and Barone, 2000) and human work has also tended to focus on this period. We are as yet uncertain as to how susceptible the human brain is to structural change beyond the main period of brain development. There is general agreement that there are other lesser bursts of brain development later in the lifespan, particularly through adolescence (2–4 yrs, 6–8 yrs, 10–12 yrs, 14–16 yrs) and, in theory, these might also be periods of enhanced nutritional influence but this has been little studied. Yet to be verified by research, it seems that nutrition in later life may affect the physiology of the brain while nutrition in infancy is more likely to have long-term structural effects.

1.2.3 In what ways might the brain be affected? Brain development is a cascade of events that follow a strict timetable (de Graaf-Peters and Hadders-Algra, 2005). Thus, for example, the generation of neurons in the human brain is more or less complete by the 20th week of gestation; foetuses born as early as this do not survive and so post-natal nutrition is unlikely to be a factor in neurogenesis in humans. During the period of the ‘brain growth spurt’, the main developmental processes taking place are the production of glial cells, myelination of nerve processes (insulation with a fatty layer to facilitate nerve conduction) enabled by the appearance of the glial cells and the establishment of connections between neurons (synaptogenesis). These provide clues as to where nutritional effects might be seen in the brain, e.g. in white matter. While the sequence of processes within all brain structures is invariant, the timing may vary from structure to structure (Herschkowitz, 1988), implying that the same nutritional influence might differ in the locus of its effects depending on when in the timetable of development it is applied. Table 1.1 (adapted from Herschkowitz, 1988) shows the sequence of developmental processes in the human brain.

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Table 1.1 The sequence of events in structural development in the human brain (WG = weeks gestation) with the average time at which they occur. Marked differences occur in timing between neural regions 1 2 3 4 5 6 7 8

Neural induction Proliferation of neuroblasts Neuronal migration Neuronal selective aggregation Neuronal differentiation, formation of connections Neuronal death (cortex) Selective synapse elimination or ‘priming’ (cortex) Myelination

3–4 WG 8–25 WG 8–34 WG 8–34 WG 5 WG–4 years 2–16 years 2–16 years 25 WG–20 years

Source: adapted from Herschkowitz, 1988.

Because postnatal nutrition becomes a factor relatively late in the brain’s development, its effects are likely to be subtle in nature. Dobbing (1981) pointed out that there may be abnormalities of cell migration and reduction of glial cell numbers, for example, but not the gross lesions that can result from insults that occur during the early phase of neuron production. He described the pathology as one of ‘quantitative deficits and distortions’. For a long time, these were impossible to detect and, in fact, Dobbing speculated that they might never be demonstrated directly. The advent of neuroimaging, however, provided new opportunities to visualise these structural anomalies and, using knowledge about the cognitive architecture in the brain, to predict which aspects of cognition might be most affected.

1.3 Research example – the preterm cohort 1.3.1 Setting of the study The large wealth of animal data examining the effect of nutrition on cognition and the brain raised the hypothesis that the same might be true in humans, but it was difficult to extrapolate between species. Many human observational studies also supported the idea (Barrett and Frank, 1987), but their interpretation was confounded by factors such as poverty, low levels of parental education and limited intellectual stimulation, any or all of which could affect cognition independent of nutrition. Randomised, controlled trials (RCTs) were needed to allow a clear interpretation of the role of nutrition and to establish causation, but it is only in the past 25 years or so that these have been reported in the literature (Super et al., 1990; Grantham-McGregor et al., 1991; O’Connor et al., 2003). Very few of these were set in western, developed countries; one of the first took place between 1982 and 1985, when Lucas et al. (1984) conducted a randomised, controlled trial of infant feeding in preterm infants carried out in five centres in the

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UK. This preterm cohort is used as an example to illustrate the effects of early diet on cognition and the brain.

1.3.2 Study design In term infants, postnatal nutrition begins at approximately 40 weeks gestational age, but in the preterm infant this takes place earlier and at varying gestational ages. The preterm infant, therefore, born at a time of particularly rapid growth of the CNS, provides a good model for studying the effects of early nutrition on the developing brain. Between 1982 and 1985, 926 preterm infants were enrolled in parallel studies that formed a prospective, randomised multicentre study of infant feeding. If the mother chose not to breast feed, infants were randomly assigned to one of two diets as their sole source of nutrition. In the first study, allocation was to either a standardnutrient formula, the formula used to feed both term and preterm infants at the time, or a formula that was nutrient-enriched to meet the increased nutritional needs of preterm infants, especially designed for this study. The nutrient-enriched diet provided approximately 40 % more energy and 20 % more protein than the standard diet; for the main nutritional components of these diets, see Lucas et al. (1998). A shortened, adapted version is shown in Table 1.2. In the second study, the two diets were the nutrient-enriched

Table 1.2 Major constituents (per 100 ml) of the trial diets used in the preterm cohort. Values were not measured for every batch and approximate figures are given Constituent Protein (g) Fat (g): Saturated (%) Unsaturated (%) Carbohydrate (disaccharide, g): Energy (MJ) Sodium (mg) Potassium (mg) Chloride (mg) Calcium (mg) Magnesium (mg) Phosphorus (mg) Iron (μg) Copper (μg) Manganese (μg) Zinc (μg) Iodine (μg) Taurine (mg)

Enriched formula

Standard formula

2.0 4.9 39.3 60.5 7.0 0.334 45 65 60 70 5 35 40 120 3 1000 7 5.1

1.5 3.8 39.5 60.5 7.0 0.284 19 57 45 35 5.2 29 650 43 3.4 350 4.5 Trace

Source: adapted from Lucas et al., 1998.

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formula or unfortified breast milk provided by donors. Infants thus received either a standard-nutrient diet (donor breast milk or term formula) or an enriched-nutrient one (the preterm formula) and this formed their sole diet while in hospital. The infants of mothers who chose to breast feed were also randomly allocated to one of these diets for use as a supplement should the mother fail to provide the required complement of milk; intake varied between 0 and 100 % in this group of infants depending on the amount of breast milk provided by the mother. Life-long follow-up was planned for these children to look at anthropometric measures, cardiovascular function, bone minerals and cognition. Only the last will be discussed in this chapter.

1.4 Cognitive outcomes at different ages 1.4.1 18 months Lucas et al. (1990) reported developmental status in relation to early diet when the children were aged 18 months. Evaluation showed a major developmental advantage for the children who had had the nutrient-enriched diet (n = 213) compared to the standard-nutrient diet (n = 211). They had significantly higher scores on the Mental and, particularly, on the Psychomotor Development Indices from the Bayley Scales of Infant Development (Bayley, 1969), as well as higher social quotients from the Vineland Social Maturity Scale (Doll, 1965). Bigger differences were found in the children fed the study diet exclusively rather than as a supplement, i.e. in those whose intake of the supplement was greater. The authors also examined the frequencies of Index scores below 85, indicating less than optimal performance, and found that the nutrient-enriched diet was associated with a lower incidence of such scores. In addition, sub-group analyses indicated that the effects were greater in children born small-for-gestational age (birth weight less than the tenth percentile) compared to those whose weight was age-appropriate. There was also a significantly greater impact of diet on developmental scores in males than in females. It is worth noting that the median period from birth to discontinuation of the diet (at discharge from the neonatal unit or when body weight was 2000 g, whichever was sooner) was just over four weeks.

1.4.2 Seven to eight years Formal cognitive tests (Wechsler Intelligence Scale for Children – Revised [WISC-R], Psychological Corporation, 1974) were administered to 181 children who had been given the standard-nutrient formula and to 179 fed the enriched-nutrient diet in infancy (Lucas et al., 1998). While there were no differences between the randomised groups overall in the cognitive outcomes reported: Verbal IQ (VIQ), Performance IQ (PIQ) and Full

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Scale IQ (FSIQ), an impact of sex was seen once again. There were no significant differences between the diet groups in girls, but boys who had been fed the standard-formula showed a disadvantage, particularly, on VIQ, compared to their nutrient-enriched peers. Sub-optimal feeding in boys had resulted in diminished performance on the IQ test. More boys than girls had VIQ scores below the 85th percentile (45 % compared to 13 %). As before, more children in the standard-formula group had IQ scores below 85 than in the nutrient-enriched formulas group (by a factor of 2). The authors noted that, unexpectedly, cerebral palsy was significantly more common in the children in the standard-formula group. This interesting post-hoc finding has not been formally tested but is of potential clinical importance. Wharton et al. (2004) examined a more specific aspect of cognitive function in a study relating low plasma neonatal taurine levels to later neurodevelopment. Taurine was of interest because the standard formula contained only a trace while the enriched formula contained around 5 μmol/100 ml (as does breast milk). After controlling for a large variety of factors, there was a significant correlation (p = 0.006) between minimum plasma taurine level and scores on the Arithmetic sub-test of the WISC-R at 7 years. The authors suggest that taurine should be regarded as a conditionally essential nutrient, as a dietary supply was required for optimum outcome. They also point out that this is one more example of short-term nutritional differences having long-term effects.

1.4.3 Adolescence A further study was undertaken to assess cognition when the cohort reached adolescence. The aim in the two studies reported above was to include as many of the original members of the cohort as possible. At adolescence, however, the recruitment strategy differed because it was decided to include a neuroimaging component in the study that limited the numbers who could be assessed, due to factors such as scanning costs and unwillingness to travel to the hospital. The criteria used for selection were normal neurological status when examined at 7–8 years and a gestational age of 30 weeks or below. The participants completed a detailed neuropsychological battery including measures of overall cognitive assessment (IQ testing) in common with the earlier reports. IQ scores were reported for 49 adolescents who had received an enriched-nutrient diet as infants and 46 who had received the standard-nutrient diet (Isaacs et al., 2009). Earlier dietary effects on VIQ were shown to have persisted into adolescence by comparing childhood and adolescent scores for the same children. The difference in VIQ at adolescence between the two diet groups of around 7 points, or almost half a standard deviation, has educational implications, particularly since a more detailed analysis of the VIQ sub-tests showed that the effects of early diet were mainly on Verbal Comprehension. The persistence of the effects

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of just four weeks on average of post-natal dietary intervention on IQ in adolescence is striking.

1.5 Imaging studies 1.5.1 Why neuroimaging? The series of studies reported above provided evidence that diet in the early weeks after preterm birth, at least in those born at or below 30 weeks gestational age, could influence how the children performed cognitively right into adolescence. These results imply that underlying these cognitive effects, at some level, there exist neural differences between the groups. As Herschkowitz (1988) has pointed out, while the basic mechanisms that underlie the specific events occurring in the course of neural development (cell proliferation, syanaptogenesis, myelination, etc.) are determined genetically, a wide range of epigenetic and environmental factors can modulate these parameters. Als et al. (2004) reported that preterm infants randomly assigned to individualised programmes of care in the immediate post-natal period did better on measures of neurodevelopment (at 2 weeks and at 9 months) compared to those receiving standard care and also demonstrated a more mature pattern of neurophysiological function. In another study, Milgrom et al. (2010) found that training parents to reduce stressful experiences in preterm infants was associated with improved cerebral white matter microstructural development at term age. It seems likely that nutrition might act as another such factor. If it does, it could exert its effects on the brain either structurally, at the anatomic level, or functionally by affecting physiology or in both. Since the dietary intervention in the preterm cohort was very early, during a period of rapid development in brain anatomy, we hypothesised that structural differences in the brain would exist between the diet groups. This hypothesis seemed biologically plausible in view of the classic animal literature that has shown, for example, that animals reared in an ‘enriched’ environment demonstrated a thicker cortex due to denser networks of connections between cells (Rosenzweig and Bennett, 1972). We here view nutrition as a factor that could be manipulated to alter the level of environmental enrichment.

1.5.2

Why clinical methods of interpreting magnetic resonance imaging (MRI) scans are not useful in this situation While the literature examining the effects of diet on cognition is extensive, this is not true for studies relating early diet and the human brain. Such studies are only now beginning to appear, made possible by the advent of new methods for studying the brain. MRI scanners produce ‘pictures’ of the brain based on the different MR signal properties of white and grey matter, cerebrospinal fluid and bone. The usual clinical method for examining

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structural scans is visual inspection by specialist neuroradiologists. Although very powerful at revealing clinical abnormalities, the effects of nutrition proved too subtle to be revealed by this method and had to await the development of more specialist techniques of post-acquisition scan analysis. Our hypothesis that early diet results in structural brain differences was tested in two studies presented below using one such technique of structural analysis called volumetrics. Other methods will be discussed when we suggest directions for future research.

1.5.3 Study 1 – Infant formula and the caudate nucleus We hypothesised that we would be able to identify structural brain differences between the two diet groups that underpinned the cognitive differences we had observed over time. Imaging was carried out on a standard clinical 1.5 Tesla scanner, using a scanning protocol that gave a set of images allowing us to reconstruct the brain in three dimensions post-acquisition. We then used a technique developed by Fischl et al. (2002; 2004) that first segmented the scans and then automatically labelled the neuroanatomic structures on the basis of probability information obtained from a training set of images manually labelled by neuroanatomists. The volumes of these structures were then calculated and reported in cubic millimetres and analysed statistically to determine significant differences between the two dietary groups and relationships with IQ scores (Isaacs et al., 2008). Useable scans were available for 76 of the 95 adolescents who took part in the cognitive study, 38 in each original diet group (enriched and standard). When the scans were visually inspected in the conventional way by a paediatric neuroradiologist, the majority were found to be normal, confirming the view that nutritional effects are likely to be subtle and undetectable by clinical inspection. Volumes of the sub-cortical structures as well as that of the total brain and total cortical grey matter were compared for the two diet groups – the only significant difference was that the two caudate nuclei, one in each hemisphere, were larger in the enriched-diet group (see Fig. 1.1). There were no differences between the two groups in either total brain volume or in the volume of grey matter in the cortex. The enriched group, in fact, had greater volumes for all comparisons but these did not reach significance. The dietary intervention had not resulted in larger brains but had exerted a selective effect on the volume of the caudate nuclei. This is an interesting finding because a relationship between the volume of the caudate nucleus and IQ had been demonstrated in a group of 7 year-olds born preterm (Abernethy et al., 2004). The authors speculated that dietary insufficiency in the post-natal period might have hindered the development of the caudate nucleus. Was the relationship with IQ also present in our study?

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The effects of early diet on cognition and the brain Basal ganglia (caudate nucleus)

Cerebrum (cerebral cortex)

Thalamus

4200 4100 4000 3900 3800 3700 3600 3500 3400 3300 3200

Amygdala

* *

Left

Hypothalamus (a)

Hippocampus

13

(b)

Right Standard Enriched

Fig. 1.1 (a) Drawing showing the location of the two caudate nuclei deep within the white matter of the brain. (b) Bar chart showing the significant differences in caudate volumes (in mm3) between the standard- and enriched-nutrient diets.

Overall, the enriched-diet group had significantly higher VIQ than the standard-diet group, but they did not differ in PIQ. There was also a significant correlation overall between the volumes of the left and right caudate nuclei and IQ; once again, the effect was selective to VIQ. Further analyses showed that there were significant correlations between VIQ and bilateral caudate volumes only in boys. To some extent, the results agreed with those of Abernethy and Cooke (2004) in demonstrating a link in these preterm subjects between caudate volume and IQ, but differed in that our selective effect on VIQ contrasted with their finding of differences in all three IQ indices. They did not look at the gender groups separately so we do not know if the same gender effect existed in their data.

1.5.4 Study 2 – Breast milk, IQ and brain structure With the same basic hypothesis that infant diet would result in neural differences, our next study examined the relationships between breast milk, IQ at adolescence and brain structure (Isaacs et al., 2010). The literature on breastfeeding and cognition is extensive and although there is little disagreement that breastfeeding has positive effects on rates of infection and some future health outcomes, there is no consensus about its positive effects on cognition. The majority opinion is that it has some small beneficial effect on IQ development, particularly in preterm infants (Anderson et al., 1999; Uauy and Peirano,1999), but Der et al. (2006), for example, found that controlling for mothers’ IQ level (rather than using proxy measures such as level of education) eliminated the advantage. It is a difficult research area because of the very large numbers of potentially confounding variables

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and because of the ethical impossibility of randomly assigning infants to breastfeeding or non-breastfeeding conditions. Kramer et al. (2008) used a different approach by comparing more than 13 000 children in Belarus who had been randomised to two groups, in one of which the mothers received breastfeeding promotion intervention. Both the duration and period of exclusivity of breastfeeding were significantly longer in the promotion group and the infants showed higher IQ and academic scores at 6.5 years. Participants in this study came from the trial that included the infants of mothers who had chosen to provide their own breast milk and who had received varying amounts of supplementary diet as adjunct to the amount of milk produced by the mothers. The volumes of all enteral intakes were recorded daily and these precise volumes allowed the calculation of the percentage of expressed maternal breast milk in each infant’s diet (%EBM); the proportion varied from 0 to 100 %. We examined the relationships between brain volumes, %EBM and IQ in 50 adolescents who had been in the breast milk group as infants. We first looked to see if IQ scores increased as the %EBM in the diet increased and found this to be true, but only for VIQ, and only in the boys. There was no difference between the IQ scores for boys and girls, but only in the boys were these scores, at least VIQ, related to the %EBM in the diet. Percentage EBM was an even more powerful predictor of VIQ than social class. Was this pattern reflected in the structure of the brain? We looked at the relationships between %EBM and various neural volumes: total brain volume and volumes of white matter and of grey matter in the left and right hemispheres separately. In boys only, %EBM was significantly associated with both the volume of the total brain and the volume of white matter, in left and right hemispheres. In fact, in boys, almost 50 % of the variance in white matter volumes was accounted for by %EBM, a very large effect. There was some effect on white matter in girls as well, but these relationships were only at a trend level. These analyses looked at the absolute volumes of grey and white matter in isolation from the overall size of the brain. When we repeated the analyses with relative volumes, controlling for total brain size, the relationships in girls became more significant but were weak compared to the boys. In both genders, to varying extents, the proportion of white matter in the brain was related to the early intake of maternal breast milk. It would be possible for %EBM to be related to each of the two outcome measures of IQ and neural volumes without any necessary relationship existing between the two outcome measures themselves. The final link was to examine the relationship between neural volumes and IQ directly and here we found that in the boys only the volumes of the total brain and white matter were both significantly related to VIQ. There were no relationships in the girls or between grey matter volume and IQ in either group.

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1.5.5 Are these studies important? The importance of these two studies is that they offer proof of the principle that subtle nutritional effects can be demonstrated in the brain despite early pessimism about the chances of this becoming a reality. The original trial was not designed to explore which particular nutrients influenced neurodevelopment, nor to design the optimal formula, but to determine whether failing to meet overall nutrient needs during this critical period of brain growth had significant consequences for overall development. The cognitive studies had shown that it does, and the most recent that the same is true for developing brain structure. The emphasis on the failure to meet nutritional needs is important. These studies are sometimes misinterpreted as suggesting that the enriched-diet has acted to boost IQ to some superior level. Examination of the results shows that the enriched-formula results in IQ levels in the average range while the standard-formula is associated with below-average IQ scores. The enriched formula appears to ‘rescue’ these preterm infants, raising their IQ scores up to an average level. We have mentioned the tendency amongst psychologists and cognitive neuroscientists to ignore nutrition as a variable of interest. Evidence of structural brain changes might persuade this community to give greater consideration to this variable in future research. This is particularly important as nutrition is probably the easiest of environmental factors to manipulate, with extremely important medical and social consequences.

1.6 Issues raised by these studies 1.6.1 The effects of early diet persist over time By following these infants over time, we have been able to see that the effects of early nutrition on cognition persist into adolescence, covering the period when most formal education takes place. We do not yet know whether this will be true in adulthood, but it seems likely that the changes may turn out to be permanent. Many studies have not conducted later follow-up studies and so it cannot be known if the effects persisted or not. Some cognitive effects of nutrition seen in early childhood have not always been observed later. Walker et al. (2000), for example, gave nutritional supplements to stunted children in Jamaica who were recruited between 9 and 24 months of age. While they observed cognitive effects in early childhood, none were detected when the children were re-assessed at 11 to 12 years. These children were term infants rather than preterm which might explain the difference in outcome and raises a testable question for future investigation. More salient may be the difference in age, and therefore stage of brain development, at supplementation: immediately post-natal versus an average age of 18.7 months, towards the end of the brain growth spurt. Studies of early supplementation with long-chain polyunsaturated fattyacids (LC-PUFAs) have shown some short-term effects on development,

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particularly in the visual system, but two systematic reviews of outcome in both term (Simmer et al., 2008a) and preterm infants (Simmer et al., 2008b) have concluded that there is no evidence that these effects persist later in childhood.

1.6.2 The effects of early diet may be different in males and females The gender differences in the effect of nutrition on cognitive outcomes demonstrated above and in other studies (Fewtrell et al., 2004; Kennedy et al., 2010) suggest that there might also be demonstrable differences between genders at the neural level. These could take various forms. Boys and girls might differ in whether diet has an effect on brain structure at all or both might be affected but in different areas of the brain, leading to different cognitive outcomes. A brain structure might be affected in all children but, if that structure serves as a neural substrate for a cognitive function in only one gender, then differential outcome will be observed. Although it might seem surprising at first glance, the gender finding accords quite well, in fact, with the literature in at least three areas of research. The development of neuroimaging has precipitated a very large number of studies of the normal human brain both during development and at maturity. Many of these studies have reported gender differences in structure and in function. During childhood and adolescence, boys and girls have been shown to vary in their trajectories of grey and white matter development (De Bellis et al., 2001). Adult females across the lifespan from 7 to 87 years have a thicker cortex in posterior areas of the brain compared to males (Sowell et al., 2007), while Reed et al. (2004) have shown that the speed with which impulses travel along the nerves is faster in males despite their greater physical size. Luders et al. (2004) showed that cortical complexity, measured by the amount of folding of the brain surface, was greater in females than in males. This same observation has been made in preterm infants soon after birth (Vasileiadis et al., 2009) with female infants having greater cortical folding compared to male infants with similar cerebral volumes. Research, often in preterms, has shown that males and females may react differently to environmental variables. Male sex is known to be a risk factor for poor progress after preterm birth (Mayoral et al., 2009). Lauterbach et al. (2002) reports an appreciable female advantage in cognitive recovery after Respiratory Distress Syndrome, which increases the risk for brain insult, and Raz et al. (1995) showed a similar female advantage on cognitive tasks after intracranial haemorrhage. Male children showed widespread neural abnormalities at 12 years after preterm birth while females were not different from term female children (Kesler et al., 2008). Environmental stress has different effects in male and female rats exposed to postnatal hypoxia (Mayoral et al., 2009), particularly on the volumes of the hippocampus, a structure very important in humans for memory, and of white

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matter which show greater reductions from normal levels in males. Using different stressors, Lin et al. (2008) and Reich et al. (2009) have also shown effects of gender. Finally, with implications for nutrition, Kodama et al. (2008) have reported that early weaning had differential gender effects on both cognitive performance and some neural parameters. The relationship between brain and behaviour may also differ by gender. Pfleiderer et al. (2004), for example, used another imaging technique, magnetic resonance spectroscopy, to show that there was a significant correlation between the level of N-acetylaspartate, a brain metabolite, in the left frontal cortex and VIQ in women but not in men. The size of the hippocampus has been shown to be positively correlated with VIQ in boys but not in girls (Schumann et al., 2007). Animal studies, such as that by Levant et al. (2006), showing that varying the availability of docosahexaenoic acid (DHA) in the diet of rats affected locomotor activity only in males, may prove informative for nutrition studies in humans. Particularly relevant is a report by Constable et al. (2008) showing that the relationships between white matter abnormalities in 12 year old former preterms were significantly related to cognitive outcomes in males but not in females.

1.6.3

Early diet may affect certain areas of the brain and cognition selectively It is striking that the effects of early diet in the preterm cohort were almost always selective to VIQ, a measure based on a combination of sub-tests that all involve verbal input mainly through the auditory channel. Other studies, although not all, have also found greater effects on VIQ. In the large Belarus study by Kramer et al. (2008) in which 13 889 children followed up for IQ assessment at 6.5 years, after early randomisation of breastfeeding mothers to either a standard care or a breastfeeding promotion intervention, the promotion group had higher IQ scores. This was particularly true for VIQ (+7.5 points) compared to PIQ (+2.9 points). Horwood et al. (2001) related duration of breastfeeding to IQ at 7–8 years and found that, after adjustment for a wide variety of factors associated with the receipt of breast milk, VIQ scores, but not PIQ, increased with duration of breastfeeding. Gale et al. (2009) found that VIQ at four years was related to the proportion of fruit, vegetables and home-made foods in the diet at 6 and 12 months, after adjustment for social and educational factors, while PIQ was not. Effects on verbal function are often attributed to differences in factors such as socioeconomic status and maternal intelligence. The advantage in IQ frequently seen in breastfed babies, for example, is typically ‘explained’ by higher maternal status on such factors. As noted above, Der et al. (2006) measured maternal IQ directly, rather than depending on these proxy measures, and found that there was no cognitive advantage for breastfed infants once this was controlled. A recent paper by Edmonds et al. (2010), however, examined the effects of different birthweights (reflecting differences in

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prenatal nutrition) in monozygotic twin pairs who were, of course, matched for parental intelligence, socioeconomic status and home environment, and found selective effects on VIQ despite this rigorous control. It is interesting that studies conducted later in childhood have usually, in contrast, found that nutrition affects Performance IQ, which involves processing of largely visual stimuli presented by eye. Benton (2001) reviewed the results of 13 double-blind, placebo-controlled studies, which had investigated whether supplementation with micronutrients would affect scores on an intelligence test. In ten of these, supplementation had a significant effect and always on non-verbal measures that are thought to reflect basic biological function. The most obvious difference between the two groups of studies reporting VIQ or PIQ differences is the age at intervention. This raises the hypothesis that early dietary intervention during the brain growth spurt exerts maximum influence on the developing structure of the brain and mainly on the areas involved in verbal functioning. Later interventions, once brain structural development is largely accomplished, tend to exert more effect on the functioning of the brain, probably mediated by effects on the neurochemical efficiency and the transmission of information and, thus, on PIQ (Benton and Cook, 1991). The implication of this is that the dietary effects seen on PIQ in older adults and children would not continue after the intervention was discontinued. This remains to be tested. There are, of course, other differences between the studies and it may turn out to be that protein/calorie supplementation affects different neural areas than does vitamin/mineral supplementation or that the duration of supplementation is important. Diets that vary in protein/calorie content often differ as well in the constituent micronutrients, making interpretation complex. These are important issues that need to be resolved by future research.

1.6.4 A short period of dietary intervention may have lasting effects It may seem unlikely that exposure to the dietary intervention for a period of weeks after birth could have effects that persist for years. The children in the preterm cohort, as a whole, spent a mean of six weeks on the diet. This dropped to a mean of four weeks for the neurologically normal samples described above. After discharge from hospital, and therefore from the study, infants were fed as the parents chose. Once again, however, there is evidence that events of short duration in the very early vulnerable stages of life can have a very large impact on development. The best known example of this is probably imprinting in birds, first described by Spalding (1873), when birds show following behaviour to a visual stimulus to which they are exposed in a critical period soon after hatching. Sex in turtles is determined by the environmental temperature before the egg is hatched. During a short period during development, the brain in a female rat foetus can be programmed to exhibit male behaviour (Angelbeck and DuBrul,

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1983). Bagley and Hayes (1983) showed that a single dose of phenobarbitol administered to a neonatal rat had life time metabolic effects on p450 cytochrome mono-oxygenase activity. This same dose administered outside the critical window induces temporary drowsiness only. In humans, visual experience in infancy and in childhood has a major influence on how the visual pathways in the brain develop. A disturbance to normal visual development, such as squint, can have a life-long effect on visual function in the form of conditions like amblyopia (Adams and Sloper, 2003). These examples illustrate the biological plausibility of life-long effects caused by very short exposures to stimuli at a critical time. Determining critical or sensitive periods for nutritional intervention to affect the human brain is an important area of research to pursue.

1.6.5

The effects of dietary intake are not restricted to extreme deprivation Early studies examining the effects of nutrition on cognition were usually observational and looked at conditions of extreme nutritional deprivation, i.e. malnutrition. Understandably, the emphasis was often on obtaining favourable outcomes after some intervention and not on isolating the effects of specific nutrients. Recently the focus has shifted to include more subtle dietary differences in developed countries. Being generally well-fed in terms of calorie intake does not preclude the existence of what might be called ‘under-nutrition’ rather than frank malnutrition, particularly of some micronutrients. It took some time for the nutrition community to accept that such a state could exist in the absence of clinical signs of malnutrition. Benton (2001) reports that there was a widely-held belief that children consumed adequate levels of micronutrients and, in the absence of clinical symptoms, deficiencies could not be present. The positive results in some early studies examining whether supplementation with vitamins/minerals could increase IQ scores in school children (Benton and Roberts, 1988) were dismissed as spurious by nutritionists. Benton (1992) made the important observation that the first symptoms associated with a deficiency might be psychological. There is now a wider acceptance that a sufficient diet may not be an optimal diet, providing the context for further work uncovering the links between nutrition, cognition and the brain. Cognitive results from various studies show that early diet is related to future outcome even in a setting where overall levels of nutrition, both pre- and postnatal, are adequate and severe malnourishment is no longer seen as a prerequisite for less than optimal outcome. Gale et al. (2009), for example, found that IQ at 4 years was related to the proportion of fruit, vegetables and home-made foods in the diet at 6 and 12 months. That effects can also now be demonstrated in the brain should make the point more clearly. Studies, preferably RCTs, in these more adequately-fed populations can further refine answers to the

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question of whether effects on brain and cognition can occur as a result of relatively minor fluctuations in intake.

1.7 Nutrition, cognition and brain relationships: some general considerations The advent of neuroimaging has vastly increased the number of questions that can be asked about the interaction between the brain and environmental factors. Since the field of nutrition deals with one of the most important of these factors, the opportunities for important and meaningful research in nutrition have increased dramatically. To take full advantage of these opportunities, a series of issues needs to be considered in planning effective research.

1.7.1 Age at study The number of possible research questions is vast, but the general form of the question will often be dictated by the age group chosen for study, partly because different methods are suitable for use with certain age groups and also because the effects we expect to see may differ. Prenatal nutrition is not considered here because of space constraints, but determining how variations in maternal nutrition may affect the future cognitive and neural development of the child is of immense importance. The brain growth spurt, when the effects of nutrition may be particularly relevant, will continue to be of interest. The preterm infant offers a model in which the introduction of postnatal nutrition varies with gestational age at birth, ranging from around 23 weeks to 36 weeks (≥37 weeks is considered full term), allowing the study of the effects of nutrition at different stages of brain development. Chi et al. (1977) examined post-mortem brains from infants ranging from 10 to 44 weeks gestation and carefully mapped the development of the pattern of convolutions in the cortex of the brain. The infant brain between, for example, 24 and 27 weeks is developing in quite different areas from that between 28 and 31 weeks. Nutritional intervention at these two time points might have effects on different parts of the brain and on their associated cognitive functions. The plasticity of the brain at this time means that it is the most likely period in which nutrition can bring about structural change. These studies are often long-term in nature with the outcome measures – brain scans and cognitive measures – being collected some time after the intervention. For cognition, in particular, many functions can only be assessed once the child’s repertoire of skills has developed, and failure to take the long view may result in an incorrect assumption that nutrition has not affected outcome. Early nutritional information, however, should be collected at the time of the intervention and not as an afterthought with reliance on hospital records

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or parental recall. A very active area of research into infant nutrition at present, not without controversy, is that of supplementation with LC-PUFAs (Eilander et al., 2007; Schuchardt et al., 2010). Structural brain studies in those whose diet was supplemented or not as infants should prove fruitful. Although structural change is most likely in the under 2 year-olds, more immediate effects of nutrition can also be studied with other methods in these children. Using psychological paradigms, Valiante et al. (2006) showed that healthy 2–3 day-old newborns had better memory for a spoken word after a typical feed than before. Horne et al. (2006) found, in a randomised trial, that 24 day-old infants had better memory for a spoken word after a 2 g/kg glucose feed than after a water feed. Johnston et al. (2002) found that a high repeated exposure to sucrose in preterm infants born under 31 weeks gestational age was associated with deficits in motor development, alertness and orientation five weeks after birth. The use of electrophysiological methods, EEG and ERPs (event-related potentials) to monitor the electrical activity in the brain, mentioned earlier, provide another set of methods to look at more short-term effects of diet during the early years. Although we are concerned here with the effects of diet early in infancy and childhood, brain growth spurts later in development may also be times when neural structure is vulnerable to nutritional influence, but this has not been explored. Past early childhood, when structural change is less likely, the use of other neuroimaging methods to examine the effects of nutrition in the short term become more appropriate.

1.7.2 Imaging methods The volumetric method that we have described is designed to obtain information about the structure of the brain. Voxel-based morphometry (Ashburner and Friston, 2000) is another neuroimaging analysis technique that provides information about brain structure. It was designed to investigate local differences in the distribution of grey and white matter in the brain, the sort of subtle changes that we might expect to be associated with nutrition. It is an unbiased whole-brain technique and does not depend on selecting regions of interest to examine (as does volumetrics). The scans are pre-processed by registering them to a template to eliminate large differences in anatomy and then segmenting them into separate grey and white matter images. Two groups of scans can then be compared voxel-by-voxel to determine where there are significant differences in grey (or white) matter. The results are displayed on an SPM (statistical parametric processing map) and/or on an image of the brain – an example is shown in Fig. 1.2. This technique can be used to compare two groups of subjects (e.g. two groups who had received different dietary interventions as infants) but also to correlate some environmental or behavioural variable with brain structure, e.g. %EBM with white matter.

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Fig. 1.2 Illustration of how a significant difference in grey (or white) matter between two groups appears on an SPM map. The cursor points to the same area in each of three planes.

Diffusion imaging is a structural MRI method that is sensitive to the diffusion of water in the brain. Since water will diffuse more quickly in the direction aligned with internal structure, such as nerve fibres, we can obtain information about the microstructure of white matter by using data about the rate and preferred direction of water diffusion. The breastfeeding results described above indicated a dietary influence on white matter, and the synthesis and development of myelin is known to be affected by malnutrition (Wiggins, 1982; Chase et al., 2007), so this might prove to be a valuable technique for use in early nutrition studies. Magnetic resonance spectroscopy (MRS) also examines brain structure, providing biochemical information about tissues in the body. It provides a non-invasive means of studying tissue metabolism in vivo (Gadian, 1995). Clinically, it is usually used to compare the spectra of certain brain metabolites in regions of interest (typically, ratios amongst Nacetylaspartate, choline-containing compounds and creatine) against normal

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data to determine the presence of pathology. The method has not been widely used in cognitive studies, but a report by Levy et al. (1999), showing metabolic abnormalities in a single case of dyscalculia, illustrates how this could be done. It is conceivable that nutrition studies could be devised to examine whether brain metabolites are related in any way to early diet and to link these with cognition, but these have not been undertaken so far. Other imaging methods have been developed to look at function rather than structure. Functional MRI (fMRI), for example, is sensitive to changes in blood oxygenation level (the BOLD signal) and provides information about areas of the brain that are consuming oxygen and are, therefore, active during the performance of specific cognitive tasks. This is likely to be useful in studying the more immediate effects of nutrition in children who are over the age of 6 or so and able to comply with carrying out cognitive tasks in the scanner while staying still to avoid motion artefacts. It could be useful in trying to determine the neural underpinnings of the cognitive and behavioural effects seen after the consumptions of different ratios of macronutrients (e.g. at breakfast). Some studies with adults could be adapted for children: Boujraf et al. (2006), for example, looked at the effects of a period of restricted diet on the BOLD response and found effects in the motor cortex, while Noseworthy et al. (2003) observed that the BOLD signal showed a significant bilateral decrease, also in the motor cortex, following a high-fat meal. Optical imaging is another technique that promises to be useful in infants and children. A near-infrared laser source is placed on the scalp and the signal that ‘bounces’ back is picked up by detectors. When there is electrical activity in the neurons, there are two other main changes that take place besides those in blood oxygenation: blood volume changes and light scattering changes that are caused by the movement of ions and water. These active regions of the brain reflect less light and this is imaged by the optical imaging system, providing similar information to fMRI. Since the method is non-invasive and relatively portable (unlike an MRI scanner), it is well suited for use with small infants and could provide information that is very basic, but not yet available, about which areas of the infant brain become active during/after a feed and whether they differ between diets. Although neuroimaging is poised to make a significant contribution to the study of the effects of early diet, there are several things to bear in mind. If an imaging study fails to find an effect of diet on brain structure it does not mean necessarily that there has been no effect but that the method of imaging used was not sensitive enough to demonstrate it. Breast milk might have an important effect on the brain in girls that was undetected in our study by the methods used. As imaging becomes ever more capable of examining finer structure, other effects may become apparent. It would be equally misguided, however, to assume that this is always the case. Imaging

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might not show an effect simply because there is no effect to demonstrate. Neuroimaging is simply an investigative tool to be used judiciously.

1.7.3 Gender analyses In view of the results obtained in prior studies of cognition and brain structure, as well as the literature on male–female differences generally, it would seem prudent to always include pre-planned gender analyses. This is a lesson not only for nutrition. Much theory in psychology is based on studies using laboratory rats most of whom have been male, thus eliminating any possibility of finding gender effects. Many nutrition studies have included both males and females, but the results are conflated and considered as a whole so that differences between the sexes have not been examined. Valuable information may be lost if significant interaction between sex and the effect in question is untested.

1.7.4 How general are the effects? An important question is whether effects of nutrition can be observed in the entire population or whether they are restricted to certain groups. Much of the work on early diet has been carried out in preterm infants who may be vulnerable to nutritional intervention in some way that the full-term infant is not. Around 10 % of births are premature so this is still a substantial number of individuals, but it is important to extend these studies to full-term infants to see if the effects are the same, are attenuated or do not occur at all. There has also been much discussion as to whether only those who are deficient in some nutrient will benefit from supplementation. Benton (2001) points out that the evidence supports the conclusion that the positive effects of supplementation with micronutrients on IQ occur in a minority who have normal diets low in micronutrients and this may be true for many other nutrients, such as LC-PUFAs. Whether the effect is targeted or general will need to be worked out on an individual nutrient basis.

1.8 Suggestions for further research and sources of further information and advice 1.8.1 Design of future studies Various aspects of experimental design that should be taken into account for studies in this field have been mentioned above. Where possible, they should be randomised, controlled trials so that information about causation can be obtained. Data, as detailed as possible, about the subjects and the effects should be obtained at the time of intervention and not retrospectively as is often the case. Numbers of male and female subjects should be large enough to allow analysis of gender effects. Cognitive measures should

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include not only assessment of overall ability but also a battery of tests of specific cognitive function chosen with regard to the known effect of the nutrient on the brain and of the relevant cognitive architecture (Burger et al., 1993; Isaacs and Oates, 2008). To fully determine the extent of the effects, follow-up should be carried out when the child is old enough to be assessed in all areas of function and, where possible, further follow-up studies should take place to look for the later emergence of effects as well as the persistence of any noted earlier on. Care should be taken to select the most appropriate methods for the collection and analysis of brain scans with reference to the research question.

1.8.2 Future research questions Suggestions for further research have been made throughout the chapter: the study of different nutrients, the effects across the age range, establishing susceptibility to intervention. Determining optimal diets is of great public health importance, but it should be recognised that these may vary by gender, by age, by birth status and by a variety of environmental factors all of which may interact with one another. This is a complex task as well as an important one. One area of research not so far mentioned is that of determining the mechanisms mediating the effects of nutrition on brain and cognition. The brain studies conducted so far were designed to test a principle and not to determine the optimal nutrient(s)/diet for brain development. This remains an important question for research. The enriched and standard diets used in the preterm cohort were designed to vary in overall protein/ energy content, which might have caused the effects, but they also varied in the content of certain micronutrients, so one or more of these could be responsible. One thing that did not vary between the two diets was the LC-PUFA content so what might seem like a likely candidate cannot be contributing to the difference in outcome between the diets. Wharton et al. (2004) suggested that the amount of taurine in the diet, markedly different between the standard and enriched formulas, was important and linked it to both a general effect on mental development at 18 months and arithmetic scores at 7 years. It is possible that specific nutrients affect specific cognitive functions because they have effects on different regions of the brain. The dose–effect relationship between %EBM and white matter in the brain suggests that it is some component(s) of breast milk that underlies the observation; Isaacs et al. (2010) speculate that cholesterol might be important. While breast milk contains significant amounts of cholesterol, infant formula does not (Uauy et al., 2000). Cholesterol is known to be an important component of myelin (Saher et al., 2005) and, of interest because of the gender effect, dietary manipulation in neonatal rats has shown that the expression of myelin basic protein was affected more in males than in

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females. Only further research will contribute to answering these questions.

1.8.3 Additional sources of information There is a great deal of information available both about the effects of early diet on cognition and about neuroimaging but very little about the confluence of these two areas of knowledge. This will not be surprising given the sparseness of the research literature in this area. The interested reader will need to pursue each of these threads separately. If they should want to design a study, the best approach is to decide on the dietary intervention of interest, study the literature to determine which areas of the brain seem most vulnerable to its effects and then choose both cognitive tests and method of brain imaging in the light of this information. Brain studies will need to be carried out in collaboration with the appropriate neuroimaging and neuropsychological departments within a university/hospital setting. The chapters in this book that examine the cognitive effects of specific nutrients, along with their references, will provide valuable information. There is a series of systematic reviews from The Cochrane Collaboration (www.thecochranelibrary.com) comparing the cognitive effects of whole diets that differ in nutrient content that are instructive. The Nestlé Nutrition Institute Workshop also publishes a series of single-issue volumes, many of which are pertinent to this area. Internet databases such as PubMed are invaluable. The best basic source of information about all methods of neuroimaging is probably the internet. A useful starting point is the website of the Functional Imaging Laboratory at the Institute of Neurology, University College London (www.fil.ion.ucl.ac.uk) where much of the methodology used in the analysis of brain scans was developed. Two other websites that discuss different methods of imaging analyses are also recommended: www.surfer. nmr.mgh.harvard.edu (Freesurfer) and www.fmrib.ox.ac.uk/fsl (FSL). The journal Neuorimage is a good resource.

1.8.4 Suggestions for the food industry This is a new area of research with a broad spectrum of questions to investigate, some of interest to the food industry. It provides a level of evidence about the efficacy of nutritional intervention that was not previously available, providing information that is of scientific interest but also of great importance in the wider social context to consumers. It does not seem probable that the food industry will undertake many original studies although, within funding constraints, this is quite possible in collaborative studies between nutritionists and cognitive neuroscientists. It will become increasingly important, however, for the industry to keep in close contact with developments in this research area.

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lucas a, morley r, cole t j, gore s m, lucas p j, crowle p, pearse r, boon a j and powell r (1990) Early diet in preterm babies and developmental status at 18 months. Lancet, 335, 1477–1481. lucas a, morley r and cole t j (1998) Randomised trial of early diet in preterm babies and later intelligence quotient. BMJ, 317, 1481–1487. luders e, narr k l, thompson p m, rex d e, jancke l, steinmetz h and toga a w (2004) Gender differences in cortical complexity. Nature Neurosci, 7, 799–800. mayoral s r, omar g and penn a a (2009) Sex differences in a hypoxia model of preterm brain damage. Pediatr Res, 66, 248–253. milgrom j, newham c, anderson p j, doyle l w, gemmill a w, lee k, hunt r w, bear m and inder t (2010) Early sensitivity training for parents of preterm infants: impact on the developing brain. Pediatr Res, 67, 330–335. noseworthy m d, alfonis j and bells s (2003) Attenuation brain BOLD response following lipid ingestion. Hum Brain Mapp, 20, 116–121. o’connor d l, jacobs j, hall r, adamkin d, auestad n, castillo m, connor w e, connor s l, fitzgerald k, groh-wargo s, hartman e e, janowsky j, lucas a, margeson d, mena p, neuringer m, ross g, singer l, stephenson t, szavo j and zemon v (2003) Growth and development of premature infants fed predominantly human milk, predominantly premature infant formula, or a combination of human milk and premature formula. J Pediatr Gastroenterol Nutr, 37, 437–446. pfleiderer b, ohrmann p, suslow t, wolgast m, gerlach a l, heindel w and michael n (2004) N-Acetylaspartate levels of left frontal cortex are associated with verbal intelligence in women but not in men: a proton magnetic resonance spectroscopy study. Neuroscience, 123, 1053–1058. psychological corporation (1974) Wechsler Intelligence Scale for Children, Anglicised Rev. ed. Sidcup: Psychological Corporation. raz s, lauterbach m d, riggs w w and sander c j (1995) A female advantage in cognitive recovery from early cerebral insult. Dev Psychol, 31, 958–966. reed t e, vernon p a and johnson a m (2004) Sex difference in brain nerve conduction velocity in normal humans. Neuropsychologia, 42, 1707–1714. reich c g, taylor m e and mccarthy m m (2009) Differential effects of chronic unpredictable stress on hippocampal CB1 receptors in male and female rats. Behav Brian Res, 203, 264–269. rice d and barone jr s (2000) Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect, 108, 511–533. rosenzweig m r and bennett e l (1972) Cerebral changes in rats exposed individually to an enriched environment. J Comp Physiol Psychol, 80, 304–313. saher g, brügger b, lappe-siefke c, möbius w, tozawa r, wehr m c, wieland f, ishibashi s and nave k-a (2005) High cholesterol level is essential for myelin membrane growth. Nat Neuro Sci, 8, 468–475. schuchardt j p, huss m, stauss-grabo m and hahn a (2010) Significance of longchain polyunsaturated fatty acids (PUFAs) for the development and behaviour of children. Eur J Pediatr, 169, 149–164. schumann c m, hamstra j, goodlin-jones b l, kwon h, reiss a l and amaral d g. (2007) Hippocampal size positively correlates with verbal IQ in male children. Hippocampus, 17, 486–493. simmer k, patole s k and rao s c (2008a) Longchain polyunsaturated fatty acid supplementation in infants born at term. Cochrane Database Syst Rev, CD000376. simmer k, schulzke s m and patole s k (2008b) Long–chain polyunsaturated fatty acid supplementation in infants born at term. Cochrane Databare Syst Rev, CD000375.

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smart j (1986) Undernutrition, learning and memory: review of experimental studies, In Taylor T G and Jenkins N K (eds), Proceedings of XII International Congress of Nutrition. London: John Libbey, 74–78. sowell e r, peterson b s, kan e, woods r p, yoshii j, bansal r, xu d, zhu h, thompson p m and toga a w (2007) Sex differences in cortical thickness mapped in 176 healthy individuals between 7 and 87 years of age. Cereb Cortex, 17, 1550–1560. spalding d a (1873) Instinct with original observations in young animals. MacMillans’ Magazine, 27, 282–293. (reprinted 1954) Br J Animal Behav, 2, 2–11. stein a d, zybert p a, van der bor m and lumey l h (2004) Intrauterine famine exposure and body proportions at birth: the Dutch Hunger Winter. Int J Epidem, 33, 831–836. super c m, herrera m g and mora j o (1990) Long–term effects of food supplementation and psychosocial intervention in the physical growth of Colombian infants at risk of malnutrition. Child Dev, 61, 29–49. uauy r and peirano p (1999) Breast is best: human milk is the optimal food for brain development. Am J CLin Nutr, 70, 433–434. uauy r, mize c e and castillo-duran c (2000) Fat intake during childhood: metabolic responses and effects on growth. Am J Clin Nutr, 72, 1354S–1360S. valiante a g, barr r g, zelazo p r, papageorgiou a n and young s n (2006) A typical feeding enhances memory for spoken words in healthy 2- to 3-day-old newborns. Paediatrics, 117, e476–e486. vasileiadis g t, thompson r t, han v k m and gelman n (2009) Females follow a more ‘compact’ early human brain development model than males. A case-control study of preterm neonates’, Pediatr Res, 66, 551–555. wachs t d (2000) Nutritional deficits and behavioural development. Int J Behav Dev, 24, 435–441. walker c-d (2005) Nutritional aspects modulating brain development and the responses to stress in early neonatal life. Neuro-Psychopharmacol Bio Psychiatr, 29, 1249–1263. walker s t, grantham-mcgregor a m, powell c a and chang s m (2000) Effects of growth-restrictions in early chilldhood on growth, IQ, and cognition at age 11 to 12 years and the benefits of nutritional supplementation and psychosocial stimulation. J Pediatr, 137, 36–41. wharton b a, morley r, isaacs e b, cole t and lucas a (2004) Low plasma taurine and later neurodevelopment. Arch Dis Child Fetal Neonatal Ed, 89, F497–F498. wiggins r c (1982) Myelin development and nutritional insufficiency. Brain Res Rev, 4, 151–175.

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2 Influence of long-chain polyunsaturated fatty acids (LC-PUFAs) on cognitive and visual development J. P. Schuchardt and A. Hahn, Leibniz University of Hannover, Germany

Abstract: Long-chain polyunsaturated fatty acids (LC-PUFAs), particularly docosahexaenoic acid (DHA) and arachidonic acid (AA), play a central role in infancy for normal brain development. They are involved in numerous neuronal processes, ranging from effects on membrane fluidity, signal transduction, neurotransmission to gene expression regulation. Since observational studies have indicated that the visual and cognitive performance of breastfed infants is advantaged compared to formula-fed infants, numerous randomized controlled studies have studied whether infant formulas supplemented with DHA or both DHA and AA would enhance visual and cognitive development of both term and preterm infants. This chapter gives an overview on the significance of LC-PUFAs in neurodevelopment, with a special focus on the findings from these studies. Key words: infant nutrition, maternal nutrition, pregnancy, perinatal development, brain growth, cognitive development, visual development, long-chain polyunsaturated fatty acids, LC-PUFA, omega-3 fatty acids, docosahexaenoic acid, DHA, arachidonic acid, AA, infant formula, supplementation, dietary requirements.

2.1 Introduction During pregnancy the fetal brain grows rapidly, especially during the second half of pregnancy, and growth remains high during the first several years of life. High-quality nutrition is essential to ensure that all nutrient needs are covered for an appropriate cognitive, visual and motor development. A lack of essential nutrients during the first stages of life has marked effects on the structural and functional development of the nervous system. Long-chain polyunsaturated fatty acids (LC-PUFA) – especially the omega-3 FAs docosahexaenoic acid (DHA) and the omega-6 FA arachidonic acid (AA) – play an essential role in the development of neuronal

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tissues, in particular by affecting the structural composition of neuronal membranes in the brain and myelin sheaths. An adequate supply of LCPUFAs is of critical importance for visual, motor and cognitive development. A lack of omega-3 LC-PUFAs in particular is associated with a functional impairment and likely involved in neurodevelopmental disorders. During pregnancy the developing fetus is dependent on the maternal supply of LC-PUFAs via placental transfer and fetal lipid transport. After birth, breast milk is the best source for LC-PUFAs, while LC-PUFAenriched infant formula is the only appropriate alternative if exclusive breastfeeding is impossible for any reason. The maternal LC-PUFA transfer to the fetus during pregnancy and lactation is influenced by maternal dietary intake and lifestyle. This chapter gives an overview on the structure and metabolism of relevant LC-PUFAs, as well their structural and functional role in neuronal mechanisms. The results from observational and randomized controlled trials on the significance of an adequate LC-PUFA supply for neonates and infants on cognitive and visual outcomes are critically reviewed. Finally, current recommendations regarding LC-PUFA intake are presented.

2.2

Structure, metabolism and general physiological functions of polyunsaturated fatty acids (PUFAs)

The classification of PUFAs differs from the rational chemical nomenclature, since the position of the first double bonds from the methyl end of the molecule defines whether PUFAs belong to either omega-3 (n-3) FAs or omega-6 (n-6) FAs (Fig. 2.1). The first double bond of n-3 FA parent compound α-linolenic acid (ALA, C18:3n-3) and its long-chain derivatives, eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3), is located at the third carbon atom. In contrast, the first double bond of n-6 FAs is located at the sixth carbon atom; the most well-known FAs in this group is the parent compound linoleic acid (LA, C18:2n-6) and its long-chain derivatives, γ-linolenic acid (GLA, C20:3n-6) and arachidonic acid (AA, C20:4n-6). In contrast to saturated and monounsaturated FAs, mammals are not able to synthesize the parent compounds of both the n-6 FA LA and the corresponding n-3 FA ALA. Therefore, LA and ALA must be obtained through the diet and are considered as essential fatty acids (EFAs). However, humans are capable of converting LA and ALA to longer chain, more highly unsaturated FAs through a multistage enzymatic chain elongation and desaturation process, which primarily takes place in the endoplasmatic reticulum of liver cells (Sinclair, 1990). Whereas LA is converted to AA, ALA is converted to EPA, and subsequently to DHA. The chain elongation/desaturation enzymes are shared by both n-3 and n-6 FAs with

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Lifetime nutritional influences on behaviour and psychiatric illness Omega-6 series

Omega-3 series Parent compounds

Omega-6

Omega-3 O C

ω 1 6 Linoleic acid (LA) C18:2n–6

O C

ω OH

1

Multistage enzymatic conversion

3 a-Linoleic acid (ALA) C18:3n–3

Longer chain, more highly unsaturated derivatives

O C

O C OH

Arachidonic acid (AA) C20:4n–6

OH

OH Eicosapentanoic acid (EPA) C20:5n–3

O C OH

Docosahexanoic acid (DHA) C22:6n–3

Fig. 2.1 Classification and structure of physiologic important long-chain polyunsaturated fatty acids (LC-PUFAs).

competition between substrates for these enzymes (Burdge and Calder, 2005; Innis, 2005). Although n-3 FAs have the greatest affinity for the corresponding enzyme systems, the synthesis of EPA and DHA from ALA is extremely slow and low yielding (Salem et al., 1986; Pawlosky et al., 2001). Beside the amount of precursor FAs available in the diet, the conversion process is dependent on genetics and gender. Several studies identified single nucleotide polymorphisms (SNPs) in the FADS1 and FADS2 (Fatty Acid Desaturase 1 and 2) gene clusters (Brookes et al., 2006; Schaeffer et al., 2006; Koletzko et al., 2008a), which code for the enzymes delta-5 desaturase and delta-6 desaturase that play a major role in the conversion of LA and ALA into the long-chain derivatives. Likewise, in vivo metabolism studies have shown that the conversion of ALA into EPA and DHA is much more efficient in young women than in young men (Burdge and Wootton, 2002; Burdge et al., 2002), which might explain the higher prevalence of specific neuropsychiatric disorders such as attention deficit hyperactivity disorder (ADHD) and autism among boys as opposed to girls. Increased oxidative stress and lipid peroxidation, caused by an overproduction of free radicals, may likewise influence LC-PUFA levels of the body by increasing the cleavage of LC-PUFAs from phospholipids in the cell membrane (Ross, 2000; Ross et al., 2003). Enhanced oxidative stress and low LC-PUFA levels have been observed in people with neurodevelopmental disorders such as schizophrenia (Yao et al., 1998; Mahadik and Mukher-

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jee, 1996). It has been suggested that an increase in free radical activity in people with schizophrenia may be a consequence of increased catecholamine turnover (Cadet and Lhor, 1987) and would require an increased intake of antioxidants (Ross, 2000). Many physiological functions of LC-PUFAs are based on similar mechanisms. The influence of LC-PUFAs on the maintenance and function of cells is due to their involvement in numerous processes, ranging from gene transcription regulation to effects on cellular signal processes. While some of these influences have long been known, others have recently become evident.

2.3 Placental transfer of PUFA and fetal lipid transport It is assumed that both preterm and term infants are capable of converting ALA to DHA and LA to AA, since the necessary enzymes are present in the fetal liver early in gestation (Demmelmair et al., 1995; Carnielli et al., 1996; Salem et al., 1996; Sauerwald et al., 1997). However, this capacity appears to be low before birth (Uauy et al., 2000). Studies showed that infants fed with cow-milk-based formula containing neither AA nor DHA but their precursors LA and ALA had lower levels of AA and DHA in plasma and red blood cell (RBC) membranes, as well as lower DHA levels in the cerebral cortex compared to infants receiving human milk (Makrides et al., 1994; Farquharson et al., 1995). These results suggest that LC-PUFA synthesis from the precursors LA and ALA may be inadequate to meet infants’ needs during the first month of life. Experimental studies revealed that preformed DHA provided in the maternal diet leads to much higher DHA accretion rates in developing the fetal brain and other organs than its precursor ALA (Arbuckle and Innis, 1993; Greiner et al., 1997; Su et al., 1999; 2001; Innis and de La Presa Owens, 2001). Therefore, the fetus needs to receive sufficient amounts of preformed AA and DHA by placental transfer to ensure the LC-PUFA accretion rates in membrane rich tissues (Larqué et al., 2002; Krauss-Etschmann et al., 2007). The exact molecular mechanisms of placental LC-PUFA uptake and transport are not completely understood; however, the multistep process is considered to be mediated by specific FA binding and transfer proteins (Dutta-Roy, 2000). These proteins favour n-6 and n-3 FAs over other FAs, as well as AA and DHA over LA or ALA, respectively (Campbell et al., 1996, 1998a, b; Dutta-Roy, 2000). Furthermore, it has been clearly demonstrated that DHA is preferably transferred across the placenta, supporting the physiological importance of DHA. This active maternal–fetal placental DHA transfer is mediated by specific FA transfer and membrane binding proteins (Larqué et al., 2006; Koletzko et al., 2007). The placenta is therefore of critical importance for the selective transport of DHA from the maternal diet and body stores to the fetus (Hanebutt et al., 2008).

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Several studies have shown that the levels of LC-PUFAs available for transfer to the fetus can be influenced by maternal dietary LC-PUFA intake (Dutta-Roy, 2000; Haggarty, 2002; Agostoni et al., 2005; Krauss-Etschmann et al., 2007). Controlled interventional trials showed that DHA supplementation in relatively high doses (>1 g/d) resulted in significant increasing infantile DHA levels in several studies, in contrast to high ALA doses (>10 g/d) or low DHA doses (200 mg/d) (Decsi and Koletzko, 2005). Likewise, the placenta actively modulates the FA supply for its own metabolism and also for the fetus. The relevant enzymes for the conversion of LA to AA or ALA to EPA have been identified (Shand and Noble, 1981; Cho et al., 1999), enabling the placenta to influence the AA and EPA contents in the fetal circulation (Innis, 2005).

2.4

PUFA levels in human milk

Human milk contains LA, ALA, DHA, AA and other LC-PUFAs for provision to breastfed infants. Worldwide observations have demonstrated that the AA level is relatively stable while the DHA level is more variable (Agostoni et al., 1998, 2003; Marangoni et al., 2002; Smit et al., 2002; Yuhas et al., 2006, Brenna et al., 2007). The mean population levels of AA in human milk range from 0.35 to 0.7 weight % (wt%) of total FAs (Marangoni et al., 2002; Smit et al., 2002; Yuhas et al., 2006; Brenna et al., 2007), whereas means of DHA range from 0.17 to 1.0 wt% of total FAs (Yuhas et al., 2006; Brenna et al., 2007). This variation clearly suggests a dependence of the DHA levels in milk on maternal diet and lifestyle, primarily on differences in fish intake. Indeed, women from coastal populations with high marine food consumption exhibited the highest DHA levels (Brenna et al., 2007). Another observational study on a multinational basis indicated the highest DHA levels in the breast milk of Japanese women, with traditionally high seafood consumption (Hibbeln, 2002). Interventional studies demonstrated that supplementation of lactating women with preformed DHA or AA was the only effective way to raise blood or breast milk DHA or AA levels in contrast of supplementing their precursors ALA or LA (Chirouze et al., 1994; Jensen et al., 1996; Fidler et al., 2000; Makrides et al., 2000b; Jensen et al., 2005; Brenna et al., 2009). The relationship between maternal DHA consumption and DHA levels in human milk was reported to be dose-dependent (Gibson et al., 1997).

2.5 Significance of PUFAs in the development and function of brain and retina LC-PUFAs are the predominant PUFAs in mammalian brains and neuronal tissues (Wijendran et al., 2002), where they play a central role in maintaining normal physiological functions. Furthermore, DHA is a major

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structural component of the membrane-based phosphoglycerides in the photoreceptors of the retina and consequently involved in the development of sight. Accordingly, sufficient amounts of n-3 LC-PUFAs such as EPA and DHA, as well n-6 LC-PUFAs such as AA and dihomo-gamma-linolenic acid (DGLA, C20:3n-6), are essential during the embryonal stage and early phase following birth (Wainwright, 2002). It is important to point out that not only absolute, but also relative, dietary FA content is important to developmental status (Wainwright, 2002). A lack of n-3 LC-PUFAs, or an imbalance between n-3 and n-6 LC-PUFAs, is associated with a number of behavioural abnormalities, as well as neurological and psychiatric disorders in both children and adults (Schuchardt et al., 2010).

2.5.1 Accretion of LC-PUFAs in the developing human brain The major proportion of mammalian brain tissue is composed of lipids which comprise different saturated, monounsaturated, and polyunsaturated FAs. Lipids comprise 50–60 wt% of the dry weight of an adult brain and about 35 % of these lipids are present in the form of LC-PUFAs (Wainwright, 2002). The principal n-6 LC-PUFA found in brain is AA, with DHA is the major n-3 LC-PUFA, comprising 10–20 wt% of total FA composition, with the ALA, EPA, and docosapentaenoic acid (DPA1, 22:5n-3) comprising less than 1 wt% of total brain FAs. The highest accumulation of LC-PUFAs in the brain occurs during the phase of rapid brain growth in the last trimester of gestation and the first two years after birth. During that time, the fetus is most dependent on an adequate supply of LC-PUFAs, in particular DHA and AA, for the development of optimal cognitive and visual development (Clandinin et al., 1980; Martinez, 1992). DHA in particular is indispensable for the brain and retina due to its central structural role in synapses and photoreceptors (Salem et al., 1999; Brenna, 2002; Stillwell and Wassall, 2003; Burdge and Calder, 2005; Innis, 2005; Sinn and Bryan, 2007). Deficits in perinatal brain DHA accrual have serious consequences on brain maturation and function. Studies with rhesus monkeys demonstrate that DHA deficiency during gestation and postnatal development caused considerably reduced DHA levels in the retina and cerebral cortex compared to control animals, which was accompanied by psychomotor and cognitive deficits as well as impaired visual function (e.g., visual acuity) (Neuringer et al., 1984, 1986). Within brain tissues, DHA preferentially accumulates in astrocytes, synaptosomes, myelin, growth cones, microsomal and mitochondrial membranes (Bourre et al., 1992; Yeh et al., 1993; Grandgirard et al., 1994; Jones et al., 1997; Suzuki et al., 1997). The majority of DHA accumulation in human brain tissue occurs during 1 DPA isomers exists in the n-3 configuration (DPA 22:5n-3) but also in the n-6 configuration (DPA 22:5n-6).

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the last trimester of normal gestation with an accumulation rate of app. 14.5 mg per week (Clandinin et al., 1980; Martinez, 1992). About 9 % of all cortical FAs are represented by DHA in term birth infants (Carver et al., 2001). DHA continues to accumulate throughout postnatal brain maturation and comprises about 15 wt% of total cortical FA composition at the age of 20 (Carver et al., 2001). The accumulation of other n-3 LC-PUFAs in the growing brain and eye is negligible (Martinez, 1992). However, the accretion of AA into the brain tissue during pre- and postnatal development is also considerable. The accretion of LC-PUFAs into fetal brain and other tissues of the central nervous system (CNS) depends on maternal intake and adequate placental transport. Dietary preformed DHA and AA are more effective for the accumulation of brain DHA and AA compared to their dietary FA precursors ALA and LA. The DHA content in fetal and infant brains in particular is relatively more affected by the diet than AA content, which is a sign that the endogenous metabolic regulation of cerebral AA contents is more effective (Makrides et al., 1994). Experimental studies with rats showed that the incorporation of DHA in the neuronal tissue membrane increases with its supply (Chalon et al., 1998).

2.5.2 Effect of LC-PUFAs on neuronal mechanisms The effects of LC-PUFA within the nervous system are mediated through various processes, which predominantly emerge through the effects of LCPUFAs on biophysical properties of neuronal membranes (Fig. 2.2). Thereby LC-PUFAs influence, for example, neurotransmitter contents, corresponding electrophysiological correlates as well as gene expression of the developing retina and brain. Neuronal membrane biophysical properties The LC-PUFAs AA and DHA are integral components of neuronal membrane phospholipids, especially phosphatidylethanolamine, where they modulate the properties of the lipid phase, which has an impact on structure, fluidity and function of brain membranes (Larqué et al., 2002). DHA plays a significant role in maintaining optimal membrane integrity and fluidity, which is necessary for signal processes within the cell (Stubbs and Smith, 1984; Kamada et al., 1986; Holte et al., 1996; Mitchell and Litman, 1998; Yehuda et al., 1999). The double phospholipid membrane forms the matrix in which membrane proteins, receptors and ion channels are embedded and bound to membrane-associated proteins such as those of the second messenger system. An altered fluidity of the neuronal membrane phospholipids affects the tertiary and quaternary structure of the membrane-bound receptors, which, in turn, has an effect on their function and activity (Yehuda et al., 1999). Hence, AA and DHA can influence a variety of membrane functions, including effects on ion channels and transport, endo- and exocytosis and the

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Components of neuronal membranes Increased neurite outgrowth e.g. dendritic arborization and synaptic formation

e.g. effects on membrane fluidity, regulation of ion channels, modulation of end-and exocytosis DHA

AA

Neurotransmitter systems in particular dopaminergic and serotonergic neurotransmission

DHA

Retina photoreceptors DHA

Precursors of eicosanoids EPA

AA

EICOSANOIDS Prostaglandins, Thromboxans, Leukotriens Hormonell and immunological activities

Antiinflammatory effects EPA

Gene expression LC-PUFA

reduced neuroinflammation

Fig. 2.2 Major effects of long-chain polyunsaturated fatty acids (LC-PUFAs) in brain.

activities of membrane-bound proteins. Likewise, LC-PUFAs – especially AA, EPA and DHA – have an important role in protecting neuronal cells from the toxic actions of tumor necrosis factor-α (Das, 2003). Neurotransmitter synthesis and release and receptor binding Neurotransmission depends on membrane receptors, which in turn interact with G protein and other second-messenger systems. Alterations in membrane phospholipid–FA composition may also affect the nature of these interactions. Consequently, AA and DHA are able to influence cellular signal processes and transmissions, for example by changing the binding or release of neurotransmitters (Yehuda et al., 1999; Chalon et al., 2001; Lee, 2001; Alessandri et al., 2004). Consequently, optimal physiological membrane function – being a precondition for corresponding intercellular communication – is dependent on optimal ratio of n-6 and n-3 LC-PUFAs. From animal experiments there is evidence of an association between dietary LC-PUFA content and changes in specific neurotransmitter systems in the brain. Studies with rats demonstrated that chronic n-3 FA deficiency results in abnormalities in dopaminergic and serotonergic neurotransmission systems, which are closely involved in the modulation of attention, motivation and emotion (Delion et al., 1994; 1996; Chalon et al., 1998; Ahmad

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et al., 2008). n-3 FA deficient rats showed a reduced dopamine receptor binding activity and an increased serotonin receptor density in the frontal cortex. The exact mechanisms enlightening these interactions are not fully understood. However, these studies suggest that a higher proportion of n-3 FAs has a distinct impact on the physical properties of the neuronal cell membranes, which in turn influences the proteins (receptors, transporters) enclosed in the membrane (Chalon et al., 2001; Chalon, 2006). Visual acuity maturation The visual system comprises a complex signalling system involving retina, thalamus and primary visual cortex. DHA is a major structural component of the membrane-based phosphoglycerides in photoreceptors of the retina. Compared to other cells of the body, retinal photoreceptors have the highest DHA content. In retina lipids, DHA comprises about 50 % of total FAs of rod and cone outer segments (Stillwell and Wassall, 2003). The photochemical activity of the rod visual pigment rhodopsin requires a quick and reversible change of its conformation and therefore a high flexibility of the surrounding membrane which is maintained by DHA (Neuringer et al., 1988). Experiments in artificial membranes have shown that a high DHA content is important for a maximal photochemical activity of rhodopsin. DHA-rich phospholipids are required to ensure the activation of rhodopsin by light, which displays the initial reaction in the cascade of biochemical events resulting in a neural signal (Weidmann et al., 1988). Animal studies demonstrated that an ALA-deficient diet results in a 25 % reduction of the DHA content in retinal tissue in the offspring of rhesus monkeys (Neuringer et al., 1986). As a consequence, deficient animals also had lower visual acuity scores and a prolonged recovery time of darkadapted electroretinograms after a saturating flash. More specifically, experiments with isolated retinal rod outer segment membranes from rats demonstrated an association between DHA deficiency and an impaired G protein-coupled receptor signal transduction activity (Nui et al. 2004). Hence, an adequate supply with n-3 FA – in particular with DHA – is crucial for the development and maintenance of the normal visual process (Neuringer et al., 1994; Uauy et al., 2001). A lack of n-3 FAs is associated with disturbances in visual function of newborn infants (Neuringer et al., 1986). Gene expression Another mechanism by which LC-PUFAs – especially EPA and DHA – mediate their function in the nervous system is their ability to regulate gene expression (Berger et al., 2002, 2004; Kitajka et al., 2002, 2004; BarcelóCoblijn et al., 2003a, b; Salvati et al., 2008), which takes place primarily during adipocyte differentiation and the development of the retinal and nervous system. Genes in rat brains that were found to be regulated by n-3 FAs were involved in the control of energy and lipid metabolism, respiration (Barceló-Coblijn et al., 2003a), as well as synaptic plasticity, cytoscele-

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ton and membrane association, signal transduction, ion channel formation and regulatory proteins (Kitajka et al., 2002). These gene-regulating effects appear to be mainly independent of n-3 FAs effects on membrane composition (Kitajka et al., 2004). The regulation of gene expression by LC-PUFA occurs at the transcriptional level and is mediated by nuclear transcription factors activated by FAs. It is suggested that the influence of n-3 FAs on gene expression profiles may contribute to the observed beneficial impact of this family of LC-PUFAs on cognitive functions together with their influence on membrane architecture and its functional implications. LC-PUFAs are a prime example for the close interaction between nutrients and genetic factors. LC-PUFAs as precursors of eicosanoids Another significant pathway by which LC-PUFAs can influence neuronal function is their nutritionally relevant role as a source for eicosanoids; oxidation products derived from 20-carbon PUFAs (Greek: ‘Eicos’ = 20). AA and EPA serve as precursors for eicosanoids, which play important roles in cell division, signal transduction and many other physiologic processes relevant for the development and function of the brain. In extremely low concentrations, eicosanoids act as signalling molecules and local mediators. As a result of their hormone-like action, eicosanoids have an effect on numerous metabolic processes. When metabolized, n-3 and n-6 FAs compete for the same enzyme systems and are able to reciprocally displace each other (Ströhle et al., 2002). Depending on the precursor substance, different series of eicosanoids (prostaglandins, leukotriens and thromboxanes) are formed, all of which vary greatly with respect to their range of action. In general, eicosanoids formed from n-3 FAs (Series 3 and 5) are attributed with more favourable effects (e.g., anti-inflammatory) than those formed from n-6 FAs (Series 2 and 4). The formation of mediators depends on the content of respective precursors supplied in the diet. Based on this precursor function, LC-PUFAs can modulate the eicosanoid profile and thus regulate intracellular signalling cascades, which results in alterations in metabolism, growth and cell differentiation (Ströhle et al., 2002).

2.6 Significance of an adequate LC-PUFA supply for neonates and infants on cognitive and visual outcomes Due to their manifold functions, an adequate supply of LC-PUFAs is crucial for an optimal development and maintenance of cognitive and visual functions. Hence, the maternal organism ensures a sufficient provision of LC-PUFAs to the fetus. Since the necessity of an adequate supply with LC-PUFAs persists after birth, human breast milk contains corresponding portions of AA and DHA. In contrast, natural cow milk, which is

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historically the basis for infant formula, contains only small amounts of AA and the precursor FAs ALA and LA. Since the relevance of LC-PUFAs – especially of DHA – for an optimal development of the neonate became evident, several manufacturers of infant formulas began to add LC-PUFA – especially DHA and AA – to their products and claimed a resulting benefit for the development of preterm and term infants. Numerous observational trials and randomized, controlled interventional trials (RCTs) investigated the connection between cognitive and visual development of infants and the supply with certain LC-PUFAs. The results of relevant RCTs published prior to January 2010 are critically reviewed and summarized in Section 2.6.2. Medical and health databases were searched for RCTs written in English, investigating the effect of LC-PUFA supplementation on visual and cognitive development of infants, whereas supplementation occurred in different developmental stages of the fetus or infant: • prenatal phase: maternal LC-PUFA-supplementation and transfer via placenta (summarized in Table 2.1); • neonate/infant phase: LC-PUFA-supplementation of infant via formula or follow-on formula (summarized in Tables 2.2 and 2.3); • neonate/infant phase: maternal LC-PUFA-supplementation and transfer via breast milk (summarized in Tables 2.2 and 2.3). The effects of LC-PUFA supply in both observational and interventional trials were determined by using different cognitive and visual outcome measures.

2.6.1 Cognitive outcomes measures The cognitive and mental outcomes were assessed by using different neurodevelopmental scales, dependent on infants’ or toddlers’ ages. In several studies the Bayley Scales of Infant Development, 2nd edition (BSID-II), was used to assess mental (Mental Development Index, MDI) and psychomotor (Psychomotor Developmental Index, PDI) development. The sub-scales of MDI assess discrimination, memory, language, problem solving, classification and social skills, while the PDI assesses control of gross and fine muscle groups, including walking, running, jumping, comprehension, use of writing implements and imitation of hand movements. The Griffiths Mental Development Scales (GMDS), for example, used for assessing children aged 21/2 years, comprise six sub-scales of development (locomotor, personal, social, speech and hearing, eye and hand coordination, performance and practical reasoning). The Knobloch, Passamanick and Sherrard’s Developmental Screening Inventory (KPS–DSI) comprises five sub-scales (adaptive, gross motor, fine motor, language and personal– social). Cognitive development was also evaluated with the Ages and Stages Questionnaire (ASQ), a parent-administered standardized questionnaire,

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–

–

–

4.7

n3-groupa

n3-groupd

n3-groupa

b

Dunstan et al., 2008

Judge et al., 2007a

Helland et al., 2008

n6-group

1.8 –

– 2.25

n3-groupa n6-groupc

Tofail et al., 2006

–

0.8

–

1.1

0.8 –

n3-groupa – n6-groupb 4.7

–

1.2

0.2

2.2

1.2 –

1.2 –

1.2 –

EPA DHA

Helland et al., 2003

LA

0.8 –

Diet group

Cognitive outcomes n3-groupa Helland – et al., 2001 n6-groupb 4.7

Reference

Daily maternal LC-PUFA dosis (g/d) End-point

Method

14 (n3-group) 15 (C-group)

33 (n3-group) 39 (C-group)

125 (n3-group) 124 (n6-group)

Mental & psychomotor development Mental development Verbal intelligence Cognitive development Recognition memory, visual attention Mental development

4y

6, 9 mo

Infant age of testing

7y

9 mo

FT

K-ABC

9 mo

2.5 y

PPVT IPT

2.5 y

GMDS

BSID-II MDI 10 mo & PDI

144 (n3-group)e Recognition FT memory, 118 (n6-group)e visual attention 48 (n3-group) Mental K-ABC 36 (n6-group) development

Average no./group

gw18 until 82 (n3-group) 3 mo after 61 (n6-group) delivery

gw24 until delivery

gw20 until delivery

gw17–19 until 3 mo after delivery gw18 until 3 mo after delivery gw25 until delivery

Intervention time

n3 = n6

n3 = C

n3 > C

n3 = C

n3 > Cf

n3 = n6

n3 > n6

n3 = n6

Results

Table 2.1 Randomized controlled trials on the effect of maternal LC-PUFA supplementation during pregnancy on cognitive and visual functions of infants’

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Diet group

Continued

–

–

0.15

–

–

–

0.5

0.2

0.2

0.2

EPA DHA

–

–

LA

Daily maternal LC-PUFA dosis (g/d)

gw24 until delivery gw22 until delivery

gw15 until delivery

gw15 until delivery

Intervention time

n3 = C

Visual acuity

VEP

ACP

Mental BSID-II MDI 6 mo development

n3 = C

n3 = C

Results

n3 > C n3 = C n3 = C

Near birth, 12.5, 16.5 mo Near birth

Infant age of testing

4 mo 6 mo 2 mo

Visual acuity

16 (n3-group)e 14 (C-group)e 69 (n3-group) 72 (C-group)

transient VEP

Method

Retinal ERG development

Visual acuity

End-point

30 (n3-group) 26 (C-group)

28 (n3-group)e 27 (C-group)e

Average no./group

a Fish oil; b Corn oil; c Soy oil; d Functional food; e No. of infants per group (n) that completed first test point; f Trend, statistically not significant except for eye and hand coordination. Abbreviations: y – year; mo – month; gw – gestational week. Abbreviations diet groups: n3-group – mother/infant pairs from omega-3 FA-supplemented mothers; n6-group – mother/infant pairs from omega-6 FAsupplemented mothers; C-group – control group, mother/infant pairs from unsupplemented mothers. Abbreviations test methods: ACP – Acuity card procedure; BSID-II – Bayley Scales of Infant Development II (MDI – Mental Development Index, PDI – Psychomotor Developmental Index); ERG – Electroretinogram; FT – Fangan Test for infants’ intelligence; GMDS – Griffiths Mental Development Scales; IPT – Infant Planning Test; K-ABC – Kaufman Assessment Battery for Children; PPVT – Peabody Picture Vocabulary Test; VEP – Visual Evoked Potentials.

Malcolm n3-groupa et al., 2003b n3-groupd Judge et al., 2007b Kraussn3-groupb Etschmann et al., 2007

Visual outcomes Malcolm n3-groupa et al., 2003a

Reference

Table 2.1

© Woodhead Publishing Limited, 2011

DHA1group DHA2group CF-group BM-groupa

LF-group CF-group BM-groupa

Clandinin et al., 2005

Henriksen et al., 2008

0.64 0.64 n.d. –

6.7 – 0.5

–

18.8 27.1 12.9

19.4 19.4 19.5

–

0.04 n.d. –

12.3 11.5

LF-group CF-group BM-groupa

0.6 0.7

12.0 10.6

LF-group CF-group

–

18.7 19.1

DHAgroup CF-group

Fewtrell et al., 2004

Werkman and Carlson, 1996 Fewtrell et al., 2002

– –

Supplemented preterm infants Carlson and DHA21.2 Werkman, group 21.2 1996 CF-group

2.3 3.4 1.2

2.4 2.4 2.4 –

0.9 trace –

0.31 n.d.

3.1 3.0

2.4 2.4

ALA

n6 LC-PUFAs

AA

Diet group

– – 0.2

n.d. 0.1 n.d. –

0.1 n.d. –

0.04 n.d.

0.3 n.d.

0.06 n.d.

EPA

6.9 – 0.7

0.32 0.32 n.d. –

0.5 n.d. –

0.17 n.d.

0.2 n.d.

0.2 n.d.

DHA

n3 LC-PUFAs

FA composition of the study formulas and human breast milk (FA%) enriched FAs in bold

Near birth until ~9 wk

Near birth until 12 mo after term

Near birth until 9 mo

Near birth until 1 mo

Near birth until 9 mo

Near birth until 2 mo

Start and duration of intervention

Preterm

Preterm

Preterm

Preterm

Preterm

Preterm

Gestational age

DHA1group DHA2group 62 CF-group 76 BM-group 50 LF-group 55 CF-group

65

52

62 LF-group 55 CF-group

78 LF-groupb 80 CF-groupb

33 LF-group 34 CF-group

12 DHAgroupb 15 CF-groupb

Average no./group

Cognitive development

Recognition memory, visual attention Recognition memory, Visual attention Mental development Psychomotor development Cognitive development Mental development Psychomotor development Mental development Psychomotor development

End point

ASQ ERP

BSID-II MDI BSID-II PDI BSID-II MDI BSID-II PDI

BSID-II MDI BSID-II PDI KPS–DSI

FT

FT

Method

6 mo after birth 6 mo after birth

1.5 y after birth 1.5 y after birth 18 mo after term 18 mo after term

9, 18 mo corrected age

6.5, 9, 12 mo

12 mo

Infant age of testing

LF > CF LF > CF

DHA1/ DHA2 > CF DHA1/ DHA2 > CF

LF > CF LF > CF

LF = CF LF = CF LF = CF

DHA > CF

DHA > CF

Results

Randomized controlled trials on cognitive functions of preterm and term infants’ in relation to LC-PUFA supply in early nutrition

LA

Reference

Table 2.2

© Woodhead Publishing Limited, 2011

0.44 n.d.

term infants LF-group 10.8 CF-group 11.1

LF-group CF-group

Supplemented Agostoni et al., 1995 Agostoni et al., 1997

Willatts et al., 1998a Willatts et al., 1998b Lucas et al., 1999

0.44 n.d.

DHA1group DHA2group

Smithers et al., 2010

0.30 n.d.

11.5–12.8 11–4

15.9 12.4

LF-group CF-group

LF-group CF-group

1.4 1.1

0.6–0.65 0.7

0.6–0.65 0.7

0.73 0.70

0.73 0.70

– –

– –

ALA

0.01 n.d.

– –

– –

0.05 n.d.

0.05 n.d.

– –

– –

EPA

Near birth until 4 mo Near birth until 4 mo

Near birth until term corrected age

Near birth until term corrected age

Start and duration of intervention

Near birth until 12 mo 0.15–0.25 Near birth – until 4 mo 0.32 Near birth n.d. until 6 mo

0.15–0.25 –

0.30 n.d.

0.30 n.d.

1.0 0.35

1.0 0.35

DHA

n3 LC-PUFAs

FA composition of the study formulas and

0.3–0.4 <1.1

11.5–12.8 11–4

0.3–0.4 <1.1

0.6 0.6

0.6 0.6

AA

LF-group CF-group

10.8 11.1

– –

– –

DHA1group DHA2group

Makrides et al., 2009

LA

n6 LC-PUFAs

Diet group

Reference

FA composition of the study formulas and human breast milk (FA%) enriched FAs in bold

Continued

Table 2.2

Term

Term

Term

Term

Term

Preterm

Preterm

Gestational age

154 LF-group 155 CF-group 138 BM-group

20 LF-group 20 CF-group

27 LF-groupb 29 CF-groupb 30 BM-groupb 26 LF-groupb 30 CF-groupb 25 BMgroupb 21 LF-group 23 CF-group

298 DHA1group 316 DHA2group 298 DHA1group 316 DHA2group

Average no./group

Mental development Psychomotor development Cognitive development

Cognitive behaviour

BSID-II MDI BSID-II PDI KPS-DSI

MEPS

MEPS

BLPD

Psychomotor development Cognitive behaviour

BLPD

MCDI SDQ STSC

BSID-II MDI

Method

Psychomotor development

Mental and linguistic development

Mental development

End point

18 mo 18 mo 9 mo

9 mon

10 mo

2y

4 mo

26 mo corrected age 3 to 5 y corrected age

18 mo corrected age

Infant age of testing

BM/LF = CF BM/LF = CF BM/LF = CF

LF > CF

LF > CF

BM/LF = CF

BM/LF > CF

DHA1 = DHA2 (boys) DHA1 > DHA2 (girls) DHA1 = DHA2 DHA1 = DHA2 DHA1 = DHA2

Results

© Woodhead Publishing Limited, 2011

0.72 0.02 n.d. 0.56

14.9 15.1 14.6 12.7

Birch et al., 2007

LF-group DHAgroup CF-group BM-groupa

Bouwstra et al., 2005

0.39 – 0.34

0.39 – 0.34

LF-group DHAgroup CF-group

Auestad et al., 2003

11.0 11.56 13.6

11.0 11.56 13.6

LF-group CF-group BM-groupa

Bouwstra et al., 2003

0.34 n.d. n.d. 0.39

16.6 16.8 16.8 13.4

LF-group CF-group BM-groupa

LF-group DHAgroup CF-group BM-groupa

Makrides et al., 2000a

0.72 – –

~15.0 ~15.0 ~15.0

AA

0.43 – –

LF-group DHAgroup CF-group

Birch et al., 2000

LA

1.53 1.54 1.49 0.8

1.30 1.27 1.11

1.9 1.9 2.2

1.30 1.27 1.11

1.0 1.2 1.5 0.95

~1.5 ~1.5 ~1.5

ALA

n6 LC-PUFAs

21.7 20.7 21.9

Diet group

Reference

n.d. n.d. n.d. 0.1

0.06 – 0.06

– – –

0.06 – 0.06

n.d. 0.1 n.d. 0.09

– – –

EPA

0.35 0.36 n.d. 0.29

0.19

–

0.23

–

0.12 0.23

0.19

–

0.23

0.34 0.35 n.d. 0.2

–

0.36 0.35

DHA

n3 LC-PUFAs

human breast milk (FA%) enriched FAs in bold

Near birth until 4 mo

Near birth until 2 mo

Near birth until 12 mo

Near birth until 2 mo

Near birth until 12 mo

Near birth until 4 mo

Start and duration of intervention

Term

Term

Term

Term

Term

Term

Gestational age

17 LF-group 16 DHAgroup 19 CF-group 32 BM-group

135 LF-group 154 CF-group 149 BMgroup

Neurological examination Mental development Psychomotor development IQ tests (performance, verbal)

IQ test Receptive vocabulary Expressive vocabulary

Quality of general movements

Mental development Psychomotor development

21 LF-groupb 23 DHAgroupb 21 CF-groupb 22 BM-groupb

119 LF-group 131 CF-group 147 BMgroup 65 DHAgroup 66 LF-group 65 CF-group

Mental development Psychomotor development

End point

19 LF-group 17 DHAgroup 20 CF-group

Average no./group

WPPSI-R

HA BSID-II MDI BSID-II PDI

SB IQ PPVT-R MLU

n.s.

BSID-II MDI BSID-II PDI

BSID-II MDI BSID-II PDI

Method

4y

1.5 y 1.5 y 1.5 y

3.25 y 3.25 y 3.25 y

3 mo

1, 2 y 1, 2 y

1.5 y 1.5 y

Infant age of testing

LF = DHA = CF LF = DHA = CF LF = DHA = CF LF = CF = BM LF = CF = BM LF = CF = BM LF = DHA = BM > CF

LF/ DHA > CF LF = DHA = CF BM = LF = DHA = CF BM = LF = DHA = CF LF / BM > CF

Results

© Woodhead Publishing Limited, 2011

Diet group

Reference

LA

AA

msBM-gr. BM-gr.a

16.3 15.9

0.4 0.4

1.2 1.07

0.07 0.07

0.3 0.13 0.22

EPA

0.35 0.2

1.34 0.41 0.74

DHA

n3 LC-PUFAs

Near birth until 4 mo

Near birth until 4 mo

Start and duration of intervention

Term

Term

Gestational age

hfBMgroupb

mpBFgroupb

msBFgroupb

msBMgroupb 79 BM-groupb

81

42

38

48

Average no./group

Mental development Psychomotor development

Cognitive development Linguistic development

End point

BSID-II MDI BSID-II PDI

IPT CDI

Method

1, 2.5 y 1, 2.5 y

9 mo 1, 2 y

Infant age of testing

msBM = BM msBM > BM (2.5 y)

msBM = mpBM = BM msBM = mpBM = BM

Results

a Breast-fed infants’ served as gold standards; b No. of infants per group (n) that completed first test point. Abbreviations: y – year; mo – month; wk – week; d – day; n.s. – not specified, n.d. – not detected. Abbreviations diet groups: LF-group – formula-fed infants’ supplemented with LC-PUFAs; DHA-group – formula-fed infants supplemented with DHA; DHA1-group – DHA from algal oil; DHA2-group – DHA from fish oil; CF-group – unsupplemented control formula-fed infants; BM-group – breast milk-fed infants from unsupplemented mothers; msBM-group – breast milk-fed infants from LC-PUFAs supplemented mothers; mpBM-group – breast milk-fed infants from mothers receiving placebo; hfBM-group – breast milk-fed infants from mothers with habitual high fish intake. Abbreviations test methods: ASQ – Ages and Stages Questionnaire; BLPD – Bruneet-Lézine psychomotor development; BSID-II – Bayley Scales of Infant Development II (MDI – Mental Development Index, PDI – Psychomotor Developmental Index); CDI – Communicative Development Inventory; ERP – Event-Related Potentials; FT – Fangan Test for infants intelligence; HA – Hempel assessment; IPT – Infant Planning Test; KPS-DSI – Knobloch, Passamanick and Sherrard’s Developmental Screening Inventory; MCDI – McArthur Communicative Development Inventory; MEPS – Means-Ends Problem-solving Test; MLU – mean length of utterance; PPVT-R – Peabody Picture Vocabulary Test, revised; SB IQ – Stanford Binet IQ; SDQ – Strengths and Difficulties Questionnaire; STSC – Short Temperament Scale for Children; WPPSI-R – Wechsler Preschool and Primary Scale of Intelligence, revised.

Jensen et al., 2005

1.31 1.25 1.5

ALA

n6 LC-PUFAs

FA composition of the study formulas and human breast milk (FA%) enriched FAs in bold

Term infants of supplemented mothers Lauritzen msBM-gr. 11.26 0.51 et al., mpBM-gr. 11.09 0.48 2005 hfBM-gr. 10.67 0.5

Continued

Table 2.2

© Woodhead Publishing Limited, 2011

LF-group CF-group

21.2 21.2

– –

Supplemented term infants Carlson LF-group 21.8 et al., CF-group 21.9 1996b BM-group 15.8 Jørgensen LF-group 14.4 et al., BM-group 10.93 1996 Auestad LF-group 21.7 et al., DHA-group 20.7 1997 CF-group 21.9 BM-group 5.7–17.2

1.9 1.9 2.2 0.1–1.8

–

0.43 n.d. n.d 0.2–1.2

– – – –

0.6 trace 0.49

2.4 2.4

1.4 0.5 2.8 0.8

2.0 2.2 0.8 1.7 1.44

0.4

Preterm infants of supplemented mothers – 0.43 Smithers msBM– 0.45 et al., groupb mpBM– – 2008 groupc – – DHAgroupb CF-groupc

Carlson et al., 1996a

– – – –

Supplemented preterm infants Birch 18.1 LF1-group et al., 21.1 LF2-group 1992a, 20.3 LF3-group a b 12.7 BM-group

ALA

n6 LC-PUFAs

AA

Diet group

n.d. 0.07 n.d. 0–0.6

n.d. n.d. 0.1 trace 0.16

0.02 0.16 – –

0.06 n.d.

0.9 n.d. 0.1 0.5

EPA

0.12 0.23 n.d. 0.1–0.9

0.1 n.d. 0.1 n.d. 0.48

1.06 0.26 0.70 0.35

0.2 n.d.

DHA

n3 LC-PUFAs

FA composition of the study formulas and human breast milk (FA%) supplemented FAs in bold

Near birth until 4 mo

Near birth until 4 mo

Near birth until 2 mo

Near birth until reaching estimated due date

10 d after birth until 14 mo postconception Near birth until 2 mo

Start and duration of intervention

Term

Term

Term

Preterm

Preterm

Preterm

Gestational age

26 28 28 38

LF-group DHA-group CF-group BM-group

18 LF-group 20 CF-group 18 BM-group 16 LF-group 17 BM-group

54 msBM/ DHA-groupe 61 mpBM/ CF-groupe

26 LF-group 33 CF-group

81 all groupsd

Average no./ group

Visual acuity

Visual acuity

Visual acuity

Visual acuity

Visual acuity

Retinal development Visual acuity

End-point

Sweep VEP TAC

TAC

TAC

Sweep VEP

TAC

ERG Sweep VEP FPL

Method

2, 4, 6, 9, 12 mo 2, 4, 6, 9, 12 mo

2 mo 4, 6, 9, 12 mo 1, 2, 4 mo

2 mog 4 mog

2 mo 4, 6, 9, 12 mo

9, 14 mof 9, 14 mof 9, 14 mof

Infant age of testing

LF = DHA = CF = BM LF = DHA = CF = BM

BM > LF

LF > CF LF = CF

msBM (DHA) = mpBM (CF) msBM (DHA) > mpBM (CF)

LF3 > LF1/ LF2 LF1 = BM LF1 > LF2/ LF3 LF > CF LF = CF

Results

Randomized controlled trials on visual functions of term and preterm infants’ in relation to LC-PUFA supply in early nutrition

LA

Reference

Table 2.3

© Woodhead Publishing Limited, 2011

LF-group DHA-group CF-group BM-groupa

LF-group DHA-group CF-group

LF-group DHA-group CF-group BM-groupa LF4-group LF5-group BM-groupa LF-group CF-group

Birch et al., 1998

Hoffmann et al., 2000

Makrides et al., 2000a

Auestad et al., 2003

LF-group DHA-group CF-group

Diet group

Reference

Makrides et al., 2000b Birch et al., 2002

Continued

Table 2.3

1.9 1.9 2.2

1.0 1.2 1.5 0.95 1.7 3.3 0.92 1.53 1.49

1.53 1.54 1.49

1.53 1.54 1.49 0.8

ALA

– – –

n.d. 0.1 n.d. 0.09 – – 0.08 – –

n.d. n.d. n.d.

n.d. n.d. n.d. 0.1

EPA

0.12 0.23 –

0.34 0.35 n.d. 0.2 – – 0.18 0.36 –

0.36 0.35 n.d.

0.35 0.36 n.d. 0.29

DHA

n3 LC-PUFAs

FA composition of the study formulas and human breast milk (FA%) supplemented FAs in bold

0.43 – –

0.34 n.d. n.d. 0.39 – – 0.38 0.72 –

16.6 16.8 16.8 13.4 16.9 16.6 11.9 14.9 14.6

21.7 20.7 21.9

0.72 n.d. n.d.

0.72 0.02 n.d. 0.56

14.9 15.1 14.6 12.7

14.9 15.1 14.6

AA

LA

n6 LC-PUFAs

FA composition of the study formulas and human breast milk (FA%) supplemented FAs in bold

Near birth until 12 mo

Term

Near birth until 8.5 mo After weaning (6 wk) to 13 mo Term

Term

Term

Term

Term

Gestational age

Near birth until 12 mo

Near birth until 4.25 mo

Near birth until 4 mo

Start and duration of intervention

LF-group DHA-group CF-group BM-group

65 DHA-group 66 LF-group 65 CF-group

9 LF-group 7 DHA-group 8 CF-group 22 LF-group 21 DHA-group 20 CF-group 21 BM-group 24 LF-group 23 DHA-group 21 CF-group 46 BM-group 29 LF4-groupe 28 LF5-groupe 61 BM-group 32 LF-groupe 33 CF-groupe

27 26 26 29

Average no./ group

Sweep VEP IRDS

Visual acuity Stereo-acuity

BVMI TAC

Transient VEP

Visual acuity

Visual-motor function Visual acuity

Transient VEP

Sweep VEP

Visual acuity

Visual acuity

ERG

Sweep VEP FPL

Method

Retinal development

Visual acuity

End-point

1.5, 4.25, 6.5, 13 mo 1.5, 4.25, 6.5, 13 mo 3.25 y 3.25 y

4, 8.5 mo

4 mo 8.5 mo

4.25, 13 mo

1.5, 4.25, 6.5, 13 mo 1.5, 4.25, 6.5, 13 mo 1,5, 4.25 mo

Infant age of testing

LF = DHA = CF LF = DHA = CF

LF > CFi LF > CFj

BM = LF = DHA = CF BM > LF = DHA = CF LF4 = LF5 = BM

LF/DHA > CF (1.5 mo) BM/DHA > CF

LF/ DHA > CFh LF/ DHA > CFh

Results

© Woodhead Publishing Limited, 2011

LF-group CF-group

LF-group DHA-group CF-group BM-groupa DHA1group DHA2group DHA3group CF-group

Hoffman et al., 2003

Birch et al., 2007

11.26 11.09 10.67

0.51 0.48 0.5 0.3 0.13 0.22

0.07 0.07

n.d. n.d. n.d. 0.1 – – – –

– –

EPA

1.34 0.41 0.74

0.35 0.2

0.35 0.36 n.d. 0.29 0.32 0.64 0.96 –

0.36 –

DHA

n3 LC-PUFAs

After birth until 4 mo

After birth until 4 mo

Near birth until 12 mo

After weaning (4-6 mo) to 12 mo Near birth until 4 mo

Start and duration of intervention

Term

Term

Term

Term

Term

Gestational age

DHA2group

DHA1group

LF-group DHA-group CF-group BM-group

msBMgroupe 79 BM-groupe 55 msBMFgroupe 51 mpBMgroupe 51 hfBM-groupe

81

DHA3group 86 CF-group

88

85

17 16 19 32 84

31 LF-groupe 29 CF-groupe

Average no./ group

Sweep VEP TAC Sweep VEP

Visual acuity

Sweep VEP

ATS, EVA

Sweep VEP IRDS

Method

Visual acuity

Visual acuity

Visual acuity

Visual acuity Stereo-acuity

End-point

2, 4 mo

4, 8 mo 4, 8 mo

12 mo

4y

4, 6, 12 mo 4, 6, 9, 12 mo

Infant age of testing

msBM = mpBM = hfBM

msBM = BM

DHA1 = DHA2 = DHA > CF

BM > CF DHA > CF

LF > CF LF = CF

Results

a Breast-fed infants’ served as gold standards; b same group, weaned infants’ were fed with DHA-supplemented formula; c same group, weaned infants’ were fed with unsupplemented control formula; d participants per group not specified; e No. of infants per group (n) that completed first test point; f post-conception; g corrected age; h at 1.5, 4.25, and 13 mo of age; i at 4.25, 6.5, and 13 mo of age; j at 4.25 wk of age. Abbreviations: y – year; mo – month, wk – week; d – day; n.d. – not detected. Abbreviations diet groups: LF-group – formula-fed infants supplemented with LC-PUFAs; LF1-group – soy/fish oil; LF2-group – corn oil; LF3-group – soy oil; LF4-group – LA:ALA ratio of 10:1; LF5-group – LA:ALA ratio of 5:1; DHA-group – formula-fed infants supplemented with DHA; DHA1 – 0.32 % DHA of total FAs; DHA2 – 0.64 % DHA of total FAs; DHA3 – 0.96 % DHA of total FAs; CF-group – unsupplemented control formula-fed infants; BM-group – breast milk-fed infants from unsupplemented mothers; msBM-group – breast milk-fed infants from LC-PUFA-supplemented mothers; mpBM-group – breast milk-fed infants from mothers receiving placebo; hfBM-group – breast milk-fed infants from mothers with habitual high fish intake. Abbreviations test methods: ATS – Amblyopia Treatment Study protocol; BVMI – Beery Visual-Motor Index; ERG – Electroretinogram; EVA – Electronic Visual Acuity; FPL – Forced-choice Preferential Looking; IRDS – Infant Random Dot Stereocards; TAC – Teller acuity cards; VEP – Visual Evoked Potentials.

msBMgroup mpBMgroup hfBMgroup

1.31 1.25 1.5

1.53 1.54 1.49 0.8 1.61– 1.68 1.61– 1.68 1.61– 1.68 1.61– 1.68

Lauritzen et al., 2004

0.72 0.02 n.d. 0.56 0.64 0.64 0.64 –

14.9 15.1 14.6 12.7 16.9– 17.5 16.9– 17.5 16.9– 17.5 16.9– 17.5

1.53 1.49

ALA

1.2 1.07

0.72 –

AA

14.9 14.6

LA

n6 LC-PUFAs

Term infants of supplemented mothers 16.3 0.4 Jensen msBM15.9 0.4 et al., group 2005 BM-groupa

Birch et al., 2010

Diet group

Reference

52

Lifetime nutritional influences on behaviour and psychiatric illness

or standard IQ tests (Stanford Binet IQ, SB-IQ; Fangan Test for infants’ intelligence, FT; Wechsler Preschool and Primary Scale of Intelligence, WPPSI-R). In some other studies the Infant Planning Test (IPT) was used to test the problem solving ability of the infants. Infants’ linguistic development was assessed using the Communicative Development Inventory (CDI) forms for infants (8–16 months) and toddlers (16–30 months), or standard tests for receptive vocabulary (Peabody Picture Vocabulary Test, PPVT) or expressive vocabulary (Mean Length of Utterance, MLU).

2.6.2 Visual outcome measures To assess the infants’ visual development, two main aspects of the visual system are important: 1. The retinal development using electroretinography (ERG). ERG is a technique to measure the electrical responses of various light-sensitive cell types in the retina, including photoreceptors (rods and cones), inner retinal cells and ganglion cells. Clinically, the eye test is used to detect abnormal functions of the retina for the diagnosis of various retinal diseases. During the test, the eyes are exposed to standardized stimuli while an electrode, placed on the cornea at the front of the eye, measures the electrical responses of the retina cells at the back of the eye. 2. The visual processing at the level of the primary visual cortex. Visual evoked potential (VEP) is a very small electrical signal originated in the visual cortex in response to periodic visual stimulation. VEP tests measure an electrical potential, recorded from the nervous system using electroencephalography (EEG), caused by sensory stimulation of the visual field (occipital cortex). Commonly used visual stimuli are flashing lights, or checkerboards on a video screen that flicker between black on white to white on black. In case that repeated stimulation of the visual field causes no changes in EEG potentials, it is likely that the brain doesn’t receive any signals from the eyes. VEPs are useful in the investigation of basic functions of visual perception in subjects that cannot communicate, such as babies. Transient VEPs result from transient changes in brain activity after intermittent stimulation, while the sweep VEP procedure is used to measure grating visual acuity. The behavioural response can be measured with the forced-choice preferential-looking (FPL) method, which requires integrative cortical processing. The FPL method is well established to assess visual acuity and other visual detection performance in infants up to 6 months of age. For example the ‘acuity card’ techniques (acuity card procedure, ACP) and (Teller Acuity Cards, TAC) have been developed for a rapid assessment of visual acuity in infants. In this procedure, an adult observer shows the infant a series of cards that contain grating targets of various spatial frequencies and estimates acuity as the highest spatial frequency that the infant is judged to see.

© Woodhead Publishing Limited, 2011

Influence of LC-PUFAs on cognitive and visual development 2.6.3

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Results from observational studies

Maternal and infant PUFA status and cognitive development of infants Several observational studies demonstrated positive relationships between the LC-PUFA status – in particular DHA – of mothers and neonates at birth and the later cognitive and visual performance of infants and children, respectively (Cheruku et al., 2002; Ghys et al., 2002; Dijck-Brouwer et al., 2005; Bouwstra et al., 2006a, b). Cheruku et al. (2002) investigated the association of maternal LC-PUFAs concentrations and the CNS integrity in neonates, measured with sleep recordings. Sleeping and waking states of newborns provide a tool for assessing the functional integrity of the CNS from the time of birth. While the active sleep phase is accompanied by rapid eye movements (REM), thinking and most physiological activities slow down during quiet sleep. The authors found that infants from mothers with high DHA status (>3.0 wt% of total FAs) had a significantly lower ratio of active sleep to quiet sleep and less active sleep than did infants of mothers with low DHA status. In conclusion, these results suggest a greater CNS maturity of infants born to mothers with higher plasma phospholipid DHA. Likewise, Colombo et al. (2004) showed that infants from mothers with a high DHA status at birth had an accelerated decline in looking over the 1st year, and increases in examining during single-object exploration and less distractibility in the 2nd year. In these earlier ages, look-duration is negatively correlated to childhood cognitive and language outcomes. Therefore, shorter looking represents the more mature form of attention. Consequently, a better DHA status at birth appears to positively influence infants’ later performance on attentional variables from habituation measures. Dijck-Brouwer et al. (2005) demonstrated in 317 term infants associations between a low fetal LC-PUFA (LA, AA, ALA and DHA) status and the early postnatal neurological condition, summarized as a clinical classification and a ‘neurological optimality score’. Neurologically abnormal infants’ (n = 27) had lower DHA and EFA status in the umbilical artery blood detected immediately after birth. Likewise, birth weight (Richards et al., 2001; Seidman et al., 1992; Sorensen et al., 1997), breastfeeding (Anderson et al., 1999), maternal intelligence (IQ) (Whiteside-Mansell et al., 1996; Silva and Fergusson 1976; Bacharach and Baumeister 1998) and parental education (McCall and Carriger 1993) are associated with cognitive development. Therefore, potential confounders such as parents’ intelligence, socioeconomic status, health condition, maternal age, education, alcohol consumption and smoking habits during pregnancy, as well as infant’s condition immediately after birth or type and duration of postnatal feeding were collected and taken into account in the statistical analyses of the different studies. However, none of the discussed results changed after adjustment for potentially confounding factors. Bouwstra et al. (2006a) investigated the relationship between FA compositions of umbilical blood vessels at birth of healthy term infants and the

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quality of their general movements at 3 months to evaluate their neurologic condition. Infants with mildly abnormal general movements had a lower LC-PUFA status and a higher total n-9 FA and monounsaturated FA status compared with infants with normal general movements. The associations between FA compositions of the umbilical artery remained statistically significant when taking into account important confounders such as type of postnatal feeding, age at investigation and obstetric and social factors including smoking and maternal alcohol consumption during pregnancy. The neurologic condition of the same children was checked again at the age of 18 months (Bouwstra et al., 2006b). Study end-points were the Hempel neurologic examination and the BSID-II (PDI and MDI). The results showed that neonates with a relatively low DHA status and those with high trans-FA levels had a less favourable neurologic condition even at the age of 18 months. Other studies investigated associations between perinatal DHA and AA levels and cognitive development at 4 years of age (Ghys et al., 2002). The cognitive status of neonates was measured by the Dutch adaptation of the Kaufman Assessment Battery for Children (K-ABC). Beside plasma, DHA and AA levels were observed in RBC phospholipids, which is a useful marker for the LC-PUFA status. Postmortem examinations demonstrated significant associations between DHA levels in RBCs and brain DHA lipid levels in infants (Makrides et al., 1994). However, no significant associations were observed between the cognitive status and the AA or DHA levels. Likewise, Bakker et al. (2003) didn’t show significant associations with both DHA or AA levels in umbilical venous plasma phospholipids at birth and the cognitive performance (K-ABC) of 306 children at 7 years of age. Maternal PUFA intake during pregnancy and cognitive development of infants Observational studies have revealed an association between maternal dietary intake of fatty fish or oils providing n-3 LC-PUFAs during pregnancy and/or lactation and visual and cognitive development as well as other functional outcomes of the infants (Daniels et al., 2004; Oken et al., 2005; Hibbeln et al., 2007). The associations remained statistically significant after adjustment for diverse potential confounding variables such as maternal age, race/ethnicity, education, prenatal smoking, prenatal alcohol use, stressful life events at 18 weeks of gestation, marital status, had partner at time of birth, housing status, crowding, quality of the parent and home environment, infant sex, gestational age at birth, birth weight for gestational age, breastfeeding duration and age at cognitive testing. A prospective cohort study in the US investigated the associations of maternal fish intake during pregnancy with infants’ cognitive performance at 6 months of age among 135 mother–infant pairs (Oken et al., 2005). The study outcomes showed that higher maternal fish consumption in pregnancy was associated with better cognitive scores in infants at 6 months of age. These results were substantiated by the findings of cohort study in the

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UK (ALSPAC study collective), where the connection between the seafood consumption of 11 875 pregnant women and the neurodevelopmental outcomes of their children at the age of 6 months to 8 years was examined (Hibbeln et al., 2007). The study findings clearly demonstrated an association between infant’s/child’s cognitive development and high maternal seafood intake. Infants from mothers who consumed less than 340 g seafood per week during pregnancy had an increased risk for a low verbal intelligence quotient compared to children from mothers who consumed more than 340 g per week. The amount of 340 g fish per week equates to two portions, which conforms to intake recommendations for pregnant women from several expert societies and does not necessarily exceed the admissible intake levels for chemical contaminants such as metals and organic pollutants (Domingo et al., 2007). The authors concluded that low maternal seafood intake was also associated with an increased risk of sub-optimum outcomes for pro-social behaviour, fine motor, communication and social development scores. Similarly, a British study with 7421 mother–infant pairs reported higher developmental scores in children at 15 months of age from mothers who consumed more fish during pregnancy (Daniels et al., 2004).

2.6.4

Results from randomized controlled interventional trials

Prenatal LC-PUFA supplementation The effect of supplementing pregnant woman with LC-PUFAs – mainly LC n-3 PUFAs – on visual and cognitive functions of infants was investigated in several RCTs. Nearly all studies evaluated the effect of fish oil capsules with EPA and DHA vs placebo, while some studies further examined the effect of the n-6 precursor FA LA. In these studies, daily intakes of up to 1 g DHA or 2.7 g n-3 LC-PUFAs did not induce significant adverse effects in either mothers or infants. Cognitive development High doses of fish oil (4 g/d) in pregnant mothers from 20 weeks gestation until delivery resulted in markedly higher levels of n-3 LC-PUFAs EPA and DHA but considerably lower levels of n-6 FA AA in cord blood RBC membranes of neonates compared to control group (Dunstan et al., 2004, 2008). Similarly, fish oil supplementation of 311 pregnant women in a European randomized multicenter trial improves the fetal status of n-3 LCPUFAs (Krauss-Etschmann et al., 2007). Children who received EPA and DHA prenatally via fish oil tended to perform better in all sub-scales of cognitive development – although not significant in every case – and had higher scores for receptive language, average phrase length and vocabulary scores when assessed at an average age of 34 months (Dunstan et al., 2008). The eye and hand coordination scores correlated with the levels of n-3 LCPUFAs in cord blood RBC membranes and inversely correlated with the

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n-6 LC-PUFA AA (Dunstan et al., 2008). However, beneficial effects of maternal supplementation of n-3 LC-PUFAs regarding cognitive development of infants as compared with n-6 FAs could not be observed in all studies (Helland et al., 2001, 2008) or measured end-points (Judge et al., 2007a). Visual development Although the study of Malcolm et al. (2003a) failed to show significant differences in any of the VEP measures observed between the DHA supplementation and the control group, the results clearly showed an association between the DHA status of infants and early postnatal development of the pattern-reversal VEP, suggesting that the DHA status itself may influence maturation of the central visual pathways. Likewise, retinal development was measured by ERG in the same infant groups and did not differ significantly between infants in the two groups (Malcolm et al., 2003b). However, there was a correlation between infant DHA status and maturity of the retina at birth, regardless of maternal supplementation group. A measure of retinal sensitivity correlated significantly (P < 0.005) with DHA status in infant cord blood. These findings demonstrated an association between the DHA status of term infants and visual sensitivity, suggesting an essential role of DHA in the visual development process. The lack of significant differences between the DHA and control group was possibly accountable to the relatively low DHA dose. It is difficult to directly extrapolate the pregnancy dosage to supplementation of the infant. Judge et al. (2007b) demonstrated that term infants of mothers who consumed a DHA-functional food during pregnancy had higher visual acuity scores at 4 months of age compared to controls, indicating a better visual development. At 6 months there were no group differences measurable. The authors concluded that DHA supplementation during pregnancy plays a role in the maturation of the visual system. However, at present it is unclear whether LC-PUFAs supplementation of mothers during pregnancy provides long-term benefits for infants’ visual development. Infant LC-PUFA supplementation via infant formula or maternal LC-PUFA supplementation in lactation Numerous interventional studies were carried out to evaluate whether infant formulas that are supplemented with DHA or both DHA and AA would enhance cognitive (Table 2.2) and visual (Table 2.3) development of term and preterm infants or whether levels of the essential FA precursors LA and ALA, found in unsupplemented infant formulas, are sufficient to support adequately visual and cognitive development. Further studies aimed to clarify whether LC-PUFA supplementation of breastfeeding mothers would enhance the developmental outcome of their infants. Whereas the beneficial effect of an LC-PUFA supplementation for cognitive and visual development of formula-fed preterm infants was verified in

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some earlier studies (Birch et al., 1992a, b; Carlson et al., 1993), the added value of an additional LC-PUFA supply in term infant is still a permanent research topic. In several of these studies, visual and cognitive outcomes of breastfed infants served as gold standards. In order to evaluate the effect of the type of feeding, in all studies adjustment for confounders such as birth weight, sex, maternal education, maternal age, socioeconomic level, etc. were carried out. Cognitive development The majority of interventional studies demonstrated a beneficial effect in diverse cognitive developmental indices in preterm and term infants after LC-PUFA supplementation (mainly DHA) of formulas compared to unsupplemented control formulas (Agostoni et al., 1995; Carlson and Werkman, 1996; Werkman and Carlson, 1996; Willatts et al., 1998a, b; Birch et al., 2000; Bouwstra et al., 2003; Fewtrell et al., 2004; Clandinin et al., 2005; Henriksen et al., 2008). These positive effects on cognitive performance do not seem to be dose-dependent. A study showed that feeding preterm infant milk with a high DHA (1 wt% of total FAs) content did not result in any clinically meaningful changes in language or behaviour in early childhood compared to infant milk with a three times lower content (0.35 wt% of total FAs) (Makrides et al., 2009; Smithers et al., 2010). Overall, the studies clearly demonstrated that the cognitive performance of infant groups fed with LC-PUFA-supplemented formulas was never superior to those of the breastfed reference cohorts. These findings are in agreement with two Cochrane reviews, which show that LC-PUFA supplementation of term and preterm infants does not have a statistically significant effect on neurodevelopmental outcomes at doses equal to breast milk levels in Western countries (Simmer et al., 2008a, b). It can be therefore concluded that human breast milk is the optimal early nutrition for infants in view of their cognitive development. There appears to be a strong correlation between the LC-PUFA composition of RBCs and higher neurodevelopmental performance (Agostoni et al., 1995), which is irrespective of dietary or genetic factors. The benefits in infants’ cognitive performance were predominantly reported when cognitive assessments were carried out during or shortly after LC-PUFA supplementation (Agostoni et al., 1995; Willatts et al., 1998b; Bouwstra et al., 2003; Henriksen et al., 2008). Although some studies demonstrated that a relatively short period of LC-PUFA supplementation can produce significant effects on later cognitive outcomes (Carlson and Werkman, 1996; Birch et al., 2000, 2007), most follow-up studies fail to show long-term benefits (Agostoni et al., 1997; Lucas et al., 1999; Auestad et al., 2003; Fewtrell et al., 2004; Bouwstra et al., 2005). These observations can be interpreted as transient effects. However, other explanations are likely to be causative for this circumstance: The intervention periods in those studies lasted from shortly after birth to several months of age, and the cognitive

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assessments were sometimes carried out years after the intervention period. For example, a beneficial neurodevelopmental effect measured at 3 months of age after two months of LC-PUFA supplementation in healthy term infants (Bouwstra et al., 2003) couldn’t be detected at the age of 1.5 years in a follow-up study (Bouwstra et al., 2005). However, infants’ brain growth remains accompanied by a persistent requirement for LC-PUFAs. It can be therefore assumed that an early LC-PUFA supplementation, which is limited for a few months, is not sufficient to improve cognitive and visual performance years after the supplementation took place, even if the time period is critical for appropriate cognitive and motor development. In contrast, studies with a relatively long intervention period of up to one year or even longer clearly showed an advantage over unsupplemented formulas (Werkman and Carlson, 1996; Willatts et al., 1998a; Clandinin et al., 2005). Nevertheless, there is still a demand for longitudinal LC-PUFA supplementation studies with higher DHA doses than used in former studies to clarify the long-term benefits of LC-PUFAs (Simmer et al. 2008a, b). To guide LC-PUFA intake recommendations these studies should focus on well-defined, age-specific cognitive outcomes in specific age groups. Likewise, genetically responsive gender sub-groups should be analysed, since it is possible that genetic differences may contribute clinical outcomes in addition to dose. Furthermore, it is necessary to adjust the existing mental or psychomotor development test methods for healthy term infants, since most of the tests used were designed to ascertain sub-optimal performance. Another question is whether LC-PUFA levels (especially DHA), which are found in human breast milk, can be influenced via the maternal diet and if an increase of such levels would likewise influence cognitive outcomes of infants. Indeed, DHA supplementation of breastfeeding mothers resulted in higher DHA contents in milk lipids (Jensen et al., 2005) and infant plasma phospholipids (Jensen et al., 2005; Lauritzen et al., 2005) compared to control groups (unsupplemented breastfeeding mothers) at four months postpartum. However, neurodevelopmental indices of infants from DHA-supplemented mother–child pairs didn’t show significant differences to those of control groups (Jensen et al., 2005; Lauritzen et al., 2005). Effects were only found in one scale: the BSID-II PDI of the DHAsupplemented group (∼200 mg/day) was significantly higher at 30 months of age (Jensen et al., 2005) suggesting a small further effect of DHA levels in breast milk on cognitive development of breastfed infants. Visual development The results of the studies that evaluated the effect of LC-PUFA supplementation on visual development of term and preterm infants predominantly demonstrated an association between the dietary supply of DHA and an optimal visual development. Most studies reported positive results after supplementing LC-PUFAs to infants’ formula from shortly after birth

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for various amounts of time (two to 13 months) compared to control formula, although not at all test points (Carlson et al., 1996a, b; Birch et al., 1998, 2002, 2007; Hoffman et al., 2000, 2003). In contrast to the results from studies that focused on cognitive outcomes, where the benefits of an early and limited supplementation period tend to be transient, several studies that investigated the visual performance likewise observed short-term and long-term benefits. For example, full-term breastfed infants and infants fed for two to four months with DHA- or DHA+AA-enriched formula had better visual acuity scores at the age of 2 months (Carlson et al., 1996b) or even at the age of 4 years (Birch et al., 2007), compared to the control formula groups. However, the existing data on the long-term advantages of a relatively short and early LC-PUFA supplementation are inconsistent among the different studies. For example, studies from Carlson and co-workers (Carlson et al., 1996a, b) demonstrated a beneficial effect at the end of two months of DHA supplementation, but failed to show a benefit at the ages of 4, 6, 9 and 12 months. It is likely that the control groups simply catch up after dropping the LC-PUFA supplementation in the verum groups. The increase in visual acuity developed more rapidly in breastfed infants compared to infants fed with a formula that did not contain LC-PUFA, but 1.7 wt% ALA, and an LA :ALA ratio of 8.5 (Jørgensen et al., 1996), suggesting the precursors ALA and LA are not sufficient to improve visual development, probably due to a low conversion rate into LC-PUFAs. Likewise, Jørgensen et al. (1996) observed a decrease of DHA levels in RBCs of formula-fed infants, and significantly lower levels at 2 and 4 months as compared to breastfed infants. The authors concluded that the difference in visual acuity between the two feeding groups could be due to differences in DHA status as reflected by RBC levels. Birch et al. (2002) showed that breastfed infants, weaned to formula that did not provide AA and DHA, had significantly poorer visual acuity at 17, 26 and 52 weeks of age and significantly poorer stereo-acuity at 17 weeks of age than did infants who were weaned to AA/DHA-supplemented formula. Better acuity and stereo-acuity was correlated with higher levels of DHA in plasma and RBCs. Likewise, the results were in agreement with those of a meta-regression analysis of 14 trials, which showed that the DHA dose in milk formula was positively related to visual acuity measures of 4 month-old healthy term infants (Uauy et al., 2003). In contrast, some studies reported no statistically significant difference between formula and breastfed groups (Makrides et al., 2000b; Auestad et al., 2003; Simmer et al. 2008a, b), although the measured visual acuity and motor function of the supplemented infants was equal to breastfed infants. Nevertheless, these results can be explained by the use of study formulas containing low DHA levels (Auestad et al., 2003) or the precursor LCPUFAs LA and ALA (Makrides et al., 2000b). The intention of Makrides et al. (2000b) was to compare the FA status of term infants fed formula

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containing an LA :ALA of either 10 : 1 or 5 : 1 with those of a breastfed reference cohort. In view of the results, the study revealed that infants may have limited ability to synthesize DHA out of its precursor ALA. Although infants fed the 5 : 1 formula had greater DHA concentrations in plasma and RBC phospholipids than did infants fed the 10 : 1 formula, the DHA levels of infants of the 5 : 1 formula group remained less than those in breastfed infants. Studies that evaluated the effect of supplementing lactating women with either DHA or placebo failed show a difference between groups (Lauritzen et al., 2004; Jensen et al., 2005; Smithers et al., 2008). However, the supplementation of mothers with fish oil resulted in a significant increase in the DHA levels in milk and infant RBCs taken after four months of supplementation (Lauritzen et al., 2004). Although there was no significant difference observable between randomized groups, infants’ visual acuity was positively associated with infant DHA levels in RBCs, clearly demonstrating that infants with higher DHA levels in RBCs have a better visual acuity at early age.

2.7 Potential consequences of PUFA deficiency or imbalances Human infants require an adequate dietary supply of both n-3 and n-6 LCPUFAs to maintain normal FA composition of plasma and RBC membrane lipids, and presumably of brain and retina. Dietary deficiency of n-3 PUFAs during development leads to characteristic changes in the FA composition of the brain and retina, which includes a decrease in DHA levels and a reciprocal increase in the n-6 LC-PUFAs AA and DPA (Wainwright, 2002; Nui et al., 2004). Such alterations in membrane properties interfere with intra- and intercellular cellular signalling pathways in many ways, leading to deficits in function. A number of studies have shown that depletion of DHA is associated with reduced visual function, neurodevelopmental and behavioural abnormalities due to decreased membrane protein, receptor and ion channel activities and alterations in the metabolism of several neurotransmitters (Neuringer et al., 1986; Innis, 2003). Experimental studies with animals have shown that the dopaminergic and serotoninergic systems in particular are influenced by LC-PUFA deficiencies, with associated behaviours (Wainwright, 2002). A deficiency in n-3 LC-PUFAs in newborns results in reduced light sensitivity of retinal rod photoreceptors and abnormal cognitive development (Uauy et al., 2001). Preterm infants are particularly at risk for the effects of PUFA deficiency and imbalances (Martinez, 1992). In primates and humans, preterm delivery is associated with deficits in fetal cortical DHA accrual. Preterm infants fed formulas lacking DHA have lower DHA levels in RBC phospholipids compared to those fed human milk (Carlson et al., 1986). A

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deficit in brain DHA accrual during critical perinatal periods in particular may therefore represent a preventable neurodevelopmental risk factor for the subsequent emergence of psychopathology.

2.8

PUFA intake recommendations and supply situation

In view of the rapid growth and development of the brain and retina, both the fetus during pregnancy and the young child during the first several years of life should receive LC-PUFAs in amounts sufficient to ensure optimal cognitive and visual development. Considering the data from diverse clinical studies, the LC-PUFA supplementation of infants via infant formula provides the greatest benefit compared to supplying the mother during pregnancy or lactation. It is also important to note that not only preterm but also term infants benefit from such a supplementation.

2.8.1 Pregnant and lactating women The Perinatal Lipid Nutrition Project (PeriLip) and The Early Nutrition Programming Project (EARNEST) together with other international scientific societies recommend a DHA intake of at least 200 mg/day for pregnant and lactating women to support optimal visual and cognitive development of their infants (Koletzko et al., 2008b). This recommendation is in agreement with the 4th policy statement of the International Society for the Study of Fatty Acids and Lipids (ISSFAL). The recent dietary reference intakes (DRIs) of the US National Institutes of Healths established an adequate intake (AI) for ALA during pregnancy and lactation of 1.4 and 1.3 g/d and an acceptable macronutrient distribution range (AMDR) of 0.6–1.2 % of energy (En%) for n-3 PUFAs with up to 10 % of the AMDR consumed as EPA and/or DHA (IOM-FNB, 2005). Estimating a daily energy intake of 2400 kcal (10 MJ) and an intake recommendation of 0.2 En% would result in a daily EPA/DHA requirement of 300 mg/day. According to the harmonized reference nutrient intake values of nutrition societies from Germany (D), Austria (A) and Switzerland (CH; D–A–CH, 2008), adults should derive app. 0.5 En% and 2.5 En% of their total energy in the form of the precursor FAs ALA and LA, respectively. Estimating a daily energy intake of 2400 kcal (10 MJ) would result in a daily requirement of ∼1.25 g ALA and ∼6.25 g LA. In addition to these basic n-3 FA requirements, D–A–CH recommends a daily intake of 200 mg DHA for pregnant and lactating women. However, for many pregnant and lactating women, as well as the population in modern industrial countries in general, there is a great difference between the desired recommended intake and the actual intake, as the content of n-3 FAs – especially EPA and DHA – in the prevailing western style diet is extremely low. Investigations with pregnant women in the US

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and Canada revealed that the DHA intakes are well below the recommended dietary intake of 300 mg/day (Lewis et al., 1995; Simopoulos et al., 2000; Judge et al., 2003; Denomme et al., 2005). For example, of the investigated women in Canada 90 % consumed less than 300 mg/day; the mean DHA intake was 82 +/− 33 mg/day (Denomme et al., 2005). The situation is similar to that in Germany. According to the diet report of the German Nutrition Society (DGE, 2004) the mean DHA intake of German women is also below 100 mg/day. Quantitatively significant concentrations of EPA and DHA are only found in a few types of high-fat cold-water fish such as salmon, mackerel or herring. Two servings of fatty sea fish per week could therefore be a suggested contribution to meet the recommended DHA intake. The consumption of such amounts of fish is considered safe and does not necessarily exceed the tolerable intake levels for environmental contaminants such as methylmercury, dioxins and polychlorinated biphenyls (Domingo et al., 2007). However, the type of fish, the frequency of consumption and the meal size are essential issues for the balance of health benefits and risks of regular fish consumption (Domingo et al., 2007). ALA can be found in a number of green vegetables as well as in certain nuts and seeds. The supply of n-6 FAs is sufficient, as there are many sources of n-6 FAs in westernstyle food (e.g., LA in various vegetable oils). In healthy individuals, an n-6 FA deficiency is therefore unknown. Moreover, the typical diet in western countries is high in meat, which gives rise to a high supply of preformed AA. There is also no evidence that women of childbearing age, whose dietary intake of LA is adequate, need an additional dietary intake of AA. Taken together, with respect to the low conversion rate and the comparatively low consumption of fish in western countries, the supply situation of women in childbearing age with n-3 FAs – in particular EPA and DHA – can to be regarded as inadequate and should be improved in view of an optimal cognitive and visual development of infants. However, in view of the low popularity of fish in general, other sources of n-3 LC-PUFAs such as enriched functional foods and dietary supplements are likely to improve the supply situation.

2.8.2 Infants For healthy infants born at term, breastfeeding should be the preferred method of feeding in the first six months of life to provide infants adequately with LC-PUFAs in an optimal ratio. For those infants who are not breastfed for any reason, infant formula or follow-on formula should be enriched with DHA and AA (Koletzko et al., 2008b). After weaning, dietary LC-PUFA supply should continue during the second six months of life. With the introduction of complementary foods, breast milk or formula consumption of infants – and hence the intake of LC-PUFAs – declines unless the introduced foods contain appropriate LC-PUFA contents. Good sources

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Table 2.4 Dietary recommended intakes (DRIs) for LA and ALA in infants’ and children Linoleic acid (g/d) Infants 0 to < 4 mo 4 to 12 mo 0 to 6 mo 7 to 12 mo Children 1 to <4 y 4 to <7 y 1 to 3 y 4 to 8 y

α-linolenic acid (g/d)

4.0 3.5 4.4 4.6

0.5 0.5 0.5 0.5

D–A–CH, 2008

3.0 2.5 7 10

0.5 0.5 0.7 0.9

D–A–CH, 2008

IOM-FNB, 2005

IOM-FNB, 2005

for LC-PUFAs during the 1st year and later life include egg yolk and meat (AA), fatty sea fish (DHA) or other LC-PUFA-fortified foods. The intakes of the preformed n-3 LC-PUFAs EPA and DHA per kg body weight appear to be low in many 2–12 year-old children, in relation to intakes per kg body weight of breastfed infants and adult intakes (Koletzko et al., 2010). However, the available information is insufficient. Likewise, the existing data on long-term benefits of increasing dietary intakes of EPA or DHA on physical or mental function or other health end-points in children are scarce and not sufficient to establish quantitative dietary intake recommendations for the EPA and DHA. A workshop report on desirable dietary intake of EPA and DHA suggested that dietary guidelines for adults supporting health and preventing chronic diseases should also be valid for infants, children and toddlers (Koletzko et al., 2010). These recommendations focus predominantly on the consumption of at least one to two meals of fatty sea fish per week. The recommendation to eat more fish is, however, in conflict with the reluctance of many children to eat fish at all. EPA- and DHA-enriched functional foods or supplements are therefore a consideration in order to improve the supply situation. Likewise, there is no exact intake recommendation for the preformed n-6 LC-PUFA AA, although it can be assumed that the intake in general is sufficient. Table 2.4 gives an overview on the intake recommendations (DRI) of the precursors LA and ALA for infants and children dependent on age.

2.9 Implications for the food industry, nutritionists and policy-makers Evidence is becoming stronger that ALA is ineffective in contributing to an optimal DHA status due to extremely low conversion rates into DHA and is therefore insufficient to support preferable levels of DHA deposition

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in the fetal brain (Greiner et al., 1997; Brenna, 2002). Likewise, the official 5th ISSFAL policy statement declares that the evidence available demonstrates that for most people under modern dietary conditions, there is no nutritionally significant conversion of ALA to EPA or more especially DHA’ (Brenna et al., 2009). Therefore, controversy exists amongst nutrition and health experts over whether EPA and DHA should be likewise considered as essential nutrients, which must be provided with the diet. The available evidence from numerous RCTs supports benefits of enriched infant formulas and baby foods with DHA and AA for an optimal cognitive and visual development at early age. In contrast to human milk, the infant formula in the past, based on cow’s milk, contained neither AA nor DHA. Currently, exact recommendations for the addition of LC-PUFA to formula, follow-on formula or complementary foods cannot be specified. It is estimated that the DHA levels in infant formula should reach at least 0.2 En% and not exceed 0.5 En% of total FAs, while the levels of added AA should be at least equal to those of added DHA (Koletzko et al., 2008b). It is important that manufacturers of the food industry prepare their formula and baby food products in accordance to the recommendations on the composition of infant formula, established in the Codex Alimentarius proposal for a global infant formula standard (CAC, 2006) and the EU Commission Directive on infant formula and follow-on formula (Commission Directive 2006/141/EC). Likewise, the use of infant complementary and toddler foods providing DHA and AA in sufficient amounts should be further evaluated. The complementary feeding period is clearly dominated by commercial food products, and a study that evaluated LC-PUFA patterns in the complementary feeding period against the present dietary guidelines in Germany demonstrated a less favourable n-6 : n-3 LC-PUFA ratio in the diet (Schwartz et al., 2010).

2.10 Future trends Fish oil is well known and generally recognized as an appropriate source for DHA. For use in infant formula and weaning foods, these fish oils should be highly purified and safe. Moreover, the composition of fish oils should be specific, ensuring that the amount of EPA does not exceed the amount of DHA. However, in view of ecological concerns such as commercial overfishing, other DHA sources become of increasing interest. For example, with specific algae and fungal sources, it is possible to produce highly pure DHA oils. These sources provide the possibility to produce DHA under well-controlled and resource-conserving conditions. Algae and fungal DHA-rich oils are free of side-effects such as eructation, which is a frequently reported problem with fish oils. Likewise, such oils are also available for vegans. However, there is a debate about whether

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LC-PUFAs from different sources (e.g., marine or plant) as well as different chemical LC-PUFA forms (e.g., triacylglycerides or ethyl-esters) have an identical bioavailability. Future studies need to compare these differences. Other likely future trends for innovative n-3 FA products focus on the form of administration, where galenics play a pivotal role. Examples for product improvements are micro-encapsulation of fish oil or coating of fish oil capsules with gastric acid-resistant layers. Flavorizing fish oil, in order to improve and modulate the taste and smell, is another trend in the food industry, which might be helpful to prevent fish oil-induced eructation with an undesired fishy taste. More advanced technologies include inertization techniques to form hydrophilic n-3 FA compounds that can be added to a broader spectrum of supplements or functional foods. In order to better understand the functional roles of LC-PUFAs, in particular DHA, in cognitive and visual development and to determine quantitative dietary intakes recommendations, further research studies (RCTs, cohort studies, mechanistic studies) are necessary. Referring to Koletzko et al. (2008b, 2010), future research studies should pay more attention on the following aspects: • Short- and long-term effects of LC-PUFA administration during pregnancy, lactation and infancy on infants’ LC-PUFA status. • Specific benefits of LC-PUFA supplementation for sub-groups with dysfunctional FA metabolism (genetic and gender-specific differences in PUFA metabolism). • Special emphasis on certain sub-groups with potential specific needs and benefits (women with risk pregnancies or restricted dietary LC-PUFA intakes, multiple pregnancies, closely spaced pregnancies). • Consideration of various DHA and AA levels in order to determine an optimal combination and dose, as well as to elucidate potential immediate and long-term benefits. • Dose–response studies of LC-PUFA intake during the second six months of life should be undertaken with sufficient duration of intake and adequate sample sizes. • Methodology for visual and cognitive outcome measurements should be harmonized for a better comparison between studies in order to obtain assured findings on potential effects. • Longitudinal studies should include more sensitive cognitive measures with respect to possible advantages of DHA on mental development. • Besides visual and cognitive outcome measures, studies should examine the effects on growth, body composition, bone mineralization, immune system (e.g., allergy and inflammatory disorders) and cardiovascular function. • Longitudinal studies should likewise focus on possible relations between early LC-PUFA supply/status and behavioural disorders in childhood

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such as attention deficit hyperactivity disorder (ADHD), dyslexia, dyspraxia and autism spectrum disorders. • Studies should evaluate the possible link between relative n-3 FA deficiency or n-3 : n-6 FAs imbalances and behavioural disturbances. • The measures of dietary LC-PUFA supply and the assessment of its status should be simplified. • Elucidating more precisely potential mechanisms by which n-3 LC-PUFAs aid the development and maintenance of cognitive performance.

2.11 Sources of further information and advice The following key books and reviews published in this field of research should be highlighted: • The book Fatty Acids in Foods and Their Health Implications from Chow (2007) gives a general overview about dietary fat, FAs, and their relation to health and disease. The book likewise includes highly detailed chapters on the role of LC-PUFA consumption for cognition, behaviour, brain development and mood disease. • The book Fatty Acids: Physiologic and Behavioural Functions from Mostofsky et al. (2001) provides an in-depth review on possible effects of dietary EFAs on the visual and cognitive development of infants and on certain psychiatric disorders with special emphasis on the role of DHA in neural membranes, and its effects on the CNS. • The book Omega-3 Fatty Acids, the Brain and Retina by Simopoulos and Bazan (2009) discusses not only the role of n-3 FAs in maintaining homeostasis and normal development of brain and retina, but also their importance in the prevention and management of neurodegenerative diseases. • A current review from Su (2010) reports on the potential mechanisms by which especially the n-3 PUFAs DHA and EPA promote the development and maintenance of spatial learning memory performance, which could be in turn linked to neurodegenerative diseases during age. For example, reduced spatial learning memory performance – appearing in the brain disorder Alzheimer’s disease – is associated with decreased hippocampal DHA levels.

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judge m p, loosemore e d, demare c i, keplinger m r, mutungi g, cote s, ryan m, ibarolla b and lammi-keefe c j (2003) ‘Dietary docosahexaenoic acid (DHA) intake in pregnant women’. J Am Diet Assoc, 103, A82. judge m p, harel o and lammi-keefe c j (2007a) ‘Maternal consumption of a docosahexaenoic acid-containing functional food during pregnancy: benefit for infant performance on problem-solving but not on recognition memory tasks at age 9 mo’. Am J Clin Nutr, 85(6), 1572–7. judge m p, harel o and lammi-keefe c j (2007b) ‘A docosahexaenoic acid-functional food during pregnancy benefits infant visual acuity at four but not six months of age’. Lipids, 42(2), 117–22. kamada t, yamashita t, baba y, kai m, setoyama s, chuman y and otsuji s (1986) ‘Dietary sardine oil increases erythrocyte membrane fluidity in diabetic patients’. Diabetes, 35(5), 604–11. kitajka k, sinclair a j, weisinger r s, weisinger h s, mathai m, layasooriya a p, halver j e and puskás lg (2004) ‘Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression’. Proc Natl Acad Sci USA, 101(30), 10931–6. kitajka k, puskás l g, zvara a, hackler l jr, barceló-coblijn g, yeo y k and farkas t (2002) The role of n-3 polyunsaturated fatty acids in brain: modulation of rat brain gene expression by dietary n-3 fatty acids. Proc Natl Acad Sci USA, 99(5), 2619–24. koletzko b, larqué e and demmelmair h (2007) ‘Placental transfer of long-chain polyunsaturated fatty acids (LC-PUFA)’. J Perinat Med, 35, S5–11. koletzko b, demmelmair h, schaeffer l, illig t and heinrich j (2008a) ‘Genetically determined variation in polyunsaturated Fatty Acid metabolism may result in different dietary requirements’. Nestlé Nutr Workshop Ser Pediatr Program, 62, 35–49. koletzko b, lien e, agostoni c, böhles h, campoy c, cetin i, decsi t, dudenhausen j w, dupont c, forsyth s, hoesli i, holzgreve w, lapillonne a, putet g, secher n j, symonds m, szajewska h, willatts p and uauy r; world association of perinatal medicine dietary guidelines working group (2008b) ‘The roles of long-chain polyunsaturated fatty acids in pregnancy, lactation and infancy: review of current knowledge and consensus recommendations’. J Perinat Med, 36(1), 5–14. koletzko b, uauy r, palou a, kok f, hornstra g, eilander a, moretti d, osendarp s, zock p and innis s (2010) ‘Dietary intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in children – a workshop report’. Br J Nutr, 103(6), 923–8. krauss-etschmann s, shadid r, campoy c, hoster e, demmelmair h, jimenez m, gil a, rivero m, veszpremi b, decsi t and koletzko b (2007) ‘Effects of fish-oil and folate supplementation of pregnant women on maternal and fetal plasma concentrations of docosahexaenoic acid and eicosapentaenoic acid – a European randomized multicenter trial’. Am J Clin Nutr, 85(5), 1392–400. larqué e, demmelmair h and koletzko b (2002) ‘Perinatal supply and metabolism of long-chain polyunsaturated fatty acids: importance for the early development of the nervous system’. Ann N Y Acad Sci, 967, 299–310. larqué e, demmelmair h, klingler m, de jonge s, bondy b and koletzko b (2006) ‘Expression pattern of fatty acid transport protein-1 (FATP-1), FATP-4 and heartfatty acid binding protein (H-FABP) genes in human term placenta’. Early Hum Dev, 82(10), 697–701. lauritzen l, jørgensen m h, mikkelsen t b, skovgaard m, straarup e m, olsen s f, høy c e and michaelsen k f (2004) ‘Maternal fish oil supplementation in lactation: effect on visual acuity and n-3 fatty acid content of infant erythrocytes’. Lipids, 39(3), 195–206.

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lauritzen l, jørgensen m h, olsen s f, straarup e m and michaelsen k f (2005) ‘Maternal fish oil supplementation in lactation: effect on developmental outcome in breast-fed infants’. Reprod Nutr Dev, 45(5), 535–47. lee a (2001) ‘Membrane structure’. Curr Biol, 11(20), R811–14. lewis n m, widga a c, buck j s and frederick a m (1995) ‘Survey of omega-3 fatty acids in diets of midwest low-income pregnant women’. J Agromed, 2, 49–56. lucas a, stafford m, morley r, abbott r, stephenson t, macfadyen u, elias-jones a and clements h (1999) ‘Efficacy and safety of long-chain polyunsaturated fatty acid supplementation of infant-formula milk: a randomised trial’. Lancet, 354(9194), 1948–54. mahadik s p and mukherjee s (1996) ‘Free radical pathology and antioxidant defense in schizophrenia: a review’. Schizophr Res, 19, 1–17. makrides m, neumann m a, byard r w, simmer k and gibson r a (1994) ‘Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants’. Am J Clin Nutr, 60(2), 189–94. makrides m, neumann m a, simmer k and gibson r a (2000a) ‘A critical appraisal of the role of dietary long-chain polyunsaturated fatty acids on neural indices of term infants: a randomized, controlled trial’. Pediatrics, 105(1 Pt 1), 32–8. makrides m, neumann m a, jeffrey b, lien e l and gibson r a (2000b) ‘A randomized trial of different ratios of linoleic to alpha-linolenic acid in the diet of term infants: effects on visual function and growth’. Am J Clin Nutr, 71(1), 120–29. makrides m, gibson r a, mcphee a j, collins c t, davis p g, doyle l w, simmer k, colditz p b, morris s, smithers l g, willson k and ryan p (2009) ‘Neurodevelopmental outcomes of preterm infants fed high-dose docosahexaenoic acid: a randomized controlled trial’. JAMA, 301(2), 175–82. malcolm c a, mcculloch d l, montgomery c, shepherd a and weaver l t (2003a) ‘Maternal docosahexaenoic acid supplementation during pregnancy and visual evoked potential development in term infants: a double blind, prospective, randomised trial’. Arch Dis Child Fetal Neonatal Ed, 88(5), F383–90. malcolm c a, hamilton r, mcculloch d l, montgomery c and weaver l t (2003b) ‘Scotopic electroretinogram in term infants’ born of mothers supplemented with docosahexaenoic acid during pregnancy’. Invest Ophthalmol Vis Sci, 44(8), 3685–91. marangoni f, agostini c, lammardo a m, bonvissuto m, giovannini m, galli c and riva e (2002) ‘Polyunsaturated fatty acids in maternal plasma and in breast milk’. Prostaglandins Leukot Essent Fatty Acids, 66(5–6), 535–40. martinez m (1992) ‘Tissue levels of polyunsaturated fatty acids during early human development’. J Pediatr, 120(4 Pt 2), S129–38. mccall r b and carriger m s (1993) ‘A meta-analysis of infant habituation and recognition memory performance as predictors of later IQ’. Child Dev, 64(1), 57–79. mitchell d c and litman b j (1998) ‘Molecular order and dynamics in bilayers consisting of highly polyunsaturated phospholipids’. Biophys J, 74(2 Pt 1), 879–91. mostofsky d i, yehuda s, and salem n jr (2001) Fatty Acids: Physiologic and Behavioral Functions. Totowa, NJ: Humana Press. neuringer m, connor w e, van petten c and barstad l (1984) ‘Dietary omega-3 fatty acid deficiency and visual loss in infant rhesus monkeys’, J Clin Invest. 73(1), 272–6. neuringer m, connor w e, lin d s, barstad l and luck s (1986) ‘Biochemical and functional effects of prenatal and postnatal omega 3 fatty acid deficiency on retina and brain in rhesus monkeys’. Proc Natl Acad Sci USA, 83(11), 4021–5. neuringer m, anderson g j and connor w e (1988) ‘The essentiality of n-3 fatty acids for the development and function of the retina and brain’. Annu Rev Nutr, 8, 517–41.

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nui s l, mitchell d c, lim s y, wen z m, kim h y, salem n and litman b j (2004) ‘Reduced G protein-coupled signaling efficiency in retinal rod outer segments in response to n-3 fatty acid deficiency’. J Biol Chem, 279(30), 31098–104. oken e, wright r o, kleinman k p, bellinger d, amarasiriwardena cj, hu h, richedwards j w and gillman m w (2005) ‘Maternal fish consumption, hair mercury, and infant cognition in a US Cohort’. Environ Health Perspect, 113(10), 1376–80. pawlosky r j, hibbeln j r, novotny j a and salem n jr (2001) ‘Physiological compartmental analysis of alpha-linolenic acid metabolism in adult humans’. J Lipid Res, 42(8), 1257–65. richards m, hardy r, kuh d and wadsworth m e (2001) ‘Birth weight and cognitive function in the British 1946 birth cohort: longitudinal population based study’. BMJ, 322(7280), 199–203. ross m a (2000) ‘Could oxidative stress be a factor in neurodevelopmental disorders?’. Prostaglandins Leukot Essent Fatty Acids, 63(1–2), 61–3. ross b m, mckenzie i, glen i and bennett c p (2003) ‘Increased levels of ethane, a non-invasive marker of n-3 fatty acid oxidation, in breath of children with attention deficit hyperactivity disorder’. Nutr Neurosci, 6(5), 277–81. salem n jr, kim h y and yergey j a (1986) ‘Docosahexaenoic acid: membrane function and metabolism’, in Simopolous A P, Kifer R R and Martin R E (eds), Health Effects of Polyunsaturated Fatty Acids in Seafoods. New York: Academic Press, 319–51. salem n jr, wegher b, mena p and uauy r (1996) ‘Arachidonic and docosahexaenoic acids are biosynthesized from their 18-carbon precursors in human infants’. Proc Natl Acad Sci USA, 93(1), 49–54. salem n jr, pawlosky r, wegher b and hibbeln j (1999) ‘In vivo conversion of linoleic acid to arachidonic acid in human adults’. Prostaglandins Leukot Essent Fatty Acids, 60(5–6), 407–10. salvati s, natali f and attorri l, di benedetto r, di biase a, fortuna s, lorenzini p, sanchez m, ricceri l and vitelli l (2008) ‘Eicosapentaenoic acid stimulates the expression of myelin proteins in rat brain’. J Neurosci Res, 86(4), 776–84. sauerwald t u, hachey d l, jensen c l, chen h, anderson r e and heird w c (1997) ‘Intermediates in endogenous synthesis of C22:6 omega 3 and C20:4 omega 6 by term and preterm infants’. Pediatr Res, 41(2), 183–7. schaeffer l, gohlke h, müller m, heid i m, palmer l j, kompauer i, demmelmair h, illig t, koletzko b and heinrich j (2006) ‘Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids’. Hum Mol Genet, 15(11), 1745–56. schuchardt j p, huss m, stauss-grabo m and hahn a (2010) ‘Significance of longchain polyunsaturated fatty acids (PUFAs) for the development and behaviour of children’. Eur J Pediatr, 169(2), 149–64. schwartz j, dube k, alexy u, kalhoff h and kersting m (2010) ‘PUFA and LC-PUFA intake during the first year of life: can dietary practice achieve a guideline diet?’. Eur J Clin Nutr, 64(2), 124–30. seidman d s, laor a, gale r, stevenson d k, mashiach s and danon y l (1992) ‘Birth weight and intellectual performance in late adolescence’. Obstet Gynecol, 79(4), 543–6. shand j h and noble r c (1981) ‘The metabolism of 18:0 and 18:2(n-6) by the ovine placenta at 120 and 150 days of gestation’. Lipids, 16(1), 68–71. silva p a and fergusson d m (1976) ‘Socio-economic status, maternal characteristics, child experience, and intelligence in pre-school children: a path analytic model’. NZ J Educ Stud, 11(2), 180–8.

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simmer k, patole s k and rao s c (2008a) ‘Longchain polyunsaturated fatty acid supplementation in infants born at term’. Cochrane Database Syst Rev (1), CD000376. simmer k, schulzke s m and patole s (2008b) ‘Longchain polyunsaturated fatty acid supplementation in preterm infants’. Cochrane Database Syst Rev (1), CD000375. simopoulos a p and bazan n g (2009) Omega-3 Fatty Acids, the Brain and Retina (World Review of Nutrition and Dietetics, Vol. 99). Basel: Karger AG. simopoulos a p, leaf a and salem n (2000) ‘Workshop statement on the essentiality and recommended dietary intakes for omega-6 and omega-3 fatty acids’. Prostaglandins Leukot Essent Fatty Acids, 63(3), 119–21. sinclair h m (1990) ‘Essential fatty acids – an historical perspective’. Biochem Soc Trans, 18(5), 756–61. sinn n and bryan j (2007) ‘Effect of supplementation with polyunsaturated fatty acids and micronutrients on learning and behaviour problems associated with child ADHD’. J Dev Behav Pediatrics, 28(2), 82–91. smit e n, martini i a, mulder h, boersma e r and muskiet f a (2002) ‘Estimated biological variation of the mature human milk fatty acid composition’. Prostaglandins Leukot Essent Fatty Acids, 66(5–6), 549–55. smithers l g, gibson r a, mcphee a and makrides m (2008) ‘Higher dose of docosahexaenoic acid in the neonatal period improves visual acuity of preterm infants’: results of a randomized controlled trial’. Am J Clin Nutr, 88(4), 1049–56. smithers l g, collins c t, simmonds l a, gibson r a, mcphee a and makrides m (2010) ‘Feeding preterm infants milk with a higher dose of docosahexaenoic acid than that used in current practice does not influence language or behavior in early childhood: a follow-up study of a randomized controlled trial’, Am J Clin Nutr. 91(3), 628–34. sorensen h t, sabroe s, olsen j, rothman k j, gillman m w and fischer p (1997) ‘Birth weight and cognitive function in young adult life: historical cohort study’. BMJ, 315(7105), 401–3. stillwell w and wassall s r (2003) ‘Docosahexaenoic acid: membrane properties of a unique fatty acid’. Chem Phys Lipids, 126(1), 1–27. ströhle a, schmitt b and hahn a (2002) ‘Functional Foods – Eine Übersicht zur aktuellen Situation’. Journal für orthomolekulare Medizin, 10, 326–49. stubbs c d and smith a d (1984) ‘The modification of mammalian membrane polyunsaturated fatty acid composition in relation to membrane fluidity and function’. Biochim Biophys Acta, 779(1), 89–137. su h m (2010) ‘Mechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance’. J Nutr Biochem, 21(5), 364–73. su h m, bernardo m, mirmiran x h, ma t n, corso p w, nathanielsz j t and brenna j t (1999) ‘Bioequivalence of dietary a-linolenate and docosahexaenoate acids as possible sources of docosahexaenoate accretion in brain and associated organs of neonatal baboons’. Pediatr Res, 45(1), 87–93. su h m, huan m c, saad n m r, nathanielsz p w and brenna j t (2001) ‘Fetal baboons convert 18: 3n-3 to 22:6n-3 in vivo, a stable isotope tracer study’. J Lipid Res, 42(4), 581–6. suzuki h, manabe s, wada o and crawford m a (1997) ‘Rapid incorporation of docosahexaenoic acid from dietary sources into brain microsomal, synaptosomal and mitochondrial membranes in adult mice’. Int J Vitam Nutr Res, 67(4), 272–8. tofail f, kabir i, hamadani j d, chowdhury f, yesmin s, mehreen f and huda s n (2006) ‘Supplementation of fish-oil and soy-oil during pregnancy and psychomotor development of infants’. J Health Popul Nutr, 24(1), 48–56. uauy r, mena p, wegher b, nieto s and salem n jr (2000) ‘Long chain polyunsaturated fatty acid formation in neonates: effect of gestational age and intrauterine growth’. Pediatr Res, 47(1), 127–35.

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uauy r, hoffman d r, peirano p, birch d g and birch e e (2001) ‘Essential fatty acids in visual and brain development’. Lipids, 36(9), 885–95. uauy r, hoffman d r, mena p, llanos a and birch e e (2003) ‘Term infant studies of DHA and ARA supplementation on neurodevelopment: results of randomized controlled trials’. J Pediatr, 143(4), S17–25. wainwright p e (2002) ‘Dietary essential fatty acids and brain function: a developmental perspective on mechanisms’. Proc Nutr Soc, 61(1), 61–9. weidmann t s, pates r d, beach j m, salmon a and brown m f (1988) ‘Lipidprotein interactions mediate the photochemical function of rhodopsin’. Biochemistry, 27(17), 6469–74. werkman s h and carlson s e (1996) ‘A randomized trial of visual attention of preterm infants fed docosahexaenoic acid until nine months’. Lipids, 31(1), 91–7. whiteside-mansell l, pope s k and bradley r h (1996) ‘Patterns of parenting behavior in young mothers. Fam Relat, 45(3), 273–81. wijendran v, huang m c, diau g y, boehm g, nathanielsz p w and brenna j t (2002) ‘Efficacy of dietary arachidonic acid provided as triglyceride or phospholipid as substrates for brain arachidonic acid accretion in baboon neonates’. Pediatr Res, 51(3), 265–72. willatts p, forsyth j s, dimodugno m k, varma s and colvin m (1998a) ‘Effect of long-chain polyunsaturated fatty acids in infant formula on problem solving at 10 months of age’. Lancet, 352(9129), 688–91. willatts p, forsyth j s, dimodugno m k, varma s and colvin m (1998b) ‘Influence of long-chain polyunsaturated fatty acids on infant cognitive function’. Lipids, 33(10), 973–80. yao j k, reddy r, mcelhinny l g and van kammen d p (1998) ‘Reduced status of plasma total antioxidant capacity in schizophrenia’. Schizophr Res, 32, 1–8. yeh y y, gehman m f and yeh s m (1993) ‘Maternal dietary fish oil enriches docosahexaenoate levels in brain subcellular fractions of offspring’. J Neurosci Res, 35(2), 218–26. yehuda s, rabinovitz s and mostofsky d i (1999) ‘Essential fatty acids are mediators of brain biochemistry and cognitive functions’. J Neurosci Res, 56(6), 565–70. yuhas r, pramuk k and lien e l (2006) ‘Human milk fatty acid composition from nine countries varies most in DHA’. Lipids, 41(9), 851–8.

2.13 Appendix: list of abbreviations AA ACP ADHD AI ALA AMDR ASQ ATS BLPD BSID-II BVMI CDI CNS

arachidonic acid Acuity Card Procedure attention deficit hyperactivity disorder adequate intake α-linolenic acid Acceptable Macronutrient Distribution Range Ages and Stages Questionnaire Amblyopia Treatment Study Protocol Bruneet-Lézine Psychomotor Development Bayley Scales of Infant Development II Beery Visual-Motor Index Communicative Development Inventory central nervous system

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DGLA DHA DPA DRI EEG EFA EPA ERG ERP EVA FA FADS FPL FT GLA GMDS HA IPT IRDS ISSFAL K-ABC KPS-DSI LA LC-PUFA MCDI MDI MEPS MLU PDI PPVT RBC RCT REM SB-IQ SDQ SNP STSC TAC VEP WPPSI

dihomo-gamma-linolenic acid docosahexaenoic acid docosapentaenoic acid Dietary Reference Intake electroencephalography essential fatty acid eicosapentaenoic acid electroretinogram/electroretinography event-related potentials Electronic Visual Acuity fatty acid fatty acid desaturase Forced-Choice Preferential Looking Fangan Test for Infants’ Intelligence γ-linolenic acid Griffiths Mental Development Scales Hempel Assessment Infant Planning Test Infant Random Dot Stereocards International Society for the Study of Fatty Acids and Lipids Kaufman Assessment Battery for Children Knobloch, Passamanick and Sherrard’s Developmental Screening Inventory linoleic acid long-chain polyunsaturated fatty acids McArthur Communicative Development Inventory Mental Development Index Means-Ends Problem-Solving Test Mean Length of Utterance Psychomotor Developmental Index Peabody Picture Vocabulary Test red blood cell Randomized, controlled interventional trial rapid eye movements Stanford Binet IQ Strengths and Difficulties Questionnaire single nucleotide polymorphism Short Temperament Scale for Children Teller Acuity Cards Visual Evoked Potentials Wechsler Preschool and Primary Scale of Intelligence

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3 Zinc deficiency and cognitive development M. M. Black, University of Maryland School of Medicine, USA

Abstract: Zinc is a trace mineral that is essential for neurological development and central nervous system function. Young children in developing countries may be at risk for zinc deficiency due to inadequate zinc intake, diseases that interfere with zinc utilization, and high zinc requirements. This review examines the role that zinc plays in children’s development, behavior, and mental health. Although observational studies have suggested an association between zinc deficiency and poor cognitive and mental health functioning, the evidence from randomized controlled trials conducted during pregnancy, infancy, and childhood has shown few effects. The evidence linking zinc supplementation to motor development and physical activity is slightly stronger, but inconclusive. Zinc supplementation has beneficial health effects on zinc deficient children and therefore maintaining adequate zinc status is an important goal for children’s health. Key words: zinc deficiency, cognitive development, motor development, mental health, infancy.

3.1 Introduction Zinc is a trace mineral that plays fundamental roles in cell division and maturation, in the production of enzymes necessary for RNA and DNA synthesis, and in the growth and function of many organ systems (Prasad, 2003). It is present throughout the body, including the brain where it binds with proteins associated with neurogenesis and neuronal functioning. Because zinc is essential for neurological development and central nervous system function, it may play a role in children’s development and mental health. Early in life, breastfed infants are generally protected from zinc deficiency. After 6 months, with the introduction of complementary feeding, infants often require alternative sources of zinc, as the levels of zinc in breast milk decline (Hambidge and Krebs, 2007). Thus, the prevalence of

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zinc deficiency increases sharply after 6 months of age and zinc deficiency has become a major public health problem, affecting children primarily in developing countries (Black, 2003). The best sources for zinc are oysters, red meat, and poultry. Other sources are beans, nuts, seafood (such as crab and lobster), whole grains, fortified breakfast cereals, and dairy products (Institute of Medicine, 2001). However, the bioavailability of grain and plant sources of zinc is lower than that of animal sources of zinc because phytates (present in whole grains, cereals, and legumes) bind with zinc, inhibiting absorption (Sandstrom, 1997). Children in developing countries are at particular risk for zinc deficiency because they often consume diets that are low in animal source food and high in phytates and fiber, and experience intestinal losses during illnesses. Thus, zinc deficiency has been attributed to three primary causes: (i) inadequate zinc intake; (ii) diseases that create zinc losses or interfere with zinc utilization; and (iii) high zinc requirements associated with physiological states, such as rapid growth.

3.2 Measurement of zinc status Zinc status is difficult to measure because zinc is present throughout the body (e.g., in bones, teeth, hair, skin, liver, muscle, leukocytes, and testes), in combination with various proteins and nucleic acids (Hambidge and Krebs, 2007). Zinc deficiency is often measured by dietary reports of intake of zinc-rich foods and plasma zinc concentration, which is considered the best biomarker for zine deficiency in populations (Hess et al., 2007). A recent review found that plasma zinc concentration and urinary zinc excretion responded in a dose-dependent manner to dietary manipulation in multiple samples of people who vary in zinc status (Lowe et al., 2009). Although there was some evidence supporting hair zinc concentration as a biomarker, there were too few studies to reach a consensus. Dietary report of zinc-rich foods is often used as an indicator of the risk of zinc deficiency.

3.2.1 Zinc deficiency and health Much of what is known about the effects of zinc deficiency on children’s health and development has come from zinc supplementation studies. Zinc supplementation has been linked to reductions in mortality, primarily by effectively lowering the incidence of common childhood illnesses, including diarrhea, acute lower respiratory infection, and pneumonia (Yakoob et al., 2011). In developing countries and populations with inadequate dietary zinc, zinc deficiency has been linked to deficits in children’s physical growth and immune functioning, thereby increasing children’s vulnerability to multiple infections (Yakoob et al., 2011). The health implications

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of zinc supplementation have been so strong that the World Health Organization and UNICEF recommend zinc as a treatment in response to childhood diarrhea (Fischer Walker and Black, 2010; WHO and UNICEF, 2004). A meta-analysis of 33 studies reported a beneficial effect of zinc supplementation on the serum zinc and linear growth of undernourished children. Growth responses were greatest in children with low initial weightfor-age z scores or for children over 6 months of age, low initial height-forage z scores (Brown et al., 2002). In a subsequent meta-analysis, zinc-only interventions had no significant effect on height or weight gain (Ramakrishnan et al., 2009), perhaps because children were better nourished than in the prior meta-analysis. Multiple micronutrient interventions that included zinc did result in improved linear growth, although effect sizes were small. At least two small studies have examined zinc deficiency and the growth of young children in the US. In a randomized controlled trial of zinc supplementation conducted for one year among Spanish–American children with height-for-age below the 10th percentile, supplemented children had greater height velocity than control children (Walravens et al., 1983). In a placebocontrolled trial of zinc supplementation among children with failure-tothrive, those who received zinc supplements for up to three months had better weight gain than control group children (Walravens et al., 1989). These studies suggest that mild zinc deficiency may impair growth among some children in industrialized countries. Zinc deficiency has also been associated with poor appetite and hunger in some studies, although the associations lack consistency (Institute of Medicine, 2001). It is likely that associations with appetite and hunger are complex and depend on other factors, such as the overall nutritional status of the individual.

3.2.3 Zinc deficiency and cognitive development Evidence from animal models suggests that zinc deficiency may affect emotionality and response to stress (Halas et al., 1983) – factors that play critical roles in shaping infant responsiveness and development (Thelen and Smith, 1994). However, investigations of zinc supplementation on infants’ development and behavior have yielded inconsistent findings. Zinc supplementation trials during pregnancy have yielded conflicting findings. Early observational studies among children in Egypt showed an association between maternal sources of zinc and infant development (Kirksey et al., 1994). Infants of mothers who consumed bioavailable sources of zinc (animal source food) during the second and third trimesters of pregnancy had better scores on a measure of attention (habituation on the Brazelton Neonatal Behavioral Assessment Scale) administered shortly after birth. At 6 months, infant motor development was negatively related

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to maternal intake of plant sources of zinc, potentially related to low bioavailability. Positive findings linking zinc supplementation and child development have been reported from trials in Peru and Bangladesh. A trial from Peru showed fetal neuronal effects of maternal zinc supplementation during pregnancy – the fetuses of zinc-supplemented mothers were more active than fetuses of placebo-supplemented mothers (Merialdi et al., 1999). In a trial from Bangladesh (Hamadani et al., 2002), the infants of zinc-supplemented women had significantly lower scores on standardized measures of mental and motor development at 6 months of age. However, two studies that followed infants of zinc-supplemented women during pregnancy until 5 years of age found no effect on the children’s neuropsychological performance on standardized tests. In a zinc supplementation trial among low-income pregnant women in Alabama, zinc supplementation was associated with larger birth weight and greater head circumference among the offspring, but no differences in tests of neuropsychological functioning at age 5 years (Tamura et al., 2003). In a zinc supplementation trial among pregnant women in Peru (Caulfield et al., 2010), there were no differences in the children’s cognitive, social, or behavioral development at ages 4–5 years. Two randomized trials examined the effects of zinc supplementation on physical activity among zinc deficient infants showed an effect (Sazawal et al., 1996; Bentley et al., 1997). In the Guatemala trial (Bentley et al., 1997) children 8–9 months of age were recruited and, through a randomization procedure, they were assigned to intervention (10 mg oral zinc/day) for seven months or placebo, followed by an evaluation of their physical activity. Zinc-supplemented infants were more likely to sit and play, rather than lie down, than placebo children. In the India trial (Sazawal et al., 1996), 6–35 month-old children were recruited and, based on a randomization procedure, assigned to intervention (10 mg elemental zinc) or placebo for six months. At follow-up, zinc-supplemented children were more likely to engage in high activity games (e.g., running) than placebo children. There have been at least 12 trials that examined the effects of zinc alone or in combination with other micronutrients on infant mental and motor development (Ashworth et al., 1998; Friel et al., 1999; Castillo-Duran et al., 2001; Hamadani et al., 2001; Black et al., 2004a,b; Dhingra et al., 2004; Lind et al., 2004; Faber et al., 2005; Meeks-Gardner et al., 2005; Taneja et al., 2005; Olney et al., 2006) (Table 3.1). Most studies were conducted among infants from low-income families in developing countries who were thoughts to be zinc deficient, although most did not assess zinc status at baseline. Studies provided zinc supplements ranging from 3 mg to 11 mg daily; one provided 20 mg weekly, with durations ranging from seven weeks to one year. Most used an examiner-administered assessment of infant mental and motor development, either the Bayley Scales of Infant Development (8) or the

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Bangladesh

India

Black et al., 2004b

Brazil

Ashworth et al., 1998

Black et al., 2004a

Country

Author

Small for gestational age, n = 200

Rural n = 221

LBW, N= 138/205

Sample

Birth

6 months

Birth

Age at enrollment

5 groups: (a) 20 mg Fe, (b) 20 mg Zn, (c) Fe + Zn, (d) MM including Fe & Zn, (e) placebo. Weekly 2 groups: (a) MM mix with 10 mg FE and 5 mg Zn, (b) MM mix without Zn

2 groups: (a) 5 mg Zn, (b) placebo

Supplement & dose BSID, Behavior Rating Scale

BSID II, Behavior Rating Scale

BSID II, Behavior Rating Scale

6 months

9 months

Evaluation

8 weeks

Duration of supplement

No effects on mental, motor, or behavior.

No effects on mental/ motor at 6 or 12 months. Zn-supplemented infants more responsive at 12 months Fe + Zn higher motor score than placebo. Fe, Zn, and Fe + Zn beneficial effects on orientationengagement, compared to placebo

Cognitive/motor findings

Table 3.1 Randomized controlled trials of zinc or multiple micronutrient containing zinc supplementation on infant/toddler cognitive and motor development

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Country

Chile

Author

CastilloDuran et al., 2001

6–12 months

Rural, n = 292/361

Very LBW (<1500 g) n = 52 1 month, n = 212/301

South Africa

Canada

Bangladesh

Friel et al., 1993

Hamadani et al., 2001

Term infants

Birth

1–3 years

Birth

Age at enrollment

Urban, n = 633

Term neonates, n= 112/150

Sample

India

Dhingra et al., 2004 Faber et al., 2005

Continued

Table 3.1

2 groups: MM, (a) 9.6 mg Zn, (b) placebo 2 groups: (a) MM porridge with 3 mg Zn, 11 mg Fe + other nutrients, (b) placebo 2 groups: (a) 11 mg Zn, (b) 6.7 mg Zn 2 groups: (a) 5 mg Zn, (b) placebo

2 groups: (a) 5 mg Zn, (b) placebo

Supplement & dose

5 months

3 months

6 months

6 months

1 year

Duration of supplement

BSID

Griffiths

Maternal report of 25 motor skills

BSID II

BSID

Evaluation

Higher Zn dose had better motor development Zn group had lower mental scores than placebo

No effects on mental or motor scores as continuous variables. Zn group higher motor quality and likelihood of mental score within normal than placebo No effect on mental, motor, behavior, language MM-fortified infants had more motor skills (15.5 vs 14.4)

Cognitive/motor findings

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Zanzibar

India

Olney et al., 2006

Taneja et al., 2005

5–11 months

12–18 months

Urban, n = 571/650

<6 months

9–30 months

Age at enrollment

Population of Pemba, N = 354

n = 655/680

Weight-age z-score < 1.5, n = 114/126

Sample

4 groups: (a) 10 mg Zn, (b) 10 mg Fe, (c) Zn + Fe, (d) placebo 4 groups: (a) 6.25 mg Fe & 25 ug FA, (b) Zn 5 mg, (c) FeFA + Zn, (d) Placebo 2 groups: (a) 10 mg Zn – infants 20 mg Zn – older, (b) placebo

4 groups: (a) stimulation, (b) 10 mg Zn, (c) Stim + Zn, (d) placebo

Supplement & dose

BSID II

Maternal report of motor milestones

1 year

4 months

BSID

Griffiths Mental Developmental Scales

Evaluation

6 months (180 days)

7 weeks

Duration of supplement

No impact on mental or motor development

Fe + Zn group walked one month earlier than placebo

Stim + Zn had higher developmental quotient. Zn alone benefited eye-hand coordination. No effects on other developmental areas No effect of Zn or Zn + Fe on BSID scores; Fe > placebo on motor development

Cognitive/motor findings

Abbreviations: BSID = Bayley Scales of Infant Development, Fe = iron, LBW = low birth weight, MM – multiple micronutrients, Zn = zinc.

Indonesia

Jamaica

MeeksGardner et al., 2005

Lind et al., 2004

Country

Author

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Griffiths Mental Developmental Scales (2); two used mothers’ report of motor milestones. An early randomized trial among children from Canada with birth weights under 1500 g found that children who received higher doses of zinc (11 mg vs 6.7 mg) for five months had greater linear growth and better motor development than children who received the lower dose (Friel et al., 1993). Five of the remaining 11 studies found no effects of zinc-supplementation on mental or motor development. One study from Bangladesh found that at 5 months, zinc-supplemented infants had lower mental scores than infants in the placebo group (Hamadani et al., 2001). None of the other studies reported negative effects of zinc supplementation. Another study from Bangladesh found that at 12 months, infants who had received iron and zinc in combination had better motor scores than children who received a placebo (Black et al., 2004a). A study from Chile among term neonates found that at 12 months, although there were no differences using continuous scores on a standardized measure of mental and motor development, zinc-supplemented infants were more likely to have mental scores within normal and had higher motor quality scores, compared with infants in the placebo group. The two studies that used maternal report of motor milestones both reported benefits of zinc supplementation on early motor skills. A study from South Africa found that infants who receive a multiple micronutrient porridge with zinc achieved more milestones than infants who received the unfortified porridge (Faber et al., 2005) and a study from Zanzibar found that infants who received a supplement of zinc plus iron walked approximately one month earlier than children in the placebo group (Olney et al., 2006). A trial from Jamaica showed that zinc supplementation benefited children’s eye–hand coordination and, when zinc supplementation was introduced in combination with psychosocial stimulation, it benefited their motor scores (Meeks-Gardner et al., 2005). Four studies examined the effects of zinc supplementation on children’s behavior. One found that zinc-supplemented children were more responsive than placebo children (Ashworth et al., 1998) and one found that children who received zinc and iron had higher scores on orientationengagement than children in the placebo group (Black et al., 2004a). The final two studies found no effects on children’s behavior (Black et al., 2004b; Dhingra et al., 2004).

3.2.3 Zinc supplementation trials among school-age children Several studies have examined zinc supplementation and the academic performance of school-age children. In a cross-sectional study among stunted Guatemalan children, low zinc status was associated with low stature, high weight-for-height, and low taste acuity, but not related to chil-

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dren’s performance on the Detroit Tests of Learning Aptitudes (Cavan et al., 1993). A zinc supplementation trial among stunted school-age boys in Canada had no effect on the children’s performance on the Detroit Tests of Learning Aptitudes (Gibson et al., 1989). In contrast, first grade Chinese children who received zinc supplements together with other micronutrients had better performance than children who received the micronutrients only (Penland et al., 1997). Two studies examined the role of zinc supplementation on the psychosocial and cognitive functioning of first grade Mexican children exposed to lead. In a study of 6–8 year-old children, a six-month trial of iron and zinc supplementation did not alter the children’s scores on behavioral rating scales based on the Conners Rating Scales (Kordas et al., 2005) or on 11 cognitive tests of memory, attention, visual–spatial abilities, and learning (Rico et al., 2006). Although zinc deficiency was moderately high in the sample, many of the children had been lead exposed since birth, thus the six-month supplementation trial may not have been intense enough to overcome the long-term effects of lead exposure. A recent meta-analysis of trials of multiple micronutrient supplements, many containing zinc, among school-age children found marginal benefits in fluid intelligence and academic performance, but not crystallized intelligence (Eilander et al., 2010).

3.2.4 Zinc deficiency and mental health A recent review reported associations between low concentrations of zinc and mental health problems, particularly depression and attention deficit hyperactivity disorder (ADHD) (DiGirolamo and Ramirez-Zea, 2009). However, most of the evidence was gathered from clinical samples demonstrating lower plasma or serum zinc concentrations among patients diagnosed with depression, compared to non-depressed patients. It is unclear whether the low zinc concentration preceded the disorder or resulted from poor appetite, low dietary intake, or an immune/inflammatory response associated with the disorder. Evidence for the treatment potential of zinc for mental health outcomes comes mainly from patient populations and is strongest when zinc is given in combination with pharmacologic treatment. There is also some suggestion that lower serum zinc may be a marker of treatment resistance in depression. Less conclusive evidence exists for the effectiveness of zinc alone on mental health problems or in general community samples. Most studies linking zinc status with mental health symptoms have been observational and focused on clinical samples. For example, low concentrations of zinc have been associated with symptoms of depression and anxiety in both animals and humans (Golub et al., 1996; Hubbs-Tait et al., 2007; Takeda et al., 2007) and with ADHD symptoms (Toren et al., 1996; Arnold and DiSilvestro., 2005; Arnold et al., 2005).

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In a recent randomized-controlled trial of zinc supplementation among school-age children in Guatemala (DiGirolamo et al., 2010), zinc supplementation was given for six months. Although there were increases in the children’s serum zinc concentrations, there were no differences in children’s performance on standardized measures of mental health symptoms (depression and ADHD).

3.3 Implications for the food industry, nutritionists, and policy-makers Rates of zinc deficiency are difficult to estimate among toddlers from industrialized countries. Using dietary reports, national surveys in the UK have shown both excesses and deficiencies in vitamins and minerals, with specific deficiencies in micronutrients such as iron, zinc, and vitamin D (Turnbull et al., 2007). A longitudinal study of pre-schoolers from Tennessee compared mean nutrient intakes with recommended dietary allowances (RDA)/ adequate intakes (AI) and found high rates of deficient zinc intake (Skinner et al., 1999). In contrast, two national surveys conducted in the US (the Feeding Infants and Toddler Survey (FITS) representing over 3000 infants and toddlers and the Continuing Survey of Food Intakes of Individuals (CSFII) representing over 7000 pre-schoolers) reported that the prevalence of nutrient inadequacies was very low (<1 %) (Arsenault and Brown, 2003; Briefel et al., 2006). Both expressed concern about high rates of zinc intake, with many children exceeding the Tolerable Upper Intake Levels for zinc, although no harm has been identified. Part of the controversy may be explained by the release of the revised dietary reference intakes for zinc in 2001. The revised zinc RDA for pre-schoolers is lower than previous values (Arsenault and Brown, 2003). Zinc-fortified formula and infant cereals are primary sources of zinc for infants and toddlers. Participation in the Special Supplemental Nutrition Program for Women, Infants, and Children has been positively associated with zinc intake, particularly through infant formula, beef, and poultry (Arsenault and Brown, 2003). Recent evidence suggests that the inclusion of meat as an early complementary food, particularly for exclusively breastfed infants, is associated with improved zinc status and is well accepted by infants (Krebs et al., 2006).

3.4 Future trends In summary, there is very limited evidence linking zinc supplementation to early cognitive development or behavior. The evidence linking zinc supplementation to motor development is slightly stronger, but not conclusive.

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Many factors could interfere with clear interpretation of the zinc supplementation trials. First, zinc deficiency is difficult to document and lowincome infants presumed to be zinc deficient may not have been. Second, micronutrient deficiencies often co-occur; thus, providing zinc alone or with iron may not alleviate other nutritional problems. Third, there may be interactive effects between zinc and iron, resulting in adverse effects, with iron reducing the effects of zinc. Fourth, nutritionally deficient infants, who are smaller, less active, and less competent than better nourished infants, may be less able to elicit age-appropriate expectations from their caregivers. Fifth, it is also possible that the intervention trials were too brief or the dose of zinc supplement was insufficient. Finally, the low-income context surrounding zinc deficiency may interfere with children’s developmental progress, even with zinc supplementation. Although zinc is essential for neurological functioning, and observational studies have shown associations between low zinc concentration and negative performance and mental health status, randomized trials of zinc alone or in combination with other micronutrients have not resulted in clear benefits of zinc supplementation on children’s early cognitive or behavioral development. In conclusion, zinc supplementation among zinc deficient children has strong corrective effects on diarrhea, acute lower respiratory infections, pneumonia, and possibly early growth. Therefore, correcting zinc deficiency is an important goal to promote children’s health. However, given the revised zinc dietary reference intakes, many toddlers in industrialized countries may be exceeding the Tolerable Upper Intake Levels for zinc. Although it is unlikely that high zinc intake from food poses negative consequences for children (Arsenault and Brown, 2003), future studies should examine the effects of zinc intake among toddlers and possibly consider altering the recommended Upper Limits.

3.5 Sources of further information and advice Micronutrient Initiative (MI) is a non-profit organization with head offices in Ottawa, Canada and ‘dedicated to ensuring that the world’s most vulnerable-especially women and children in developing countries-get the vitamins and minerals they need to survive and thrive.’ (Micronutrient Initiative, 2010). MI has offices in 11 countries around the world and works with local governments and organizations to strengthen programs to ensure access to necessary vitamins and minerals, such as zinc. The International Zinc Nutrition Consultative Group (IZiNCG) (www. izinc.org) assist efforts to reduce zinc deficiency worldwide. The American Academy of Pediatrics (www.pediatrics.org) and the American Dietetic Association (www.eatright.org) are two resources that include scientifically-based feeding recommendations for infants and toddlers, with attention to necessary vitamins and minerals, such as zinc.

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3.6 References arnold l e and disilvestro r a (2005) Zinc in attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol, 15, 619–627. arnold l e, bozzolo h, hollway j, cook a, disilvestro r a, bozzolo d r, crowl l, ramadan y and williams c (2005) Serum zinc correlates with parent- and teacherrated inattention in children with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol, 15, 628–636. arsenault j e and brown k h (2003) Zinc intake of US preschool children exceeds new dietary reference intakes. Am J Clin Nutr, 78(5), 1011–1017. ashworth a, morris s s, lira p i and grantham-mcgregor s m (1998) Zinc supplementation, mental development, and behaviour in low birth weight infants in northeast Brazil. Eur J Clin Nutr, 52, 223–227. bentley m e, caulfield l e, ram m et al. (1997) Zinc supplementation affects the activity patterns of rural Guatemalan infants. J Nutr, 127, 1333–1338. black m m, (2003) Zinc supplementation and cognitive functioning. J Nutr, 133, 3927S–3931S. black m m, baqui a, zaman k, persson l a, el arifeen s, le k, mcnary s and black r e (2004a) Iron and zinc supplementation promote motor development and exploratory behavior among Bangladeshi infants. Am J Clin Nutr, 80, 903–910. black m m, sazawal s, black r e, khosla s, kumar j and menon v (2004b) Cognitive and motor development among low-income, Indian infants: the impact of birth weight, caregiving practices, and zinc supplementation. Pediatrics, 113, 1297–1305. briefel r, ziegler p, novak t and ponza m (2006) Feeding Infants and Toddlers Study: characteristics and usual nutrient intake of Hispanic and non-Hispanic infants and toddlers. J Am Diet Assoc, 106(1 Suppl 1), S84–S95. brown k h, peerson j m, rivera j and allen l h (2002) Effect of supplemental zinc on the growth and serum zinc concentrations of prepubertal children: a metaanalysis of randomized controlled trials. Am J Clin Nutr, 75, 1062–1071. castillo-duran c, perales c g, hertrampf e d, marin v b, rivera f a and icaza g (2001) Effect of zinc supplementation on development and growth of Chilean infants. J Pediatr, 138, 229–235. caulfield l e, putnick d l, zavaleta n, lazarte f, albornoz c, chen p, dipietro j a and bornstein m h (2010) Maternal gestational zinc supplementation does not influence multiple aspects of child development at 54 mo of age in Peru. Am J Clin Nutr, 92, 130–136. cavan k r, gibson r s, grazioso c f, isalgue a m, ruz m and solomons n w (1993) Growth and body composition of periurban Guatemalan children in relation to zinc status: a longitudinal zinc intervention trial. Am J Clin Nutr, 57, 344– 352. dhingra u, menon v p, sazawal s et al. (2004) Effect of fortification of milk with zinc and iron along with vitamins C, E, A and selenium on growth, iron status and development in preschool children. Pediatr Gastoenterol, 53, 7. digirolamo a m and ramirez-zea m (2009) Role of zinc in maternal and child mental health. Am J Clin Nutr, 89, 940S–945S. digirolamo a m, ramirez-zea m, wang m, flores-ayala r, martorell r, neufeld l m, ramakrishnan u, sellen d, black m m and stein a d (2010) Randomized trial of the effect of zinc supplementation on the mental health of school-age children in Guatemala, Am J Clin Nutr, 92, 1241–1250. eilander a, gera t, sachdev h s, transler c, van der knaap h c, kok f j and osendarp s j (2010) Multiple micronutrient supplementation for improving cognitive

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performance in children: systematic review of randomized controlled trials. Am J Clin Nutr, 91, 115–130. faber m, kvalsvig j d, lombard c j and benadé a j (2005) Effect of a fortified maizemeal porridge on anemia, micronutrient status, and motor development of infants. Am J Clin Nutr, 82, 1032–1039. fischer walker c l and black r e (2010) Zinc for the treatment of diarrhoea: effect on diarrhoea morbidity, mortality and incidence of future episodes. Int J Epidemiol, 39 Suppl 1, i63–i69. friel j k, andrews w l, matthew j d, long d r, cornel a m, cox m, mckim e and zerbe g o (1993) Zinc supplementation in very-low-birth-weight infants. J Pediatr Gastroenterol Nutr, 17, 97–104. gibson r s, vanderkooy p d, macdonald a c, goldman a, ryan b a and berry m (1989) A growth-limiting, mild zinc-deficiency syndrome in some southern Ontario boys with low height percentiles. Am J Clin Nutr, 49, 1266–1273. golub m s, takeuchi p t, keen c l, hendrickx a g and gershwin m e (1996) Activity and attention in zinc-deprived adolescent monkeys. Am J Clin Nutr, 64, 908–915. halas e s, eberhardt m j, diers m a and sandstead s s (1983) Learning and memory impairment in adult rats due to severe zinc deficiency during lactation. Physiol Behav, 30, 371–381. hamadani j d, fuchs g j, osendarp s j m, khatun f, huda s n and granthammcgregor s m (2001) Randomized controlled trial of the effect of zinc supplementation in the mental development of Bangladeshi infants. Am J Clin Nutr, 74, 381–386. hamadani j d, fuchs g j, osendarp s j m, huda s n and grantham-mcgregor s m (2002) Zinc supplementation during pregnancy and effects on mental development and behaviour of infants: a follow-up study. Lancet, 360, 290– 294. hambidge k m and krebs n f (2007) Zinc deficiency: a special challenge. J Nutr, 137, 1101–1105. hess s y, peerson j m, king j c and brown k h (2007) Use of serum zinc concentration as an indicator of population zinc status. Food Nutr Bull, 28(3 Suppl), S403–429. hubbs-tait l, kennedy t s, droke e a, belanger d m and parker j r (2007) Zinc, iron, and lead, relations to Head Start children’s cognitive scores and teachers’ ratings of behavior. J Am Diet Assoc, 107, 128–133. institute of medicine; food and nutrition board (2001) Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington DC: National Academy Press. kordas k, stoltzfus r j, lópez p, rico j a and rosado j l (2005) Iron and zinc supplementation does not improve parent or teacher ratings of behavior in first grade Mexican children exposed to lead. J Pediatr, 147, 632–639. lind t, lönnerdal b, stenlund h, gamayanti i l, ismail d, seswandhana r and persson l a (2004) A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants: effects on growth and development. Am J Clin Nutr, 80, 729–736. lowe n m, fekete k and decsi t (2009) Methods of assessment of zinc status in humans: a systematic review. Am J Clin Nutr, 89, 2040S–2051S. kirksey a, wachs t d, yunis f, srinath u, rahmanifar a, mccabe g p, galal o m, harrison g g and jerome n w (1994) Relation of maternal zinc nutriture to pregnancy outcome and infant development in an Egyptian village. Am J Clin Nutr, 60, 782–792.

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krebs n f, westcott j e, butler n, robinson c, bell m and hambidge k m (2006) Meat as a first complementary food for breastfed infants: feasibility and impact on zinc intake and status. J Pediatr Gastroenterol Nutr, 42, 207– 214. meeks gardner j m, powell c a, baker-henningham h, walker s p, cole t j and grantham-mcgregor s m (2005) Zinc supplementation and psychosocial stimulation: effects on the development of undernourished Jamaican children. Am J Clin Nutr, 82, 399–405. merialdi m, caulfield l, zavaleta n, figueroa a and depietro j (1999) Adding zinc to prenatal iron and folate supplements improves fetal neurobehavioral development. Am J Obstet Gynecol, 180, 483–490. micronutrient initiative (2010) Solutions for hidden hunger, available at: http:// www.micronutrient.org (accessed February 2011). olney d k, pollitt e, kariger p k, khalfan s s, ali n s, tielsch j m, sazawal s, black r, allen l h and stoltzfus r j (2006) Combined iron and folic acid supplementation with or without zinc reduces time to walking unassisted among Zanzibari infants 5- to 11-mo old. J Nutr, 36, 2427–2434. prasad a s (2003) Zinc deficiency. BMJ, 326, 409–410. penland j g, sandstead h h, alcock n w, dayal h h, chen x c, li j s, zhao f, yang j j (1997) A preliminary report: effects of zinc and micronutrient repletion on growth and neuropsychological function of urban Chinese children. J Am Coll Nutr, 16, 268–272. ramakrishnan u, nguyen p and martorell r (2009) Effects of micronutrients on growth of children under 5 y of age: meta-analyses of single and multiple nutrient interventions. Am J Clin Nutr, 89, 191–203. rico j a, kordas k, lópez p, rosado j l, vargas g g, ronquillo d and stoltzfus r j (2006) Efficacy of iron and/or zinc supplementation on cognitive performance of lead-exposed Mexican schoolchildren: a randomized, placebo-controlled trial. Pediatrics, 117, 518–527. sandstrom b (1997) Bioavailability of zinc. Eur J Clin Nutr, 51(1 Suppl), S17– S19. sazawal s, bentley m, black r e, dhingra p, george s and bhan m k (1996) Effect of zinc supplementation on observed activity in preschool children in an urban slum population. Pediatrics, 98, 1132–1137. skinner j d, carruth b r, houck k s, bounds w, morris m, cox d r, moran j 3rd and coletta f (1999) Longitudinal study of nutrient and food intakes of white preschool children aged 24 to 60 months. J Am Diet Assoc, 99(12), 1514–1521. takeda a, tamano h, kan f, itoh h and oku n (2007) Anxiety-like behavior of young rats after 2-week zinc deprivation. Behav Brain Res, 177, 1–6. tamura t, goldenberg r l, ramey s l, nelson k g and chapman v r (2003) Effect of zinc supplementation of pregnant women on the mental and psychomotor development of their children at 5 y of age. Am J Clin Nutr, 77, 1512–1516. taneja s, bhandari n, bahl r and bhan m k (2005) Impact of zinc supplementation on mental and psychomotor scores of children aged 12 to 18 months: a randomized, double-blind trial. J Pediatr, 146, 506–511. thelen e and smith l b (1994) A Dynamic Systems Approach to the Development of Cognition and Action. Cambridge, MA: MIT Press. toren p, eldar s, sela b a, wolmer l, weitz r, inbar d, koren s, reiss a, weizman r and laor n (1996) Zinc deficiency in attention-deficit hyperactivity disorder. Biol Psychiatry, 40, 1308–1310. turnbull b, lanigan j and singhal a (2007) Toddler diets in the UK: deficiencies and imbalances. 1. Risk of micronutrient deficiencies. J Fam Health Care, 17(5), 167–170.

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walravens p a, hambidge k m and koepfer d m (1989) Zinc supplementation in infants with a nutritional pattern of failure to thrive: a double-blind, controlled study. Pediatrics, 83(4), 532–538. walravens p a, krebs n f and hambidge k m (1983) Linear growth of low income preschool children receiving a zinc supplement. Am J Clin Nutr, 38(2), 195– 201. who and unicef (2004) Clinical management of acute diarrhoea, WHO/UNICEF Joint Statement, August, Geneva: World Health Organization and United Nations Children Fund. yakoob m y, theodoratou e, jabeen a, fmdad a, eisele t p, ferguson j, jhass a, rudan i, campbell h, black r e and bhutta z a (2011) Preventive zinc supplementation in developing countries: impact on mortality and morbidity due to diarrhea, pneumonia and malaria. BMC Public Health, 11(Suppl 3), S23–32.

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4 Iron deficiency and cognitive development S. J. M. Osendarp and A. Eilander, Unilever Research and Development, The Netherlands

Abstract: Iron deficiency (ID) remains the most prevalent single nutrient deficiency, affecting those in both developing and developed countries. There is strong evidence that iron deficiency anemia (IDA) is associated with poorer performance on developmental ratings in infants and with lower scores on cognitive function tests in children and that iron treatment can reverse some of these impairments. Ongoing investigations indicate that ID impacts both neurocognitive and neurobehavioral development, and intervention studies have confirmed that dopamine-dependent behaviors such as response to novelty and orientation, are among the core deficits in early ID. When moving forward in combating ID and associated impaired child development, it is important to realize that iron deficiency is not the only cause of altered development. Therefore, different intervention approaches are required and should be conducted as complementary to each other. Key words: iron, anaemia, child, cognitive development, policy.

4.1 Introduction Iron is an essential nutrient for the functioning of many biological processes, including electron transfer reactions, gene regulation, binding and transfer of oxygen and regulation of cell growth and differentiation.1 Despite continuing efforts for its control, iron deficiency (ID) remains the most prevalent single nutrient deficiency in both developing and developed countries. The World Health Organization2 estimates that worldwide, 1.6–2 billion people are anemic (Table 4.1 provides an overview of definitions of anemia and iron deficiency in infants and children). In Asia and Africa, anemia is prevalent in 38–57 % of the population, while in Europe and the Americas 10–19 % of the population is estimated to be anemic. Although ID is responsible for at least half the cases of anemia, there are other

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Table 4.1 Definitions of anemia and iron deficiency3

Age of child 6 months–5 years 6 years–11 years 12–14 years

Anemia

Iron deficiency

Hemoglobin (g/L) <110 <115 <120

Serum ferritin (μg/L) <12 <15 <15

possible causes, including genetic, infectious and other nutritional deficiencies. Estimates are that when anemia prevalence is 20 %, iron deficiency exists in 50 % of the population and when anemia prevalence is greater than 40 %, the entire population suffers from some degree of iron deficiency.4 Infants, children and women of reproductive age are at highest risk of developing ID and iron deficiency anemia (IDA), largely due to their high physiologic requirements associated with growth, combined with increased losses and poor dietary intake. Globally, almost half of pre-school aged children and pregnant women and close to one third of non-pregnant women suffer from anemia.2,4 The many risk factors that contribute to IDA in children are low birth weight, early cord clamping, maternal anemia, gastrointestinal blood loss due to infections such as Helicobacter pylori and helminth infections, limited access to iron-rich foods and diets high in iron-absorption inhibitors, and other nutritional deficiencies that affect erythropoesis. Anemia has been shown to depress immune status and resistance to infections5, lower work capacity6 and may depress child growth.7 Infants with anemia showed a reduced psychomotor and mental development, and many of these effects seem irreversible.8–9 Even ID without anemia affects cognition and motor development in children and adolescents.10–11 Traditionally, interventions to address nutritional anemia have focused on providing iron and folic acid supplements principally to pregnant women and, to a much lesser extent, children under 2 years of age. Iron supplementation in controlled experiments has proven to be highly efficacious in areas where anemia is not exacerbated by infections or malaria.12 Despite this success in controlled settings, however, there is general agreement that the effectiveness of iron supplementation in programs has been unimpressive.13 In addition, there is evidence to suggest that in areas with high presence of malaria and/or under-nutrition, non-ID children receiving iron supplements seem to be more susceptible to increased severity of malaria and other infectious diseases.14 Other strategies to combat ID should therefore also be taken into account. They include: iron fortification of staple foods, commonly used condiments and complementary foods; home-fortification of iron via the use of iron-fortified powders, crushable tablets, or spreads; biofortification of staple crops such as rice; food-based approaches to increase the intake of iron-rich foods; and public health interventions to

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control infections. For the long-term success and sustainability of nutritional anemia control programs, different intervention approaches need to be integrated and intensified, adjusted to specific local conditions and target groups. The role of iron in child development has been a topic of investigation for many decades. In this chapter, we will review the evidence to date on the effects of ID on cognitive development throughout different stages of development, the role of iron in the brain and during brain development and ‘subsequently’ the role of iron and impact of iron interventions during infant and child development (Section 4.2). In Section 4.3 we will elaborate further on these findings and give implications for food industry, nutritionists and policy-makers. Finally, in Section 4.4 we will describe a number of possible future trends with regard to scientific developments and public health developments.

4.2 Effects of iron deficiency on cognitive development 4.2.1 ID and child development A conceptual framework on how ID may impact child development (Fig. 4.1) suggests that the relationship between iron and development may be either direct through an impact on brain function and structure or indirect through changes in exploratory behavior of the anemic child, thereby affecting the caregiver behavior and the quality of parent–child interactions.15 As a result, we have strong evidence that IDA is associated with poorer performance on developmental ratings in infants16 and with lower scores on cognitive function tests and educational achievement tests in children.17 The negative impact of IDA on child development tends to be long-lasting: non-anemic children who had been iron deficient or anemic as infants had lower IQ scores at age 2–7 years compared to children who had not been anemic in the first year of life.9 Similarly, in a follow-up study from

Disadvantaged environment

Quality of parent–child interactions

Iron deficiency

Brain development and function

Behavior development

Level of child involvement with the environment

Fig. 4.1 Conceptual model of iron deficiency and child behavior.60

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Costa Rica, children who had been iron deficient as an infant scored persistently poorer on cognitive tests up to 19 years of age, and these effects were exaggerated in children from a high-risk environment, suggesting an interaction between environment or social stimulation and ID.18

4.2.2 Iron in the developing brain New insights are emerging from recent and ongoing investigations into the role of iron in neurocognitive and neurobehavioral development. The brain obtains iron primarily via transferrin and transferrin receptors expressed in endothelial cells on the brain microvasculature.19–20 There appears to be a regulatory role for adjacent astrocytes in the regulation of this uptake across the blood–brain barrier.19 The uptake of iron through the blood– brain barrier seems to be regulated and dependent on iron status,19 such that there is an increased rate when the iron status is low and a decreased rate when it is high.19,21 In rats fed on an iron deficient diet, both transferrin and iron uptake by the brain were significantly greater compared to control rats.21 In addition, this uptake process is highly selective and not reflective of overall blood–brain barrier permeability.19,22 There is a heterogeneous loss of iron from the brain with dietary iron deficiency19 suggesting that not all brain areas are equally affected and that there may be a regional regulation of uptake. ID impacts both neurogenesis as well as neurochemistry during brain development. Animal studies show structural impairments of the hippocampus in ID, whereas in the striatum a decreased arborization and affected dendrites have been observed.23 ID also results in a different location and impaired functioning of the oligodendrites in the rat brain, resulting in altered composition and amount of myelin in white matter.19,24 The importance of iron in neurochemistry is illustrated by the role of iron in the production of hormones from the monoaminergic pathways, particularly dopamine and norepinephrine.19,25–28 Non-invasive techniques, in particular magnetic resonance imaging (MRI), have been used to measure developmental patterns of iron accumulation in the developing brain and to map iron distribution in the brains of children and adolescents.29–30 The deposition of iron in the brain varies by region, and by age. The concentration of iron in the brain is highest at birth, decreases through weaning and then begins to increase coincident with the onset of myelination and an increased expression of transferrin mRNA. Regions of the brain rich in iron in adulthood (i.e., the substantia nigra, globus pallidus) are not the regions that have a high iron content in early life, when the highest concentrations of iron are found in globus pallidus, caudate nucleus, putamen and substantia nigra.31 In addition, regions of the brain that are rich in iron are not necessarily the ones to be most affected by dietary ID. Potentially, the different regional needs for iron in the brain

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during different stages of neurodevelopment could impart a differential sensitivity of brain regions to nutritional deprivation of iron. The impact of iron interventions may reverse the abnormalities in the affected brain regions, depending on when in development the iron repletion occurs. In rats, which had been on iron deficient diets from midgestation onwards, early iron treatment (at four days postpartum) normalized brain iron concentrations, monoamine concentrations and monoamine transporter and receptor densities in most brain regions. Compared to control animals, rats which had been exposed to gestational ID had lower dopamine transporter densities in caudate and substantia nigra, but these abnormalities were normalized after early iron repletion. In contrast, iron repletion later in life, at weaning, did not reverse the impact of gestational ID. The authors concluded that these findings suggested the existence of a critical window of opportunity for reversing the detrimental effects of ID in utero on brain development, at least in rats and probably also in humans.32 Iron deficiency is also known to affect neurochemistry in the developing brain. Iron deficiency during lactation in infant rats resulted in abnormal dopamine concentrations in the brain,19 and these abnormalities in dopamine metabolism and in behaviors that depend on striatal dopamine function were not completely restored after aggressive iron therapy.33 These findings strengthened the hypothesis that the sensitivity of a brain region to loss of iron during development is likely to be related to the regional development requirements for iron during that period.

4.2.2 Effect of iron on cognitive development The detrimental effects of IDA on cognitive development in children are substantial. Infants with IDA performed 0.5–1.3 SD lower on cognitive tests compared to non-deficient infants.34 However, the results of intervention trials studying the impact of iron treatment on cognitive and motor development scores in ID infants have been inconsistent. Four of six recent randomized controlled trials of iron supplementation in infancy that assessed soco-emotional behavior found a benefit from iron,35 but there were conflicting effects on cognitive performance tasks.17 A pooled analysis of eight studies in infants <27 months of age found no evidence of a beneficial effect of iron supplementation on motor or mental development as measured by the Bayley Scales of Infant Development.36 Six of these eight studies were performed in developed countries. A recent meta-analysis assessed the effects of iron supplementation on development of non-anemic infants <3 years of age using the Bayley Scales of Infant Development.37 Whereas also no benefit of iron supplementation was found on mental development based on five trials, limited evidence of three trials (of which two were conducted in western countries) suggested a positive effect on psychomotor development. In contrast, in children above the age of 2 years, iron treatment to anemic and non-anemic, ID children has shown improved

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scores on cognitive function tests.17,36,38 Similarly, a pooled analysis of four trials on iron supplementation in children older than 8–15 years of age living in developing countries resulted in modest improvements of 0.41 SD in scores on mental development, with greater benefits among initially anemic or ID children.35 In addition, findings of a more recent meta-analysis including 10 trials (including three trials performed in developed countries) in children aged 6–18 years suggest that iron supplementation significantly improves the cognitive domain of attention and concentration, while other domains seemed unaffected.38 The differential effects of iron treatment on development in children by age ( <2 years vs >2 years) may in part be due to the limited sensitivity of scales to measure differences in development in young infants. However, it also reflects the existence of a sensitive window in brain development in early infancy when effects of environmental impacts, such as ID, may cause irreversible structural brain changes. New emerging insights in the role of iron during brain development have allowed researchers to design intervention studies with sensitive measurements of child development, focusing on specific functions in areas of the brain known to be most sensitive to ID. Rocanglio et al.39 showed differences in maturation of central conduction time (CCT) of the auditory brain stem in infants who were anemic at 6 months of age compared to non-anemic infants. At 12 and 18 months, the initially anemic infants showed longer conduction times compared to the non-anemic infants, even though their iron status had been restored to normal and they were no longer anemic. Burden et al.40 used event-related potential (ERP) techniques to locate the corresponding brain areas involved during a delayed processing information task in ID infants. Compared to non-deficient infants, ID infants between 9 and 12 months of age were less able to distinguish a familiar face from a stranger’s face in a delayed processing information task as confirmed by ERP graphs, perhaps due to alterations in striatum and hippocampus in the ID infants. Changes in the hippocampus are of particular interest due to its role in the discrimination of novel from familiar stimuli in recognition memory. Also studies in older children demonstrate brain function is affected in children with ID. Otero et al.41 showed that ID children aged 8–10 years performed less well on a working memory task and had diminished ERP amplitude in frontal, central, parietal and temporal regions compared to control children. After iron supplementation, differences in cognitive and ERP measures between ID and control children disappeared. Similarly, in an earlier study, Otero et al.42 found that ID children aged 6–12 years had lower IQ scores and slower activity in the electroencephalogram (EEG) power spectrum compared to non-ID children. These studies in infants and children confirm and reinforce previous observations that ID severely impairs cognitive development. Knowledge on the role of iron in dopamine production, allowed researchers to better design tests on the impact of ID on socio-emotional

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development by focusing on behaviors that are known to be regulated by dopamine. In a cohort study of 77 9–10 month-old African–American infants, the iron sufficient infants showed best socio-emotional development, as illustrated by their scores on shyness, orientation/engagement and response to unfamiliar pictures, compared to ID anemic infants who showed the worst scores and ID infants who had intermediate scores.43 These findings are consistent with an early disruption of the dopamine system, due to iron deficiency, and contribute to a growing understanding that altered affect and response to novelty are among the core deficits in early ID.43

4.3 Implications for the food industry, nutritionists, and policy-makers ID was identified as one of the leading nutrition-related causes of impaired child development, along with stunting and iodine deficiency,44 and iron interventions therefore have the potential to contribute to a better child development. In a world where an estimated 200 million children are not reaching their full developmental potential due to preventable causes, correction of ID therefore will have significant public health impact. According to a global gathering of top economists assembled together at the Copenhagen Consensus 2008,45 micronutrient interventions for children, including iron fortification, were considered the most cost-effective solutions for solving the world’s biggest problems such as global warming, sanitation and water, conflicts, diseases and malnutrition. The addition of micronutrients to processed foods may lead to relatively rapid improvements in the micronutrient status of a population at reasonable costs, especially when existing technology and local distribution networks are used.46 When moving forward in combating ID and associated impaired child development, it is important to realize that different intervention approaches are required and should be practised as complementary to each other. Each party has a role to play and will need to take up its responsibility, as will be further described below.

4.3.1 Implications for the food industry The food industry needs to ensure the availability of tasty and attractive, low-cost, high bioavailable iron-fortified foods and work together with academia and public health partners in measuring the impact of these marketbased interventions. In addition, with its massive knowledge on consumer habits and behaviors and its marketing skills influencing consumer behavior, the food industry could be a useful partner for public health in the promotion of other interventions to improve iron status and/or child development, including the promotion of other food-based and non-food-based health behaviors and behaviors to simulate child development.

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To fortify food with iron it is important for the manufacturer to choose iron compounds that are well absorbed in the human body, i.e. high bioavailability, and at the same time do not cause unacceptable changes to the sensory properties of the food, such as taste, color and texture.47 In 2006, the World Health Organization released new guidelines for food fortification, which include recommendations for preferred iron compounds.46 Furthermore, the guidelines contain a procedure by which the fortification level can be defined. The recommended iron compounds for most food vehicles, in order of preference, are: ferrous sulphate, ferrous fumarate, encapsulated ferrous sulphate or fumarate, electrolytic iron (at twice the amount) and ferric pyrophosphate (at twice the amount). In addition to fortification of foods with iron, the bioavailability of iron can be improved by adding ascorbic acid in a 2 : 1 molar ratio (ascorbic acid : iron). For foods high in phytate, this ratio can be increased to 4 : 1.48 Removing phytic acid is another way to improve the bioavailability of iron. Phytic acid which is present in cereal- and legume-based foods can inhibit iron absorption. Phytic acid can be degraded by using phytases.49 Furthermore, the addition of ethylenediaminetetraacetic acid (EDTA) complexes has been proven to be effective in increasing iron absorption from ferrous sulphate-fortified foods.50–51 EDTA complexes, such as Na2EDTA and CaNa2EDTA are permitted food additives and recommended for mass fortification of high-phytate cereal flours and sauces with a high peptide content.46 In order to ensure the success of iron fortification programs, it is important to monitor the effectiveness of the programs in order to evaluate whether the target population are reached and micronutrient status improves.46

4.3.2 Implications for nutritionists and policy-makers Public health nutritionists and policy-makers should be aware that correction of iron deficiency will contribute to a better child development, particularly in those areas of the world where iron deficiency is endemic. However, it is important to realize that a number of other factors need to be taken into account as well in order to optimize cognitive development. Poverty, malnutrition, poor health and unstimulating home evironments have been identified as preventable causes in children for not reaching their full developmental potential.44 While ID was identified as one of the leading nutrition-related causes for impaired child development, also stunting, iodine and other micronutrient deficiencies are contributing to this public health problem.52 Furthermore, other causes of ID and IDA, such as worm infestations and deficiencies of vitamin A, folate and cobalamin, also need to be tackled. Therefore, policy-makers should develop public health strategies that ensure an adequate intake of energy, protein, essential fats and micronutrients (e.g. iodine, iron, vitamin A, zinc and B-vitamins) along with programs to improve health services and educational systems.34 Programs

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should target children at all ages; however, the impact of the interventions is thought to be largest when started before the age of 2–3 years when the brain develops most rapidly.34 While food supplements have been effective in reducing anemia in pregnant women and food fortification is an effective strategy to combat micronutrient deficiencies in children older than 2 years, it is more difficult to target infants and young children.46 Older children usually consume adequate amounts of foods prepared in the household. In contrast, younger children consume much smaller amounts and may not yet eat the same food items as other household members. In addition, rapid growth during the first few years of life necessitates higher requirements for micronutrients per kg body weight in infants and young children compared to older children and adults.53 Therefore, infants and young children may not receive adequate amounts of micronutrients through fortified foods targeted at the general population. Fortification of complementary foods or condiments especially designed to meet the nutritional requirements of infants and young children, along with promotion of continued and adequate breastfeeding, has been shown to be efficacious in improving micronutrient status in this vulnerable age group. To reach vulnerable and low-income groups in developing countries, home-fortification with iron has been shown to be a successful strategy to improve iron status. Iron-fortified powders (sprinkles) have been efficacious in improving iron status and reducing anemia in infants and young children in malaria54–56 and non-malaria57 endemic regions. In addition, iron-fortified sprinkles were found to be acceptable and programmatically feasible in large-scale programs and were effective in reducing anemia rates.58–59

4.4 Future trends 4.4.1 Scientific developments Future science will provide us with more insights into mechanisms whereby iron interventions impact brain and child development at different ages. Simultaneously, however, future science should provide knowledge on how best to bring these insights to the field and help to reduce the public health issues of ID and anemia. In addition, it is important to perform a risk– benefit analysis to take into account safety issues due to varying needs for different populations (e.g. genetic variation in iron uptake) and regions (e.g. malaria endemic versus non-malaria endemic). Different scientific disciplines, including neuroscientists, child psychologists, iron physiologists and public health nutritionists will have to work together more in translational research to make this happen.60 Research needs in the area of ID and child development include: 1) More precise measurements of the impact of iron interventions on brain development using a combination of techniques. In particular, the

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impact of iron interventions on iron accumulation in the different brain areas in different stages of development needs to be evaluated and this needs to be associated with functional benefits such as improved performance in certain cognitive domains.60 2) The development of more precise measurement techniques to measure child development in field settings. The effect of nutritional interventions on cognitive performance in children is usually measured through a set of psychological assessments, such as the Bayley Scales of Infant Development for infants and young children and the Kaufman Assessment Battery for Children and Wechsler Intelligence Scales for Children for children older than 3 years of age. For a robust assessment of a particular cognitive domain, two or three different tests per domain are required. In addition, for future studies in developing countries in particular, the cognitive tests need a thorough adaptation which is essential to ensure their validity in a local setting. Finally, methods to assess cognitive performance in children need to be sufficiently sensitive to detect the relatively small effects of iron interventions. Therefore, it is important to use well-adapted valid cognitive tests with adequate psychometric properties. More advanced measures such as structural and functional brain imaging techniques may be added to investigate the effects of iron in the brain. Combining brain imaging techniques with the psychological assessments in future trials is recommended to more precisely understand the role of iron in the brain and relate this to functional outcomes. However, this would require adaptation of the current available technologies and equipment to enable the application of these new techniques in large-scale field studies. Research needs in the area of ID control and prevention have been reviewed recently61 and include: 1) Scaling up what works: in particular iron supplements for pregnant women, immediate and exclusive breastfeeding and delayed cord clamping. 2) Evaluation of alternative interventions that are likely to work, to find the most cost-effective strategies for a given social, economic and epidemiological context, in particular related to the implementation of appropriate complementary feeding interventions. 3) Efficacy research to discover promising practices where we lack proven interventions or where proven interventions are not feasible anymore. Examples are the search for efficacious and safe interventions in infants younger than 6 months at high risk of ID, and to investigate alternative approaches for low-dose, high-bioavailable iron sources in malaria endemic areas.14 4) Basic research to elucidate physiological processes and mechanisms underlying the risks and benefits of supplemental iron for children exposed to infectious diseases, especially malaria.

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4.4.2 Public health developments At UNICEF’s world summit for children in 1990, the United Nations agreed to reduce iron deficiency by a third by 2010.62 However, despite continued global initiatives for its control, this goal was not met and in 2010 anemia still remained the most common preventable micronutrient deficiency. An important cause of the ineffectiveness of many programs has been an inability to develop a sustainable approach in reaching the most vulnerable segments of society with appropriate, cost-effective solutions.13 Innovative approaches are needed to improve the reach of existing programs. Combined intervention approaches can become reality when taking advantage of the current momentum in the public and private sector to line up together in innovative partnerships. A limited willingness by governments and policy-makers to invest sufficiently in large-scale anemia-control programs may also have caused lack of progress in the control of anemia.13 Expressing the benefits of prevention of IDA in economic terms may help to convince policy-makers to invest in public health strategies. Alderman & Horton63 identify six categories that yield economic benefits from improved nutrition: 1) 2) 3) 4) 5) 6)

reduced infant and child mortality; reduced costs of health care for neonates, infants and children; productivity gain from improved physical capacity; productivity gain from increased cognitive capacity; reduction of costs of chronic diseases; intergenerational benefits through improved health.

With regard to the productivity gain from increased cognitive capacity, it is estimated that the impact of ID on cognitive losses during childhood results in an estimated 2.5 % loss of earnings during adulthood.63 The costs for achieving the reductions in IDA through mass fortification programs are estimated to be $0.10–1.00 per person per year, with a benefit-to-cost ratio of 6 : 1 (physical benefits to adults) to 9 : 1 (when also estimated cognitive benefits to children are included). Hence, there is now considerable evidence that not addressing iron deficiency will cost countries up to 2 % of their GNP and impair the intellectual development of their children and future productivity. The international and national health partners need to get firmly behind these messages and initiatives, and should actively contribute to improving iron nutrition and child development, as a costeffective investment for future generations.

4.5 Sources of further information and advice • Kraemer K, Zimmermann MB (eds), Nutritional Anemia. Basel: Sight and Life Press 2007.

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• Allen L, de Benoist B, Dary O, Hurrell R (eds), Guidelines on Food Fortification with Micronutrients. Geneva: World Health Organization and Food and Agricultural Organization of the United Nations 2006.

4.6 References 1. beard j l. Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr 2001;131:568S–79S. 2. who. Worldwide prevalence of anaemia 1993–2005: WHO Global Database on anaemia. de Benoist B, McLean E, Egli I, Cogswell M. (eds) Geneva: World Health Organization 2008. 3. who, UNICEF, United Nations University, Iron deficiency anaemia. Assessment, Prevention and Control. A Guide for Programme Managers. Geneva: World Health Organization 2001. 4. mclean e, egli i, de benoist b, wojdyla d, cogswell m. Worldwide prevalence of anemia in pre-school aged children, pregnant women and non-pregnant women of reproductive age. In: Kraemer K, Zimmermann MB (eds), Nutritional Anemia. Basel: Sight and Life Press 2007:1–12. 5. oppenheimer s j. Iron and its relation to immunity and infectious disease. J Nutr 2001;131:616S–33S. 6. haas j d, brownlie i v. Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship. J Nutr 2001;131:676S–90S. 7. sachdev h p s, Gera T, Nestel P. Effect of iron supplementation on physical growth in children: systematic review of randomised controlled trials. Public Health Nutr 2006;9:904–20. 8. lozoff b, jimenez e, hagen j, mollen e, wolf a w. Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy. Pediatrics 2000;105:E51. 9. lozoff b, beard j, connor j, barbara f, georgieff m, schallert t. Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr Rev 2006;64:S34–S43. 10. stoltzfus r j, kvalsvig j d, chwaya h m et al. Effects of iron supplementation and anthelmintic treatment on motor and language development of preschool children in Zanzibar: double blind, placebo controlled study. BMJ 2001;323: 1389–93. 11. beard j. Recent evidence from human and animal studies regarding iron status and infant development. J Nutr 2007;137:524S–30S. 12. mannar v. The case for urgent action to address nutritional anemia. In: Kraemer K, Zimmermann MB (eds), Nutritional Anemia. Basel: Sight and Life Press 2007:13–18. 13. darnton-hill i, paragas n, cavalli-sforza t. Global perspectives: accelarating progress on preventing and controlling nutritional anemia. In: Kraemer K, Zimmermann MB (eds), Nutritional Anemia. Basel: Sight and Life Press 2007: 359–82. 14. Conclusions and recommendations of the WHO Consultation on prevention and control of iron deficiency in infants and young children in malaria-endemic areas. Food Nutr Bull 2007;28:S621–S627. 15. black m m, lozoff b. Nutrition and child development. In: Haith M M, Benson J B (eds), Encyclopedia of Infant and Child Development. Oxford, UK: Elsevier Inc. 2008:449–59. 16. lozoff b, georgieff m k. Iron deficiency and brain development. Semin Pediatr Neurol 2006;13:158–65.

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17. grantham-mcgregor s, ani c. A review of studies on the effect of iron deficiency on cognitive development in children. J Nutr 2001;131:649S–66S. 18. lozoff b, jimenez e, smith j b. Double burden of iron deficiency in infancy and low socioeconomic status: a longitudinal analysis of cognitive test scores to age 19 years. Arch Pediatr Adolesc Med 2006;160:1108–13. 19. beard j. Iron deficiency alters brain development and functioning. J Nutr 2003;133:1468S–72S. 20. han j, day j r, connor j r, beard j l. Gene expression of transferrin and transferrin receptor in brains of control vs. iron-deficient rats. Nutr Neurosci 2003;6:1–10. 21. taylor e m, crowe a, morgan e h. Transferrin and iron uptake by the brain: effects of altered iron status. J Neurochem 1991;57:1584–92. 22. crowe a, morgan e h. Iron and transferrin uptake by brain and cerebrospinal fluid in the rat. Brain Res 1992;592:8–16. 23. rao r, tkac i, townsend e l, gruetter r, georgieff m k. Perinatal iron deficiency alters the neurochemical profile of the developing rat hippocampus. J Nutr 2003;133:3215–21. 24. beard j l. Why iron deficiency is important in infant development. J Nutr 2008;138:2534–6. 25. beard j l, wiesinger j a, connor j r. Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats. Dev Neurosci 2003;25:308–15. 26. bianco l e, wiesinger j, earley c j, jones b c, beard j l. Iron deficiency alters dopamine uptake and response to L-DOPA injection in Sprague-Dawley rats. J Neurochem 2008;106:205–15. 27. burhans m s, dailey c, beard z et al. Iron deficiency: differential effects on monoamine transporters. Nutr Neurosci 2005;8:31–8. 28. burhans m s, dailey c, wiesinger j, murray-kolb l e, jones b c, beard j l. Iron deficiency affects acoustic startle response and latency, but not prepulse inhibition in young adult rats. Physiol Behav 2006;87:917–24. 29. dwork a j, lawler g, zybert p a et al. An autoradiographic study of the uptake and distribution of iron by the brain of the young rat. Brain Res 1990;518:31–9. 30. aoki s, okada y, nishimura k et al. Normal deposition of brain iron in childhood and adolescence: MR imaging at 1.5 T. Radiology 1989;172:381–5. 31. beard j l, connor j d, jones b c. Brain iron: location and function. Prog Food Nutr Sci 1993;17:183–221. 32. beard j l, unger e l, bianco l e, paul t, rundle s e, jones b c. Early postnatal iron repletion overcomes lasting effects of gestational iron deficiency in rats. J Nutr 2007;137:1176–82. 33. felt b t, lozoff b. Brain iron and behavior of rats are not normalized by treatment of iron deficiency anemia during early development. J Nutr 1996;126:693–701. 34. engle p l, black m m, behrman j r et al. Child development in developing countries 3 – Strategies to avoid the loss of developmental potential in more than 200 million children in the developing world. Lancet 2007; 369:229–42. 35. lozoff b. Iron deficiency and child development. Food Nutr Bull 2007; 28:S560–S571. 36. sachdev h p s, gera t, nestel p. Effect of iron supplementation on mental and motor development in children: systematic review of randomised controlled trials. Public Health Nutr 2005;8:117–32. 37. szajewska h, ruszczynski m, chmielewska a. Effects of iron supplementation in nonanemic pregnant women, infants, and young children on the mental performance and psychomotor development of children: a systematic review of randomized controlled trials. Am J Clin Nutr 2010;91:1684–90.

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38. falkingham m, abdelhamid a, curtis p, fairweather-tait s, dye l, hooper l. The effects of oral iron supplementation on cognition in older children and adults: a systematic review and meta-analysis. Nutr J 2010;9:4. 39. roncagliolo m, garrido m, walter t, peirano p, lozoff b. Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brainstem responses. Am J Clin Nutr 1998; 68:683–90. 40. burden m j, westerlund a j, armony-sivan r et al. An event-related potential study of attention and recognition memory in infants with iron-deficiency anemia. Pediatrics 2007;120:e336–e345. 41. otero g a, pliego-rivero f b, porcayo-mercado r, mendieta-alcantara g. Working memory impairment and recovery in iron deficient children. Clin Neurophysiol 2008;119:1739–46. 42. otero g a, aguirre d m, porcayo r, fernandez t. Psychological and electroencephalographic study in school children with iron deficiency. Int J Neurosci 1999;99:113–21. 43. lozoff b, clark k m, jing y, armony-sivan r, angelilli m l, jacobson s w. Doseresponse relationships between iron deficiency with or without anemia and infant social-emotional behavior. J Pediatr 2008;152:696–702. 44. grantham-mcgregor s, cheung y b, cueto s, glewwe p, richter l, strupp b. Child development in developing countries 1 – Developmental potential in the first 5 years for children in developing countries. Lancet 2007;369:60–70. 45. copenhagen business school. Global Crises, Global Solutions: Costs and Benefits. Cambridge: Cambridge University Press 2009. 46. allen l, de benoist b, hurrell r f, dary o. Guidelines on Food Fortification With Micronutrients. Geneva: World Health Organization and Food and Agriculture Organization of the United Nations 2006. 47. hurrell r f, egli i. Optimizing the bioavailability of iron compounds for food fortification. In: Kraemer K, Zimmermann MB (eds), Nutritional Anemia. Basel: Sight and Life Press 2007:77–98. 48. lynch s r, stoltzfus r j. Iron and ascorbic acid: proposed fortification levels and recommended iron compounds. J Nutr 2003;133:2978S–84S. 49. hurrell r f. Phytic acid degradation as a means of improving iron absorption. Int J Vitam Nutr Res 2004;74:445–52. 50. hurrell r f, reddy m b, burri j, cook j d. An evaluation of EDTA compounds for iron fortification of cereal-based foods. Br J Nutr 2000;84:903–10. 51. macphail a p, patel r c, bothwell t h, lamparelli r d. EDTA and the absorption of iron from food. Am J Clin Nutr 1994;59:644–8. 52. walker s p, wachs t d, gardner j m et al. Child development in developing countries 2 – Child development: risk factors for adverse outcomes in developing countries. Lancet 2007;369:145–57. 53. dewey k g, brown k h. Update on technical issues concerning complementary feeding of young children in developing countries and implications for intervention programs. Food Nutr Bull 2003;24:5–28. 54. zlotkin s, arthur p, schauer c, antwi k y, yeung g, piekarz a. Homefortification with iron and zinc sprinkles or iron sprinkles alone successfully treats anemia in infants and young children. J Nutr 2003;133:1075–80. 55. zlotkin s, antwi k y, schauer c, yeung g. Use of microencapsulated iron(II) fumarate sprinkles to prevent recurrence of anaemia in infants and young children at high risk. Bull World Health Organ 2003;81:108–15. 56. zlotkin s, arthur p, antwi k y, yeung g. Treatment of anemia with microencapsulated ferrous fumarate plus ascorbic acid supplied as sprinkles to complementary (weaning) foods. Am J Clin Nutr 2001;74:791–5.

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57. hyder z, haseen f, rahman m, tondeur m c, zlotkin s. Effect of daily versus once weekly home fortification with sprinkles on haematological and iron status amoung young children in rural Bangladesh. Food Nutr Bull 2007;28:156–64. 58. de pee s, moench-pfanner r, martini e, zlotkin s, darnton-hill i, bloem m w. Home-fortification in emergency response and transition programming: experiences in Aceh and Nias, Indonesia. Food Nutr Bull 2007;28:189–97. 59. menon p, ruel m t, loechl c u et al. Micronutrient Sprinkles reduce anemia among 9- to 24-mo-old children when delivered through an integrated health and nutrition program in rural Haiti. J Nutr 2007;137:1023–30. 60. osendarp s j m, murray-kolb l, black mm. Case study on iron in mental development: In memory of John Beard (1947–2009). Nutr Rev 2010;68:48S–52S. 61. stoltzfus r j. Research needed to strengthen science and programs for the control of iron deficiency and its consequences in young children. J Nutr 2008;138:2542–6. 62. unicef. World Summit for Children. New York: United Nations 1990. 63. alderman h, horton s. The economics of addressing nutritional anemia. In: Kraemer K, Zimmermann MB (eds), Nutritional Anemia. Basel: Sight and Life Press 2007:19–35.

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5 Iodine and cognitive development S. A. Skeaff, University of Otago, New Zealand

Abstract: Iodine is an integral component of the thyroid hormones, which are needed for normal growth and development, particularly of the brain and central nervous system. A lack of iodine in the diet is the single most common cause of preventable mental retardation in the world. Cretinism has been suggested as the severe end of a spectrum of effects on cognition that continues in varying degrees of intellectual impairment to normality as iodine status improves. This view implies that anyone who is iodine deficient may be at risk of sub-optimal cognitive and psychomotor function. Key words: iodine, iodine deficiency, cognition, cretinism, children.

5.1 An overview of iodine, thyroid hormones, and the consequences of iodine deficiency Iodine is an essential micronutrient and is an integral component of the thyroid hormones. The thyroid hormones play a critical role in maintaining the body’s metabolic rate and in normal growth and development. They regulate many important biochemical reactions in the body. Organs such as the developing brain, muscle, heart, pituitary gland, and kidney are especially dependent on thyroid hormones. Not surprisingly a decrease in the production of the thyroid hormones can have significant repercussions for the body.

5.1.1 Synthesis of thyroid hormones Iodine is ingested in several different forms from the diet and reduced to iodide in the gut before being rapidly absorbed. Once absorbed, iodide follows one of two pathways: 90 % is filtered by the kidneys and excreted in the urine, while the remaining 10 % is taken up by the thyroid gland. The thyroid gland is a globular, butterfly-shaped organ found at the base of the neck, made up of spherical follicles lined with epithelial cells

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Colloid Thyrocyte

(T4) (T3) DIT MIT DIT DIT Follicle Thyroglobulin

Endocytosis

Sodium-iodine transporter T4, T3 Iodide

Fig. 5.1 Simplified schematic of thyroid follicle and pathway of iodide incorporation into the tyrosyl residues of thyroglobulin to form mono-iodotyrosine (MIT) and di-iodotyrosine (DIT) and subsequent release of thyroid hormones.

or thyrocytes and a lumen filled with a secretory substance called colloid (see Fig. 5.1) (Braverman and Utiger, 2005). A sodium–iodide symporter protein located at the basal membrane of the thyrocyte actively transports iodide up a concentration gradient, effectively trapping the iodide in the thyroid gland. Iodide then migrates to the apical membrane of the thyrocyte and crosses into the follicular lumen. Thyroperoxidase and hydrogen peroxidase oxidize iodide, which is attached to tyrosyl residues of thyroglobulin (Tg) to form mono-iodotyrosine (MIT) and diiodotyrosine (DIT). MIT and DIT are coupled to make tri-iodothyronine (T3) and thyroxine (T4) within the thyroglobulin (Tg) molecule; T4 is the inactive precursor of T3. Tg enters the thyrocyte by endocytosis of the colloid and is proteolysed releasing T3 and T4, which subsequently enter the circulation (Braverman and Utiger, 2005). Within the blood, more than 99 % of the thyroid hormones are bound to proteins including thyroxinebinding globulin, transthyretin, albumin, and lipoproteins (Braverman and Utiger, 2005). At receptors on the surfaces of target cells in organs around the body, T4 is converted to T3 by various iodothyronine 5′-deiodinase enzymes. The half-life of T4 is approximately seven days but only 24 hours for T3. The majority (∼80 %) of T3 is formed extra-thyroidally from deiodination of T4.

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5.1.2 Regulation of the thyroid hormones Regulation of the thyroid hormones involves a negative feedback mechanism between the pituitary gland and the thyroid gland. When availability of iodine is low, there is an increase in the activity of the sodium/iodide transporter protein; a progressive increase in the ratio of MIT to DIT and T3 to T4, leading to preferential synthesis of T3; a decrease in the amount of fully iodinated Tg; proteolysis of Tg; growth and division of the thyrocytes, thereby causing an increase in the size of the gland or goitre; and release from the thyroid gland of more T3 than T4 (Obregon et al., 2005). Thus, circulating T4 decreases, serum T3 concentration remains unchanged and may even increase, and thyroid-stimulating hormone (TSH) increases. Goitre is an adaptive mechanism to an environment that contains insufficient dietary iodine. It is important to note that these mechanisms are very efficient in the adult human but are not applicable to the foetus and newborn as thyroid autoregulation is not fully operative. Furthermore, when dietary iodine is very low, as observed in severe iodine deficiency, the thyroid may be unable to respond sufficiently, resulting in hypothyroidism (i.e. decreased T3 and elevated TSH).

5.1.3 The role of the thyroid hormones The thyroid hormones play critical roles in growth, metabolism, and cellular differentiation in the human body (Braverman and Utiger, 2005). Nuclear T3 receptors are found in the cells in the pituitary, liver, heart, kidney, and brain, and by influencing genetic transcription in these tissues, the thyroid hormones can modify their physiological functions. Thyroid hormone mediated gene transcription in the pituitary gland results in an increase in growth hormone synthesis and secretion, causing growth. The basal metabolic rate is influenced through the systemic effects of the thyroid hormones on respiratory and heart function, increasing both heart rate and respiratory rate resulting in increased oxygen consumption. In liver cells, thyroid hormones regulate carbohydrate metabolism and lipogenesis (Braverman and Utiger, 2005). However, one of the most critical roles that the thyroid hormones play is in brain development. Nutrition can influence brain development in three ways: (i) on the macrostructure of the brain (i.e. differentiation of brain cells); (ii) on the microstructure of the brain (i.e. myelination); and (iii) via neurotransmitters (Hughes and Bryan, 2003; Bryan et al., 2004). Changes to the macrostructure and microstructure of the brain or the ‘neural architecture’ are likely to be long-term and may have a bigger impact on future brain development than changes in neurotransmitters. With regard to effects on cognition, the influence of iodine on the macrostructure and microstructure of the brain would be expected to have effects on overall cognition and IQ, while the influence of iodine on neurotransmitters may affect specific aspects of cognition such as processing speed or memory and be short-term (Isaacs and Oates, 2008).

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The elucidation of the role of iodine in the brain is in its early stages, with the majority of research to date focusing on the role of iodine and thyroid hormones in pregnancy and early infancy. Thyroid hormones are involved in myelination of the central nervous system, which begins in early in the second trimester of pregnancy and continues until 40 years of age; hence, iodine has the potential to mediate its effect throughout childhood and into adulthood.

5.1.4 Iodine deficiency disorders The term iodine deficiency disorders (IDD) was coined by Basil Hetzel to describe the wide range of adverse affects of iodine deficiency on the body (Table 5.1) (Hetzel and Dunn, 1989). The most critical period is from the first trimester of pregnancy to the third year after birth, the period when the brain grows and develops rapidly but, as stated earlier, the brain continues to develop throughout childhood and into early adulthood. Impaired brain development, resulting in poor cognition and psychomotor skills, is the most serious adverse effect of iodine deficiency, of which the most extreme example is cretinism. The presence of cretinism in a community is said to be the tip of the ‘IDD iceberg’ (Chen and Hetzel, 2010).

5.1.5 Assessment of iodine status Because approximately 90 % of dietary iodine is excreted in the urine (Nath et al., 1992), urinary iodine excretion can provide a good estimate of iodine intake. Iodine status is typically assessed by determining the median urinary iodine concentration (UIC) of the population; adequate iodine status occurs with a median UIC >100 μg/L (>150 μg/L in pregnant women), while a median UIC of 50–99 μg/L indicates mild iodine deficiency, 20–49 μg/L moderate iodine deficiency, and <20 μg/L severe iodine deficiency (WHO, UNICEF and ICCIDD, 2001). The concentration of serum T3 and T4 can be measured; however, these only fall outside normal references ranges when iodine deficiency is severe, so are not recommended for the routine assessment of iodine status. Nonetheless, it appears that even if total T3 and T4 concentrations in the blood are normal, sub-optimal levels of thyroid hormones in the brain can occur. Goitre can be assessed by palpation; however, this is not particularly sensitive in very young children or when there is only a small increase in thyroid volume. Thyroid volume can also be measured using ultrasonography, although reference ranges have only be published for children aged 5–15 years (Zimmermann et al., 2003). Increasingly, serum Tg is being used as a surrogate marker of thyroid volume, as it appears to be more sensitive to mild iodine deficiency than T3 and T4 and responds more quickly to short-term changes in iodine status than thyroid volume (Vejbjerg et al., 2009).

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Table 5.1 The spectrum of iodine deficiency disorders throughout the life cycle Foetus

Neonate Child and Adolescent Adult

Abortions Stillbirth Congenital abnormalities Increased perinatal mortality Neurological cretinism Mental deficiency Deaf mutism Spastic diplegia Squint Mxyeodematous cretinism Dwarfism Mental deficiency Neonatal goitre Neonatal hypothyroidism Goitre Juvenile hypothyroidism Impaired mental function Retarded physical development Goitre with its complications Hypothyroidism Impaired mental function Iodine-induced hyperthyroidism

Source: Hetzel et al., 1990.

Foods that are rich sources of iodine are generally derived from the sea and include fish, seafood, and kelp. Dairy products provide a major contribution to the iodine intake of diets in many countries because the mammary gland also contains a sodium–iodide symporter and is able to concentrate iodine into cow’s milk. The amount of iodine in the soil will be reflected in the concentration of iodine in water and in foods grown in that soil; thus, in regions with low levels of soil iodine, the amount of iodine in cereals, fruits, and vegetables will also be low. A low soil iodine concentration is common in many parts of the world. It is estimated that almost two billion people worldwide consume diets lacking in iodine, making iodine deficiency one of the most common micronutrient deficiencies in the world.

5.2 The effect of iodine deficiency on cognition 5.2.1 The role of thyroid hormones in foetal brain development Three animal models have been used to elucidate the role of iodine in brain function; initially work was done in sheep and the marmoset, and then in the rat. Scientists have also studied brain development in human infants from terminated or aborted pregnancies (Morreale De Escobar

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et al., 2007). Together, these studies have led to two main findings: first, both maternal and foetal hormones are needed for normal brain development; and second, intracellular brain T3 is dependent on T4 and not T3 concentration. This explains why, even if T3 concentrations remain normal, suggesting no evidence of clinical hypothyroidism, cerebral hypothyroidism may occur, causing adverse effects on brain development and function. Animal and human studies have shown that nuclear receptors for thyroid hormones are present in the foetal brain from ∼8–9 weeks gestation, and reach adult levels by 18 weeks gestation. Maternal T4 is found in embryonic cavities soon after conception (Morreale De Escobar et al., 2007). Before mid-gestation, the mother is the only source of cerebral T3, which is generated locally by conversion of maternal free T4 through type II 5′iodothyronine deiodinase activity (D2). The concentration of D2 is highest in the cerebral cortex before mid-gestation. D3 is another deiodinase enzyme and the major physiological deactivator of thyroid hormones (Obregon et al., 2005). D3 is thought to be important to prevent a surge in maternal free T4, which could be caused by iodine deficiency and might hinder the development of the cerebral cortex. D3 is found in high concentrations in the midbrain, basal ganglia, brain stem, spinal cord, and hippocampus until mid-gestation, from which time it declines. Morreale de Escobar et al. suggest that D3 protects brain regions from excessive T3 until differentiation is required (Morreale De Escobar et al., 2007). Furthermore, they state that both a very high and low concentration of free T3 and free T4 could alter the ‘timely sequence of thyroid-sensitive developmental events in the human brain’. The full development of the pituitary-portal vascular system in the foetus takes place ∼18–20 weeks gestation, although the foetus does synthesise thyroid hormones, albeit at low levels, prior to this time. After the onset of foetal thyroid function, both T4 and free T4 concentrations steadily increase with foetal age, reaching maternal and adult concentrations by the beginning of the third trimester. In a review on the topic, Zoeller and Rovet discuss the role of thyroid hormones on brain development using data obtained from studies of maternal hypothyroidism, hypothyroxinaemia, and congenital hypothyroidism (Zoeller and Rovet, 2004). They suggest that decreased thyroid hormones early in pregnancy may cause problems in visual attention, visual processing, and gross motor skills, a lack of thyroid hormones later in pregnancy results in further problems with visual skills, slower processing speeds, and fine motor skills, while after birth, a lack of thyroid hormones affects language and memory. It is important to note that low thyroid hormones in these and other models are caused by thyroid dysfunction or disease, and not by iodine deficiency per se. Despite this distinction, the assumption made by scientists working in this area is that the functional consequences of low thyroid hormones, regardless of origin, are the same.

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5.2.2 Severe iodine deficiency and cretinism Cretinism is the most serious IDD and occurs when a pregnant women is severely iodine deficient. The definition of cretinism involves three features: (i) an association with endemic goitre (i.e. prevalence of goitre >5 %) and severe iodine deficiency; (ii) clinical symptoms which includes some form of mental deficiency and/or defects in hearing, speech, stance, gait, hypothyroidism, and stunted growth; and (iii) when iodine deficiency is corrected in the area cretinism is no longer observed (WHO, UNICEF and ICCIDD, 2001). There are two main types of cretinism (Hetzel et al., 1990; Chen and Hetzel, 2010). Neurological cretinism is characterised by mental retardation, deaf mutism, squint, spastic diplegia, and disorders of stance and gait. Myxoedematous or hypothyroid cretinism is less common and characterised by mental retardation (although less severe than in neurological cretinism), dwarfism, and hypothyroidism with associated physical symptoms (e.g., coarse and dry skin, husky voice, delayed sexual maturation). Some countries and regions have a higher prevalence of one type of cretinism than the other, and sometimes the symptoms of both types of cretinism can manifest in the same individual. A study of 112 cretins (neurological, myxoedematous, and mixed) living in Thailand reported that their mean IQ score was 30.8 ± 8.8 (Rajatanavin et al., 1997). In addition to the presence of cretins in a community, Chen and Hetzel state that mild mental retardation (IQ 50–69) is found in 5–15 % of children living in areas of endemic cretinism; these children are sometimes referred to as ‘sub-cretins’ (Chen and Hetzel, 2010). Other factors such as the presence of goitrogens in the diet, thyroid immunity, and interactions with other trace elements such as selenium have also been postulated to have a role in the development of cretinism (Zimmermann, 2009). Nonetheless, the lack of iodine in the diets of pregnant women in the first trimester appears to be a common factor in both forms of cretinism, suggesting that maternal hypothyroidism is responsible for irreversible damage to the foetal brain. In the landmark trial of 165 000 people living in an area of Papua New Guinea with severe iodine deficiency and endemic cretinism (Pharoah et al., 1971), families were allocated to iodine (iodised oil) or placebo (saline) and subsequent follow-up studies of the original cohort found that an injection of iodised oil before conception or in early pregnancy reduced the incidence of cretinism and improved the motor and cognitive functions of children compared with placebo treatment. Another study was undertaken in 1990 in a remote province in China with endemic cretinism (Cao et al., 1994). The effect of iodised oil given during pregnancy and to children up to 2 years of age on neurological outcomes was investigated by comparing treated children with untreated children at two years (Cao et al., 1994), and again when treated children were school-aged (O’Donnell et al., 2002). Children of mothers given iodine earlier in pregnancy had improved cognitive outcomes compared to mothers given iodine later in pregnancy and to children treated after birth.

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30

40

50

Cretinism

60

70

80

90

100

Sub-cretins

Severe

Moderate Mild Iodine deficiency

Fig. 5.2 The estimated effect of various degrees of iodine deficiency on IQ score.

Cretinism has been suggested to be the severe end of a spectrum of effects on cognition that continues in varying degrees of intellectual impairment to normality as iodine status improves. Iodine deficiency is the single most common cause of preventable mental retardation in the world. This view implies that anyone who is iodine deficient may be at risk of suboptimal cognitive and psychomotor function. Figure 5.2 illustrates the estimated effect different degrees of iodine deficiency could have on IQ score. Poor cognitive and psychomotor development may be a result of irreversible damage sustained early in life when the central nervous system is developing, but may also be exacerbated by a current poor iodine status (Delange, 2001), which may be reversible. Although there is overwhelming evidence showing that severe iodine deficiency can cause a variety of adverse effects on neurodevelopment, there is less but growing data to show that moderate to mild iodine deficiency may have detrimental effects.

5.2.3

The effect of moderate and mild iodine deficiency in pregnancy on cognition A number of studies have been undertaken in women living in areas of adequate iodine status who have low T4 concentrations in pregnancy; as stated earlier, such studies are utilised by iodine researchers to examine the effects of low thyroid hormones on neurodevelopment. Pop et al reported that Dutch women with free T4 < 10th percentile had children with poorer psychomotor development at 10 months of age (Pop et al., 1999), and again at 1 and 2 years of age (Pop et al., 2003), than children whose mothers had higher serum T4 levels, despite living in an environment of adequate iodine

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intake. Haddow et al. reported that American women with serum TSH concentrations higher than the 98th percentile in pregnancy had children 7–9 years later with IQ scores four points lower than similarly-aged children of matched women with normal TSH values (Haddow et al., 1999). If mothers remained untreated for hypothyroidism in pregnancy, then the IQ scores of their 7–9 year-old children were seven points lower than the IQ of matched control children. Unfortunately, this study did not report on the serum T3 and T4 levels in these women. A more recent study by Kooistra et al. found that women with free T4 < 10th percentile at 12 weeks gestation had infants with significantly lower orientation scores as assessed using the Neonatal Behavioural Assessment Scale than mothers with free T4 between the 50th and 90th percentiles (Kooistra et al., 2006). These observational studies provide further evidence that an adequate amount of maternal hormones, in particular T4, is needed for normal brain development. To date, there have been only two randomised trials conducted in moderately iodine deficient pregnant women supplemented with iodine that have assessed cognition in offspring. Berbel et al. recruited three groups of pregnant women living in a mildly iodine deficient area of Spain at different phases of gestation (i.e. 4–6 weeks, 12–14 weeks, and full-term), who had low (< 10th percentile) T4 concentrations at recruitment but normal TSH concentrations, and supplemented them with iodine until the end of lactation (Berbel et al., 2009). When the children were 18 months old, the development quotient of children in mothers supplemented in the first trimester (i.e. 4–6 weeks gestation) was significantly higher than that of children whose mothers received supplements from 12–14 weeks gestation or after delivery. Although this study has a number of methodological limitations, including a lack of information on UIC and small sample size, it provides further evidence of the need for adequate iodine in the first trimester of pregnancy. A second Spanish study by Velasco et al. in moderately iodine deficient pregnant women found that infants of mothers supplemented with iodine in the first trimester had higher psychomotor development scores than infants from mothers who did not start supplementation until the last month of pregnancy (Velasco et al., 2009). Unfortunately, neither of these studies was a randomised controlled trial; hence, they must be interpreted with caution. To date, there are no published studies examining the effect of iodine supplementation of mildly iodine deficient pregnant women on neurodevelopment in children. However, by 2015 the results of several ongoing randomised, placebo-controlled, intervention trials being conducted in Thailand and India (Melse-Boonstra and Jaiswal, 2010), should be available. In summary, there is conclusive evidence that severe iodine deficiency in pregnancy has serious effects on cognition, which is convincingly demonstrated by the mental retardation seen in cretinism. At present, there are limited data on the cognitive deficits of children born to mothers who are moderately or mildly iodine deficient in pregnancy.

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5.2.4

The effect of moderate and mild iodine deficiency in children on cognition The adverse effects of iodine deficiency on children, like any stage in the life cycle, is purported to manifest through hypothyroidism (Hetzel et al., 1990). Hypothyroidism itself will cause a lowered metabolic rate accompanied by a lack of energy, which in turn may prevent a child from participating fully in the activities of life. Of greater significance is whether hypothyroidism can adversely affect cognitive functioning in children and, if so, whether this is reversible. Because one of the symptoms of neurological cretinism is deafness, iodine deficiency may result in poor hearing, which in turn could affect cognitive ability. Valeix et al. found that hearing loss at 4000 Hz and average hearing impairment at 500, 1000, and 2000 Hz was more severe in 2 and 4 year-old French children who were iodine deficient (i.e. UIC < 100 μg/L) than in those children who had adequate iodine status (Valeix et al., 1994). Soriguer et al. report that in Spanish children with goitre, there was an inverse relationship between UIC and hearing threshold (Soriguer et al., 2000). In Beninese children, Van den Briel et al. found that children with high serum TSH levels had significantly higher hearing thresholds than children with lower TSH levels, and children with lower hearing thresholds performed better on mental tests (Van Den Briel et al., 2001). The evidence for the link between iodine deficiency and cognitive impairment in children consists of data from both observational and intervention studies. Two meta-analyses have combined some of these data in an attempt to strengthen the associations found. Bleichrodt and Born published a meta-analysis in 1994 collating data from 19 studies in moderately and severely iodine deficient populations (Bleichrodt and Born, 1994). Cognitive function was measured using 10 different intelligence scales and the authors concluded that iodine deficiency results in the loss of 13.5 IQ points. A more recent large meta-analysis by Qian et al. of Chinese studies that used only two types of cognitive tests estimated an approximate 10 IQ point difference between moderately to severely iodine deficient and iodine sufficient or supplemented groups (Qian et al., 2005). In addition to the two meta-analyses mentioned above, there have also been a number observational studies published on this topic (Boyages et al., 1989; Vermiglio et al., 1990, 2004; Aghini-Lombardi et al., 1995; Azizi et al., 1995; Tiwari et al., 1996; Huda et al., 1999; Fenzi et al., 1990; PinedaLucatero et al., 2008). The majority of these are case control studies that have compared the results of cognitive tests of children who lived in iodine deficient villages with similarly aged children from iodine sufficient villages; some authors have attempted to control for factors that might also influence childhood cognition, such as parental education and income. In general, the children who lived in iodine deficient areas or villages performed more poorly on a range of cognitive tests than children living in iodine sufficient areas, including slower reaction times, lower IQs, and poorer problem

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solving skills. A large cross-sectional study of Spanish children found that those children with poorer iodine status had an increased likelihood of having a lower IQ than children with better iodine status (Santiago-Fernandez et al., 2004). Vermiglio et al. compared children born to healthy mothers living in a moderately deficient area of Sicily to control children born to age-matched women from an area of marginal iodine sufficiency (Vermiglio et al., 2004). They found that attention deficit hyperactivity disorder (ADHD) affected 11 of 16 children from the moderately iodine deficient area, and none from the iodine sufficient area. In the same study, Vermiglio et al. reported that IQ was on average 18 points lower in the iodine deficient area. These results led the authors to suggest a direct causal relationship between iodine deficiency and ADHD; however, this study has many limitations (i.e. casecontrol, small sample size) and this finding has yet to be confirmed in other studies. To date, there have been eight published randomised trials investigating the effect of iodine supplementation on cognition in school children; the first seven studies discussed below have used a single dose of iodised oil, while the eighth and more recent study used daily iodine supplements. In a study of severely iodine deficient 5–12 year-old Bolivian children, the iodine status of the placebo group improved because of the introduction of iodised salt (Bautista et al., 1982), whereas in a study of severely iodine deficient 7–11 year-old Beninese children, an unknown exogenous source of iodine increased iodine intakes, as assessed by an increased concentration of urinary iodine, in the placebo children (Van Den Briel et al., 2000). Consequently, in both studies, the effects of the iodine intervention could not be compared against a placebo, which limited the interpretation of the results; however, re-analysis of the data showed that children with improved iodine status performed better on cognitive tests. A study conducted in Malaysian children also reported an increase in iodine status in their control subjects, making the results of this study inconclusive (Isa et al., 2000). In a double-blind, placebo-controlled study of moderately iodine deficient Malawian school children, a significant improvement in all aspects of cognitive and psychomotor function and an increase of 21 IQ points was reported in the iodine supplemented children (Shrestha, 1994). Again, however, this study was limited by the absence of pretreatment scores of the children. Huda et al. supplemented moderately iodine deficient Bangladeshi children with low urinary iodine but normal T4 and TSH and found no significant differences between the placebo and iodine-treated children with regard to any of the motor and cognitive tests four months after treatment (Huda et al., 2001). In 2006, Zimmermann et al. published the results of a well-designed study of children living in a remote area of Albania. After 24 weeks, the placebo children were still moderately iodine deficient while the treated children were classified as iodine sufficient; in addition to an increase in UIC and a

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decrease in thyroid volume in these children, supplementation also increased T4 concentration. The authors reported that supplemented children performed better on four sub-tests of the Weschler Intelligence Scale for Children (WISC) than children receiving the placebo (Zimmermann et al., 2006). A similar finding was reported in the recent study of Gordon et al. in mildly iodine deficient New Zealand children who were given daily iodine tablets for 28 weeks (Gordon et al., 2009). As in the previous study, the iodine status of the supplemented children improved, as assessed by an increase in UIC and a decrease in Tg, but in this study T4 concentration remain unchanged. Supplemented New Zealand children performed better on tests of perceptual reasoning and problem solving but, unlike the Albanian children, tests involving reaction speed and memory were not different between the two groups. These two latter studies provide strong evidence that improving iodine status in iodine deficient children can improve aspects of their cognition; whether such improvements are permanent or reversible is unknown.

5.2.5 The effect of iodine deficiency on cognition in adults Although the majority of research in this area has focused on the effect of iodine deficiency in pregnancy and childhood on brain function, it is highly likely that the cognitive abilities of adults are also affected by iodine status. One of the symptoms of adult-onset hypothyroidism is its effect on specific cognitive domains, including concentration, memory, and language (Mennemeier et al., 1993; Dugbartey, 1998; Burmeister et al., 2001). Thus one could assume that hypthyroidism caused by iodine deficiency would have a similar adverse effect on cognition. This might be mediated through changes in the microarchitecture of the brain, but could also be facilitated by changes in neurotransmitters; there is negligible research investigating the effect of iodine deficiency on neurotransmitters. There is anecdotal evidence, however, that iodine deficiency affects cognitive abilities in adults. Chen and Hetzel relate a story from Dr R Djokomeoljanto who visited the village of Sengi in Central Java in 1973 and said ‘. . . the village was so quiet, there were no activities seen or observed by visitors, everyone looked lethargic and gave the impression of being lazy.’ Following a campaign of iodised oil injections ‘Dramatic changes were seen within a year. . . . Public activities increased. Fishing and farming boomed . . . The socio economic condition has improved accordingly’ (Chen and Hetzel, 2010). This story indicates the effect iodine deficiency can have on adults in a community, and the impact of improving iodine status on the local economy. It is no surprise that the 2008 Copenhagen Consensus, a panel of economic experts including some of the world’s most distinguished economists who were asked to address 10 great global challenges, ranked the elimination of iodine deficiency as the world’s third best economic investment.

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5.3 Implications for the food industry, nutritionists and policy-makers One of the primary causes of iodine deficiency is the low soil iodine concentration found in many parts of the world. This means that the local water is likely to be low in iodine, plants grown in the soil are low in iodine, and animals that eat these plants are also low in iodine. The World Health Organization recommends Universal Salt Iodisation (USI) whereby all salt used for animal or human consumption is iodised (WHO, UNICEF and ICCIDD, 2007). In a review, Zimmermann outlines the reasons for using salt as a vehicle to improve iodine intakes (Zimmermann, 2009). China, for example, has successfully adopted USI but few other countries have done so, often due to reluctance on the part of the food industry. There are a diversity of other strategies employed throughout the world to improve iodine intakes including iodine fortification of some staple foods (e.g., bread, pasta), addition of iodine to the drinking water, and a ban on the sale of non-iodised salt. In many parts of the world, iodine intakes are sufficient and the populace has good iodine status. This may reflect dietary habits that include the consumption of foods that are rich in iodine; for example, people living in Korea and Japan eat large quantities of seafood such as fish and seaweed. Farming practices can also increase the amount of iodine in foods such as dairy products, eggs and meats through the use of iodine-containing disinfectants, iodine-containing medicines, and iodine-supplemented feeds. Of course, some areas of the world also have a higher concentration of iodine in the soil. Given the relative simplicity of improving iodine intakes, it is surprising that it is estimated that up to two billion people are still iodine deficient. As stated previously, this is of particular concern for pregnant and lactating women and children, when the brain is growing and developing and an adequate amount of iodine is needed for the production of thyroid hormones. The use of iodised oil, typically given as a single dose of 400 mg, has been successfully used to improve iodine intakes for such groups and can be effective for several years. Iodised oil is recommended for people living in isolated parts of the world or in situations where severe iodine deficiency is observed, particularly in pregnant women, and other methods to improve iodine intakes would be difficult to implement. Another strategy that has been recommended to improve iodine intakes is the use of iodine supplements. In the US, there is concern that a small proportion of pregnant and lactating women may not be obtaining adequate amounts of iodine from the diet, which has led The American Thyroid Association to recommend a daily iodine supplement of 150 μg of iodine for all pregnant and lactating women living in the US (American Thyroid Association, 2006). In countries with moderate to severe iodine deficiency and no strategies implemented to improve iodine status (i.e. iodised salt), WHO recommends pregnant

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women consume a supplement containing 250 μg I/day (WHO and UNICEF, 2007). Monitoring iodine status in a population is important, particularly in areas that have previously reported iodine deficiency. The re-emergence of iodine deficiency in New Zealand since the 1990s is a case in point. New Zealand has a low soil iodine concentration, and studies conducted in the 1920s and 1930s reported moderate iodine deficiency and ∼30 % of schoolchildren with goitre (Thomson and Skeaff, 2009). The introduction of iodised table salt containing 50 ppm iodine in 1939 meant that goitre was virtually eradicated by the 1950s. Iodophors, used as a sanitiser by the dairy industry, introduced an adventitious source of iodine and further increased iodine intakes from the 1960s through to the late 1980s. However, changing food patterns including a decline in the use of iodised salt used at the table and in cooking, an increase in the intake of processed foods made with non-iodised salt (food manufacturers in New Zealand do not typically use iodised salt), an increase in the use of non-iodised rock or sea salt, and the replacement of iodophors in the dairy industry, together have resulted in a drop in iodine intakes since the early 1990s (Mann and Aitken, 2003). A lack of a routine iodine monitoring programme by the New Zealand government meant that iodine deficiency was not confirmed until 2002, and it was not until 2009 that a change in legislation was introduced requiring the mandatory fortification of commercial breads with iodised salt. The effect of this change in legislation on improving iodine intakes is not known, particularly in pregnant and lactating women. In contrast, Switzerland is an example of a country where food manufacturers have voluntarily used iodised salt in their products such that >90 % of processed foods are made with iodised salt, and where there is routine monitoring to determine if the amount of iodine added to iodised salt is sufficient to ensure adequate iodine status in the population (Hess et al., 2001; Zimmermann et al., 2005). It is clear that governments should ensure that iodine status is routinely monitored, even if there has been a history of adequate iodine status. Food patterns can change rapidly in today’s world. There is increasing pressure on food manufacturers to decrease the amount of sodium in their products; thus the addition of less salt, particularly if this is iodised salt, will also decrease iodine intakes. If this occurs, it is important that the concentration of iodine in salt is increased in order to ensure iodine intakes remain adequate.

5.4 Future trends As awareness regarding the importance of iodine in growth and development grows, even in populations with relatively good iodine status, it is likely that more foods and dietary supplements in the future will contain additional iodine. Although most combined vitamin and mineral supple-

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ments contain iodine, there is increasing focus by supplement companies to produce targeted supplements. For example, dietary supplements containing iodine that claim to improve specific cognitive abilities in children are likely to become popular with parents eager to give their children a scholastic edge. Foods and supplements aimed at children and adolescents for this reason could be considered ‘brain food’. In a similar vein, there are iodine-only tablets aimed at women planning a pregnancy, pregnant women, and lactating women; the New Zealand government recently launched an iodine tablet for this purpose called ‘NeuroKare’. In countries that have not implemented USI, food manufacturers may voluntarily add iodised salt rather than non-iodised salt to more of their food products. Given an increasing focus on iodine, of concern, however, is misleading advertising of products implying they are a good source of dietary iodine. For example, a rock salt sold in New Zealand sourced from the foothills of the Himalayas states on the front of the package that it contains iodine. Although this is technically true, a person would need to eat 1 kg of this salt a day to obtain their recommended daily requirement of iodine! There are, of course, responsible food manufacturers who are now adding iodine to sea salt at recommended levels. Conversely, the promotion of kelp tablets needs to be monitored as these contain variable and often exceedingly high levels of iodine. There is a small group of people who believe that iodised salt should be avoided; this unwarranted concern stems from the use of anti-caking agents added to iodised salt, one of which contains aluminium. Such individuals try to obtain dietary iodine from ‘natural’ sources such as rock or sea salts, kelp products, or by drinking iodine solutions made by adding drops of Lugol’s solution or tincture of iodine to water or juice. Such practices are not recommended as they provide either negligible amounts of iodine to the diet (i.e. rock or sea salt), or very high and unregulated amounts of iodine to the diet; for example, one drop of Lugol’s solution can contain ∼6500 μg of iodine, well above the Upper Tolerable Limit of 1100 μg of iodine per day. Clearly, the most important future trend is to ensure that all salt sold is iodised, and that iodised rather than non-iodised salt is used in food manufacturing and home cooking.

5.5 Sources of further information and advice The International Council for the Control of Iodine Deficiency Disorders (http://www.iccidd.org/) or ICCIDD is a non-governmental organisation that aims to eliminate iodine deficiency and promote good nutrition throughout the world. The ICCIDD publishes a quarterly IDD newsletter that highlights important recent publications in the area, news items, upcoming conferences, and human interest stories (http://www.iccidd.org/ pages/idd-newsletter.php). ICCIDD is part of the Network for Sustained

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Elimination of Iodine Deficiency (http://www.iodinenetwork.net/), which is an alliance of 11 organizations committed to eliminating iodine deficiency including WHO (http://whqlibdoc.who.int/publications/2004/9241592001. pdf) and UNICEF (http://www.unicef.org/nutrition/index_iodine.html). The Iodine Network produces the Global Scorecard (http://www. iodinenetwork.net/documents/scorecard-2010.pdf), an annual summary table of the iodine status of over 150 countries around the globe. Together, WHO, UNICEF, and ICCIDD have produced a number of publications that can be accessed through WHO or ICCIDD websites; the third edition of Assessment of Iodine Deficiency Disorders and Monitoring their Elimination is particularly useful for scientists working in this area (WHO, UNICEF and ICCIDD, 2007). The American Thyroid Association is also a source of information about iodine and the effects of iodine deficiency on health, particularly in pregnancy (http://www.thyroid.org/patients/patient_ brochures/iodine_deficiency.html). In addition to the resources listed in the previous paragraph, there are a number of books that the reader might also wish to consult. The Damaged Brain of Iodine Deficiency edited by John Stanbury is a seminal piece of work in this area (Stanbury, 1994). The text Werner and Ingbar’s The Thyroid, now in its 9th edition, is an essential reference text (Braverman and Utiger, 2005). Chance and Commitment is the autobiography of Basil Hetzel, who at the age of 87 in 2009 was awarded the Pollin Prize for Research in Paediatrics for his discovery that maternal iodine deficiency caused brain damage in newborns (Hetzel, 2005); the chapters on IDD describe this discovery and the studies that followed on from this finding. Finally the Comprehensive Handbook of Iodine was recently published to provide a reference book on all aspects of iodine (Preedy et al., 2009).

5.6 References aghini-lombardi f, pinchera a, antonangeli l, rago t, chiovata l, bargagna s, bertucelli b, ferretti g, sbrana b, marcheschi m and vitti p (1995) Mild iodine deficiency during fetal/neonatal life and neuropsychological impairment in Tuscany. Journal of Endocrinological Investigation, 18, 57–62. american thyroid association the public health committee (2006) Iodine supplementation for pregnancy and lactation-United States and Canada: recommendations of the American Thyroid Association. Thyroid, 16, 949–51. azizi f, kalani h, kimiagar m, ghazi a, sarshar a, nafarabadi m, rahbar n, noohi s, mohajer m and yassai m (1995) Physical, neuromotor and intellectual impairment in non-cretinous schoolchildren with iodine deficiency. International Journal of Vitamin and Nutrition Research, 65, 199–205. bautista a, barker p a, dunn j t, sanchez m and kaiser d l (1982) The effects of oral iodized oil on intelligence, thyroid status, and somatic growth in school-age children from an area of endemic goiter. American Journal of Clinical Nutrition, 35, 127–134. berbel p, mestre j l, santamaria a, palazon i, franco a, graells m, gonzaleztorga a and de escobar g m (2009) Delayed neurobehavioral development in

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children born to pregnant women with mild hypothyroxinemia during the first month of gestation: the importance of early iodine supplementation. Thyroid, 19, 511–19. bleichrodt n and born m p (1994) A metaanalysis on iodine and its relationship to cognitive development. In Stanbury J B (ed.) The Damaged Brain of Iodine Deficiency. New York: Cognizant Communications, 195–200. boyages s, collins j k, maberly g f, jupp j j, morris j and eastman c j (1989) Iodine deficiency impairs intellectual and neuromotor development in apparentlynormal persons. Medical Journal of Australia, 150, 676–82. braverman l e and utiger r d (eds) (2005) Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text. New York: Lippincott-Raven. bryan j, osendarp s, hughes d, calvaresi e, baghurst k and van klinken j (2004) Nutrients for cognitive development in school-aged children. Nutrition Reviews, 62, 295–306. burmeister l a, ganguli m, dodge h h, toczek t, dekosky s t and nebes r d (2001) Hypothyroidism and cognition: preliminary evidence for a specific defect in memory. Thyroid, 11, 1177–85. cao x-y, jiang x-m, dou z-h, rakeman m a, zhang m-l, o’donnell k j, ma t, amette k, delong n and delong r (1994) Timing of vulnerability of the brain to iodine deficiency in endemic cretinism. New England Journal of Medicine, 331, 1739–44. chen z-p and hetzel b s (2010) Cretinism revisited. Best Practice & Research Clinical Endocrinology & Metabolism, 24, 39–50. delange f (2001) Iodine deficiency as a cause of brain damage. Postgraduate Medical Journal, 77, 217–20. dugbartey a t (1998) Neurocognitive aspects of hypothyroidism. Archives of Internal Medicine, 158, 1413–18. fenzi g f, giusti l f, aghini-lombardi f, bartalena l, marococci c and santini f (1990) Neuropsychological assessment in schoolchildren from an area of moderate iodine deficiency. Journal of Endocrinologial Investigation, 13, 427–31. gordon r c, rose m c, skeaff s a, gray a r, morgan k m d and ruffman t (2009) Iodine supplementation improves cognition in mildly iodine deficient children. American Journal of Clinical Nutrition, 90, 1264–71. haddow j e, palomaki g e, allan w c, williams j r, knight g j, gagnon j, o’heir c e, mitchell m l, hermos r j, waisbren s e, faix j d and klein r z (1999) Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. New England Journal of Medicine, 341, 549–55. hess s y, zimmermann m b, torresani t, burgi h and hurrell r f (2001) Monitoring the adequacy of salt iodization in Switzerland: a national study of school children and pregnant women. European Journal of Clinical Nutrition, 55, 162–6. hetzel b s (2005) Chance and Commitment. Kent Town, South Australia: Wakefield Press. hetzel b s and dunn j t (1989) The iodine deficiency disorders: their nature and prevention. Annual Review of Nutrition, 9, 21–38. hetzel b s, potter j d and dulberg e m (1990) The iodine deficiency disorders: nature, pathogenesis and epidemiology. World Reviews of Nutrition and Dietetics, 62, 59–119. huda s n, grantham-mcgregor s m, rahman k m and tomkins a (1999) Biochemical hypothyroidism secondary to iodine deficiency is associated with poor school acheivement and cognition in Bangladeshi children. Journal of Nutrition, 129, 980–7. huda s n, grantham-mcgregor s m and tomkins a (2001) Cognitive and motor functions of iodine-deficient but euthyroid children in Bangladesh do not benefit from iodized poppy seed oil (Lipiodol). Journal of Nutrition, 131, 72–7.

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hughes d and bryan j (2003) The assessment of cognitive performance in children: considerations for detecting nutritional influences. Nutrition Reviews, 61, 413– 22. isa z m, alias i z, kadir k a and ali o (2000) Effect of iodized oil supplementation on thyroid hormone levels and mental performance among Orang Asli schoolchildren and pregnant mothers in an endemic goitre area of Peninsular Malaysia. Asia Pacific Journal of Clinical Nutrition, 9, 274–81. isaacs e and oates j (2008) Nutrition and cognition: asessing cognitive abilities in children and young people. European Journal of Clinical Nutrition, 47, 4–24. kooistra l, crawford s, van baar a l, brouwers e p and pop v j (2006) Neonatal effects of maternal hypothyroxinemia during early pregnancy. Pediatrics, 117, 161–7. mann j and aitken e (2003) The re-emergence of iodine deficiency in New Zealand. New Zealand Medical Journal, 116. melse-boonstra a and jaiswal n (2010) Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development. Best Practice & Research Clinical Endocrinology & Metabolism, 24, 29–38. mennemeier m, garner r d and heilman k m (1993) Memory, mood and measurement in hypothyroidism. Journal of Clinical and Experimental Neuropsychology, 15, 822–31. morreale de escobar g, jesus obregon m and escobar del ray f (2007) Iodine deficiency and brain development in the first half of pregnancy. Public Health Nutrition, 10, 1554–70. nath s k, moinier b, thuillier f, rongier m and desjeux j f (1992) Urinary excretion of iodine and fluoride from supplemented food grade salt. International Journal of Vitamin and Nutrition Research, 62, 66–72. o’donnell k j, rakeman m a, zhi-hong d, xue-yi c, mei z y, delong n, brenner g, tai m, dong w and delong g r (2002) Effects of iodine supplementation during pregnancy on child growth and development at school age. Developmental Medicine and Child Neurology, 44, 76–81. obregon m, escobar del rey f and morreale de escobar g (2005) The effects of iodine deficiency on thyroid hormone deiodonation. Thyroid, 15, 917–29. pharoah p o d, buttfield i h and hetzel b s (1971) Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. The Lancet, 297, 308–10. pineda-lucatero a, avila-jimenez l, ramos-hernandez r i, magos c and martinez h (2008) Iodine deficiency and its association with intelligence quotient in schoolchildren from Colima, Mexico. Public Health Nutrition, 11, 690–98. pop v j, kuijpens j l, van baar a l, verkerk g, van son m m, vijlder j j, vulsma t, wiersinga w m, drexhage h a and vader h l (1999) Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clinical Endocrinology, 50, 149–55. pop v j, brouwers e p, vader h l, vulsma t, van baar a l and vijlder j j (2003) Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3 year follow-up study. Clinical Endocrinology, 59, 282–8. preedy v r, burrow g n and watson r r (eds) (2009) The Comprehensive Handbook of Iodine. London, UK: Academic Press. qian m, wang d, watkins w e, gebski v, yan y q, li m and chen z p (2005) The effects of iodine on intelligence in children: a meta-analysis of studies conducted in China. Asia Pacific Journal of Clinical Nutrition, 14, 32–42. rajatanavin r, chailurkit l, winichakoon p, mahachoklertwattana p, soranasataporn s, wacharasin r, chaisongkram v, amatyakul p and wanarata l (1997) Endemic cretinism in Thailand: a multidiciplinary study. European Journal of Endocrinology, 137, 349–55.

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santiago-fernandez p, torres-barahona r, muela-martinez j a, rojo-martinez g, garcia-fuentes e, garriga m j, garcia leon a and soriguer f (2004) Intelligence quotient and iodine intake: a cross-sectional study in children. Journal of Clinical Endocrinology & Metabolism, 89, 3851–7. shrestha r m (1994) Effect of iodine and iron supplementation on physical, psychomotor and mental development in primary school children in Malawi. Wageningen: Grafisch Service Centrum. soriguer f, millon m c, munoz r, mancha i, lopez siguero j p, martinez aedo m j, gomez-huelga r, garirga m j, rojo-martinez g, esteva i and tinahones f j (2000) The auditory threshold in a school-age population is related to iodine intake and thyroid function. Thyroid, 10, 991–9. stanbury j b (ed.) (1994) The Damaged Brain of Iodine Deficiency. New York: Cognizant Communication Corporation. thomson c d and skeaff s a (2009) Iodine status and deficiency disorders in New Zealand, in Preedy V R, Burrow G N and Watson R R (eds), The Comprehensive Handbook of Iodine. London: Academic Press, 1251–1258. tiwari b d, godbole m m, chattopadhyay n, mandal a and mithal a (1996) Learning disabilities and poor motivation to achieve due to prolonged iodine deficiency. American Journal of Clinical Nutrition, 63, 782–6. valeix p, preziosi p, rossignol c, farnier m a and hercberg s (1994) Relationship between urinary iodine concentration and hearing capacity in children. European Journal of Clinical Nutrition, 48, 54–9. van den briel t, west c e, van de vijver a j r, ategbo e a and hautvast j g (2000) Improved iodine status is associated with improved mental status of school children in Benin. American Journal of Clinical Nutrition, 72, 1179–85. van den briel t, west c e, hautvast j g and ategbo e a (2001) Mild iodine deficiency is associated with elevated hearing thresholds in children in Benin. European Journal of Clinical Nutrition, 55, 763–8. vejbjerg p, knudsen n, perrild h, laurberg p, carlé a, pedersen i, rasmussen l, ovesen l and jørgensen t (2009) Thyroglobulin as a marker of iodine nutrition status in the general population. European Journal of Endocrinology, 161, 475. velasco i, carreira m, santiago p, muela j a, garcia-fuentes e, sanchez-munoz b, garriga m j, gonzalez-fernandez m c, rodriguez a, caballero f f, machado a, gonzalez-romero s, anarte m t and soriguer f (2009) Effect of iodine prophylaxis during pregnancy on neurocognitive development of children during the first two years of life. Journal of Clinial Endocrinology and Metabolism, 94, 3234–41. vermiglio f, sidoti m, finocchiaro m d, battiato s, presti v p l, benvenga s and trimarchi f (1990) Defective neuromotor and cognitive ability in iodinedeficiency schoolchildren of an endemic goiter region of Sicily. Journal of Clinical Endocrinology and Metabolism, 70, 379–84. vermiglio f, lo presti v p, moleti m, sidoti m, tortorella g, scaffidi g, castagna m g, mattina f, violi m a, crisa a, artemisia a and trimarchi f (2004) Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries. Journal of Clinical Endocrinology & Metabolism, 89, 6054–60. who and unicef (2007) Reaching Optimal Iodine Nutrition in Pregnant and Lactating Women and Young Children. Geneva: World Health Organization who, unicef and iccidd (2001) Assessment of Iodine Deficiency Disorders and Monitoring Their Elimination: a Guide for Programme Managers. Geneva: World Health Organization. who, unicef and iccidd (2007) Assessment of Iodine Deficiency Disorders and Monitoring Their Elimination: a Guide for Programme Managers (3rd edn). Geneva: World Health Organization. zimmermann m b (2009) Iodine deficiency. Endocrine Reviews, 30, 376–408.

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zimmermann m b, moretti d, chaouki n and torresani t (2003) Development of a dried whole-blood spot thyroglobulin assay and its evaluation as an indicator of thyroid status in goitrous children receiving iodised salt. American Journal of Clinical Nutrition, 77, 1453–8. zimmermann m b, aeberli i, torresani t and burgi h (2005) Increasing the iodine concentration in the Swiss iodized salt program markedly improved iodine status in pregnant women and children: a 5-y prospective national study. American Journal of Clinical Nutrition, 82, 388–92. zimmermann m b, connolly k j, bozo m, bridson j, rohner f and grimci l (2006) Iodine supplementation improves cognition in iodine-deficient schoolchildren in Albania: a randomized, controlled, double-blind study. American Journal of Clinical Nutrition, 83, 108–14. zoeller r t and rovet j (2004) Timing of thyroid hormone action in the developing brain: clinical observations and experimental findings. Journal of Neuroendocrinology, 16, 809–18.

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6 Macronutrients and cognitive performance L. Dye, D. Lamport, N. Boyle and A. Hoyland, The University of Leeds, UK

Abstract: Macronutrients have the potential to alter cognitive function by exerting effects on neuronal cell structure, neurotransmission, energy supply to the brain and metabolism. The current chapter discusses evidence for the effects of macronutrients on cognitive performance with consideration of potential moderating factors and mechanisms of action. Portion size and macronutrient composition of meals and the time of day meals are taken are considered. The effect of glucose on cognitive performance is discussed with a focus upon the impact of Glycaemic Index, Glycaemic Load and evidence for the moderating effect of fibre on glucoregulatory function. Stress and cortisol are also considered as potential moderators of the relationship between macronutrients on cognitive performance. The implications of these findings for the food industry, nutritionists and policy-makers are discussed, and future trends and opportunities for this research area are identified. Key words: macronutrients, cognition, glucose, Glycaemic Index, Glycaemic Load, stress, cortisol.

6.1 Introduction There has been widespread research interest into the possibility that cognitive function, alertness and ability to concentrate may be differentially affected by macronutrient manipulation. Food components may have the potential to alter cognitive function by exerting effects on neural cell structure, neurotransmission, energy supply to the brain and metabolism (Schmitt et al., 2005a). This chapter considers the relationships between macronutrients and cognitive performance outcomes. In particular, an overview of the effects of meals on cognitive performance is provided, and the impact of Glycaemic Index, Glycaemic Load and stress on these relationships are considered.

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The implications of these findings for the food industry, nutritionists and policy-makers are discussed, and future trends and opportunities for this research area are identified.

6.2 The effects of meals on cognitive performance 6.2.1 Meal size and time of day effects A number of studies have examined the effects of meals on cognitive performance at different times of day (see Dye et al., 2000; for a review). One common finding is the observation of a reduction in subjective arousal accompanied by declines in performance on objective cognitive measures after lunch (e.g. Smith and Kendrick, 1992). This natural circadian rhythm may be exacerbated by metabolic activity as a result of the intake of food, and therefore this effect may be greater with larger meal sizes (Smith et al., 1991). However, the composition of a meal may have a greater influence on cognition than the size of a meal (Gibson and Green, 2002). Both protein-rich and carbohydrate-rich lunches have been shown to induce feelings of lethargy (Smith et al., 1988). Alertness and performance are significantly lower two and a half hours after a high-fat, lowcarbohydrate lunch, when compared with an equi-energetic low-fat, high-carbohydrate lunch (Lloyd et al., 1994). Other research suggests that the cognitive effects of meals eaten in the evening may not be as potent as at breakfast or lunch (Smith et al., 1994), but there are far fewer studies of evening meal effects. Kaplan et al. (2001) demonstrated that protein-, fat- and carbohydraterich meals at breakfast can enhance performance in healthy elderly participants. The facilitation was independent of the level of blood glucose induced by the manipulations, but fractionation of effects was observed. Initially, all three manipulations improved performance, but only carbohydrate intake resulted in sustained improvements on a paragraph recall task across the morning. Furthermore, both fat and carbohydrate intake led to improved psychomotor performance, but only fat improved measures of attention. Other studies suggest that fat ingestion may improve reaction times, while carbohydrate loads have been associated with the slowing of reaction times (Cunliffe et al., 1997; Fischer et al., 2001). Reaction times were also faster following a protein-rich meal, compared with meals rich in carbohydrates from sugar or starch (Smith et al., 1988). This might be explained by the finding that carbohydrate intake is associated with increased fatigue (Reid and Hammersley, 1999). A review of the effects of macronutrients on cognitive function suggests that whilst carbohydrate may impair reaction time along with peripheral processing and attention, it may improve memory (Dye and Blundell, 2002). These effects may be dependent on the type of carbohydrate ingested as well as the carbohydrate:protein ratio within a meal.

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6.2.2 Mixed macronutrient meals The macronutrient composition of a meal should be considered when examining dietary effects on cognition. Macronutrients in mixedcomposition meals may have interaction effects on performance, effects which may be further moderated by the presence of fibre in the meal. Moreover, meals designed to deliver different macronutrient compositions may differ in energy content, volume, and sensory properties (taste, pleasantness and consistency), all features that may influence behaviour and mental performance. Effects produced through the ingestion of pure macronutrients are likely to be less subtle than macronutrients ingested through more usual means, i.e., during meals of mixed macronutrient composition. Research has tended to focus upon the effects of carbohydrate and protein, and carbohydrate and fat mixed macronutrient manipulations. However, there is a lack of research examining the combined effect of meals comprising all three major macronutrients. One potentially limiting factor in studies which compare mixed macronutrient meals is the appropriateness of the meals designed. To control for confounding variables, study conditions should be matched for energy content, appearance and weight or volume in order to be able to attribute the effect to the macronutrient comparison under investigation. However, this matching process may force meals to become very large (in volume or energy) resulting in the loss of ecological validity. Carbohydrate and protein manipulations A number of psychological changes are predicted from diets differing in carbohydrate and protein content. Carbohydrates and proteins are proposed to have differing effects on mood and cognitive functions mediated by the effect of these macronutrients on the synthesis of neurotransmitters implicated in cognitive function. Carbohydrate:protein macronutrient manipulations have the potential to mediate brain serotonin and catecholamine synthesis via changes in the ratio between tryptophan (Trp) and tyrosine (Tyr) to other large neutral amino acids (LNAA; Lieberman et al., 1985). Synthesis of serotonin and catecholamines is dependent upon the availability of precursor dietary amino acids tryptophan and tyrosine, respectively (Fischer et al., 2002). As tryptophan and tyrosine compete with each other and other LNAA for the same transport system across the blood–brain barrier (BBB), manipulation of carbohydrate:protein ratio is proposed to affect the availability and consequent uptake of these neurotransmitter precursors. Carbohydrate-rich/protein-poor meals stimulate increased insulin production and subsequent uptake at peripheral tissues of competing LNAA, favouring tryptophan entry to the brain (Gibson and Green, 2002). Conversely, protein-rich/carbohydrate-poor meals tend to reduce the Trp:LNAA ratio due to modest insulin stimulation and scarcity of tryptophan in most protein sources. Protein-rich meals can increase the Tyr : LNAA ratio favouring tyrosine delivery to the brain.

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However, high-protein meals have not been shown to consistently increase plasma tyrosine (Schweiger et al., 1986). Several studies have found that high-carbohydrate meals tend to produce greater drowsiness, sleepiness, and calmness. In general, studies comparing carbohydrate and protein have found slower reaction time and impaired attention after high-carbohydrate meals. High-protein meals produce susceptibility to distraction and slower memory scanning. These results suggest that the two macronutrients are operating on different cognitive processes and may be task specific. For example, Smith et al. (1988) examined performance on categoric search and focused attention tasks after a high-starch, high-sugar or high-protein lunch. Slower reaction times to peripheral stimuli on the search task were observed after both carbohydrate meals than after the high-protein meal. High-protein meals resulted in greater distraction from stimuli in the focused attention task. Other studies have suggested that differential effects of carbohydrate and protein meals on cognitive performance may be modulated by temporal, metabolic and hormonal factors. Fischer et al. (2002) examined the effect of different carbohydrate: protein ratio meals (similar in volume and sensory properties) on cognitive performance in a repeated-measures crossover design. Participants were given three isoenergetic (400 kcal) morning test meals comprising different carbohydrate: protein ratios: carbohydraterich (CHO[4 : 1]), balanced (BAL[1 : 1]) and protein-rich (PRO[1 : 4]). Postmeal cognitive performance in relation to post-prandial metabolic and hormonal changes (glucose, glucagon to insulin ratio (GIR) and Trp/LNAA and Tyr/LNAA in plasma and respiratory indices) were assessed. Overall meal and temporal effects related to metabolic and hormonal post-prandial changes were found. Aside from a short, transient effect of improved performance mediated by rising blood glucose following the carbohydrate-rich meal, overall cognitive performance was superior after BAL[1 : 1] and PRO[1 : 4] meals. Superior performance was concomitant with the least variation in glucose metabolism and GIR. Overall, the findings suggest post-prandial performance is best following the BAL[1 : 1] and PRO[1 : 4] meals compared to a medium to high glycaemic carbohydrate-rich meal. This superior performance is proposed to be mediated by less variation in glucose metabolism and/or greater modulation in LNAA ratios. Carbohydrate and fat manipulations There has been more research comparing carbohydrate and fat macronutrient manipulations. However, few decisive conclusions can be drawn because methodological inconsistencies between studies make comparisons difficult. In comparisons of low- versus high-carbohydrate and low- versus high-fat lunches, no effects were seen on psychomotor tasks (Kelly et al., 1994), but with only six subjects the statistical power was very low. Wells and Read (1996) compared the effects of a high-fat, low-carbohydrate and a low-fat, high-carbohydrate meals eaten either as a brunch or a lunch.

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Results demonstrated that subjective lethargy increased after ingestion of all meals. However, there was relatively little change in cognitive performance. It was proposed that fat in the morning caused a greater depression of alertness and mood. In a well-controlled, repeated-measures design study, reaction time was slower after a high-fat lunch than after a low-fat lunch (Lluch et al., 2000). Higher-than-usual proportions of either fat or carbohydrate caused participants to be more drowsy, uncertain and muddled. Overall, studies demonstrate the lack of clarity of effect of these macronutrient manipulations on different measures of cognitive performance.

6.3

Carbohydrate and cognitive performance

An important area of research which has received a great deal of attention is the capacity for an exogenous supply of glucose (or carbohydrate) to improve cognitive function. Glucose provides the primary metabolic fuel for the brain and is essential for the normal functioning of the central nervous system. To meet energy requirements of the brain, 120 g of glucose is oxidised by the brain per day (Sieber and Trastman, 1992). Suggestions that an increase in the availability of glucose in the brain may enhance cognition in animals (e.g. Gold, 1986; Wenk, 1989) have led to a plethora of studies examining the relationship between glucose and cognition in humans. Studies in this area tend to examine the effects of glucose versus placebo drinks, often within a single- or double-blind design. Commonly these studies are conducted at breakfast time, thereby exploiting the provision of an overnight fast.

6.3.1 Observed effects of glucose on cognitive performance Glucose has been reported to improve vigilance (Reay et al., 2006), reaction times (Owens and Benton, 1994), verbal fluency (Donohoe and Benton, 1999) and performance on an intelligence test (Benton and Parker, 1998), and to decrease the Stroop effect (Benton et al., 1994). However, the majority of studies have implicated glucose in the enhancement of memory performance (see Messier, 2004). Raising the level of blood glucose has been found to improve verbal memory in healthy young adults in many studies (e.g. Benton and Owens, 1993; Messier et al., 1998, 1999; Sünram-Lea et al., 2001), as well as working memory (e.g. Kennedy and Scholey, 2000; Scholey et al., 2001) and performance on visuo-spatial tasks (e.g. Metzger, 2000; Scholey and Fowles, 2002; Sünram-Lea et al., 2002a). These studies all provided a dose of glucose and examined its effect on cognition. It is also possible to manipulate glycaemic response via the use of dairy proteins or novel carbohydrates, alone or in combination. Dye et al. (2010) reported that manipulation of glycaemic response using

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isomaltulose – a naturally occurring disaccharide with a slower digestion rate than sucrose – delivered in a milk-based drink, had no consistent effects on verbal or working memory or psychomotor performance measured within two hours of ingestion. This was despite large and significant fluctuations in circulatory glucose induced by sucrose, and attenuated in amplitude and prolonged in duration by isomaltulose. However, it is worth noting that the method used to modulate glycaemic response was different to that commonly used in macronutrient manipulations. For example, Nabb and Benton (2006) administered mixed macronutrient breakfasts and found effects on verbal memory within two hours after ingestion in individuals with better glucose tolerance given meals that produced small rises in blood glucose. Effects are not limited to healthy young adult populations, and may be more potent in other populations where there is some disruption to metabolic or cognitive activity. Glucose has been shown to facilitate cognitive function in healthy older individuals (Hall et al., 1989; Messier et al., 1997), and in those with cognitive pathologies such as Alzheimer’s disease (Craft et al., 1992), Down’s syndrome (Manning et al., 1998) and schizophrenia (Stone et al., 2003). A complication of Type I and Type II diabetes is the impairment of certain cognitive proficiencies during hypoglycaemic episodes (Greenwood et al., 2003; Brands et al., 2005), and it has been shown that improvements to glycaemic control can correct for these deficits (Gradman et al., 1993; Ryan et al., 2006).

6.3.2 Blood glucose and cognition Level of blood glucose has been shown to affect cognitive performance in animals and humans (e.g. Benton and Sargent, 1992; Benton et al., 2003), and there are reports that cognitive performance correlates positively with participants’ blood glucose level at the time of testing (Bellisle et al., 1998). An inadequate supply of glucose to the brain results in a significant loss to mental function (Amiel, 1994), and hypoglycaemia has been found to induce cognitive impairment in normal samples (Gold et al., 1995). In rats, it was observed that cognitive demand was accompanied by increased glucose metabolism in relevant brain areas required to perform tasks (McNay et al., 2000). Kennedy and Scholey (2000) suggest that periods of intense cognitive activity will lead to a measurable decrease in peripheral blood glucose as available glucose circulating in the bloodstream is shunted to the brain. This effect has been observed in humans (Scholey et al., 2001; Fairclough and Houston, 2004). Magnetic resonance imaging (MRI) studies have shown that during cognitive effort there are specific drops in extracellular concentrations of glucose in the brain areas being activated. For example, visual stimulation can result in significant decreases in glucose concentration in the visual cortex (Chen et al., 1993). Research has shown

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that there is an equilibrium between plasma glucose concentrations and glucose in the extracellular fluid such that the concentration of glucose in the brain is 20–30 % of the concentration in blood plasma (Seaquist et al., 2001; Messier, 2004; Convit, 2005). Therefore, increasing plasma blood glucose levels results in a relative increase in brain extracellular glucose levels (Silver and Erecinska, 1994; Abi-Saab et al., 2002). However, increases in brain extracellular glucose following changes in blood glucose levels are unlikely to affect uptake of glucose by neurons and brain activity. This is because uptake of glucose is not driven by changes in the glucose concentration of the extracellular fluid but by neuronal activity (Messier, 2004). Increases in plasma glucose can provide benefit for neuronal activity when brain extracellular glucose levels are depleted. Glucose depletion in extracellular fluid can occur as a result of high neuronal activity (McNay and Gold, 2002) or due to abnormalities in the transfer of glucose across the blood–brain barrier via GLUT 1 transporters. The distribution of GLUT 1 transporters can be affected by factors such as ageing, chronic hypoglycaemia, impaired glucose tolerance and Type 2 diabetes. The relationship between blood glucose level and cognitive performance may not simply be correlative (Messier, 2004). Rather than a direct effect of absolute blood glucose level on performance, studies have begun to indicate that change in blood glucose during cognitive activity is important. Therefore, an individual’s glucoregulatory efficiency may moderate the effect of glucose (or carbohydrate-rich food) on performance (for review see Lamport et al., 2009). Better glucose tolerance has been associated with better memory in healthy young adults (Benton et al., 1994; Messier et al., 1999) and elderly adults (Manning et al., 1990). The effects of glucose on cognition are clearly not limited to healthy young adult populations. Indeed, they may be more potent in other populations. Give the physiological coupling between glucose and insulin, it is not surprising that research shows there is a relationship between insulin and cognition. Epidemiological studies have shown that administration of drugs which improve insulin sensitivity and reduce abnormally elevated blood insulin concentrations also improves cognitive function (Watson and Craft, 2004; Strachan, 2005). The mechanisms which associate insulin with cognition are unclear, but it is known that the brain contains insulin receptors (Banks et al., 1997). Therefore, a reduction of insulin in the brain, or insulin sensitivity could result in cognitive deficits (Strachan, 2003). For example, Type 2 diabetes which is characterised by poor insulin sensitivity is associated with decreased transport of insulin into the brain (Kaiyala et al., 2002). Research shows that intravenous or intranasal injection of insulin can improve cognition in healthy adults (Kern et al., 2001; Watson et al., 2003; Benedict et al., 2004). Furthermore, there are insulin-sensitive glucose transporters in the brain which suggests insulin also affects glucose uptake in the brain.

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6.3.3 Inconsistencies in the glucose–cognition relationship Studies of the effects of glucose are far from consistent and some studies report fractionation of the enhancement effect, with facilitation of some cognitive skills but not others (e.g. Craft et al., 1994; Foster et al., 1998; Winder and Borrill, 1998; Ford et al., 2002; Scholey and Kennedy, 2004). The consistency of the effect of glucose on cognition has been questioned in previous reviews (e.g. Riby, 2004; Gibson, 2007; Hoyland et al., 2008). Facilitation by glucose may be moderated by the age and gluco-regulatory control of the sample under study (Meikle et al., 2004), the difficulty or the domain of the cognitive measure (Meikle et al., 2005), or the emotionality of the experimental stimuli (Mohanty and Flint, 2001). It has been hypothesised that effects on memory are more easily demonstrable under conditions of high cognitive demand. For example, SünramLea et al. (2002a) report a facilitation of free word recall by glucose, but this was limited to when participants performed a simultaneous secondary psychomotor task. Time of administration and dose and format of carbohydrate may also be important (Sünram-Lea et al., 2002b). An inverted-U dose–response curve has been proposed, such that optimal performance may occur with the administration of 25 g glucose (Riby, 2004). This is supported by the finding that in some studies, cognitive performance was worse following glucose compared with placebo (e.g. Flint and Turek, 2003; Wesnes et al., 2003). A systematic review of the best evidence pertaining to the effects of macronutrients on cognitive performance in healthy young adults revealed that whilst findings were mixed, strongest support was for the facilitation of memory by glucose, particularly verbal memory in a delayed context (Hoyland et al., 2008).

6.3.4 Glycaemic Index In addition, there are some suggestions that the rate of delivery of glucose into the bloodstream and, by implication, into the brain, may affect cognitive performance (e.g. Donohoe and Benton, 1999, 2000). The observation of a facilitatory effect of glucose on cognitive performance has led to the hypothesis that meals which induce sustained blood glucose may enhance cognitive function throughout the morning. This aligns well with research which reports a benefit of low Glycaemic Index (GI) carbohydrates on health. GI is an index of the blood glucose raising potential of foods and provides a basis for prediction of post-prandial glycaemic response (Jenkins et al., 1981). GI is therefore a function of the available carbohydrate in foods. The GI of a food is defined as ‘the incremental area under the blood glucose curve elicited by 50 g available carbohydrate portion of a food expressed as a percentage of the response after 50 g anhydrous glucose taken by the same subject’ (Wolever, 2006, p.12). Therefore, in order to calculate the GI of a food item, a portion of the food item containing exactly

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50 g of available carbohydrate needs to be consumed. The glycaemic response to consumption of this portion must then be compared to the glycaemic response to consuming 50 g glucose, in the same individual. Given that foods vary in the amount of available carbohydrate they contain, the portion size required to measure GI varies with the nature of the food being measured. It is therefore erroneous to assume that foods which contain low amounts of available carbohydrate are also low-GI foods. The GI values of a wide range of foods have been published (e.g. Aston et al., 2008; Atkinson et al., 2008; Henry et al., 2008). Scores range from 0–100 with 100 reflecting a glycaemic response identical to that produced by consumption of 50 g glucose. Low-GI (LGI) foods elicit a lower glycaemic response than high-GI (HGI) foods. Glycaemic responses to HGI foods are typically characterised by a rapid rise in blood glucose to a relatively high peak followed by a sharp decline, whereas LGI foods are characterised by a low peak and more sustained decline. Whilst the GI of individual foods can be measured precisely, the GI of mixed meals can only be calculated using the GI values and the carbohydrate contents of the individual foods present in the mixed meal. First, the total available carbohydrate in the meal is calculated. Then the percentage of total available carbohydrate provided by each food is calculated and, for each food, this value is multiplied by its GI value. The sum of the resulting values is the GI of the meal. A peak in glucose, whilst facilitating immediate performance (e.g. Scholey et al., 2001; Sünram-Lea et al., 2002a) leads to an insulin response designed to restore homeostasis by bringing circulating glucose down to baseline levels. This can result in overshoot and lead to the release of other substances, such as free fatty acids (Ludwig et al., 1999). Meals that produce a lower but sustained glucose level are considered to confer relative benefits for health, compared with meals that produce rapid, elevated and enduring fluctuations in glucose. For example, LGI foods are associated with a lower risk of developing heart disease (Barclay et al., 2008), obesity (Ludwig, 2002), diabetes (Salmeron et al., 1997a) and cancer (Gnagnarella et al., 2008). Findings regarding the effect of GI on cognitive performance generally report that LGI foods are beneficial for cognitive performance compared to HGI foods in a variety of populations. In young healthy adults, verbal memory performance is better after consumption of LGI biscuits for breakfast compared to HGI bars (Benton et al., 2003; Benton and Nabb, 2004), and a study whereby the glycaemic profiles of high- and low-GI foods were replicated by asking middle-aged adults to either consume a bolus load of glucose or sip glucose over 120 minutes showed the LGI condition produced better working memory (Nilsson et al., 2009). In children low GI breakfasts have been shown reduce the decline in attention, verbal memory, spatial memory and digit span over the morning compared to HGI breakfasts (Wesnes et al., 2003; Mahoney et al., 2005; Ingwersen et al., 2007). Research also suggests that individuals with impairments in glucose regulation, such as adults with Type 2 diabetes, gain the greatest cognitive

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benefit from LGI foods because these foods improve the post-prandial glycaemia of these individuals. Papanikolaou et al. (2006) reported that verbal memory, working memory, executive function and selective attention were better following a LGI breakfast compared to a HGI breakfast, and these improvements in cognition were related to better post-prandial glycaemia induced by the LGI meal. However, research has not found unequivocal beneficial effects of LGI. Kaplan et al. (2000) reported that older adults showed no difference in cognitive performance after three different meals varying in GI (glucose drink, mashed potato meal and barley meal). Furthermore, in studies which measured post-prandial glycaemic responses, significant differences in cognitive performance were observed at time points at which there were no differences in glucose levels between the two conditions (Benton et al., 2003; Benton and Nabb, 2004; Nilsson et al., 2009). Therefore, although there is good evidence that LGI foods are associated with cognitive benefits (compared to HGI foods), there is limited evidence that these cognitive differences are directly driven by changes in post-prandial glycaemic responses. These cognitive effects are most likely explained by other postprandial metabolic events such as changes in insulin and free fatty acid concentrations. Investigations into the cognitive effects of manipulating the GI of meals have focused almost exclusively on breakfast and cognitive function over the morning. One study has reported consumption of a HGI evening meal was associated with better verbal memory performance the next morning (both before and after breakfast) compared to a LGI evening meal (Lamport et al., under review). This suggests that the effects of GI on cognition persist to the next meal even after an overnight fast, an effect the authors termed the second meal cognitive effect. This is similar to the second meal effects in which the glycaemic response to the next meal is associated with the glycaemic response to the previous meal (Wolever et al., 1988). Further research is required to investigate the cognitive effects of GI meal manipulations throughout the course of the day, since the current literature is focused exclusively on breakfast. It is also important to consider the potential role for fibre in a meal to influence cognition. Ingestion of fibre is known to prolong mastication and gastric emptying and decrease the rate at which glucose (and other food metabolites) is released into the bloodstream (Slavin, 2005). Indeed, fibre is an important confounder of GI because LGI foods are often rich in dietary fibre. It is therefore difficult to wholly attribute effects to GI when the fibre content is not matched across study conditions (e.g. Ingwersen et al., 2007).

6.3.5 Glycaemic load Whilst GI provides an index of the quality of the carbohydrate present in food, it does not consider the quantity of carbohydrate provided in any one

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serving. Given that both the quality and the quantity of carbohydrate are important determinants of a glycaemic response to a food serving, glycaemic load (GL) was introduced to account for both these factors and quantify the overall glycaemic effect of a portion of food (Salmeron et al., 1997a,b). GL for individual foods is defined as the food GI multiplied by the amount of carbohydrate (g) divided by 100 (Foster-Powell et al. 2002; Bell and Sears 2003; Brand-Miller et al., 2003). Thus the GL of a food serving is a product of the amount of available carbohydrate in that serving and the GI of the food (Foster-Powell et al., 2002). More recently, attention has turned to the possibility that GL is also a predictor of cognitive function (e.g. Nabb and Benton, 2006). A recent review of the association between GL and cognitive performance concluded that the evidence from the existing eight studies was insufficient to suggest a consistent directional effect of GL on short-term cognitive performance (Gilsenan et al., 2009). The evidence tentatively points towards better cognition, particularly memory, following low-GL breakfasts compared to high-GL breakfasts in young adults (Benton et al., 2003; Benton and Nabb, 2004), children (Wesnes et al., 2003; Benton et al., 2007; Ingwersen et al., 2007), and Type 2 diabetics (Papanikolaou et al., 2006). However, other methodological inconsistencies between studies render firm conclusions regarding the association between GL and cognition premature. For example, few studies require dietary restrictions and/ or measured physical activity the day prior to testing, both factors which can influence glycaemic responses the next day. Furthermore, Gilsenan et al. (2009) reported that 16 different cognitive tests were employed across the eight studies reviewed and suggested a lack of consistency and an absence of a theoretical rationale for choosing appropriate tests. It is also notable that both between subjects designs and within groups designs have been employed. Using a within groups design to control for individual differences is important as the relationship between GL and cognition can vary depending on the glucose regulation status of the individual (Kaplan et al., 2000; Nabb and Benton, 2006). Therefore, the findings from studies with between groups designs can be less robust. On the other hand, an inherent problem of within groups designs is the impact of practice effects. There is a risk that participants’ performance will improve with each test administration, which may overshadow any effect associated with the experimental manipulation. This highlights the importance of applying counterbalancing for within subjects designs and judicious selection of both the design and the cognitive tests for studies of this nature. Beyond the acute effects of GL on cognition, longitudinal research has failed to document a relationship between dietary glycaemic load and cognitive performance. A recent six-month, randomised, controlled trial examined the impact of high-GL and low-GL energy restricted diets on the cognitive performance of healthy overweight adults (Cheatham et al., 2009). There were no differences in memory, reaction time, vigilance and logical

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reasoning between the two diets. Thus, there is presently insufficient evidence to support a strong association between GL and cognitive performance. Future research should control for previous nutritional intake and physical activity over a suitable timeframe, and have a clear theoretical rationale for the selection of appropriate cognitive tests. It should be noted that the concept of GL attracts some criticism. Researchers often use GL to estimate the glycaemic responses to mixed meals because the GI concept can only be applied to individual carbohydrates. This can be problematic because the addition of fat and protein to carbohydrate affects the expected glycaemic response. Therefore, caution should be taken when applying the concept of GL to mixed meals.

6.3.6 Glucose regulation The consumption of an identical food item will not necessarily produce the same glycaemic response in all individuals. This is due to individual differences in glucose regulation. Good glucose regulation is characterised by low fasting blood glucose levels (<5.6 mmol/l: ADA, 2003) and efficient removal of glucose from the blood into the muscle and fat tissue cells. Therefore poor glucose regulation is characterised by higher fasting glucose levels and higher post-prandial glucose levels. Medically, there are three types of abnormalities in glucose regulation; diabetes, impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), the clinical criteria for which are shown in Table 6.1. The diagnostic test for these conditions is the oral Table 6.1 Diagnostic criterion for type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and normoglycaemia (NG)

Diabetes Fasting glucose level 2 hour glucose level* IGT Fasting glucose level 2 hour glucose level* IFG Fasting glucose level 2 hour glucose level* NG Fasting glucose level 2 hour glucose level*

World Health Organization (WHO) 1999

American Diabetes Association (ADA) 2003

≥7.0 mmol/l or ≥11.1 mmol/l

≥7.0 mmol/l or ≥11.1 mmol/l

<7.0 mmol/l (if measured) and ≥7.8 and <11.1 mmol/l

Not required

6.1–6.9 mmol/l and (if measured) <7.8 mmol/l

5.6–6.9 mmol/l Not required

<6.1 mmol/l and <7.8 mmol/l

<5.6 mmol/l and <7.8 mmol/l

≥7.8 and <11.1 mmol/l

* Venous plasma glucose 2 hours after ingestion of a 75 g oral glucose load.

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glucose tolerance test (OGTT) which involves an oral administration of a 75 g glucose load after a minimum of an eight-hour fast (WHO, 1999). IGT is a less severe abnormality in glucose regulation than diabetes. Research suggests that impairments in glucose regulation are associated with impairments in cognitive performance. Several reviews have concluded that Type 2 diabetes is associated with cognitive deficits (Stewart and Liolitsa, 1999; Strachan et al., 1999; Biessels et al., 2002; Awad et al., 2004), and longitudinal research has shown that Type 2 diabetes can result in accelerated cognitive decline (Allen et al., 2004; Cukierman et al., 2005). IGT, which is often a precursor to the development of Type 2 diabetes, has also been associated with cognitive deficits (Awad et al., 2002; Lamport et al., 2009). Verbal memory appears to be the cognitive domain most sensitive to the detrimental effects of poor glucose regulation, which is consistent with the literature reporting that the glucose ingestion is most likely to benefit verbal memory (Messier, 2004). It might be expected that there is a positive association between glucose regulation and cognitive performance such that worse glucose regulation is associated with worse cognition. Indeed, research tends to support this hypothesis. Even in healthy young adults, variations in glucose regulation within the normal range are associated with cognitive performance. Within these studies, good and poor glucose regulation is typically defined using a median split. For example, glycaemic response to glucose ingestion is measured, the median glycaemic response at a particular time point post ingestion (e.g. 60 minutes) is calculated and, subsequently, individuals whose response falls below the median are defined as good regulators, with those above this median defined as poor glucose regulators. Using this approach, several studies of healthy young adults have reported that poor glucose regulation is associated with worse cognition (Craft et al., 1994; Messier et al., 1997, 1999, 2003; Vanhanen et al. 1997). Other studies have adopted an alternative approach of correlating a parameter of the glucose response (e.g. one or two hours post-ingestion) with cognitive performance. These report that worse glucose regulation is associated with worse cognition (Allen et al., 1996; Donohoe and Benton, 2000; Kaplan et al., 2000; Convit et al., 2003; Rollandson et al., 2008). The correlational approach is statistically stronger than the median split. Other methods of classifying glucose regulation include using the area under the curve (Kaplan et al., 2000; Convit et al., 2003), recovery of glucose levels from one hour to two hours post-ingestion (Awad et al., 2002) and baseline fasting glucose (Donohoe and Benton, 2000; Convit et al., 2003; Rollandson et al., 2008). There are clearly problems with the varied and arbitrary approaches to defining glucose regulation. However, despite this, studies consistently show that worse glucose regulation is associated with poorer cognitive performance. Surprisingly, the evidence associating the clinical definition of IGT with cognitive impairment is much less compelling than the research within the normal glucose tolerance range. This is probably because far fewer © Woodhead Publishing Limited, 2011

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studies have examined the relationship between IGT and cognition (Lamport et al., 2009). Numerous studies with adults with Type 2 diabetes strongly support the conclusion that there is an association between worse glucose regulation and poorer cognition. However, in this age related cognitive decline can be confounded with disease state. Future research should aim to address the important question of determining the level at which impairments in glucose regulation are associated with detrimental effects on cognition. This type of research is challenged by methodological difficulties and potential confounds. There is currently no consensus regarding which parameter of the glycaemic response should be used to define glucose regulation. Lamport et al. (2009) reported that 11 different parameters had been applied by 11 different studies! Awad et al. (2002) correlated no fewer than 14 parameters of the glucose response with cognition, and subsequently chose the parameter which most consistently correlated with performance to classify good and poor glucoregulators. This post hoc approach is common, but problematic. There should be a strong theoretical rationale for choosing a particular parameter. For example, applying the two hour post-ingestion parameter would be compatible with the parameter used to clinically define IGT and diabetes, because of its strong predictive value in relation to other health outcomes such as risk of developing diabetic retinopathy, cardiovascular disease and risk of premature mortality (Gabir et al., 2000; Levitan et al., 2005; Santaguida et al., 2005). Another potential confound is the volume and nature of the carbohydrate used to produce the glycaemic response from which glucose regulation is determined. Clinically, a 75 g OGTT is always used. However, studies of glucose regulation within the normal range use different volumes of glucose (e.g. 25 g, 50 g, 75 g) and even carbohydrate meals. Duration of the fasting period, and nutritional consumption and exercise activity the previous day should also be considered, as these can affect glycaemic response and subsequent cognitive performance. Another issue is whether cognitive testing should take place during the assessment of glucose regulation. Intense cognitive effort can result in reductions in blood glucose levels (Kennedy and Scholey, 2000; Perlmuter et al., 2008). Therefore cognitive testing could impact upon the assessment of glucose regulation. In summary, there is substantive evidence that impairments in glucose regulation are associated with cognitive impairments and poor glucose regulation is associated with an increased risk of cognitive decline. Good glucose regulation may serve to prevent the onset of age-associated cognitive decline and therefore it is important to preserve glucose regulation in the healthy range. Future research should apply careful methodology to examine whether interventions which improve glucose regulation and prevent or delay the onset of diabetes (such as exercise and LGI diets) are associated with better cognitive performance and a reduced risk of cognitive decline.

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6.4 Macronutrients, stress and cognitive performance A potential modulating factor in relationship between macronutrients and cognitive performance is stress. Cognitive performance after administration of glucose, and other macronutrients, may interact with glucocorticoid secretion. Glucocorticoids (cortisol in humans; corticosterone in rodents) are the primary endocrine end-point of the hypothalamic– pituitary–adrenal (HPA) axis which forms part of the psychoneuroendocrine stress response system. Physiological variations in cortisol have been shown to have significant and direct effects on the metabolism of macronutrients, including increased gluconeogenesis, lipolysis (Dinneen et al., 1995) and proteolysis (Simmons et al., 1984). Cortisol has also been shown to affect cognitive performance independent of food ingested. Cortisol secretion may increase as a result of participants finding an experimental context stressful. Challenging cognitive tests, such as the Stroop task, are known to increase cortisol secretion and are often used as stress induction procedures (Kirschbaum and Hellhammer, 1994). Evidence also suggests the facilitation of cognitive performance after a glucose load may be moderated by the emotionally arousing property of experimental stimuli (Mohanty and Flint, 2001). It has been proposed that glucose ingestion and individual glucose tolerance may affect cortisol responses to stress (Gibson and Green, 2002). Hence, macronutrient interactions with cortisol/stress could affect cognitive performance and may need to be considered when interpreting cognitive outcomes ascribed to the effect of dietary manipulations. Macronutrient manipulations may also have the potential to protect cognitive performance under conditions of psychosocial and/or physical stress.

6.4.1 Glucose and cortisol There are a number of reasons to consider the potential for cortisol to mediate the relationship between glucose and cognitive performance. A wealth of research has shown that glucocorticoids can affect cognitive performance. This has been demonstrated in exogenous glucocorticoid administration and in psychosocial stress induction procedures (see Lupien et al., 2007 for a review). For example, working memory (Luethi et al., 2009), declarative memory (Wolf et al., 2001) and spatial thinking tasks (Kirschbaum et al., 1996) have all been shown to be impaired by increased cortisol levels. Such effects are likely to be modulated by glucocorticoid receptors being expressed in high density in neural regions associated with such cognitive functions (e.g. the hippocampus and prefrontal lobes; De Kloet et al., 1993; Qin et al., 2009). Importantly, glucocorticoids have also been shown to have an inhibitory effect on glucose uptake into the hippocampus (Horner et al., 1990), which could attenuate effects of ingested glucose or other macronutrients.

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The increased cortisol secretion profile typically demonstrated after psychosocial laboratory stress exposure has been shown to be modulated by nutritional status and macronutrient intake. Kirschbaum et al. (1997) showed that participants given a 100 g/400 ml glucose load one hour prior to stress exposure demonstrated the typical increased cortisol response. However, participants that were fasted prior to stress exposure failed to show this response. Furthermore, the magnitude of stress-induced cortisol increase was predicted by plasma glucose level, whereas there was no cortisol response following the glucose load in the absence of stress induction. Subsequent research demonstrated only glucose – not fat or protein administration – restored cortisol responses to a stressor in fasted participants (Gonzalez-Bono et al., 2002). Gibson and Green (2002) propose the interaction between cortisol response and nutritional state can potentially explain some of the equivocal findings in macronutrient research. For example, dependence of a typical cortisol stress response on a non-deprived state may explain improved memory reaction times in adults fasted overnight prior to testing (Benton and Owens, 1993). Improved cognitive performance may reflect blunted cortisol activation in fasted individuals, mediated by low blood glucose concentrations, reducing HPA axis responsivity. However, this proposal is based on the assumption that participants find aspects of study participation or cognitive testing stressful.

6.4.2 Glucoregulation, cortisol and cognitive performance Individual glucoregulation may also impact upon the relationship between glucose, cortisol and cognitive performance. We have previously discussed findings of individual glucose tolerance interacting with glucose load to influence cognitive function. Although the evidence is mixed, some research has demonstrated improved cognitive performance after a glucose load in participants with better glucose tolerance (e.g. Nabb and Benton, 2006). Evidence also suggests cortisol response to a stressor is blunted under conditions of low blood glucose. Subsequently, an individual with better glucose tolerance is more likely to demonstrate faster uptake and disposal of glucose. This more efficient glucoregulation may result in a smaller rise in cortisol when the participant undertakes a challenging cognitive test or experiences stress due to taking part in an experimental procedure. Reduced levels of cortisol in individuals with better glucoregulation may act to minimise impairment of performance of cognitive functions sensitive to the effect of cortisol (Gibson and Green, 2002).

6.4.3 Macronutrients and cognitive performance under stress Stress may also potentiate the effects of food on mental performance by modulating brain serotonin function. Cognitive performance tends to dete-

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riorate under conditions of chronic stress. One potential mechanism for this effect is the depletion of serotonin, resulting in reduced serotonergic function with consequent cognitive performance impairment. In a series of studies, Markus and colleagues have attempted to improve cognitive performance under conditions of stress by augmenting brain serotonin synthesis. Dietary manipulations using mixed ratio carbohydrate/protein meals and a whey protein have been used to increase uptake across the blood– brain barrier of the serotonin precursor tryptophan. Early research demonstrated improved cognitive performance in ‘stress vulnerable’ participants. Markus et al. (1999) reported that performance on a Sternberg memory scanning task following a controllable stressor improved after a carbohydrate-rich, protein-poor diet compared with a protein-rich, carbohydrate-poor diet. Improved cognitive performance in stress vulnerable participants on the same cognitive measure was also reported following dietary intake of α-lactalbumin – a bovine whey protein with the highest tryptophan content of all protein sources (Markus et al., 2002). In both these studies, the dietary interventions produced an increase in plasma Trp:LNAA ratio. The proposed mechanism underpinning improved cognitive performance in these interventions is that increasing levels of the serotonin precursor tryptophan augments brain serotonin synthesis. Increased brain serotonin has been implicated in maintenance of control over information processing (Spoont, 1992) and plays a role in learning and memory (Altman and Normile, 1988). So far, the effect has only been demonstrated in stress vulnerable participants. Similarly, premenstrual women who are also at risk of depleted brain serotonin levels, and are vulnerable to greater reactivity to stress, showed selective effects α-lactalbumin intake on cognition with improved long-term memory for abstract figures – but not for words (Schmitt et al., 2005b). However, increased plasma tryptophan is an indirect measure of brain serotonin synthesis, so this mechanism is yet to be confirmed directly in humans. There is evidence to suggest that a number of protein amino acids have a specific effect of protecting cognitive performance under conditions of challenge or stress. A tyrosine drink resulted in improved cognitive performance (compared to carbohydrate) under conditions of physical and psychological stress. Cadets undergoing a demanding military combat-training course were given either five daily doses of a protein-rich drink containing 2 g of tyrosine or a carbohydrate-rich drink, each with 255 kcal (Deijen et al., 1999). Assessments were made both immediately before the combat course and on day six of the course. The group supplied with the tyrosinerich drink performed better on a memory and a tracking task than the group supplied with the carbohydrate-rich drink. Supplementation of tyrosine under conditions of psychosocial and/or physical stress is proposed to reduce the impairing effect of stress and fatigue upon cognitive performance. This is supported by the finding that tyrosine has little or no effect on the cognitive performance of rested, non-stressed participants

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(Lieberman et al., 1983). Pharmacologically administered tyrosine supplementation has been shown to affect a wide range of cognitive parameters under a number of stress contexts. This includes reduced impairment to psychomotor performance, vigilance, choice reaction time, pattern recognition and short-term memory performance, under cold exposure and hypoxia conditions (Banderet and Lieberman, 1983; Shurtleff et al., 1994). Such observed effects are proposed to be modulated by the augmentation of central neurotransmitters crucial to cognitive functioning. Tyrosine is a precursor of norepinephrine and dopamine which are implicated in a number of key cognitive processes (e.g. attention; Smith and Nutt, 1996). Increased tyrosine augmentation may prevent cognitive performance decrements by reducing stress-induced depletion of norepinephrine levels. However, as with tryptophan manipulations, increased plasma tyrosine is an indirect measure of norepinephrine synthesis. Furthermore, the majority of evidence of the effect of tyrosine on cognition comes from pharmacological administration of tyrosine supplements. Increased plasma Tyr/LNAA ratio has been demonstrated following dietary consumption of protein-rich meals (Melamed et al., 1980). However, there is a lack of research exploring the potential for dietary augmentation of plasma tyrosine to influence cognitive performance under conditions of stress. Protein fractions may also improve cognitive performance under conditions of stress by acting to reduce physiological and hormonal responses to stress. In addition to protecting cognitive performance, tyrosine has been reported to significantly lower blood pressure in participants exposed to psychosocial and physical stress (Deijen et al., 1999; Deijen and Orlebeke, 1994). Firk and Markus (2009) reported that the dietary intake of a hydrolysed protein, which increased tryptophan levels, dampened cortisol response to psychosocial stress induction procedure (Trier Social Stress Test (TSST); Kirschbaum et al., 1993). In contrast to earlier work by Markus et al. (1999, 2002), the effects of this dietary augmentation of tryptophan were not moderated by stress vulnerability, with all participants demonstrating a blunted cortisol response. Although Fink and Markus did not measure cognitive performance, such a reduction of cortisol response may have a protective effect on cognitive performance under conditions of stress. Dietary manipulations to increase levels of tyrosine and tryptophan may improve cognitive performance when faced with psychosocial and/or physical stress by improving stress coping. Finally, macronutrients may themselves elicit a cortisol response which may affect cognitive performance during nutritional interventions. Gibson et al. (1999) reported 1.5–2-fold increase in salivary cortisol following a protein-rich midday meal (30–40 % of energy as protein). Gibson and colleagues suggest this significant moderation of cortisol response by macronutrient composition can be considered a potential mechanism which may underlie nutrient-dependent changes in cognitive performance. Increased cortisol has the potential to act upon neural areas

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associated with cognitive function to impair performance on cognitive tasks.

6.5 Implications for the food industry, nutritionists and policy-makers The research reviewed in this chapter has considered not only the effects of macronutrients on cognitive performance but has recognised that macronutrients are not consumed singularly by a standard healthy average person. Hence our conclusions about the effects of macronutrients on mental performance must reflect the mixed macronutrient composition of most meals, which leads these meals to vary in terms of GI and/or GL and the nature of the person consuming these meals, particularly in relation to their glucose handling. Another individual factor which may affect the cognitive effects of a food consumed is the individual’s responsivity to stress, generally and in the testing environment. Nevertheless, even with these caveats in mind, there is substantial evidence that the macronutrient composition and subsequent metabolic effects induced by particular meals can impact on cognitive performance. The foods we consume could exert effects on cognitive function directly because they contain certain nutrients or functional ingredients which alter our metabolic response or neurotransmitter function, in order to exert effects on certain brain structures or processes which are integral to effective cognitive functioning. Alternatively, positive effects of foods on cognitive function in the longer term could be implied by the effect of that food on our general health. For instance a LGI diet which maintains healthy glucoregulatory capability in a person could lead to fewer smaller postprandial glycaemic excursions, greater insulin sensitivity and lower risk of Type 2 diabetes and thereby maintain optimal cognitive functioning as the person ages. Understanding the impact of food on health and cognitive function is important against the background of increasing prevalence of overweight, obesity and the diseases associated with this, particularly Type 2 diabetes, which we have demonstrated is associated with cognitive impairment (e.g. Stewart and Liolitsa, 1999; Biessels et al., 2002; Awad et al., 2004). We have also provided some evidence to indicate poorer cognitive function as glucose regulation gets worse (e.g. Allen et al., 1996; Donohoe and Benton, 2000; Kaplan et al., 2000; Convit et al., 2003). These cognitive effects of increasingly common disorders exacerbate the effects of these diseases of the developed world, reducing quality of life and independence for the affected, and increasing the burden on health services with economic and social consequences. The food industry and health promotion can take a decisive role in the prevention of these conditions by developing products which do not

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contribute to the development and maintenance of the disease state. Foods which contain protective ingredients or functional properties to improve health and which could impact directly on cognitive function would be welcome additions to the diet. Similarly, there is a demand for products which provide an acute boost to cognitive function in a manner similar to caffeine and which could be used to maintain optimal performance under conditions of high demand or stress.

6.6

Future trends and opportunities for this research field

Future trends reflect the changes that have been taking place in the nature of our diets and the structure of our eating behaviour over the last few decades. We are now faced with an abundance of highly palatable foods, coupled with hectic lifestyles. Our eating patterns have changed with the habit of consuming a large breakfast before a physically demanding day’s work, giving way to more sedentary occupations and large evening meals. The effects of evening meals have not been studied in terms of the cognitive effects of the meal directly nor of the potential health effects of this changed eating pattern which has important implications for our health – insulin resistance is relatively worse in the evening, yet we now challenge our physiology to deal with greater demands by consuming a large evening meal. If we cannot change this meal patterning because of the demands of modern living, then there is scope to understand food components which have the potential to modulate these demands, e.g. the presence of fibre in a meal can reduce its glycaemic response and this could attenuate any deleterious effects of the meal. There are also a number of methodological improvements which researchers can make to strengthen the conclusions which can be drawn from their studies. There is a need for researchers to adopt a randomised, controlled trial (RCT) approach to testing of foods and food ingredients to eliminate or reduce the impact of experimental noise and extraneous variables which render findings difficult to compare. To achieve ecologic validity, the three macronutrients need to be examined concurrently in experimental manipulations. The carbohydrate, fat and protein content of a meal affects the rate of gastric emptying and modifies the GI and insulin response. Ingestion of mixed composition meals means that macronutrient interactions may occur. The effects of the interaction of all three macronutrients on metabolism, and the implications for mental performance, have rarely been considered by previous research. Carbohydrates may not necessarily exert their effect purely by altering availability of glucose but, rather, may alter serotoninergic function with consequences for performance (Altman et al., 1988). Further, clarification of the role of glycaemic response to cognitive function is overdue. What are the useful concepts for future research here?

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We should also develop a greater understanding of the impact of glucose intolerance – where for instance does cognitive impairment start to become apparent? Is this most readily detectable under high fasting levels or during extended (but not clinical) post-prandial glucose excursion? And what are the cognitive implications for Type II diabetic patients and those not yet with Type II diabetes, but with impaired glucose tolerance; can cognitive deficits be reversed by improvements in glucose handling and how should we examine this?

6.7 Sources of further information and advice Further useful information on the effects of macronutrients on cognitive performance can be found in the following journal reviews and research papers: Hoyland et al., 2008, 2009; Lamport et al., 2009; Dye and Blundell, 2002; and Dye et al., 2010. Further information and advice is also available on the webpage of the International Life Sciences Institute (www.ilsi.org). A comprehensive list of GI values for a variety of foods can be found at www.glycemicindex.com.

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schmitt j a, benton d and kallus k w (2005a) General methodological considerations for the assessment of nutritional influences on human cognitive functions. European Journal of Nutrition, 44, 459–464. schmitt j a j, jorissen b l, dye l, markus c r, deutz n e p and riedel w j (2005b) Memory function in women with premenstrual complaints and the effect of serotonergic stimulation by acute administration of an alpha-lactalbumin protein. Journal of Psychopharmacology, 19(14), 375–384. scholey a b and fowles k a (2002) Retrograde enhancement of kinaesthetic memory by alcohol and by glucose. Neurobiology of Learning and Memory, 78(2), 477–483. scholey a and kennedy d o (2004) Cognitive and physiological effects of an ‘energy drink’: an evaluation of the whole drink and of glucose, caffeine and herbal flavouring fractions. Psychopharmacology, 176(3–4), 320–330. scholey a, harper s and kennedy d (2001) Cognitive demand and blood glucose. Physiology and Behaviour, 73, 585–592. schweiger u, warnhoff m, pahl j and pirke k m (1986) Effects of carbohydrate and protein meals on plasma large neutral amino acids, glucose, and insulin plasma levels of anorectic patients. Metabolism, 35, 938–943. seaquist e r, damberg g s, tkac i and gruetter r (2001) The effect of insulin on in vivo cerebral glucose concentrations and rates of glucose transport/metabolism in humans. Diabetes, 50, 2203–2209. shurtleff d, thomas j r, schrot j, kowalski k and harford r (1994) Tyrosine reverses a cold-induced working memory deficit in humans. Pharmacology, Biochemistry and Behaviour, 47, 935–941. sieber f e and trastman r j (1992) Special issues: glucose and the brain. Critical Care Medicine, 20, 104–114. silver i a and erecinska m (1994) Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation of oxygen supply in normo-, hypo-, and hyperglycemic animals. Journal of Neuroscience, 14, 5068–5076. simmons p s, miles j m, gerich j e and haymond m w (1984) Increased proteolysis: an effect of increases in plasma cortisol within the physiological range. Journal of Clinical Investigation, 73, 412–420. slavin j l (2005) Dietary fibre and body weight. Nutrition, 21, 411–418. smith a p and kendrick a m (1992) Meals and performance. In Smith A P and Jones D M (eds), Handbook of Human Performance, vol 2, Health and Performance. London: Academic Press, 2–23. smith a and nutt d (1996) Noradrenaline and attention lapses. Nature, 380, 291. smith a p, leekham s, ralph a and mcneill g (1988) The influence of meal composition on post-lunch performance efficiency and mood. Appetite, 10, 195–203. smith a p, ralph a and mcneill g (1991) Influence on meal size on postlunch changes in performance efficiency, mood, and cardiovascular function. Appetite, 16, 85–91. smith a p, kendrick a, maben a and salmon j (1994) Effects of fat content, weight, and acceptability of the meal on postlunch changes in mood, performance, and cardiovascular function. Physiology and Behaviour, 55, 417–422. spoont m r (1992) Modulatory role of serotonin in neural information processing: implications for human psychopathology. Psychological Bulletin, 112, 330–350. stewart r and liolitsa d (1999) Type II diabetes mellitus, cognitive impairment and dementia. Diabetic Medicine, 16, 93–112. stone w s, seidman l j, wojcik j d and green a i (2003) Glucose effects on cognition in schizophrenia. Schizophrenia Research, 62(1–2), 93–103. strachan m w (2003) Insulin and cognitive function. The Lancet, 18, 1253. strachan m w j (2005) Insulin and cognitive function in humans: experimental data and therapeutic considerations. Biochemical Society Transactions, 33, 1037–1040.

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strachan m w j, abraha h d, sherwood r a, deary i j, ewing f m e, perros p and frier b m (1999) Evaluation of serum markers of neuronal damage following severe hypoglycaemia in adults with insulin-treated diabetes mellitus. Diabetes Metabolism Research and Reviews, 15(1), 5–12. sünram-lea s, foster j, durlach p and perez c (2001) Glucose facilitation of cognitive performance in healthy young adults: examination of the influence of fast-duration, time of day and preconsumption plasma glucose levels. Psychopharmacology, 157, 46–54. sünram-lea s, foster j, durlach p and perez c (2002a) Investigation into the significance of task difficulty and divided allocation of resources on the glucose memory facilitation effect. Psychopharmacology, 160, 387–397. sünram-lea s, foster j, durlach p and perez c (2002b) The effect of retrograde and anterograde glucose administration on memory performance in healthy young adults. Behavioural Brain Research, 134, 505–516. vanhanen m, koivisto k, karjalainen l, helkala e-l, laakso m, soininen h and riekkinen p (1997) Risk for non-insulin-dependent diabetes in the normoglycaemic elderly is associated with impaired cognitive function. Neuroreport, 8, 1527–1530. watson g s and craft s (2004) Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer’s disease. European Journal of Pharmacology, 490, 97–113. watson g s, peskind e r, asthana s, purganan k, wait c, chapman d, schwartz m w, plymate s and craft s (2003) Insulin increases CSF Abeta42 levels in normal older adults. Neurology, 60, 1899–1903. wells a s and read n w (1996) Influences of fat, energy and time of day on mood and performance. Physiology and Behaviour, 59, 1069–1076. wenk g l (1989) An hypothesis on the role of glucose in the mechanism of action of cognitive enhancers. Psychopharmacology, 89(4), 431–438. wesnes k a, pincock c, richardson d, helm g and hails s (2003) Breakfast reduces declines in attention and memory over the morning in schoolchildren. Appetite, 41, 329–331. who (1999) Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Geneva: World Health Organisation. winder r and borrill j (1998) Fuels for memory: the role of oxygen and glucose in memory enhancement. Psychopharmacology, 136, 349–356. wolever t m s (2006) The Glycaemic Index: a Physiological Classification of Dietary Carbohydrate. Cambridge, MA: CABI. wolever t m, jenkins d j, ocana a m, rao v a and collier g r (1988) Second meal effect: low-glycemic-index foods eaten at dinner improve subsequent breakfast glycemic response. American Journal of Clinical Nutrition, 48, 1041–1047. wolever t m, yang m, zeng x y, atkinson f and brand-miller j c (2006) Food glycemic index, as given in glycemic index tables, is a significant determinant of glycemic responses elicited by composite breakfast meals. American Journal of Clinical Nutrition, 83, 1306–1312. wolf o t, convit a, mchugh p f, kandil e, thorn e l, de santi s, et al. (2001) Cortisol differentially affects memory in young and elderly men. Behavioral Neuroscience, 115(5), 1002–1011.

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7 Carbohydrate consumption, mood and anti-social behaviour D. Benton, Swansea University, UK

Abstract: Although there is a widespread popular assumption that the consumption of refined carbohydrate rapidly increases blood glucose and therefore enhances mood, controlled studies do not support such a view. It is also commonly suggested that a marked increase in blood glucose is followed by a rapid fall, resulting in a hypoglycaemic reaction with associated anxiety-like symptoms. It is, however, uncommon for blood levels to fall to the levels required to diagnose clinical hypoglycaemia. There are, however, several reports of an association between a tendency for blood glucose to fall rapidly, but not to levels necessary to diagnose hypoglycaemia, irritability and aggression. The consumption of meals that are almost entirely carbohydrate can increase the levels of tryptophan in the blood with consequences for the synthesis of serotonin in the brain and hence an improvement in mood. The evidence is, however, that this mechanism is blocked by relatively small amounts of protein in the diet, such that it occurs very rarely when normal meals are consumed. Similarly, there is no support from well-controlled studies for the suggestion that sugar consumption causes hyperactivity in children. There is, however, evidence that pleasant tasting foods, for example chocolate, release endorphins with associated improvements in mood. Key words: anti-social behaviour, carbohydrate, chocolate, hypoglycaemia, mood, pre-menstrual syndrome, seasonal affective disorder, serotonin, tryptophan.

7.1 Introduction In the general population, there is a widespread assumption that the consumption of refined carbohydrate, in particular sugar, results in a rapid enhancement of mood and increased alertness. A ‘sugar rush’ is experienced. It is suggested that in children hyperactivity may be observed following the consumption of sugar. However, it is also suggested that this supposed short-term stimulating effect is followed by a downward swing so that you subsequently become fatigued, irritable and feel low. A similar

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pattern is suggested to follow the consumption of any highly refined carbohydrates, such as those found in white bread or pasta. A related idea is that we should attempt to eat a low-glycaemic diet; one that causes only small changes in the level of blood glucose. Another suggested consequence is that a diet high in refined carbohydrate will have been stripped of micronutrients to the extent that subclinical deficiencies result, with further consequences for behaviour. Some have even suggested that sugar is physically addictive (Avana et al., 2008), although this is disputed (Benton, 2010). The consequences for mood of carbohydrate consumption are therefore considered, although many of these ideas have gained little support when examined in well-controlled studies.

7.2 Carbohydrate metabolism and mood 7.2.1 Short-term effects of carbohydrate intake The consumption of a sugary drink or snack is a common response to feeling low or tired, but does mood reflect the level of blood glucose? The examination of the short-term influence of carbohydrate on mood has either contrasted sugar or starch with high-protein foods, or has compared sucrose- or glucose-containing drinks with a placebo. Benton (2002) reviewed studies that compared the response to carbohydrate-rich and protein-rich foods. Several hours after eating a high-carbohydrate rather than protein-containing food, there is a tendency to report feeling less energetic. The effect is calming rather than stimulating. In the first hour after drinking a sugar-containing drink, there are some reports of small increases in subjective energy, but others report no effect. The response is small and not easily demonstrated. For example, Benton and Owens (1993) reported a small increase in energy 15–30 minutes after combining several studies to produce a sample of 354. There was no evidence of a ‘sugar rush’. Benton (2002) concluded that a major variable is the time when mood was assessed. The majority of studies measured mood about two hours after the taking the drink or meal, something true of the studies that reported an association between decreased subjective energy and carbohydrate consumption. The studies that found that energy increased after a sugarcontaining drink measured mood after 15, 30 or 60 minutes. Benton and Owens (1993) stated that short-term increases in reported energy seemed a robust phenomenon; it was, however, a limited effect that could not be expected to be observed with a small sample size.

7.2.2 Mood under demanding conditions The above findings involved studies in which subjects sat quietly after consuming carbohydrate. In contrast, Owens et al. (1997) suggested that there

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would be a stronger association between mood and blood glucose levels when subject to cognitive demand. As the brain has a high metabolic rate, it was proposed that the supply of glucose would be more influential while performing demanding tasks. When mood was assessed while performing three cognitively demanding tasks, falling levels of blood glucose were associated with feeling less energetic. Similarly, Benton and Owens (1993) found that those whose blood glucose remained at lower levels reported feeling more tense, possibly reflecting the activation of the autonomic nervous system in an attempt to increase blood glucose values.

7.3 The incidence of hypoglycaemia In the general population, there is a widespread belief that raising blood glucose levels will give mood a short-term boost, although as discussed above this is a false belief. However, in addition there is a common belief that such short-term gains are at the expense of a longer term hypoglycaemic reaction. The suggestion is that following a highglycaemic meal, the associated release of high levels of insulin will cause blood glucose to fall to a level at which the functioning of the brain is adversely influenced. Nabb and Benton (2006) gave eight breakfasts that varied in the speed at which they released glucose into the blood stream. They found that those with better tolerance reported generally better mood and those eating breakfasts that contained more carbohydrate were in the late morning tired rather than energetic. Is it, however, reasonable to describe such a reaction as hypoglycaemic? Benton (2002) discussed this question. A series of homeostatic mechanisms attempt to maintain blood glucose in a range of 70–100 mg/dl. Raising levels of blood glucose stimulates the release of insulin that causes glucose to be taken up by muscle and stored in the liver. When levels fall below the optimal range, steps are taken to increase the level of glucose including the release of glucagon that acts broadly in an opposite manner to insulin, releasing stored glucose from the liver. However the release of catecholamines, growth hormone and glucocorticoids also plays a role. If catecholamines are released these result in sweating, palpitations, weakness and anxiety, something that occurs when blood glucose is about 40 mg/dl, although there are individual differences. As these symptoms are similar to anxiety, they are often interpreted by the patient as such. Harris (1924) observed in non-diabetic patients symptoms similar to those that result from insulin-induced hypoglycaemia. He coined the term spontaneous hypoglycaemia as these symptoms were a reaction to food consumption. There is also a distinction between ‘reactive hypoglycaemia’ where blood glucose values are low and ‘essential reactive hypoglycaemia’

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in which such values are associated with spontaneous symptoms. In some individuals, the consumption of high-glycaemic meals has been related to feeling tired, ill, inadequate, anxious, depressed and even to psychotic disorders, alcoholism and violence. The question is the frequency with which such reactions occur. The writers of many popular books have suggested that reactive hypoglycaemia occurs commonly, although such a view has not been supported by systematic study. A glucose tolerance test (GTT) can be used to assess an individual’s ability to control blood glucose levels. After fasting overnight, the blood glucose profile is monitored following the consumption of 75 g of glucose. When 650 normal subjects took a GTT, Lev-Ran and Anderson (1981) found a large range of glucose nadirs. The median lowest value was 65 mg/dl and the 2.5th percentile was 39 mg/dl. Superficially, this might suggest that one in 40 healthy individuals have a tendency to have a hypoglycaemic reaction to their diet. However, when 135 individuals who were believed to have reactive hypoglycaemia were considered, only four proved to have the disorder. Arguably a GTT, although valuable when diagnosing diabetes, tells us little about our reaction to a normal diet. The picture that emerges when the response to normal diets is monitored is one of relative glucose stability. Alberti et al. (1975) monitored 19 normally fed individuals and reported ‘. . . very little variation in glucose concentration during the day’. They found that the pattern of glucose was quite different to that obtained during a GTT. Hansen and Johansen (1970) found that blood glucose levels never fell below 71 mg/dl and Genuth (1973) that they were never below 80 mg/dl. Thus, in most normally fed healthy individuals blood glucose values rise following a meal and then fall, but not to the level required to diagnose clinical hypoglycaemia. Various professional bodies have issued public statements. The American Diabetes Association, The Endocrine Society and The American Medical Association jointly issued a statement on hypoglycaemia (Statement, 1973). They stated that the public had been led to ‘to believe that there is a widespread and unrecognized occurrence of hypoglycemia in this country. Furthermore, it had been suggested repeatedly that the condition is causing many of the common symptoms that affect the American population. These claims are not supported by medical evidence.’ It is clear that only rarely does a meal induce levels of blood glucose low enough to attract a diagnosis of clinical hypoglycaemia. In a normal diet, the presence of protein and fat will slow the rate at which glucose is released into the blood. Yet Nabb and Benton (2006) found that meals containing larger amounts of carbohydrate were associated with feeling tired in the late morning, although blood glucose levels were not low enough to attract a diagnosis of hypoglycaemia. It seems possible that the rate at which blood glucose falls, rather than the lowest level reached, may be important.

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7.3.1 The control of blood glucose and mood The Quolla Indians in Peru and are known for their high murder rate and family feuds. Bolton (1973, 1979) noticed a strong craving for sugar and considered the possibility that their aggression reflected a tendency to develop low levels of blood glucose. He found in a GTT an association between a tendency for blood glucose to fall to low values and a history of being aggressive. Similarly, in Finland those with a history of violent crime have been found to develop low levels of blood glucose (Virkkunen, 1982; Virkkunen and Huttunen 1982; Virkkunen and Narvanem,1987). The study of Benton et al. (1998b) found a similar tendency in the normal population. In young adult males, those whose blood glucose levels fell more rapidly in a GTT were more likely to make aggressive comments when faced with a frustrating situation and were more likely to think that aggressive acts were justified. A similar study, using young adult females, found that those who had a tendency for blood glucose levels to fall to low levels during a GTT were more likely to display aggression (Donohoe and Benton, 1999). Gray and Gray (1983) suggested that an association between blood glucose levels and aggressiveness could not occur unless levels were low enough to be described clinically as hypoglycaemic. Donohoe and Benton (1999) illustrated that this was not the case. They found that a nadir of 63 mg/dl in a GTT was a value that distinguished those with greater tendency towards aggression; that is, blood glucose levels higher than those that can be described as hypoglycaemic are associated with irritability. As these relationships are only correlations, it is possible that a third factor might influence both aggression and blood glucose. However, there are reports in both children (Benton et al., 1987) and adults (Benton and Owens, 1993) that the giving of a sugar-containing drink reduced irritable behaviour; data suggesting a causal role for blood glucose values. In summary, the data, although limited, have shown an association between a tendency for blood glucose levels to fall rapidly, irritability or even aggression. In susceptible individuals, it will be of value to consider the effect on mood of the frequency that meals are eaten and the effect of their nutritional composition.

7.4 Serotonin synthesis after the consumption of carbohydrate A frequently quoted suggestion is that the intake of carbohydrate influences the rate at which the amino acid tryptophan is taken up into the brain, with consequences for the synthesis of the neurotransmitter serotonin and hence mood. There have been consistent reports that meals high in carbohydrate as opposed to protein increase the ratio of tryptophan to long-chain neutral amino acids (LNAA) in the blood (Lieberman et al., 1986a; Teff et al., 1989; Christensen and Redig, 1993) with potential consequences for

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serotonin synthesis in the brain. The question is the extent to which these findings have relevance when trying to understand normal food consumption. What does this laboratory observation tell us of our reaction to a typical diet? The rate at which the brain synthesizes serotonin depends on the availability of tryptophan, that is converted to 5-hydroxytryptophan by tryptophan hydroxylase, the rate limiting step. Subsequently, 5-hydroxytryptophan decarboxylase, with pyridoxal phosphate as a co-enzyme, forms 5-hydroxytryptamine, also known as serotonin. Thus, the availability of brain tryptophan, that in turn depends on the rate at which it is taken up by the brain, determines the rate at which serotonin is synthesized. A major theory of the aetiology of depression is that it reflects a low level of brain serotonin. Tryptophan in the blood competes with other LNAA, isoleucine, leucine, methionine, phenylalanine, tyrosine and valine, for transport across the blood–brain barrier. Normally, the proportion of tryptophan to these other LNAAs is relatively low. However, the consumption of carbohydrate and the consequent release of insulin influences the relative proportions of LNAAs. Insulin increases the rate at which most LNAAs are taken up into muscle. In contrast, tryptophan remains in the blood bound to albumin. The result is that the relative proportion of tryptophan in the blood increases and more crosses the blood–brain barrier where it is available for metabolism into serotonin. In contrast, a meal high in protein will decrease the plasma tryptophan ratio as less tryptophan than other competing LNAAs is provided. These phenomena have been demonstrated in many studies. For example, when rats ate a meal of carbohydrate and no protein, the ratio of tryptophan to the other LNAAs in the blood increased (Yokogoshi and Wurtman, 1986). However, the ability to increase the tryptophan/LNAA ratio was blunted by the addition of as little as 2.5 % protein, and either 5 % or 10 % protein failed to increase tryptophan levels. That is, although a meal without protein increased the availability of tryptophan, as little as 5 % protein prevented this phenomenon (Yokogoshi and Wurtman, 1986). Benton and Donohoe (1999) considered 30 human studies that had examined the influence of meals that differed in the energy coming from protein rather than carbohydrate. Although the consumption of exclusive carbohydrate increased the tryptophan/LNAA ratio, when protein provided as little as 5 % of the calories the phenomenon did not to occur. Wurtman et al. (2003) noted that there were few data associated with actual meals so they contrasted the response to two breakfasts. One, based on waffles, offered 80 % of calories as carbohydrate and only 6 % as protein. The other meal was based on turkey, eggs and cheese and provided 52 % of calories as protein and 17 % as carbohydrate. The two meals produced marked differences in the ratio of trypophan to LNAA, a response due more to the high-protein rather than high-carbohydrate meal. After four hours,

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the eating of the high-protein meal decreased the ratio by 35 %, whereas after the high-carbohydrate meal it had increased by a more modest 10 %. If the proposed mechanism was working, then any difference between the meals should not be due to a negative response to a high-protein meal but rather a positive response to a high intake of carbohydrate. Although the authors claimed that these meals were similar to those consumed by Americans, there are reasons to question this statement. The findings reflected to a large extent the response to a high-protein meal, rather than the high-carbohydrate meal that was theoretically predicted to be influential. How often are meals with three different sources of protein consumed without bread, pasta or another source of starch? Arguably, these findings illustrate the improbability of typical meals producing significant differences in tryptophan availability, as the meals were highly prescribed and not typical of normal dietary patterns. In reality, it is rare to consume meals that contain so little protein that the provision of tryptophan will increase. When the proportion of dietary energy provided by protein has been calculated, it has been found to be relatively constantly in the range of 13 +/−2 % of daily calories. The ratio of carbohydrates to protein eaten is similarly fairly constant, typically, there are four or five time the amount of carbohydrate as protein (de Castro et al., 1987; Kim et al., 1987). A diet of this nature will not generally increase the availability of tryptophan to the brain. Most foods that would be described as being high in carbohydrate provide sufficient protein to ensure that tryptophan availability in the blood is not increased. For example, white bread offers 14 % of calories as protein, the figure for potatoes and rice is 7 %, yet the phenomenon described by Wurtman occurs only when a meal is consumed that is almost entirely carbohydrate. Nevertheless, protein must be eaten at some stage as tryptophan is an essential amino acid and hence must be consumed for the mechanism to function. Another problem is that a diet that is exclusively of carbohydrate would be unpalatable and unbalanced. In fact, a chronic lack of protein in the diet would decrease rather than increase levels of tryptophan, as protein consumption is the only source of tryptophan. Ultimately, we need to consider brain serotonin synthesis rather than the amino acid profile of peripheral blood. In animals, after a carbohydraterich/protein-poor meal, enhanced serotonin synthesis occurred only following a meal that was almost entirely carbohydrate (Fernstrom, 1988). In fact, there is some doubt as to whether data from rats can be extrapolated to humans, as in humans changes in plasma tryptophan following high-carbohydrate meals may be less. Ashley et al. (1985) gave a breakfast containing only 1.6 % of the energy as protein and found only a 16 % increase in the tryptophan/LNAA ratio. In rats the ratio between tryptophan and LNAAs needed to at least double if an increase in serotonin synthesis was to be demonstrated (Fernstrom and Wurtman, 1972). Importantly, in humans the consumption of a meal entirely made up of carbohydrate failed to increase the level of tryptophan in cerebral spinal fluid (Teff et al., 1989).

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In conclusion, although there is good evidence that a meal that is almost exclusively carbohydrate will increase the tryptophan/LNAA ratio, there is little reason to believe that this is a mechanism that is relevant other than on rare occasions when food items that are entirely carbohydrate are consumed.

7.4.1 Carbohydrate consumption and depression Wurtman and Wurtman (1989) suggested that one way of addressing depression was to increase the intake of carbohydrate, a view based on those suffering with pre-menstrual syndrome (PMS), seasonal affective disorder (SAD) or carbohydrate-craving obesity. As discussed above, it was proposed that the consumption of carbohydrate increases the level of serotonin in the brain and reduces depression. Pre-menstrual syndrome (PMS) One symptom of PMS is an increased appetite towards the end of the monthly cycle. Sayegh et al., (1995) found that a carbohydrate-rich drink (48 g carbohydrate/no protein) in a double-blind study decreased the depression, anger and confusion of those with PMS. The generality of this response should, however, be questioned as a meal containing no protein would rarely if ever be consumed. Although Christensen (1996) concluded that ‘individuals with PMS increase their carbohydrate consumption in the pre-menstrual stage’, we need to consider whether carbohydrate intake specifically increases or, alternatively if there is a more general increase in food intake? A study of dietary intake found that carbohydrate consumption increased in the pre-menstrual stage (Wurtman et al., 1989). Although these data were used as evidence that carbohydrate intake is greater in those with PMS, there was in fact an increase in both the intake of fat and carbohydrate. As the increased intake was not specifically carbohydrate, it may well have reflected an increased consumption of palatable foods in general, irrespective of the macronutrient composition. When Wurtman et al. (1989) offered high-carbohydrate meals (4 % of energy as protein), the mood of those with PMS improved. However, the levels of protein offered were sufficiently high to question whether the provision of tryptophan would have been increased and, consistent with this view, the amino acid profile in the blood did not change. Importantly, improved mood had been found even though the level of blood tryptophan did not increase. In addition, as most meals contain more than 4 % protein, even if the levels of blood amino acids had differed, the observation would not generalise to the consumption of a more typical meal. Is there evidence that the diets of those with PMS are distinctive? Surveys tend to report that the pre-menstrual stage is associated with cravings for sweet items, particularly chocolate, but there is also a general increase in

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appetite. Vlitos and Davies (1996) found 13 studies that reported an increase in energy intake during the luteal phase that varied from 87 to 674 kilocalories a day. For example, a survey of 384 women found that in 58 % there was an increase in appetite in the pre-menstrual period, in particular a raised liking for sweet foods (Friedman and Jaffe, 1985). The findings are sufficiently consistent for food cravings and changes in food intake to be seen as symptoms of PMS. Does this increased liking for sugary items result in a changed overall profile of macronutrient intake? Does the intake of carbohydrate increase as predicted? An isolated study supported the hypothesis. Dalvit-McPhillips (1983) reported that protein and fat intake was similar in the pre- and postmenstrual stages, whereas the intake of carbohydrate increased from 133 to 257 g. However, when Vlitos and Davies (1996) reviewed the topic, they found seven other studies that did not find a selective increase in carbohydrate intake. The weight of evidence does not support the suggested selective increase in carbohydrate intake in the pre-menstrual stage. There are reports of an increased eating of sweets, cake and chocolate (Davies et al., 1993) and a greater preference for chocolate-containing foods while bleeding (Tomelleri and Grunewald, 1987). As the foods that are craved are pleasant tasting and are high in fat and carbohydrate, there is little support for the hypothesis that the intake of carbohydrate is selectively enhanced. In addition, the amount of protein in chocolate (4–6 % of energy), cakes (4–10 %) and cookies (5–6 %) will ensure that there will not be an increased availability of tryptophan in the blood. Although the suggestion of Wurtman and Wurtman (1989) was that the change in the pattern of food consumption was an attempt to influence mood, there is also substantial evidence of changes in basal metabolic rate over the menstrual cycle (Buffenstein et al., 1995). For example, Webb (1986) found that eight out of ten women showed a rise of between 8 % and 16 % in basal metabolic rate between the first and second halves of the menstrual cycle. Thus, there are parallels between increased pre-menstrual appetite, increased energy intake and increased metabolic rate: the change in food consumption may simply reflect an increased need for energy rather than an attempt to manipulate mood. In summary there is no consistent evidence of a selective increase in carbohydrate consumption in the pre-menstrual stage. There is, however, evidence that appetite, metabolic rate and caloric intake all rise and that the consumption of pleasant tasting foods increases, foods that contain high levels of both fat and carbohydrate. Seasonal affective disorder (SAD) Wurtman and Wurtman (1989) also proposed that a distinguishing feature of those suffering with SAD is a specific hunger for carbohydrate, a desire to decrease depression by increasing serotonin synthesis. Consistent with this view, a survey found that those suffering with SAD in the winter con-

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sumed more carbohydrate-rich foods, such as pasta and rice, although the intake of high-protein foods such as meat and fish did not vary with the seasons (Krauchi and Wirz-Justice, 1988). It should, however, be noted that the high-carbohydrate foods contained enough protein to prevent an increased level of blood tryptophan. Rosenthal et al. (1989), however, found in those with SAD that a carbohydrate-rich protein-poor meal improved mood, although the meal contained high levels of both carbohydrate (105 g) and fat (43 g). As the meal contained only 0.7 g protein (0.4 % of energy), the expected increase in the level of blood tryptophan occurred. It is, however, clear that this was a very unusual meal and the findings cannot be generalised to more normal dietary patterns that include protein consumption. To distinguish the relative contribution of carbohydrate as such from palatability, it would be instructive to offer those suffering with SAD snacks that were equally palatable, although they differed in their carbohydrate content. An obvious hypothesis is that there is differential response to palatability rather than carbohydrate content; that it is the taste rather than carbohydrate content that is important. The mood modifying properties of chocolate are discussed below. Carbohydrate craving depression Wurtman and Wurtman (1989) in addition suggested that there is a sub-set of obese patients whose weight problems are characterised by depression and uncontrolled carbohydrate consumption. Again it was proposed that carbohydrate intake reflected a supposed psychopharmacological action. Lieberman et al., (1986b) distinguished obese individuals who ate almost entirely high-carbohydrate snacks from those who consumed high-fat/highcarbohydrate snacks. Two hours after eating a high-carbohydrate lunch, the mood of the two groups differed. Those who crave carbohydrate felt less depressed and the non-carbohydrate cravers were less alert, more fatigued and sleepy. It is possible to calculate from the data supplied the nutritional composition of the snacks on offer. The five so-called high-carbohydrate snacks provided on average 45 % of the total energy as carbohydrate, 5 % as protein and 50 % as fat. Only one snack contained a level of protein low enough (2.5 % of energy) to even suggest that if eaten exclusively the level of blood tryptophan would have risen. In fact, it is very improbable that a particular snack would have been eaten exclusively and therefore protein from other food items would have limited the provision of tryptophan. In fact, the existence of ‘carbohydrate craving’ obesity has been questioned. Toornvliet et al. (1997) gave three types of snack to ‘carbohydrate craving’ and ‘non-carbohydrate craving’ obese patients. The snacks variously offered energy as 100 % carbohydrate; 70 % carbohydrate, 29 % fat and 1 % protein; 35 % carbohydrate, 3 % fat and 62 % protein. As predicted, the level of tryptophan in the blood was greater after the high-carbohydrate and high-fat/high-carbohydrate meals. Mood was, however, similar after all

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three snacks. The responses of the ‘carbohydrate craving obese’ were similar to others. They concluded that ‘from a therapeutic point of view it was useless to maintain the concept of carbohydrate craving . . . the existence of carbohydrate craving patients has never been established. . . .’ That the only two studies of this topic produced different findings may reflect the methodology. Lieberman et al. (1986b) offered palatable cookies whereas the Dutch study gave liquids of a similar taste and appearance. As the response to food is known to be influenced by its palatability, this may be more important than the actual macronutrient composition. Studies of the influence of macronutrient composition need to control for taste and palatability if they are to establish a role for nutrition.

7.5 Anti-social behaviour and refined carbohydrate consumption Refined carbohydrate intake has been repeatedly related to the hyperactivity of children. In particular, there is a widespread popular belief that sugar induces hyperactivity. In the US simply advertising for parents who believed that sugar consumption causes their child to become hyperactive has on many occasions readily provided an experimental sample. In fact, there are few topics in this area that have been subject to more well-designed doubleblind trials. Following a meta-analysis of these trials, Wolraich et al. (1995) concluded that sugar does not adversely influence the behaviour of children. As an illustrative example, Wolraich et al. (1994) provided the meals for three weeks for families living in their own home. They found that the behaviour of children was similar, irrespective of whether meals were sweetened with either sucrose or artificial sweeteners. There are, however, many in the general population who are so convinced that an adverse reaction to sugar occurs that they have tried to explain away the failure to support their preconceptions. It may be that the adverse response only occurs in a sub-set of children who are sugar reactive; only those with a particular clinical diagnosis might respond; the reaction may occur in those who are younger as there is a tendency for some adverse reactions to food to decline with age. Benton (2008) using meta-analysis considered these types of suggestion but again was unable to find any evidence of an adverse reaction to sugar. Although there is no evidence of a general or even a common adverse response to sugar, there is evidence that on occasions an individual might respond adversely. Benton (2007) used meta-analysis to integrate studies of the impact of food intolerance on hyperactivity and found a significant influence in samples pre-chosen because parents believed their child responded to one food item or another. The response was idiosyncratic and no two children responded in the same way. Of the many dozens of foods to which at least one child reacted, the problems resulted most commonly

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from cows milk, chocolate, grapes and wheat. Although some children respond to sucrose, there were 13 other foods that were more likely to induce a reaction (Egger et al., 1985). In fact, there are reports that a sugar-containing drink can improve the behaviour of children. In the afternoon, Benton and Stevens (2008) gave children, aged 9–11 years, either a glucose-containing drink or a placebo. After the glucose-containing drink, the children’s memories were better and they spent more time on task when working in class. As in childhood the brain uses relatively more glucose than when adult, children may be particularly susceptible to the provision of blood glucose. Compared to the size of the body, children have relatively larger brains than adults. In addition, a given weight of brain tissue from a child uses more glucose than if it came from an adult (Kalhan and Kilic, 1999). From birth to 4 years of age the use of glucose by the brain increases greatly, such that by 4 years of age it uses twice as much glucose as a similar amount of adult brain (Chugani, 1998).This high rate of usage continues until 9–10 years after which it gradually declines to reach adult levels in the late teenage years.

7.5.1

Micronutrient status, anti-social behaviour and refined carbohydrate consumption Typically, parents report that their child responds to sugar within an hour of consumption and therefore the short-term reaction to a single drink is a valid test. Although it has been shown repeatedly that in these circumstances sugar is without effect (Wolraich et al., 1995), such studies do not preclude the possibility that a diet high in sugar might have a longer term influence. One mechanism by which the consumption of refined carbohydrate has been suggested to influence anti-social behaviour is by decreasing micronutrient status. The ‘empty calorie’ hypothesis suggests that the consumption of refined carbohydrates leads to micronutrient deficiencies. There are several well-controlled studies that have found that micronutrient supplementation decreases violence. Schoenthaler et al. (1997) studied anti-social behaviour in imprisoned juveniles. Over three months, the incidence of violence was 28 % less in those who received a multivitamin/mineral supplement rather than placebo. Similarly, Gesch et al. (2002) in a double-blind trial found that the disciplinary record of young offenders improved following supplementation with vitamins/minerals and fatty acids. The greatest reduction occurred in more serious violent offences. It was, however, unclear whether this sample was responding to vitamins, minerals or fatty acids, although it has been suggested that the dose of fatty acids was too low to have been influential. Zaalberg et al. (2010) replicated the finding using young Dutch prisoners who received nutritional supplements containing vitamins, minerals and essential fatty acids and found that the incidence of aggressive and rule-breaking behaviour decreased by 34 %.

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The finding of Schoenthaler and Bier (2000) suggested that these findings might generalise to samples other than those with a criminal history. They considered school-children who had been disciplined at least once over an eight-month period. During a subsequent four-month intervention, those receiving a multivitamin/mineral supplement infringed rules significantly less often than those taking a placebo. Although these findings suggest that a decline in micronutrient status is a possible mechanism by which a high sugar might influence anti-social behaviour, how plausible is it to suggest that such a diet will result in micronutrient deficiencies? Benton (2008) reviewed studies of the relationship between the amount of sugar in the diet and micronutrient status and found that micronutrient intake was more closely associated with total energy rather than sucrose intake. Typically, the amount of sucrose in the diet does not lead to micronutrient deficiency. Gibney et al. (1995) used the rule of thumb that an intake of two thirds of the RDA gives grounds for concern and found ‘that a greater proportion of those consuming low amounts of sugars did not meet at least two-thirds of the RDA for some micronutrients compared with consumers of moderate amounts’. Thus it was a low rather than high intake of sugar that caused potential problems. If a low amount of energy was consumed by those consuming low levels of sugar then micronutrient deficiencies could occur; a reflection of the low energy rather than sucrose intake. As one specific example, Forshee and Storey (2001) considered data from the 1994–1996 USDA Continuing Survey of Food Intakes. They found that children who ate more added sugars consumed more, not less, vitamin C, iron and folate, whereas adolescents consumed more iron and vitamin C. Perhaps the most important conclusion was that any positive or negative associations with sugar intake were ‘always so small as to be of no clinical significance’. To illustrate this point, the greatest negative relationship observed was a negative association between the amount of sugar added to the diet and the intake of fruit. Although this could be portrayed as undesirable, you needed 119 extra teaspoons of sugar to account for the consumption of one less piece of fruit. The associations between sugar intake and micronutrient status were even weaker. The UK Department of Health (1989) considered diets low in energy. They found if you controlled for energy intake, a higher intake of sugar was associated with a lower micronutrient intake. However, those who eat a lot of sugar also tend to eat more in general. Total energy consumption is a better predictor of micronutrient status than the level of sugar and, as those who consume higher levels of sugar generally eat more, they therefore have a higher energy intake.Thus micronutrient intake tends not to be a concern. Logically, with this analysis a group that gives grounds for concern are those with a low energy intake. The UK Department of Health (1989) concluded that ‘in people who eat only small amounts, dietary sugars may compete with other nutrients.’ Simple mathematics suggests that a lowenergy diet that obtains a high percentage of its energy from refined

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carbohydrate may result in sub-optimal deficiencies of micronutrients. However, if such instances occur, the problem is likely to reflect the lowenergy rather than sugar intake. There is a risk that if pleasant tasting sweet food is removed from the diets of those who are only prepared to eat a limited range of food items, the quality of the diet may further decline. To the extent that a pleasant sweet taste can be used to encourage the eating of foods, that would not otherwise be consumed, it could even be part of the solution.

7.6 Chocolate – macronutrients or palatability? In several places it has been suggested that the response to aspects of diet might reflect palatability rather than the macronutrient composition. In various studies referred to above, that considered so-called highcarbohydrate foods, an increased intake of chocolate occurred. Although attention was directed to the macronutrient composition, and in particular the carbohydrate content, should we be focusing solely on macronutrients? The palatability of chocolate needs to be considered as it is uniquely attractive, with an appeal unmatched for many by any other food item. Many will admit readily to craving chocolate (Weingarten and Elston, 1991) and some even claim to be addicted (Hetherington and MacDiarmid, 1993). The example of chocolate will illustrate various points about attempts to simplistically relate changes in mood to macronutrients, rather than looking at the entire experience of eating. In a popular rather than scientific book Waterhouse (1995) stated ‘Chocolate can cause a rush of both serotonin and endorphins into your brain cells . . . it has been called the most effective non-drug anti-depressant . . . the “prozac of plants.” ’ It was claimed that the sugar in chocolate increases the synthesis of serotonin and that the fat in chocolate released endorphins, inducing a sense of wellbeing. The improbability of carbohydrate influencing serotonin synthesis is discussed above. However, as we will see, it may induce the release of endorphins. In addition to macronutrients, chocolate supplies substances such the phenylethylamine, a chemical related to amphetamine, theobromine that acts in a similar manner to caffeine and anandamide, an endogenous cannabinoid neurotransmitter. These have all been suggested to account for the attractiveness of chocolate. Benton (2004), however, argued that chocolate cannot be consumed in amounts sufficient to offer a physiologically active dose of any of these substances. There is good evidence that chocolate, or in fact any highly palatable food, will be consumed when mood is low, you are fatigued or under stress. A desire for chocolate has been reported to be associated with depression (Lester and Bernard, 1991). Benton et al. (1998a) found that those who craved chocolate did so when under emotional stress. A colloquial way of

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describing this phenomenon is that it is ‘comfort eating’. That a low mood causally increases chocolate consumption was demonstrated by Willner et al. (1998) who induced differences of mood by playing either happy or miserable music. After the sad music, subjects were prepared to work harder to receive chocolate. The question arises as to the mechanism by which chocolate enhances mood. Rather than influencing tryptophan levels, it seems plausible that the mechanism involves endorphins, the family of endogenous peptides that act in the brain in a similar way to morphine. In animals, the intake of sweet solutions is increased by an opiate agonist and decreased by an opiate antagonist such as naloxone or naltrexone (Reid, 1985). The consumption of chocolate by rats releases beta-endorphin (Dum et al., 1983). Palatability is important; naloxone decreased the eating of chocolate-chip cookies rather than standard rat food (Giraudo, et al. 1993). The suggestion that opiate mechanisms selectively influence the pleasure associated with palatable food was supported by a study in which human males were given nalmefene, a long-lasting opioid antagonist (Yeomans et al., 1990). Nalmefene did not influence the intake of particular macronutrients, but rather it influenced the intake of palatable foods, for example high-fat cheese such as brie. The choice was between various savoury food items; chocolate and sweet foods were not on offer. In a similar study, naloxone differentially decreased the intake of palatable high-fat/high-sugarcontaining foods (Drewowski et al., 1989). In summary, a major theory is that the eating of palatable foods is associated with the release of endorphins. The blocking of the action of endorphins with drugs such as naloxone or naltrexone selectively decreases the intake of palatable foods. The response is to palatability rather than macronutrient composition. However, the attractiveness of foods reflects many factors other than macronutrient composition.

7.6.1 A psychological or physiological reaction? One study has compared the relative contributions of the psychological and physiological mechanisms that underlie chocolate consumption (Michener and Rozin, 1994). The approach taken was to see which of the various constituents of chocolate satisfies craving. Cocoa butter is the fat that when removed from chocolate liquor leaves cocoa powder. The known pharmacological ingredients are all in the cocoa powder. Therefore, if you eat white chocolate, made from the cocoa butter, you have the fat and sugar intake of chocolate but not the pharmacological constituents. If you consume cocoa powder you take the pharmacological ingredients but not the fat and sugar. In the event, only chocolate satisfied chocolate craving. Capsules containing the possible pharmacological ingredients had a similar effect to taking nothing. The adding of cocoa-containing capsules to white chocolate

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did not increase the less than optimal response to white chocolate. The obvious conclusion was that it was the sensory experience associated with eating chocolate, rather than macronutrient profile or pharmacological constituents, that was important. In conclusion, what seems to be important is that chocolate tastes good. Animals, including humans, prefer foods that are both sweet and high in fat. When we eat something that tastes pleasant endorphin mechanisms in the brain are stimulated. The attractiveness of chocolate reflects its taste and mouth feel; for many, it offers a near optimally pleasant taste that potently stimulates endorphin release. There is also a range of learnt and cultural factors associated with particular foods that influence their desirability.

7.7 Future trends Various themes that would benefit from further study have gained support from this review. Meals high in carbohydrate, with a high glycaemic load, depress mood several hours after consumption. The opportunity arises to develop food items to ‘keep you going’ for longer periods. The approach might be to manipulate the relative amounts of the various macronutrients or to ensure that the carbohydrate used was released slowly into the blood stream. In carrying out such work, it should be remembered that highly palatable foods enhance mood and that any novel food item needs to be palatable if it is to become part of a freely chosen diet. The modification of the pattern of meals and snacks is another approach that could be taken, although any advice to eat ‘little and often’ should not become ‘a lot and often’ with consequences for weight gain. Although snacks have the opportunity to prevent a fall in blood glucose levels, they are often highly palatable and should not offer high levels of fat.

7.8 Sources of further information and advice The topics discussed can be considered in further detail in a series of reviews: • Benton D (2002) Carbohydrate ingestion blood glucose and mood. Neuroscience and Biobehavioral Reviews, 26, 293–308. • Benton D and Nabb S (2003) Carbohydrate memory and mood. Nutrition Reviews, 61, S68–S74. • Benton D (2007) The impact of diet on anti-social behaviour. Neuroscience Biobehavioral Reviews, 31, 752–774. • Benton D (2008) Sucrose and behavioural problems. Critical Reviews in Food Science and Nutrition, 48, 385–401.

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• Benton D (2010) The plausibility of sugar addiction and its role in obesity and eating disorders. Clinical Nutrition, 29, 288–303. Those wanting an overview of glycaemic load should consult the Glycemic Index and GI Database created at the University of Sydney by Jenny Brand-Miller: http://www.glycemicindex.com. As well as an overview of the topic, and good general advice, a comprehensive database of the glycaemic index of a wide variety of foods is provided.

7.9 References avena n m, rada p and hoebel b g (2008) Evidence for sugar addiction: Behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev, 32, 20–39. alberti k g m, dornhorst a and rowe a s (1975) Metabolic rhythms in normal and diabetic man. Isr J Med Sci, 11, 571–580. ashley d v m, liardon r and leathwood p d (1985) Breakfast meal composition influences plasma tryptophan to large neutral amino acid ratios of healthy lean young men. J Neural Trans, 63, 271–283. benton d (2002) Carbohydrate ingestion blood glucose and mood. Neurosci Biobehav Rev, 26, 293–308. benton d (2004), Chocolate craving, in Nehlig A (ed.), Coffee, Tea, Chocolate and the Brain. Boca Raton, FL CRC Press, 205–218. benton d (2007) The impact of diet on anti-social behaviour. Neurosci Biobehav Rev, 31, 752–774. benton d (2008) Sucrose and behavioural problems. Crit Rev Food Sci Nutr, 48, 385–401. benton d (2010) The plausibility of sugar addiction and its role in obesity and eating disorders. Clin Nutr, 29, 288–303. benton d and donohoe r t (1999) The effects of nutrients on mood. Public Health Nutr, 2, 403–409. benton d and owens d (1993) Is raised blood glucose associated with the relief of tension? J Psychosom Res, 37, 1–13. benton d and stevens m k (2008) The influence of a glucose containing drink on the behavior of children in school. Biol Psychol, 78, 242–245. benton d, brett v and brain p f (1987) Glucose improves attention and reaction to frustration in children. Biol Psychol, 24, 95–100. benton d, greenfield k and morgan m (1998a) The development of the attitudes to chocolate questionnaire. Pers Individ Diff, 24, 513–520. benton d, kumari n and brain p f (1998b) Mild hypoglycaemia and questionnaire measures of aggression. Biol Psychol, 14, 129–135. bolton r (1973) Aggression and hypoglycemia among the Quolla: a study in psychobiological anthropology. Ethology, 12, 227–257. bolton r (1979) Hostility in fantasy: a further test of the hypoglycaemia-aggression hypothesis. Aggress Behav, 2, 257–274. buffenstein r, poppitt s d, mcdevitt r m and prentice a m (1995) Food intake and the menstrual cycle: a retrospective analysis with implications for appetite research. Physiol Behav, 58, 1067–1077. christensen l (1996) Diet-behavior Relationships., Washington, DC: American Psychological Association. christensen l and redig c (1993) Effect of meal composition on mood. Behav Neurosci, 107, 346–353.

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chugani h t (1998) A critical period of brain development: studies of cerebral glucose utilization with PET. Prevent Med, 27, 184–188. dalvit-mcphillips s p (1983) The effect of the human menstrual cycle on nutrient intake. Physiol Behav, 31, 209–212. davies g j, collins a l p and mead j j (1993) Bowel habit and dietary fibre intake before and during menstruation. J Royal Soc Health, 113, 64–67. department of health (1989) Dietary Sugars and Human Disease. London: Her Majesty’s Stationery Office. drewowski a, gosnell b, krahn d d and canum k (1989) Sensory preferences for sugar and fat: evidence for opioid involvement. Appetite, 12, 206. dum j, gramsch c h and herz a (1983) Activation of hypothalamic beta-endorphin pools by reward induced by highly palatable food. Pharmacol Biochem Behav, 18, 443–447. de castro j m (1987) Macronutrient relationships with meal patterns and mood in spontaneous feeding behavior of humans. Physiol Behav, 39, 561–569. donohoe r t and benton d (1999) Blood glucose control and aggressiveness in females. Pers Individ Diff, 26, 905–911. egger j, carter c m, graham p j, gumley d and soothill j f (1985) Controlled trial of oligoantigenic treatment in the hyperkinetic syndrome. Lancet, 1, 540–545. fernstrom j d (1988) Carbohydrate ingestion and brain serotonin synthesis: relevance to a putative control loop for regulating ingestion and effects of aspartame consumption. Appetite, 11 (Suppl), 35–41. fernstrom j d and wurtman r j (1972) Brain serotonin content: physiological regulation by plasma neutral amino acids. Science, 178, 414–441. forshee r a and storey m l (2001) The role of added sugars in the diet quality of children and adolescents. J Am Coll Nutr, 20, 32–43. friedman d and jaffe a (1985) Influence of life-style on the premenstrual syndrome. Analysis of a questionnaire survey. J Reprod Med, 30, 715–719. genuth s m (1973) Plasma insulin and glucose profiles in normal, obese and diabetic persons. Ann Int Med, 79, 812–822. gesch c b, hammond s m, hampson s e, eves a and crowder m j (2002) Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young prisoners. Randomised, placebo-controlled trial. Brit J Psychiat, 181, 22–28. gibney m, sigman-grant m, stanton j l jr and keast d r (1995) Consumption of sugars. Am J Clin Nutr, 62 (Suppl 1), 78S–193S. gray g e and gray l k (1983) Diet and juvenile delinquency. Nutr Today, 18, 14–22. giraudo s q, grace m k, welch c c, billington c j and levine a s (1993) Naloxone’s anoretic effect is dependent upon the relative palatability of food. Pharmacol Biochem Behav, 46, 917–921. hansen a p and johansen k (1970) Diurnal patterns of blood glucose, serum free acids, insulin, glucagon and growth hormone in normals and juvenile diabetics. Diabetologia, 6, 27–33. harris s (1924) Hyperinsulinism and dysinsulinism. J Am Med Assoc, 83, 729–733. hetherington m m and macdiarmid j i (1993) Chocolate addiction: a preliminary study of its description and its relationship to problem eating. Appetite, 21, 233–246. kalhan s c and kilic i (1999) Carbohydrate as nutrient in the infant and child: range of acceptable intake. Eur J Clin Nutr, 53 (Suppl 1), S94–S100. krauchi k and wirz-justice a (1988) The four seasons: food intake frequency in seasonal affective disorder in the course of a year. Psychiat Res, 25, 323–338. kim w, kelay j, judd j, marshall m w, metz w and prather e s (1987) Evaluation of long-term dietary intakes of adults consuming self-selected diets. Am J Clin Nutr, 40, 1327–1332.

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lester d and bernard d (1991) Liking for chocolate depression and suicidal preoccupation. Psychol Rep, 69, 570. lev-ran a and anderson r w (1981) The diagnosis of postprandial hypoglycemia. Diabetes, 30, 996–999. lieberman h r, caballero b and finer n (1986a) The composition of lunch determines afternoon plasma tryptophan ratios in humans. J Neural Trans, 65, 211–217. lieberman h r, wurtman j j and chew b (1986b) Changes in mood after carbohydrate consumption among obese individuals. Am J Clin Nutr, 44, 772–778. michener w and rozin p (1994) Pharmacological versus sensory factors in the satiation of chocolate craving. Physiol Behav, 56, 419–422. nabb s l and benton d (2006) The effect of the interaction between glucose tolerance and breakfasts varying in carbohydrate and fibre on mood and cognition. Nutr Neurosci, 9, 161–168. owens d s, parker p y and benton d (1997) Blood glucose influences mood following demanding cognitive tasks. Physiol Behav, 62, 471–478. reid l d (1985) Endogenous opioid peptides and regulation of drinking and feeding. Am J Clin Nutr, 42, 1099–1132. rosenthal n, genhart m, caballero b, jacobsen f m, skwerer r g, coursey r d, rogers s and spring b j (1989) Psychological effects of carbohydrate- and proteinrich meals in patients with seasonal affective disorder. Biol Psychiat, 25, 1029–1040. sayegh r, schiff i, wurtman j, spiers p, mcdermott j and wurtman r (1995) The effect of a carbohydrate-rich beverage on mood appetite and cognitive function in women with Premenstrual Syndrome. Obstet Gynecol, 86, 520–528. schoenthaler s j and bier i d (2000) The effect of vitamin-mineral supplementation on juvenile delinquency among American schoolchildren: a randomized, doubleblind placebo-controlled trial. J Altern Comp lement Med, 6, 7–17. schoenthaler s j, amos s, doraz w, kelly m a, muedeking g and wakefield j (1997) The effect of randomized vitamin-mineral supplementation on violent and nonviolent anti-social behavior among incarcerated juveniles. J Nutr Environ Med, 7, 343–352. statement (1973) Statement of the Ad Hoc Committee on Hypoglycaemia. Ann Int Med, 78, 300–301. teff k l, young s n and blundell j e (1989) The effect of protein or carbohydrate breakfasts on subsequent plasma amino acid levels, satiety and nutrient selection in normal males. Pharmacol Biochem Behav, 34, 829–837. tomelleri r and grunewald k k (1987) Menstrual cycle and food cravings in young college women. J Am Dietet Assoc, 87, 311–315. toornvliet a c, pijl h, tuinenburg j c, elte-de wever b m, pieters frolich m, onkenhout w and meinders a e (1997) Psychological and metabolic responses of carbohydrate craving patients to carbohydrate, fat and protein-rich meals. Int J Obes Rel Metabol Dis, 21, 860–864. virkkunen m (1982) Reactive hypoglycemic tendency among habitually violent offenders. Neuropsychobiol, 8, 35–40. virkkunen m and huttunen m o (1982) Evidence for abnormal glucose tolerance test among violent offenders. Neuropsychobiol, 8, 30–34. virkkunen m and narvanem s (1987) Plasma insulin, tryptophan and serotonin levels during the glucose tolerance test among habitually violent and impulsive offenders. Neuropsychobiol, 17, 19–23. vlitos a l p and davies g j (1996) Bowel function, food intake and the menstrual cycle. Nutr Res Rev, 9, 111–134. waterhouse d (1995) Why Women Need Chocolate. London: Vermillion.

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webb p (1986) Twenty-four hour energy expenditure and the menstrual cycle. Am J Clin Nutr, 44, 614–619. Weingarten h p and elston d (1991) Food cravings in a college population. Appetite, 17, 167–175. willner p, benton d, brown e, cheeta s, davies g, morgan j and morgan m (1998) Depression increases craving for sweet rewards in animal and human models of depression and craving. Psychopharmacol, 136, 272–283. wolraich m l, lindgren s d, stumbo p j, stegink l d, appelbaum m i and kiritsy m c (1994) Effects of diets high in sucrose or aspartame on the behavior and cognitive performance of children. New Eng J Med, 330, 301–307. wolraich m l, wilson d b and white j w (1995) The effect of sugar on behavior or cognition in children. A meta-analysis. J Am Med Assoc, 274, 1617–1621. wurtman r j and wurtman j j (1989) Carbohydrates and depression. Sci Amer, 260, 50–57. wurtman j j, brzezinzki a, wurtman r j and laferrere b (1989) Effect of nutrient intake on premenstrual depression. Am J Obstet Gynecol, 161, 1228–1234. wurtman r j, wurtman j j, regan m m, mcdermott j m, tsay r h and breu j j (2003) Effects of normal meals rich in carbohydrates or proteins on plasma tryptophan and tyrosine ratios. Am J Clin Nutr, 77, 128–132. yeomans m r, wright p, macleod h a and critchley j a j h (1990) Effects of nalmefene on feeding in humans. Psychopharmacol, 100, 426–432. yokogoshi h and wurtman r j (1986) Meal composition and plasma amino acid ratios: Effect of various proteins or carbohydrates and of various protein concentrations. Metabolism, 35, 837–842. zaalberg a, nijman h, bulten e, stroosma l and van der staak c (2010) Effects of nutritional supplements on aggression, rule-breaking, and psychopathology among young adult prisoners. Aggress Behav, 36, 117–126.

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8 Hydration and mental performance K. E. D’Anci, Tufts University, USA

Abstract: This chapter discusses the literature on hydration status and the contribution of hydration to mental function across the lifespan. Maintaining water balance is regulated by both physiological and psychosocial factors. Individuals are most at risk for dehydration under extreme climate condition or following physical activity. Some research shows that mild levels of dehydration negatively affect cognitive performance and mood, but these findings are inconsistent. Measuring the relationship between hydration status and brain function is complicated by a lack of clear and consistent methods in altering and measuring hydration status, particularly with respect to inducing dehydration. A lack of firm recommendations on fluid intake to maintain adequate hydration further complicate the development of well-designed, rigorous studies on this important topic. Key words: hydration, dehydration, water, cognition, mood.

8.1 Introduction Water is an essential component of the human body, comprising 55–60 % of total body weight in adults. Water is required for thermoregulation, cellular function, and is critical for life. The role of water and hydration in physical activity, particularly in athletes and in the military, has been of considerable interest and is well-described in the scientific literature (Sawka and Noakes, 2007; Maughan et al., 2007; Murray, 2007). What remains less well-understood, however, is the relationship between water and hydration on mental performance. This is not to say that the topic has not received considerable attention, but rather that the current research remains inconclusive. Although definitive conclusions have yet to be made, there is evidence for cognitive impairments and mood disturbances associated with mild levels of dehydration. To date, the majority of research studies investigating the interaction between dehydration and cognitive performance have been conducted in young adults, although research in children and older individuals is expanding.

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The role of water in health is generally characterized in terms of variance from an ideal hydrated, or euhydrated, state. As described here, the concept of dehydration encompasses both the process of losing body water as well as the state of dehydration. Much of the research on water and physical or mental functioning compares a euhydrated state, usually achieved by provision of water sufficient to overcome water loss, to a dehydrated state, which is achieved via withholding of fluids over time and during periods of heat stress or high activity. There is very little evidence in the literature relating to hyperhydration and mental performance, but hyponatremia, or low blood sodium, may be associated with cognitive impairment (Atchison et al., 1993; Schnur et al., 1993).

8.2 Thirst and water intake regulation Water and fluid balance in humans is elegantly regulated and complex. While water regulation is hormonally mediated, people drink liquids in response to a variety of cultural, social, and psychological factors. The type and amount of fluid consumed is dependent upon relative palatability and temperature of the fluid, meal type and size, and water safety and availability. The act of drinking may not be directly involved with a physiological need for water intake, but can be initiated by habit, ritual, taste, or desire for a warming or cooling effect (Rolls, 1991). Similarly, individuals may abstain from drinking even with a driving physiological need, as in the case of religious observances. Several of the sensations associated with thirst are learned, such as dryness of the mouth or throat, which induce drinking. Feedback from the gut, such as distension of the stomach, can lead to a cessation of drinking before fluid balance has been restored. In general, fluid intakes are considered to be adequate to maintain fluid balance in most people. Risk for dehydration, therefore, arises under special circumstances such as illness, injury, heat stress, deliberate fluid restriction, or physical activity. The balance between loss and gain of fluids maintains body water within relatively narrow limits (Andersson, 1978). The routes of water loss from the body are the urinary system, the skin, respiratory surfaces, and the gastrointestinal tract. The primary avenues for restoration of water balance are fluid and food ingestion, with metabolic water making a minor contribution (Greenleaf, 1982). The volumes of water that individuals obtain from drinks and food are highly variable, although it is generally reported that the majority normally comes from liquids (IOM, 2005). The primary regulation of thirst is controlled separately by osmotic pressure and body fluid volume and, as such, is regulated by the same mechanisms that control central blood pressure and water and solute reabsorption in the kidneys. Despite large variations in salt and water intake, homeostatic mechanisms work to sustain a normal plasma osmolality of

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275–290 mOsm/kg and maintain normal sodium levels between 135 and 145 mEq/L. Increases in plasma osmolality, and activation of osmoreceptors and baroreceptors, stimulate hypothalamic release of argenine vasopressin, which in turn acts at the kidney to decrease urine volume and promote water retention. Sensations of thirst are generated at a higher plasma osmolality than that which stimulates vasopressin release, resulting in first a concentration of urine and conservation of body water and then a subsequent drive to increase fluid intake. In general, the sensation of thirst results in an intake of fluid adequate to restore water balance. However, under high heat conditions or following physical activity, voluntary fluid intake may be inadequate to offset fluid deficits when individuals are allowed to drink according to thirst (Bar-Or et al., 1980; Nicolaidis, 1998). Thus, mild to moderate dehydration can therefore persist for some hours after the conclusion of physical activity. This so-called ‘voluntary dehydration’ is frequently exploited in examining the role of hydration in mental functioning. At the population level, there is no conventional method of assessing hydration status. Hypertonicity, used in some studies, is not consistently predictive of hydration status for all age groups (Stookey, 2005). Urine osmolality measures are used frequently, but a major weakness of this measure is that it more directly reflects recent fluid intake rather than a state of hydration (Armstrong, 2005). Urine osmolality, therefore, is more useful in measuring recent hydration status (Bar-David et al., 1998, 2005; Shirreffs, 2000; Popowski et al., 2001; Fadda et al., 2008). Deuterium dilution techniques (isotopic dilution with D2O or deuterium oxide) allows measurement of total body water but not water balance status (Eckhardt et al., 2003), and is costly and requires high technical expertise. Urine color, ranging from pale yellow to dark yellow, has been used as a rapid and easily interpreted measure of hydration status (Armstrong, 2005). It is important to remember that urine color may be altered by use of some medications and vitamins, and should thus be used with these changes in mind. Additionally, changes in urine color may occur later in time than changes in hydration status, and this time delay might be particularly important when considering dehydration resulting from physical activity. Currently there are no adequate biomarkers to measure hydration status at the population level; thus, the absence of validated method to measure water consumption intake levels and patterns represents a major gap.

8.3

Cognition, mood, and hydration status

8.3.1 Cognitive performance and mood measures Before assessing the role of hydration in altering brain function, it is important to provide definitions of cognition and mood. Cognition and mood are the reportable or observable facets of brain function. Cognition refers to

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the processes typically thought of when using the term ‘higher mental function’. Cognitive functions can be clustered into several main domains: memory functions, attention functions, perceptual functions, executive functions, psychomotor functions, and language skills. Each of the cognitive domains can be further divided in a number of more specified functions. Memory functions, for example, include short-term and long-term memory encoding, storage and retrieval functions, and working memory. Further differentiation is made with regard to the type of information that is processed, e.g. auditory, visual, verbal, spatial, abstract, procedures. Attention can be subdivided in selective, divided, and sustained attention functions, whereas executive functions encompass more complex processes such as reasoning, planning, concept formation, evaluation, and strategic thinking (Schmitt et al., 2005). In practical terms, cognition is frequently assessed by observable performance. For example, learning and memory may be determined by an individual’s ability to learn, and then recall a list of words, or the locations of countries on a map, while verbal comprehension may be measured by evaluating an individual’s understanding of a complex reading passage. When reviewing the influence of hydration status on cognitive performance, it is important to consider that all domains may not be affected similarly. For example, thirst in dehydrated individuals may serve as a distraction, and may negatively affect performance on attention-related tasks but may not impact overall problem solving capability. While mood and cognition are often studied individually, they do not function independently, but rather work in tandem. Mood, for example, can be altered by cognitive performance, such as feeling ‘down’ after doing poorly on a test. Cognition can, in turn, be affected by mood – an individual experiencing mild anxiety may perform well on a test, but high anxiety in the same individual may result in poorer cognitive performance. Mood, which is defined as a temporary, but relatively sustained and pervasive, affective state, covers an array of affective states ranging from calm to rage, alertness to fatigue, and elation to depression. Mood is particularly labile, and is typically assessed in terms of how an individual feels ‘right now, at this moment’. It is important, in any discussion of the interaction between cognition and mood, to distinguish performance from ability or aptitude. For example, individuals suffering from confusion, considered a mood state in psychological research, may show impaired performance on an arithmetic problem solving task, a measure of cognitive performance. Overall mathematical aptitude or intelligence, however, is not expected to fluctuate with mood states.

8.3.2 Dehydration, mood, and cognition Water, or its lack, influences brain functioning. Mild levels of dehydration (approximately 2 % loss of body weight) produce disruptions in mood and cognitive performance. The very young, very old, those in hot climates, and

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those engaging in vigorous exercise may be more at risk for dehydrationrelated disturbances in mental function. Mild dehydration produces alterations in a number of cognitive domains such as concentration, alertness, and short-term memory in children (10–12 years) (Bar-David et al., 2005), young adults (18–25 years) (Gopinathan et al., 1988; Cian et al., 2000, 2001; D’Anci et al., 2009), and in the oldest adults, 50–82 years (Suhr et al., 2004). However, support for diminished cognitive performance in the presence of mild dehydration alone is weak and, in some cases, conflicting (D’Anci, 2005). Research studies differ widely in the means of inducing dehydration and the duration of dehydration, as well as in measuring dehydration status. Furthermore, ‘mild’ versus ‘moderate’ dehydration is somewhat ill-defined, and there is little understanding of how hydration status across different ages affects cognitive behavior.

8.3.3 Hydration and mental function in children Children may be at greater risk for dehydration than adults for several reasons. Young people have a greater surface-to-mass ratio allowing for greater water losses from the skin. During illness, significant water loss can occur through the gastrointestinal tract, and this can be of grave concern in the very young. In developing countries, diarrheal diseases are a leading cause of death in children resulting in approximately 1.5–2.5 million deaths per year (Kosek et al., 2003). Diarrheal illness results not only in a reduction in body water, but also in potentially lethal electrolyte imbalances. Mortality in such cases can often be prevented with appropriate oral rehydration therapy, by which simple dilute solutions of salt and sugar in water can replace fluid lost by diarrhea. Many consider application of oral rehydration therapy to be one of the signal public health developments of the last century (Atia and Buchman, 2009). Children, infants in particular, are dependent upon caregivers for provision of fluids. In the case of infants, caregivers may not be aware of the extent of insensible water loss and adequate hydration may not be provided (Finberg, 1959). As an example, inadequate breastfeeding is becoming more common as a risk factor for dehydration in infants (Laing and Wong, 2002). Nursing mothers with insufficient milk may not recognize the signs of progressive dehydration in their infants. While most parents understand what dehydration is, they may not recognize more than one signal of dehydration or at what level of dehydration symptoms are seen (Table 8.1) (Gittelman et al., 2004). During exercise, children may not recognize the need to replace lost fluids (Bar-Or et al., 1980), and children as well as coaches need specific guidelines for fluid intake (American Academy of Pediatrics, 2000). Additionally, children may require longer acclimation to increases in environmental temperature than do adults (Bytomski and Squire, 2003; Falk and Dotan, 2008). Recent work examining children living in hot-arid climates

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Table 8.1 Levels of dehydration defined as percent body weight loss in infants and adolescents and associated clinical symptoms Infants (% BW loss)

Adolescents (% BW loss)

5%

2–4 %

Moderate

10 %

5–6 %

Severe

15 %

7–9 %

Severity Mild

Clinical symptoms Slightly dry oral mucous membranes, increased thirst, slightly decreased urine output, increased irritability, alert/restless Dry oral mucous membranes, increased heart rate, little or no urine output, lethargy, sunken eyes and fontanelles, loss of skin turgor Same as moderate plus a rapid, thready pulse, no tears, cyanotic coloring, rapid breathing, low blood pressure, coma

Source: adapted from Beers et al., 2006.

indicates a high prevalence of voluntary dehydration in this population (Bar-David et al., 2009). It is recommended that child athletes or children in hot climates begin activities in a well-hydrated state and drink fluids over and above the thirst threshold. Relatively few studies have examined the effects of hydration status on cognitive performance in children, although this area has received significantly more attention in the past five years. Preliminary observations by schoolteachers in the UK indicate that programs encouraging water intake in students might improve student attention and concentration (BBC News, 2000). In support of these anecdotal observations, several recent studies have examined the utility of providing water to school children on attentiveness and cognitive functioning (Benton and Burgess, 2009; Edmonds and Burford, 2009; Edmonds and Jeffes, 2009). In these experiments, children were not fluid restricted prior to cognitive testing, but were allowed to drink as usual. Children were then provided with a drink or no drink 20–45 minutes before the cognitive test sessions. In the research led by Edmonds and colleagues (Edmonds and Burford, 2009; Edmonds and Jeffes, 2009), children in the groups given water showed improvements in visual attention. However, effects on visual memory were less consistent, with one study showing no effects of drinking water on a visual in 6–7 yearold children (Edmonds and Jeffes, 2009) and the other showing a significant improvement in a similar task in 7–9 year-old children (Edmonds and Burford, 2009). In the research described by Benton and Burgess (2009), memory performance was improved by provision of water, but sustained attention was not altered with provision of water in the same children.

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With respect to voluntary dehydration in children, the study by BarDavid et al. (2005) remains the only one investigating the interaction between measurable dehydration and cognitive performance in children. In this study, Israeli school children were divided in to normally hydrated or dehydrated groups based on urine osmolality, with urine osmolality above 800 mOsm/kg defining dehydration. Cognitive tests were administered at the beginning of the school day and again at noontime. At the beginning of the school day, there were no significant differences in cognitive performance between the groups. At noon, however, students initially classified as hydrated tended to perform better on several cognitive tasks than dehydrated students. Short-term memory scores were significantly higher in hydrated children in comparison to dehydrated children. There was a trend for hydrated students to perform better on a verbal analogy task, measuring semantic fluency, and a making-groups task, which measures semantic flexibility, relative to dehydrated children. These data seem to indicate negative effects on cognition induced by mild dehydration in children. However, much remains unknown about the short- and long-term effects of dehydration on cognitive function in children.

8.3.4 Voluntary dehydration in adults As with physical functioning, mild to moderate levels of dehydration can impair performance on tasks such as short-term memory, perceptual discrimination, arithmetic ability, visuomotor tracking, and psychomotor skills (Gopinathan et al., 1988; Cian et al., 2000, 2001; D’Anci et al., 2009). However, mild dehydration does not appear to alter cognitive functioning in a consistent manner (Cian et al., 2000, 2001; Szinnai et al., 2005; D’Anci et al., 2009). In some cases, cognitive performance was not significantly affected in ranges from 2–2.6 % dehydration (Szinnai et al., 2005; D’Anci et al., 2009). Comparing across studies, performance on similar cognitive tests was divergent under dehydration conditions (Cian et al., 2000; D’Anci et al., 2009). In studies conducted by Cian et al. (2000, 2001), participants were dehydrated to approximately 2.8 % either through heat exposure or treadmill exercise. In both studies, performance was impaired on tasks examining visual perception, short-term memory, and psychomotor ability. In a series of studies using exercise in conjunction with water restriction as a means of producing dehydration, D’Anci et al. (2009) observed only mild decrements in cognitive performance in healthy young men and women athletes. In these experiments, the only consistent effect of mild dehydration was significant elevations of subjective mood score, including fatigue, confusion, anger, and significant decreases in vigor. Finally, in a study using water deprivation alone over a 24-hour period, no significant decreases in cognitive performance were seen with 2.6 % dehydration (Szinnai et al., 2005). It is possible therefore, that heat-stress may play a critical role in the effects of dehydration on cognitive performance.

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Reintroduction of fluids under conditions of mild dehydration can reasonably be expected to reverse dehydration-induced cognitive deficits. Few studies have examined how fluid reintroduction may alleviate dehydration’s negative effects on cognitive performance and mood. One study (Neave et al., 2001) examined how water ingestion affected arousal and cognitive performance in young people following a period of 12-hour water restriction. While cognitive performance was not affected by either water restriction or water consumption, water ingestion affected self-reported arousal. Participants reported increased alertness as a function of water intake. Rogers et al. (2001) observed a similar increase in alertness following water ingestion in both high- and low-thirst participants. Water ingestion, however, had opposite effects on cognitive performance as a function of thirst. Highthirst participants’ performance on a cognitively demanding task improved following water ingestion, but low-thirst participants’ performance declined. In summary, hydration status consistently affected self-reported alertness, but effects on cognition were less consistent.

8.3.5 Dehydration in older individuals Dehydration is a risk factor for delirium and delirium presenting as dementia in the elderly and in the very ill (Lawlor, 2002; Culp et al., 2004; Voyer et al., 2009). Recent work shows that dehydration is one of several predisposing factors in observed confusion in long-term care residents (Voyer et al., 2009), although in this study daily water intake was used as a proxy measure for dehydration rather than other, more direct clinical assessments such as urine or plasma osmolality. Older people have been reported as having reduced thirst and hypodypsia relative to younger people. In addition, fluid intake and maintenance of water balance can be complicated by factors such as disease, dementia, incontinence, renal insufficiency, restricted mobility, and drug side-effects. In response to primary dehydration, older people have less thirst sensation and reduced fluid intakes in comparison to younger people. However, in response to heat-stress, while older people still display a reduced thirst threshold, they do ingest comparable amounts of fluid as younger people (Morley et al., 1998). Little research has examined voluntary dehydration and brain function in older adults. In one study, Ainslie et al. (2002) compared performance in young men (24 years) to older men (56 years) during ten days of hillwalking in the Scottish highlands. Participants were active and experienced hill-walkers who walked an average of 21 km/d and were permitted ad libitum access to food and water. Over time, the older men drank less water than younger men, and showed greater dehydration, as measured using urine osmolality, than younger men. Older men had lower reported thirst perceptions than younger men, and showed significant decrements in psychomotor performance, and these decrements were correlated with increased levels of dehydration. Although all men in this study were

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experienced hill-walkers, it is possible that older men may have also experienced more fatigue as a function of age. However, the observations related to fluid intake and dehydration measures reflect similar changes in older individuals in other studies. These data are consistent with data suggesting decreased thirst sensitivity with age, and indicate that older men may be more susceptible to activity-induced dehydration than younger men. Taken together, these studies indicate that low to moderate dehydration may alter cognitive performance. Rather than indicating that the effects of hydration or water ingestion on cognition are contradictory, many of the studies differ significantly in methodology and in measurement of cognitive behaviors. These variances in methodology underscore the importance of consistency when examining relatively subtle changes in overall cognitive performance. However, in those studies in which dehydration was induced, most combined heat and exercise; thus, it is difficult to disentangle the effects of dehydration on cognitive performance in temperate conditions, from the effects of heat and exercise. Additionally, relatively little is known about the mechanism of mild dehydration’s effects on mental performance. It has been proposed that mild dehydration acts as a physiological stressor which competes with and draws attention from cognitive processes (Cohen, 1983). However, research on this hypothesis is limited and merits further exploration.

8.4 Implications for the food industry, nutritionists, and policy-makers Bottled water, both still and sparkling, is a major sector of the beverage market. Sales in the US and Canada increased four-fold between 1990 and 2007, with growth expected to continue over the next several years. Bottled water is a multi-billion dollar industry, and large corporations such as Nestlé (Poland Spring), Danone (Evian), Coca-Cola (Dasani), and PepsiCo (Aquafina) are global leaders in the market. Recent work suggests that water (both tap and bottled) is the primary source of fluid in French (Bellisle et al., 2010) and North American (Fulgoni, 2007) individuals. While tap water in industrialized nations is safe to drink, people choose to carry bottled water for convenience, perceived better quality, and preferred taste. Recent environmental concerns about plastic water bottles have led to a ban on bottled water in a growing number of schools and communities in the US, Australia, and other countries. Increased environmental awareness of the potential burden from disposing of plastic water bottles could impact global water sales. However, plastic bottle bans currently do not extend to other beverages such as juices or soda. Some bottled water producers have reintroduced glass bottles, particularly for sparkling mineral waters, but glass may not be an optimal solution for the seemingly ubiquitous water bottle.

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With respect to policy, a recent review by Popkin et al. (2010) underscores a critical gap in our understanding of water requirements and recommendations. An important consideration when setting fluid intake requirements is the water content of foods, which for practical purposes for individuals may be difficult to estimate. To be useful for the individual, recommendations for adequate fluid intake need to be clear and easily implemented. Thus far, very few countries have developed water requirements; those that do have requirements base them on soft population-level measures of water intake and urine osmolality (IOM, 2005; Manz and Wentz, 2005). The European Food Safety Authority (EFSA) has recently revised intakes of essential nutrients, including water. The EFSA has set the daily recommended value of water at 2.0 L/d in women, and 2.5 L/d in men (EFSA, 2010) with higher recommended intake in conditions of extreme temperature and physical activity. EFSA guidelines indicate that water requirements can be met with intake of beverages of all types as well as intake of moisture from food. US Dietary recommendations for water are based on population-wide median water intakes with no measurements of dehydration status to support these recommendations. Current US guidelines are given in terms of adequate intake (AI) which is derived from population estimates using National Health and Nutrition Examination Survey (NHANES) data. However, water intake estimates from population surveys vary greatly and are likely inaccurate and inadequate for the purpose of evidence-based recommendations. An alternate approach to the estimation of water requirements can be expressed as water intake requirements in relation to energy requirements as ml/kcal (EFSA, 2010; Popkin et al., 2010). Indeed, this recommendation was made by the Food and Nutrition Board of the National Research Council over 70 years ago (Valtin, 2002). An argument for this approach is the observation that energy requirements are strongly evidence-based in each age and gender group and take into account both body size and activity level, which are crucial determinants of energy expenditure which must be met by dietary energy intake. Using a ml/kcal guideline for fluid intake would be in close alignment with present US recommendations of 2–2.5 L/d for adults. A lack of scientific evidence has led some to call into question the standard popular recommendations of 8–8oz glasses of water per day (Valtin, 2002). While this recommendation is not based on scientific recommendations, and is somewhat incompletely understood by both health professionals and the lay public (i.e. only water would meet the daily target, rather than all watercontaining beverages and watery foods contributing to the total), this nearly mythic recommendation nevertheless conveys a clear message. All too many recommendations regarding nutrition carry qualifiers and complex caveats; for individuals seeking a clear guideline of what to drink, the message ‘drink 8–8oz glasses of water a day’ is refreshingly simple and easy to implement.

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8.5 Future trends Although there has been considerable interest in the effects of mild dehydration on both physiological and psychological performance, we still know very little about to what these effects may truly be attributable. The available evidence is more suggestive of deleterious effects of heat-stress rather than dehydration per se in cognitive performance in young adults. The support for diminished cognitive performance in the presence of mild dehydration alone is weak and, in some cases, conflicting. Experimental studies differ widely in methodology of inducing dehydration as well as in measuring dehydration status. Furthermore, ‘mild’ versus ‘moderate’ dehydration is somewhat ill-defined, and there is little understanding of how hydration status across different ages affects cognitive behavior. Rigorous examination of the short-term cognitive effects of mild dehydration are noticeably lacking in children and in the elderly. One possible reason for the lack of strong experimental data is the difficulty in implementing fluid restriction studies. While mild, acute dehydration is relatively benign, it is not without potential participant risks such as headache, fainting, and other unpleasant, temporary effects. Levels of even mild dehydration are difficult to achieve in laboratory settings, requiring long-term (24-hour) fluid restriction, or exposure stressors such as heat and exercise. A common myth is that most individuals are walking around in a constant state of mild dehydration, but this is unlikely for the average person in a temperate climate. At present, there is no ‘gold standard’ in determining states of dehydration versus euhydration in individuals. Nor are there adequate biomarkers to measure hydration status at the population level. The lack of validated methods to measure water intake levels and patterns represents a major gap in understanding the true impact of hydration status on mental functioning.

8.6 Sources of further information and advice • EFSA: Scientific Opinion on Dietary Reference Values for water http:// www.efsa.europa.eu/en/scdocs/scdoc/1459.htm • Institute of Medicine: Dietary Reference Intakes for Electrolytes and Water http://www.iom.edu/Activities/Nutrition/DRIElectrolytes.aspx • Water is Cool in School http://www.wateriscoolinschool.org.uk/

8.7 References ainslie p n, campbell i t, frayn k n, humphreys s m, maclaren d p, reilly t and westerterp k r (2002) Energy balance, metabolism, hydration, and performance during strenuous hill walking: the effect of age. J Appl Physiol, 93, 714–23.

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american academy of pediatrics (2000) Climatic heat stress and the exercising child and adolescent. American Academy of Pediatrics. Committee on Sports Medicine and Fitness. Pediatrics, 106, 158–9. andersson b (1978) Regulation of water intake. Physiol Rev, 58, 582. armstrong l e (2005) Hydration assessment techniques. Nutr Rev, 63, S40–54. atchison j w, wachendorf j, haddock d, mysiw w j, gribble m and corrigan j d (1993) Hyponatremia-associated cognitive impairment in traumatic brain injury. Brain Inj, 7, 347–52. atia a n and buchman a l (2009) Oral rehydration solutions in non-cholera diarrhea: a review. Am J Gastroenterol, 104, 2596–604; quiz 2605. bar-david y, landau d, bar-david z, pilpel d and philip m (1998) Urine osmolality among elementary schoolchildren living in a hot climate: implications for dehydration. Amb Child Health, 4, 393–7. bar-david y, urkin j and kozminsky e (2005) The effect of voluntary dehydration on cognitive functions of elementary school children. Acta Paediatr, 94, 1667–73. bar-david y, urkin j, landau d, bar-david z and pilpel d (2009) Voluntary dehydration among elementary school children residing in a hot arid environment. J Hum Nutr Diet, 22, 455–60. bar-or o, dotan r, inbar o, rotshtein a and zonder h (1980) Voluntary hypohydration in 10- to 12-year-old boys. J Appl Physiol, 48, 104–8. bbc news (2000) Water improves school test results, Available at http://news.bbc. co.uk/1/hi/education/728017.stm (accessed February 2001). beers m h, porter r s and jones t v (eds) (2006) The Merck Manual of Diagnosis and Therapy. Whitehouse Station, N J: Merck. bellisle f, thornton s n, hebel p, denizeau m and tahiri m (2010) A study of fluid intake from beverages in a sample of healthy French children, adolescents and adults. Eur J Clin Nutr, 64, 350–55. benton d and burgess n (2009) The effect of the consumption of water on the memory and attention of children. Appetite, 53, 143–6. bytomski j r and squire d l (2003) Heat illness in children. Curr Sports Med Rep, 2, 320–24. cian c, koulmann p a, barraud p a, raphel c, jimenez c and melin b (2000) Influence of variations of body hydration on cognitive performance. J Psychophysiol, 14, 29–36. cian c, barraud p a, melin b and raphel c (2001) Effects of fluid ingestion on cognitive function after heat stress or exercise-induced dehydration. Int J Psychophysiol, 42, 243–51. cohen s (1983) After effects of stress on human performance during a heat acclimatization regimen. Aviat Space Environ Med, 54, 709–13. culp k r, wakefield b, dyck m j, cacchione p z, decrane s and decker s (2004) Bioelectrical impedance analysis and other hydration parameters as risk factors for delirium in rural nursing home residents. J Gerontol A Biol Sci Med Sci, 59, 813–17. d’anci k e (2005) Hydration status and cognitive performance in young adults. Nutr Clin Care, 8, 63–6. d’anci k e, vibhakar a, kanter j h, mahoney c r and taylor h a (2009) Voluntary dehydration and cognitive performance in trained college athletes. Percept Mot Skills, 109, 251–69. eckhardt c l, adair l s, caballero b, avila j, kon i y, wang j and popkin b m (2003) Estimating body fat from anthropometry and isotopic dilution: a four-country comparison. Obes Res, 11, 1553–62. edmonds c j and burford d (2009) Should children drink more water?: the effects of drinking water on cognition in children. Appetite, 52, 776–9.

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edmonds c j and jeffes b (2009) Does having a drink help you think? 6–7-year-old children show improvements in cognitive performance from baseline to test after having a drink of water. Appetite, 53, 469–72. efsa (2010) Scientific Opinion on Dietary Reference Values for Water. Parma: European Food Safety Authority, Available at: http://www.efsa.europa.eu/en/scdocs/ scdoc/1459.htm (accessed February 2010). fadda r, rapinett g, grathwohl d, parisi m, fanari r and schmitt j (2008) The benefits of drinking supplementary water at school on cognitive performance in children. Washington, DC: International Society for Developmental Psychobiology. falk b and dotan r (2008) Children’s thermoregulation during exercise in the heat: a revisit. Appl Physiol Nutr Metab, 33, 420–27. finberg l (1959) Pathogenesis of lesions in the nervous system in hypernatremic states. I. Clinical observations of infants. Pediatrics, 23, 40–45. fulgoni v l, 3rd (2007) Limitations of data on fluid intake. J Am Coll Nutr, 26, 588S–591S. gittelman m a, mahabee-gittens e m and gonzalez-del-rey j (2004) Common medical terms defined by parents: are we speaking the same language? Pediatr Emerg Care, 20, 754–8. gopinathan p m, pichan g and sharma v m (1988) Role of dehydration in heat stress-induced variations in mental performance. Arch Environ Health, 43, 15–17. greenleaf j e (1982) Dehydration-induced drinking in humans. Fed Proc, 41, 2509–14. iom (2005) Panel on Dietary Reference Intakes for Electrolytes and Water, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine of the National Academies (2005) Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington DC: National Academy Press. kosek m, bern c and guerrant r l (2003) The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000. Bll World Health Organ, 81, 197–204. laing i a and wong c m (2002) Hypernatraemia in the first few days: is the incidence rising? Arch Dis Child Fetal Neonatal Ed, 87, F158–62. lawlor p g (2002) Delirium and dehydration: some fluid for thought? Support Care Cancer, 10, 445–54. manz f and wentz a (2005) Hydration status in the United States and Germany. Nutr Rev, 63, S55–62. maughan r j, shirreffs s m and watson p (2007) Exercise, heat, hydration and the brain. J Am Coll Nutr, 26, 604S–612S. morley j e, miller d k, zdrodowski c, guitierrez b and perry iii h m (1998) Fluid intake, hydration and aging, in Arnaud M J (ed.), Hydration throughout life: International conference Vittel (France). Montrouge: John Libbey Eurotext, 107–116. murray b (2007) Hydration and physical performance. J Am Coll Nutr, 26, 542S–548S. neave n, scholey a b, emmett j r, moss m, kennedy d o and wesnes k a (2001) Water ingestion improves subjective alertness, but has no effect on cognitive performance in dehydrated healthy young volunteers. Appetite, 37, 255–6. nicolaidis s (1998) Physiology of thirst, in Arnaud M J (ed.) Hydration Throughout Life. Montrouge: John Libbey Eurotext, 3–8. popkin b m, d’anci k e and rosenberg i h (2010) Water, hydration and health. Nutri Rev, 68,:439–58.

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popowski l, oppliger r, lambert g, johnson r, johnson a and gisolfi c (2001) Blood and urinary measures of hydration status during progressive acute dehydration. Med Sci Sports Exerc, 33, 747–53. rogers p j, kainth a and smit h j (2001) A drink of water can improve or impair mental performance depending on small differences in thirst. Appetite, 36, 57–8. rolls b j (ed.) (1991) Physiological Determinants of Fluid Intake in Humans. London: Springer-Verlag. sawka m n and noakes t d (2007) Does dehydration impair exercise performance? Med Sci Sports Exerc, 39, 1209–17. schmitt j a, benton d and kallus k w (2005) General methodological considerations for the assessment of nutritional influences on human cognitive functions. Eur J Nutr, 44, 459–64. schnur d b, wirkowski e, reddy r, decina p and mukherjee s (1993) Cognitive impairments in schizophrenic patients with hyponatremia. Biol Psychiatry, 33, 836–8. shirreffs s (2000) Markers of hydration status. J Sports Med Phys Fitness, 40, 80–84. stookey j d (2005) High prevalence of plasma hypertonicity among communitydwelling older adults: results from NHANES III. J Am Diet Assoc, 105, 1231–9. suhr j a, hall j, patterson s m and niinisto r t (2004) The relation of hydration status to cognitive performance in healthy older adults. Int J Psychophysiol, 53, 121–5. szinnai g, schachinger h, arnaud m j, linder l and keller u (2005) Effect of water deprivation on cognitive-motor performance in healthy men and women. Am J Physiol Regul Integr Comp Physiol, 289, R275–80. valtin h (2002) ‘Drink at least eight glasses of water a day.’ Really? Is there scientific evidence for ‘8 × 8’? Am J Physiol Regul Integr Comp Physiol, 283, R993–1004. voyer p, richard s, doucet l and carmichael p h (2009) Predisposing factors associated with delirium among demented long-term care residents. Clin Nurs Res, 18, 153–71.

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9 Vitamin status, cognition and mood in cognitively intact adults D. Kennedy, E. Jones and C. Haskell, Northumbria University, UK

Abstract: Vitamins sequestered from the diet are intrinsically involved in all aspects of brain function. A sizeable minority of the population are potentially clinically deficient in one or more vitamins, and there is little understanding of how far the optimum level of micronutrients might lie above the biochemical criteria for ‘deficiency’. This chapter reviews evidence from epidemiological studies investigating the relationship between vitamin status/intake and cognition and mood in cognitively intact, non-diseased populations, and considers the evidence for the efficacy of supplementation in terms of psychological function. Key words: vitamins, minerals, cognition, mood, cognitively intact.

9.1 Introduction Vitamins are a group of organic compounds that are essential for normal cell function, physiological processes, growth and development that have to be obtained, with the exception of vitamin D, from the diet. Different animal species require different vitamins from their diet and, in the case of humans, four fat soluble vitamins (A, D, E, K) and nine water soluble vitamins (B1, B2, B3, B5, B6, B7, B9, B12, C) have been identified.

9.1.1 Vitamins and evolution Paradoxically, despite the fact that they are critical for life, animals have lost the ability to synthesise vitamins in sufficient quantities. In evolutionary terms, the ability to synthesise most of these essential nutrients was lost by multicellular animals several hundred million years ago. It has been suggested that this was because vitamins were in ubiquitous and plentiful supply within the food chain, and that the process of endogenous enzymatic synthesis itself entailed a disadvantageous cost in evolutionary terms,

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conferring an advantage on organisms that simply sequestered their vitamin requirements from the environment (Pauling, 1970). The most recent example of this evolutionary process for humans is the loss of the ability to synthesise vitamin C (ascorbate), which is common to the vast majority of plant and animal life. In the case of the anthropoidea (tarsiers, monkeys and apes) the ability to synthesise vitamin C was lost by a common ancestor some 35–55 million years ago due to mutations in the gene for L-gulonolactone (Nishikimi et al., 1992). A number of reasons why this would represent a beneficial adaptation have been proposed, including the simple notion that the endogenous synthesis of vitamin C not only entails an energetic and cellular cost but also an oxidative cost, in terms of the generation of hydrogen peroxide during the synthesis process, which in turn would entail a cost in terms of endogenous antioxidant requirements (Banhegyi et al., 1997). Interestingly, not only has vitamin synthesis been the subject of evolutionary pressure, but a number of authors have suggested that vitamins have also shaped aspects of human evolution (Milton, 2000). As an example, Challem (1997) suggests that the loss of the ability to synthesise vitamin C led to an increase in free radical induced mutations and a subsequent acceleration of primate evolution, whilst Lucock et al. (2003) note that B vitamin status plays an important role in genomic function and integrity and therefore human evolution. It is also interesting to note that vitamin D, which can be synthesised in the skin as well as obtained from the diet, has been suggested as a key driver, both in mammalian evolution (Holick, 2008) and in the development of the lighter skin colours that optimised ultra-violet light-induced synthesis of vitamin D and allowed the survival of the genus Homo as it spread to higher, less sunny latitudes (Yuen and Jablonski, 2010). These evolutionary hypotheses would suggest that human nutritional requirements have shaped, and been shaped by, several tens of millions of years of anthropoid primate evolutionary development, followed by approximately two million years of human existence. Human diet, on the other hand, has changed markedly over a very short period of time in evolutionary terms, with the first major step change coming with the development of agriculture approximately 12 000 years ago (Milton, 2000). It has therefore been suggested that many of the ‘diseases of civilisation’, such as diabetes, obesity and cardio-vascular disease, are predicated on the shift away from our evolutionarily determined, largely herbivorous diet, to the high-energy, highly digestible, micronutrient-depleted diet of modern humans in westernised societies (Milton, 2000; Benzie, 2003). One parallel seen in contemporary diets is the putative attenuation of cardiovascular disease rates in populations that consume a ‘Mediterranean diet’, which, it has been suggested, may be closer to the Palaeolithic diet of our ancestors (Mackenbach, 2007). Naturally, the proposition of a disjunction between the diet that might suit humans on an evolutionary basis and our contemporary diet in

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industrialised societies extends to vitamin consumption (Benzie, 2003). As a single example, reference to the rate of endogenous synthesis of vitamin C in other mammals; the diet of gorillas (Pauling, 1970); and the vitamin constituents of what might be assumed to be a typical pre-agriculture diet (Pauling, 1970; Eaton and Konner, 1997; Benzie, 2003), all suggest that our consumption of vitamin C should naturally be at least ten times the recommended daily allowance espoused by most authorities (e.g. 60 mg in the European Union). A similar, if less striking, argument can be made for the discrepancy between our pre- and post-agricultural consumption of other vitamins (Pauling, 1970; Benzie, 2003) and anti-oxidant foods in general (Benzie, 2003).

9.2 Vitamin deficiency in developed societies In terms of the consumption of vitamins, most developed nations have governmentally dictated recommended dietary allowances (RDAs), or similar, designed to prevent specific vitamin deficiency diseases, such as pellagra, rickets, beri-beri or scurvy, and more general chronic diseases, such as osteoporosis and heart disease, in the vast majority (97–98 %) of the population. These RDAs are estimated from the average requirement of individuals within a group/population and the variability in the need for the nutrient among individuals. However, for most nutrients this information is either unknown or incomplete, and the recommendations are made on the basis of a number of assumptions and considerations that could lead to large variations in the eventual RDA (Levine et al., 1996; Young, 1996). More recently, most authorities have moved towards adopting Dietary Reference Values (or Dietary Reference Intakes), but these values incorporate RDAs and simply expand on them to include an ‘estimated average requirement’ and tolerable upper limit. Whilst these various recommendations give some estimate of levels of nutrient intake required to avoid disease there is, as yet, no consensus or guidance on the optimal levels of micronutrients. However, it would seem sensible to assume that for most micronutrients it should lie some distance above the RDA. A number of analyte/survey studies have assessed the incidence of biochemical vitamin deficiencies in cross-sections of the population. For example, the UK ‘National Diet and Nutrition Survey’ (NDNS) (Ruston et al., 2004) reported the results of blood analyte samples for five B vitamins and vitamins A, C, D and E taken from a representative cross section of 1347 respondents. The survey presented the incidence within the population of those that had the abnormally low levels of each vitamin that are indicative of biochemical depletion/deficiency as defined by a number of established criteria (Ruston et al., 2004), and which may predispose the individual to specific diseases related to deficiency of the vitamin in

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question. This survey showed that 5 % of males and 3 % of females were biochemically depleted in terms of vitamin C; 2 % of males and 4 % of females were deficient in vitamin B12; 10 % of males and 11 % of females were deficient in vitamin B6, and 66 % of both males and females showed marginal or deficient status in vitamin B2 (potentially due to methodological issues). Similarly, averaged across the year, 14 % of males and 15 % of females had deficient status in vitamin D, with this peaking in the winter months and attenuating during the summer. The related ‘Low Income Diet and Nutrition Survey’ (Nelson et al., 2007) showed that several of these deficiencies were exacerbated in low socioeconomic groups. Very similar percentages of prevalence as regards vitamin C (Schleicher et al., 2009) and vitamin B12 (Evatt et al., 2010) deficiencies have also recently been reported from the US using National Health and Nutrition Examination Survey (NHANES) data. Interestingly, the NDNS data show that approximately 5 % of the UK adult population have marginal levels of folate (vitamin B9) deficiency in terms of red cell folate, but low levels (<1 %) of deficiency in terms of serum folate levels when a definition of deficiency of <6.3 nmol/l is applied. This contrasts with serum folate deficiencies of 6 % in the French population (sample size = 2102) when a cut-off of 7 nmol/l is applied (Castetbon et al., 2009), and a previous figure of 16 % in the US adult population (sample size = 7300) when a cut-off of 6.8 nmol/l was applied. In the latter case, this percentage decreased to 0.5 % following the start of mandatory fortification of cereal-grain products with folic acid in 1998 (Pfeiffer et al., 2005). However, it is noteworthy that, with regards to fortification, some researchers have raised safety concerns. For example, Morris et al. (2007) observed a direct association between high serum folate and cognitive impairment in elderly adults with low levels of B12, but protection from impairment in participants with normal B12. For a review of potential negative effects of folate fortification see Smith et al. (2008). A similar lack of consistency as regards definitions of deficiency, and therefore incidence, can be seen in the measurement of vitamin E status. For instance, Ford et al. (2006) note that a wide range of lower cut-off points (from 7–28 μmol/l) in serum α-tocopherol levels have been employed to indicate vitamin E deficiency. Their own data from 4087 participants would give rates of deficiency ranging from 0.5 % of the population at a cut-off point of 11.6 μmol/l, to more than 20 % of adults in the US when this is raised to 20 μmol/l. This latter figure would seem to be in better agreement with data showing that the habitual intake of vitamin E is below the ‘Estimated Average Requirement’ in 90 % of the adult population of the US (Ahuja et al., 2004). Similarly, whilst the NDNS Survey (Ruston et al., 2004) used a figure of 25 nmol/l of 25-hydroxyvitamin D to indicate biochemical deficiency in vitamin D, the current consensus is that a much higher cut-off of <50 nmol/l is indicative of deficiency (Bischoff-Ferrari et al., 2006;

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Holick, 2007), suggesting a much higher prevalence of deficiency in the UK population than previously reported. These figures suggest not only that there is a certain amount of inconsistency in definitions of deficiency, but also that a sizeable minority of the population may be suffering levels of deficiency that may, at the least, dispose them to a variety of chronic diseases. Given that those in the deficient category represent the tail end of a distribution, and that optimum nutrition must lie some way above the cut-off for insufficiency, it would appear from this that there may be room for improvement in micronutrient status throughout a substantial segment of the population.

9.3 Mechanisms of action of vitamins related to brain function Whilst vitamins are intrinsic to all physiological processes within the body, both fat soluble and water soluble vitamins also contribute directly to optimal brain function via a plethora of mechanisms. The two groups of vitamins differ in terms of storage. Fat soluble vitamins are stored largely in the liver and adipose tissue, and therefore they persevere for potentially long periods in the body. When taken in excessive quantities, they can also build up to toxic levels. The water soluble vitamins, on the other hand, are readily excreted from the body in urine, and therefore require more regular and consistent replacement. 9.3.1

Fat soluble vitamins

Vitamin A Vitamin A (and its bioactive derivative retinoic acid (RA)) play an important role in embryonic neural development (reviewed by Niederreither and Dolle, 2008). Its contribution includes, for instance, neuronal differentiation and neurite outgrowth (for details see Lane and Bailey, 2005; McCaffery et al., 2006). Moreover, recent evidence suggests that vitamin A and its metabolites (RA and all-trans retinoic acid (ATRA)) also have important functions in the adult nervous system (Lane and Bailey, 2005; McCaffery et al., 2006; Luo et al., 2009; Olson and Mello, 2010). For instance, they have roles in the dopaminergic system (Valdenaire et al., 1994; Krezel et al., 1998; Valdenaire et al., 1998) and hippocampal synaptic plasticity (e.g. long-term potentiation (LTP) and long-term depression (LTD) (Etchamendy et al., 2003; Mey and McCaffery, 2004; McCaffery et al., 2006). Vitamin A has direct effects on cognition, e.g. retinoid signalling influences vocal memory in song birds (Olson and Mello, 2010), and in retinoid receptor deficient mice learning and memory deficits have been observed alongside changes in LTP and LTD (Chiang et al., 1998; Wietrzych et al., 2005). Animal studies have demonstrated that vitamin A deficiency (VAD) is associated with

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impaired hippocampal LTP and LTD in mice (Misner et al., 2001) which is reversed by vitamin A administration. In addition, administration of vitamin A or retinoid derivatives ameliorates VAD-mediated learning impairments (e.g. Cocco et al., 2002; Bonnet et al., 2008) and attenuates age-related LTP deficits and associated memory decline (Etchamendy et al., 2001; Mingaud et al., 2008). High doses, however, can be detrimental (Crandall et al., 2004). Evidence also suggests a role in a number of neurodegenerative and psychiatric disorders, e.g. Parkinson’s disease, Huntington’s disease, schizophrenia and depression. Vitamin D Until comparatively recently, the steroid hormone, vitamin D, was largely associated with its established roles in the regulation of bone mineralisation and levels of calcium and phosphorus. More recent evidence has shown that the active form of vitamin D, 1,25(OH)2D3 plays a plethora of roles related to health (Holick, 2008), which include a number that are specific to brain function. In vitro/vivo evidence suggests these include a host of neuroprotective and neurotransmission functions, including homeostatic regulation of neuronal calcium, modulation of inducible nitric oxide synthase (iNOS) and upregulation of the endogenous antioxidant glutathione. It also upregulates neurotrophin factors, including neurotrophin-3 (NT-3) and glial cell line derived neurotrophic factor (GDNF), which in turn play a role in synapticity and nerve transmission in the neocortex and hippocampus (Buell and Dawson-Hughes, 2008; McCann and Ames, 2008). Recent evidence has also confirmed the presence of vitamin D receptors and the catalytic enzymes involved in the synthesis of 1,25(OH)2D3 throughout the human brain, including cognition-relevant areas (Buell and Dawson-Hughes, 2008; McCann and Ames, 2008). To date, a wealth of evidence has suggested behavioural decrements in rodents either bred with vitamin D receptor dysfunction or deprived of vitamin D during brain development and beyond (McCann and Ames, 2008). Vitamin E Vitamin E is composed of the tocotrienols and tocopherols, which are closely related groups of compounds, each of which possesses four analogs, α, β, γ and δ. It is generally accepted that α-tocopherol has the highest biological activity amongst the compounds (Yang and Wang, 2008). Vitamin E deficiency results in a host of neurological deficits, and supplementation has been suggested as a potential treatment for a variety of neurodegenerative disorders (Ricciarelli et al., 2007). On the basis of copious in vitro evidence, it is generally accepted that vitamin E is the brain’s most prevalent lipophilic antioxidant, and in support of this it is notable that it is transported across the blood-brain barrier (BBB) by lipoproteins (Goti et al., 2002; Mardones and Rigotti, 2004). However, direct in vivo evidence to support this role is scarce, and the molecular mechanisms

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underlying vitamin E’s physiological roles are still largely undelineated (Brigelius-Flohe, 2009). Animal studies suggest a beneficial effect of vitamin E on cognitive function (Joseph et al., 1998; Fukui et al., 2002; Jhoo et al., 2004) and it has been suggested that, other than its potential anti-oxidant properties, vitamin E might owe its beneficial effects to an indirect role in the inhibition and activation of a raft of essential enzymatic processes, and gene expression (Brigelius-Flohe, 2009).

9.3.2

Water soluble vitamins

B vitamins The B vitamins play key roles in brain function as co-enzymes and precursors of co-factors in enzymatic processes. In this respect, they contribute at some level to all physiological processes within the brain. However, they also have a number of specific roles that might be expected to directly affect aspects of brain function, which in turn may modify behaviour, either in the short or long term. For instance, folate (vitamin B9) supplies the methyl group for the conversion of methionine to S-adenosylmethionine (SAMe), and therefore plays a role in the synthesis and integrity of DNA and the methylation of proteins, phospholipids and monoamine and catecholamine neurotransmitters (Mattson and Shea, 2003). Similarly, adequate levels of folate and vitamin B12 are required for the remethylation of homocysteine (Hcy), which is a potentially toxic amino acid by-product of one carbon metabolism. Vitamin B6 also plays a key role in this process as a co-enzyme of cystathionine synthase and cystathioninelyase, which are required for the metabolism of homocysteine to cysteine (Mattson and Shea, 2003). Blocking of the conversion process (e.g. by deficiencies of folate or vitamins B12 and B6) leads to elevated levels of homocysteine, which in turn may contribute to a range of deleterious effects on cellular, haemodynamic, oxidative and vascular parameters, and ultimately may contribute to a range of neurodegenerative and psychiatric disorders (Reynolds, 2006). Vitamin B6 also plays a raft of roles in metabolic processes and is integral to the synthesis of a range of neurotransmitters, including dopamine and serotonin, in its role as a co-factor for aromatic l-amino acid decarboxylase (AADC), an enzyme that catalyses the decarboxylation of a variety of aromatic l-amino acids. It has also been shown to regulate the levels of serotonin (Boadlebiber, 1993; Calderon-Guzman et al., 2004). As well as playing a role in the structure and function of central nervous system cellular membranes, vitamin B1 (thiamine) plays a key role as a cofactor in several enzymatic processes essential for the cerebral metabolism of glucose. At its most extreme, thiamine deficiency, including as a consequence of chronic alcoholism, leads to Wernicke’s encephalopathy, a condition involving selective neuropathological lesions related to dysfunction in neuronal metabolic pathways (Ba, 2008).

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Vitamin C Vitamin C (ascorbate) is transported into the brain against a steep concentration gradient and accumulates in neuron-rich areas such as the hippocampus, cortex and cerebellum at high concentrations (Mefford et al., 1981; Mun et al., 2006). This suggests that it plays a pivotal role in brain function. Within the central nervous system, vitamin C plays a plethora of roles, in all of which it functions as a single electron donor. In vitro evidence suggests that vitamin C is a powerful antioxidant. In this respect, its roles include reducing oxygen, sulphur and nitrogen–oxygen radicals generated during normal cellular metabolism, and the recycling of other radicals to their previous forms. An important example of the latter is the reduction of tocopheroxyl radical back to α-tocopherol (Padayatty et al., 2003). Vitamin C also acts as an essential electron donor for a number of separate enzymes and, amongst many other effects, contributes to the synthesis of tyrosine, carnitine, catecholamine neurotransmitters and peptide hormones (Padayatty et al., 2003). Harrison and May (2009) also elaborate roles for vitamin C in neural maturation, and the neuromodulation of the activity of acetylcholine and the catecholamine neurotransmitters, with resultant direct impacts on behaviour in animal models.

9.4 Evidence from epidemiological studies The intrinsic importance of vitamins to many aspects of brain function would suggest that a relationship might exist between elements of psychological functioning and vitamin status. This relationship could be seen both in terms of the accrual of physiological damage due to the long-term effects of vitamin status, for instance as a consequence of systemic damage related to oxidative stress or homocysteine levels, or alternatively in terms of effects directly related to current circulating levels. The latter situation may be more amenable to vitamin-related improvements, with the timescale of effects potentially ranging from almost immediately, up to the maximum length of time it might take to fully replete physical stores. The majority of studies in this area have concentrated on cognitive decline and dementia in elderly, at risk or diagnosed cohorts that may well have suffered an accumulation of systemic damage over many years or decades. However, given the possibility that many healthy adults would be classified as deficient in one or more vitamins, and the fact that the, as yet unidentified, optimum level of vitamins must lie some distance above current definitions of deficiency, it would also seem likely that a relationship between vitamin consumption/status and psychological functioning should also be evident in cohorts of adults assumed to be cognitively intact or representative of the general population. A number of epidemiological studies have investigated this question in such cohorts, with the largest body of research focusing on B vitamins and the related levels of the potentially

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deleterious amino acid homocysteine. However, this work has predominantly been undertaken in older (≥65 years) cohorts. The studies published after 1994 that employed samples >100 and have utilised cohorts that were assessed or assumed to be cognitively intact at the outset of data collection are described below and shown in Tables 9.1, 9.2 and 9.3.

9.4.1

B vitamins and homocysteine levels

Biochemical status By far the most research attention in this general area has been focused on the relationship between circulating levels of B vitamins and aspects of cognitive function, including cognitive decline, and mood, including depression and anxiety. In terms of cohorts assumed to be cognitively intact (at the outset), this relationship has been examined with regard to circulating levels of folate, with or without vitamin B12, in a number of cross-sectional studies (Wahlin et al., 1996, 2001; Lindeman et al., 2000; Morris et al., 2001, 2003, 2007; Duthie et al., 2002; Bjelland et al., 2003; Miller et al., 2003; Ravaglia et al., 2003; Bunce et al., 2004; Garcia et al., 2004; Sachdev et al., 2005; Budge et al., 2008; Krieg Jr and Butler, 2009; Lin et al., 2009) and a number of longitudinal studies with follow-ups of between five and ten years (La Rue et al., 1997; Maxwell et al., 2002; Teunissen et al., 2003; Mooijaart et al., 2005; Kang et al., 2006b; Clarke et al., 2007; Middleton et al., 2007). Two additional prospective studies with follow-ups at seven years (Kado et al., 2005) and three years (Tucker et al., 2005) also included measurements of vitamin B6. A single prospective study with follow-up at four years (Dufouil et al., 2003) assessed biochemical levels of B6 and B12, but without folate, and a cross-sectional study by Merete et al. (2008) examined biochemical levels of B6 only. Across these studies, a positive relationship between circulating levels of at least one B vitamin and some aspect of cognitive performance has been reported in 14 studies (Wahlin et al., 1996, 2001; La Rue et al., 1997; Lindeman et al., 2000; Morris et al., 2001, 2007; Duthie et al., 2002; Maxwell et al., 2002; Teunissen et al., 2003; Bunce et al., 2004; Kado et al., 2005; Mooijaart et al., 2005; Tucker et al., 2005; Middleton et al., 2007). In addition, Middleton et al. (2007) demonstrated an association between low folate and the risk of developing Alzheimer’s disease five years later. In terms of mood, four studies have indicated a relationship between B vitamins and depression. Generally, these studies indicate that low levels of folate (Bjelland et al., 2003; Morris et al., 2003; Sachdev et al., 2005; Merete et al., 2008) or B6 (Merete et al., 2008) are associated with depressive symptoms or incidents. Given the intrinsic role that folate and vitamins B6 and B12 play in the metabolism of homocysteine, which is a potentially toxic amino acid by-product of one carbon metabolism and is implicated in a number of diseases, 16 of the above studies also included an assessment of blood levels

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Crosssectional, communitybased

Crosssectional, communitybased

Longitudinal (follow-up 10 years)

Bunce et al. (2004)

Clarke et al. (2007)

Crosssectional

Bjelland et al. (2003)

Budge et al. (2008)

Design

Study

N = 1648 men and women, age ≥ 65 years Serum B12 and folate, holoTC, tHcy and MMA under non-fasting conditions

Blood concentrations: tHcy, serum folate, B12, serum cystatin C Apo-E 4, serum levels of B12 and folate

N = 158, age = 60–91 years

N = 167, age ≥ 75 years

Plasma tHcy, serum folate, serum B12, MTHFR C677T genotype

Nutritional status measures

N = 5948, age = 46–49 years and 70–74 years

Sample

Free recall of semantically unrelated words and free and cued recall of category lists. Tasks varied in level of cognitive support (load) MMSE

HADS-A and HADS-D (anxiety and depression defined as corresponding HADS-score > 8) CAMCOG, MMSE, GDS

Cognition and mood outcome measures

Methods

holoTC, tHcy and MMA predicted cognitive decline. Folate did not

Hcy negatively associated with perception and memory subtests of CAMCOG Low vitamin B12 combined with Apo-E 4 genotype negatively related to free recall in highest cognitive load

High Hcy related to depression. Folate inversely related to depression only in middle-aged women

Results

Some subjects had low MMSE scores and small proportion had scores that indicated impairment

Comments

Table 9.1 Epidemiological research examining the relationship between biochemical levels of B-vitamins and/or homocysteine and psychological functioning in cognitively intact cohorts

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Plasma concentrations of Hcy, folate and B12 under fasting conditions

Plasma Hcy under fasting conditions

N = 2096 aged: 40–49 years, 50–59 years and 60–82 years

Crosssectional

Elias et al. (2005)

Plasma concentrations of Hcy, B6 and B12 under fasting conditions

N = 331, age = 63–79 years

N = 1241, age = 61–73 years

Nutritional status measures

Sub-tests from WAIS-R: Similarities; paired associates; logical memory: immediate recall, delayed recall, delayed recognition; visual reproductions: immediate recall, delayed recall, delayed recognition. Also, TMT-A and B, Hooper visual organisation test, Boston naming test

MMSE, the NART, RPM, AVLT, DSST and BD from WAIS-R

MMSE, TMT-B, DSST (WAIS-R), finger tapping test

Cognition and mood outcome measures

Methods

Crosssectional, populationbased

Longitudinal (follow-up 4 years), populationbased

Dufouil et al. (2003)

Sample

Duthie et al. (2002)

Design

Continued

Study

Table 9.1

Higher concentrations of Hcy associated with impaired cognitive performance (all tests) Folate and B12 positively associated with MMSE, NART, AVLT and DSST. Hcy negatively associated with RPM, BD and DSST (only in the oldest subjects) Hcy levels associated with cognitive impairments on all tasks (except for: logical memorydelayed, visual reproductions – immediate and delayed) only in those aged 60 or over

Results

Associations between folate, B12 NART and MMSE strengthened when adjusted for childhood IQ

Comments

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Crosssectional

Crosssectional and longitudinal (follow-up 7 years)

Kado et al. (2005)

499 high functioning 70–79 year olds (n = 370 for longitudinal analyses)

N = 281, age ≥ 65 years

N = 911 men and women, age = 26–98 years

Crosssectional

Elias et al. (2008)

Garcia et al. (2004)

Sample

Design

Study

Serum cobalamin (B12), red blood cell folate, methylcitric acid, Hcy, MMA Plasma Hcy, folate, B6 and B12 measured under non-fasting conditions at baseline

Apo-E 4 (carriers and non-carriers), plasma Hcy

Nutritional status measures

High Hcy or low folate or B6 associated with worse baseline cognitive function and with cognitive decline 7 years later

Overall cognitive function based on combined scores from: BNT, delayed verbal memory, delayed recognition span test, spatial copying, similarities sub-test of WAIS-R and abstract concept formation

CVLT, MDRS, and Stroop

Inverse relationship between Hcy and all cognitive measures which was greater in Apo-E 4 group. With adjustment for demographic characteristics alone or in combination with CVD and B-vitamins inverse relationship between Hcy and MMSE, global cognitive function, similarities and working memory observed only in Apo-E 4 group High Hcy associated with lower Stroop scores

Results

MMSE and MaineSyracuse Neuropsychological test battery (global composite score calculated based on averaged z-scores of sub-tests)

Cognition and mood outcome measures

Methods

Apo-E and non-Apo-E groups unbalanced (n = 224 and n = 667 respectively)

Comments

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Prospective (follow-up 10 years)

Crosssectional

Krieg Jr and Butler (2009)

Prospective (follow-up 2.7 years)

Kalmijn et al. (1999)

Kang et al. (2006b)

Design

Continued

Study

Table 9.1

Plasma folate and B12

Blood level of lead, serum: folate, B12 and Hcy concentrations and red blood cell folate

N = 635 (women), age ≥ 70 years

N = 2911, age = 20–59 years

Global score from telephone interview (global cognition (TICS), verbal memory (immediate and delayed), East Boston memory test, delayed recall of TICS 10-word list, category fluency (animals)) SRT, DSST and serial digit learning

MMSE

Cognition and mood outcome measures

Methods

Serum concentrations of Hcy under nonfasting conditions

Nutritional status measures

N = 702, age ≥ 55 years

Sample

Methods

No association between cognitive performance and lead, serum folate, or B12. In 20–39 year-olds digit learning enhanced with increased Hcy. In 40–59 year-olds no relationship between Hcy and cognitive measures

No relationship between Hcy levels and cognitive impairment or cognitive decline No association between vitamin levels and cognitive performance

Results

Comments

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Design

Longitudinal (follow-up 6 years)

Crosssectional

Prospective (follow-up 5 years)

Crosssectional

Study

La Rue et al. (1997)

Lindeman et al. (2000)

Maxwell et al. (2002)

Merete et al. (2008)

Serum folate

Plasma B6 under fasting conditions (dietary B6 assessed using FFQ – see Table 9.2)

N = 869, age ≥ 60 years

Plasma and erythrocyte folate and B12, plasma C, erythrocyte B2 and B1 concentrations under fasting conditions (threeday dietary records – see Table 9.2) Serum B12, serum folate, serum vitamin C (FFQ and current use of vitamin supplements – see Table 9.2)

Nutritional status measures

N = 369, age ≥ 65 years

N = 816, age ≥ 65 years

N = 137, age = 66–90 years

Sample

Adverse cerebrovascular event; 3MSE decline; dementia; AD CESD

MMSE, WAIS-R digits forward, Fuld Object Memory Evaluation, clock drawing, 2-colour TMT, self-report depression, antidepressant use, GDS

Abstraction scale; logical memory and visual reproduction (WAIS); ROCF

Cognition and mood outcome measures

Low serum folate associated with lower scores on MMSE, digits forward, Fuld Object memory test and one of the 2 colour TMTs. No association of other serum vitamins or use of vitamin supplements on cognitive function or mood Low folate compared to high folate associated with risk of cognitive decline and dementia Increased plasma B6 associated with lower CESD scores. Deficient plasma B6 increased possibility of depressive caseness (CESD ≥ 16)

Enhanced abstraction performance associated with B1, B2, B3, and folate. Improved visuospatial performance associated with vitamin C

Results

Comments

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Crosssectional

Prospective, populationbased (follow-up 5 years)

Mooijaart et al. (2005)

Longitudinal (follow-up 5 years)

Middleton et al. (2007)

Miller et al. (2003)

Design

Study

Table 9.1 Continued

Plasma Hcy, RBC folate, plasma B12 under fasting conditions

Serum Hcy, B12 and folic acid

N = 599, age = 85 years

Serum folate

Nutritional status measures

N = 1789, age = 60–101 years

N = 466, age ≥ 65 years

Sample

3MSE, delayed recall, object naming, picture association, verbal-conceptual thinking, verbal attention span, pattern recognition, CESD MMSE, Stroop, DSST and word learning

Incident cerebrovascular events, all-cause dementia and AD

Cognition and mood outcome measures

Methods

Cross-sectional analyses revealed Hcy inversely related to MMSE and folate associated with better MMSE. No association between Hcy, folate or B12 and cognition in longitudinal analyses

Low folate associated with increased risk of AD and cerebrovascular outcomes. Exercise modulated relationship between folate and AD and folate and dementia Hcy negatively associated with performance of 3MSE, picture association, verbal attention span, pattern recognition

Results

Comments

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tHcy concentrations under non-fasting conditions

Plasma Hcy, serum folate and B12 concentrations under fasting conditions

N = 1458, age ≥ 60 years

N = 1077, age = 60–90 years

N = 650 age ≥ 65 years

Crosssectional

Crosssectional, populationbased

Crosssectional, populationbased

Prins et al. (2002)

Ravaglia et al. (2003)

Morris et al. (2007)

Serum folate, RBC folate and serum Hcy concentrations after variable fasting states. Serum folate and B12

N = 2948, age = 15–39 years

Crosssectional

Morris et al. (2003)

Nutritional status measures Blood concentrations after variable period of fasting: red blood cell folate, plasma tHcy

Crosssectional, populationbased

Morris et al. (2001)

Sample

N = 1200, age ≥ 60 years

Design

Study

MMSE

MMSE, GMS, Stroop, letter-digit substitution, verbal fluency, MST and a 15-word verbal learning test to assess immediate and delayed recall

Cognitive impairment assessed as <34 digit-symbol coding

DIS examining lifetime assessment of major depression and dysthymia

MMSE; short recall and paragraph delayed recall test

Cognition and mood outcome measures

Methods

High serum folate and low B12 associated with cognitive impairment Increasing Hcy levels were associated with impaired psychomotor speed, memory, and cognitive function. Structural brain changes were not related to these findings Negative association between Hcy concentrations and cognitive function, independent of B vitamins

Lower levels of folate and increased Hcy associated with worse recall. Hcy negatively influenced memory, and this was independent of folate Folate status higher in subjects who had never been depressed

Results

Comments

© Woodhead Publishing Limited, 2011

Design

Crosssectional

Crosssectional, populationbased

Sachdev et al. (2005)

Schafer et al. (2005)

Continued

Study

Table 9.1

Serum folic acid, B12, Hcy under fasting conditions Serum Hcy, Apo-E 4 genotype

N = 1140, age = 50–70 years

Nutritional status measures

N = 412, age = 60–64 years

Sample

BNT, category fluency, letter fluency, RPM, finger tapping, SRT, purdue pegboard, purdue pegboard assembly, Stroop, TMT-A and B, RAVLT recall and recognition, ROCF, symbol digit paired associate learning

PRIME-MD, MRI

Cognition and mood outcome measures

Methods

High Hcy or low folic acid associated with increased depressive symptoms Hcy level associated with worse neurobehavioural test performance in all tests. Following adjustment effect maintained in tests relating to: simple motor and psychomotor speed, eye–hand coordination/ manual dexterity and verbal memory and learning. Effects of Hcy worse for Apo-E ε4/ ε4 haplotype

Results

Comments

© Woodhead Publishing Limited, 2011

B12, folate. Four groups based on serum concentrations: normal B12/ normal FA, low B12/ normal FA, normal B12/ low FA, low B12/ low FA

N = 230, age = 75–96 years

Crosssectional

Wahlin e t al. (2001)

Serum levels of B12 and folic acid

N = 250, age = 75–96 years

Crosssectional

Wahlin et al. (1996)

Plasma total Hcy, folate, B6 and B12 measured at baseline under fasting conditions

N = 321, age = 50–85 years (mean age = 67 years)

Longitudinal (follow-up 3 years)

Tucker et al. (2005)

Nutritional status measures Serum concentrations of Hcy, folate and B12

Prospective (follow-up 6 years)

Teunissen et al. (2003)

Sample

N = 144 age = 30–80 years

Design

Study

Free recall and recognition (slow and rapidly presented words) MMSE and cognitive test battery consisting of: the clock test, modified BD, digit span, TMT-A and B, category fluency and letter fluency tests

MMSE, BDS, word list recall, verbal fluency, constructional praxis

Letter-digit coding, Stroop, word learning test and delayed recall

Cognition and mood outcome measures

Methods

Hcy negatively correlated with Stroop and word learning throughout. Folate acid correlated to delayed recall only at baseline Plasma levels of Hcy, folate, B6 and B12 associated with reduced constructional praxis, measured by spatial copying. Folate protected against decline in spatial copying independently of other vitamins and Hcy Recall and recognition impaired as function of vitamin status Low/low vitamin grouping associated with deficits in BD, TMT-B, BDS, and letter fluency

Results

Comments

© Woodhead Publishing Limited, 2011

Crosssectional

Wright et al. (2004)

N = 2871 age ≥ 40 years

Sample

Fasting Hcy levels

Nutritional status measures MMSE

Cognition and mood outcome measures

Methods

Only in older (≥65 years) increased Hcy associated with lower MMSE score

Results

Not all healthy: subjects were only excluded if they were stroke-free study included because sample contains young adults

Comments

Abbreviations: 3MS = Modified Mini Mental State Examination; AD = Alzheimer’s Disease; Apo-E = apolipoprotein E; AVLT = Auditory Verbal Learning Test; BD = Block Design (from WAIS-R); BDS = Backward Digit Span; BNT = Boston Naming Test; CAMCOG = Cambridge Cognition Examination; CESD = Centre for Epidemiologic Studies Depression Scale; CVD = Cardio-Vascular Disease; CVLT = California Verbal Learning Test; DIS = diagnostic interview schedule; DSST = Digit Symbol Substitution Test; FA = Folic Acid; FFQ = Food Frequency Questionnaire; GDS = Geriatric Depression Scale; GMS = Geriatric Mental Schedule; HADS–A = Hospital Anxiety and Depression scale–Anxiety sub-scale; HADS–D = Hospital Anxiety and Depression scale–Depression sub-scale; Hcy = Homocysteine; HoloTC = holotranscobalamin; kcal = calorie intake; MDRS = Mattis Dementia Rating Scale; MFQ = Memory Functioning Questionnaire; MMA = methylmalonic acid; MMSE = Mini Mental State Exam; MRI = Magnetic Resonance Imaging; MST = Memory Scanning Task; MTHFR = methylenetetrahydrofolate; NART = Adult National Reading Test; PRIME-MD = Patient Health Questionnaire for syndromal depression and severity of depression symptoms; RAVLT = Rey Auditory Verbal Learning Test; RBC = red blood cell; ROCF = Rey-Osterreith Complex Figure; RPM = Raven’s Progressive Matrices; SRT = Simple Reaction Time; STAI = State Trait Anxiety Inventory; tHcy = total Homocysteine; TICS = Telephone Interview of Cognitive Status; TMT-A and B = Trail-making Test parts A and B; WAIS-R = Wisconsin Adult Intelligence Scale–Revised.

Design

Continued

Study

Table 9.1

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A, C or E plus selenium or zinc supplementation assessed from interviews Three-day dietary records (vitamins A, C, E, thiamine, riboflavin, Niacin, vitamin B6, folate, B12 and protein) and record of supplementation. (Vitamin levels – see Table 9.1)

N = 2082, age ≥ 65 years

Longitudinal (follow-up 3 and 7 years)

Longitudinal (follow-up 6 years)

Gray et al. (2003)

La Rue et al. (1997)

N = 137, age = 66–90 years

Folate, B12 and B6 intake estimated using FFQ

N = 1183, age = 39–65 years

Crosssectional, populationbased

Nutritional status measures

Bryan & Calvaresi (2004)

Sample

Design

Study

Abstraction scale; logical memory and visual reproduction (WAIS); ROCF

Self-report cognitive and memory function (CFQ, MFQ). Psychological wellbeing (CESD, PSS, STAI-Y, RSE-B) SPMSQ

Cognition and mood outcome measures

Methods

Current intake of thiamine, riboflavin and folate positively associated with abstract reasoning, dietary niacin positively correlated with ROCF, recall and abstraction. Higher past intake of vitamins E, A, B6 and B12 related to better recall and abstraction. Use of supplements associated with better visuospatial and abstraction performance

20 % men and women had folate intake lower than recommended daily intake. In men B12 and B6 related to memory. Folate related to memory in women Lower risk of cognitive decline in those who took supplements

Results

No objective cognitive measures

Comments

Table 9.2 Epidemiological research examining relationship between dietary intake of vitamins and psychological functioning in cognitively intact cohorts

© Woodhead Publishing Limited, 2011

Crosssectional

Crosssectional

Merete et al. (2008)

N = 869, age ≥ 60 years

N = 816, age ≥ 65 years

N = 419 elderly males, mean age = 80.8 years

Crosssectional

Lin et al. (2009)

Lindeman et al. (2000)

Sample

Design

Continued

Study

Table 9.2

Dietary B6 and supplementation assessed using FFQ. (plasma B6 under fasting conditions – see Table 9.1)

Serum B12 concentration. Two groups: habitual B12 (take > 250 mcg/day) and those who did not take B12 supplements FFQ (results not included) and current use of vitamin supplements (serum B12, serum folate, serum vitamin C – see Table 9.1)

Nutritional status measures

MMSE, WAIS-R digits forward, Fuld Object Memory Evaluation, clock drawing, 2-colour TMT, self-report depression, antidepressant use, GDS CESD

MMSE (Chinese version), GDS

Cognition and mood outcome measures

Methods

Total intake of B6 (diet + supplements) not associated with CSED. Dietary B6 intake associated with lower CESD score

No association of vitamin supplement use on cognitive function or mood

10.7 % reported regular B12 supplementation. No difference in cognitive impairment or depression between those with and without B12 supplementation

Results

41 % Hispanic, 22.6 % NHW

Unbalanced groups. B12: n = 45, nonhabitual: n = 374

Comments

© Woodhead Publishing Limited, 2011

Nutrient intake: 7-day weighed food record (kcal, macronutrients, cholesterol, fibre, minerals, thiamine, riboflavin, niacin, pyridoxine, folate, B12, C, A, β-carotene, D, E)

Crosssectional

Ortega et al. (1997)

N = 2889, age = 65–102

N = 260, age = 65–90 years

Longitudinal (follow-up 3.2 years)

Morris et al. (2002)

Dietary intake of thiamine, B2, B3, folic acid, B6 and B12 assessed based on parental 24-hour food recall (age 4) and 5 day food record (age 36, 43 and 53) FFQ (kcal, alcohol, vitamins: E, C and carotene and use of vitamin E and C supplements)

N = 636 women, age = 53 years

Prospective (follow-up 53 years)

Mishra et al. (2009)

Nutritional status measures

Sample

Design

Study

MMSE and PMSQ

Global cognitive score (included scores from MMSE, EBMT, DSST)

GHQ-28

Cognition and mood outcome measures

Methods

Participants with highest vitamin E intake demonstrated less decline in global cognitive score over average 3.2 years of study MMSE scores correlated with thiamine, folate and vitamin C intake. PMSQ results significantly correlated with intake of folate, vitamin C, β-carotene and vitamin E. With best results obtained from people with greater intakes of folate, vitamin C, β-carotene

Low B12 at age 53 years associated with increased psychological distress. Lowest B12 had highest GHQ-28 scores compared to high B12

Results

Associations were not observed when multiple regression employed

Comments

© Woodhead Publishing Limited, 2011

N = 110, age ≥ 65 years

N = 117, age = 69–91

Sample

Vitamin C intake measured by FFQ: supplement non-users, high vitamin C intake, non-users low vitamin C intake and users of vitamin C supplements with highest intake 3-day record of dietary intake (kcal, macronutrients, cholesterol, alcohol, caffeine, water, B6, B12, C, D, E, folate, micronutrients)

Nutritional status measures

MMSE

MMSE, Reid brief neuropsychological screen, Animals test of category fluency, FAS

Cognition and mood outcome measures

Methods

No associations of vitamins and cognitive function

High vitamin C intake at baseline associated with better MMSE scores 4 years later

Results

Comments

Abbreviations: CESD = Centre for Epidemiologic Studies Depression Scale; CFQ = Cognitive Failures Questionnaire; DSST = Digit Symbol Substitution Test; EBMT = East Boston Memory Test; FAS = F, A, S test of verbal fluency; FFQ = Food Frequency Questionnaire; GDS = Geriatric Depression Scale; GHQ-28 = General Health Questionnaire; kcal = calorie intake; MFQ = Memory Functioning Questionnaire; MMSE = Mini Mental State Exam; NHW = Non-Hispanic whites; PMSQ = Pfeiffer’s Mental Status Questionnaire; PSS = Perceived Stress Scale; ROCF = Rey-Osterreith Complex Figure; RSE-B = Rosenberg Self-esteem Scale; SPMSQ = Short Portable Mental Status Questionnaire; STAI-Y = STAI = State Trait Anxiety Inventory; TMT = Trail-making Test; WAIS = Wisconsin Adult Intelligence Scale.

Prospective (follow up 8.5 ± 3.5 months)

Crosssectional

Paleologos et al. (1998)

Velho et al. (2008)

Design

Continued

Study

Table 9.2

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Plasma concentrations of 25(OH)D under fasting conditions

Plasma concentrations of vitamin E. FFQ (daily intake: vitamin E, kcal)

N = 1080, age = 65–99 years

N = 1033, age ≥ 65 years

Crosssectional

Cohort, populationbased

Buell et al. (2009)

Cherubini et al. (2005)

Nutritional status measures

Sample

Design

Study

MMSE, NAART, WMS-III word list learning, WMS-III Logical memory, DSST, TMT, mental alternation test, WAIS-III digit span, WAIS-III BD, WAIS-III matrix reasoning, Controlled oral word association test, naming objects and fingers test, SRAS, centre for epidemiological studies depression scale (CESD) MMSE and, for those scoring between 22 and 26 on MMSE, paired words test, digit test from the WAIS and the Caltagirone drawings

Cognition and mood outcome measures

Methods

Other vitamins and vitamin combinations

Bottom tertile vitamin E status more likely to have impaired cognitive function (and dementia) compared to highest tertile

25(OH)D associated with better performance on TMT(A and B), DSST, matrix reasoning and BD

Results

Included subjects with dementia (n = 58), cognitive impairment (n = 168), normal cognitive function (n = 807)

Subjects not necessarily healthy – sample were home-bound elderly

Comments

Table 9.3 Epidemiological research examining relationship between biochemical levels of vitamins A, C, D and E and cognitive function and mood

© Woodhead Publishing Limited, 2011

N = 858 (female), age ≥ 70 years

N = 3133 males, age = 40–79 years

Prospective (follow-up 10 years)

Crosssectional

Kang and Grodstein (2008)

Lee et al. (2009)

N = 1282, age = 65–95 years

Cohort, populationbased

Hoogendijk et al. (2008)

Sample

Design

Continued

Study

Table 9.3

Serum 25(OH)D under nonfasting conditions Plasma total carotenoids (sum of: α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein/ zeaxanthin) and total tocopherols (sum of: α-tocopherol and γ-tocopherol 70 % fasting) Serum 25(OH)D

Nutritional status measures

ROCF, CTRM, DSST, physical activity, functional performance and mood/ depression

TICS, EBMT, recall tasks, category fluency and BDS

CESD

Cognition and mood outcome measures

Methods

Other vitamins and vitamin combinations

Lower levels of 25(OH)D associated with worse DSST performance

CESD scores associated with decreased 25(OH)D levels No overall associations between baseline plasma levels and cognitive function at the 10 year assessment

Results

Comments

© Woodhead Publishing Limited, 2011

N = 11 232, age = 12–17 years (n = 1676), age = 20–60 years (n = 4747), age 60–90 years (n = 4809)

N = 120, age = 65–91 years

N = 3262, age = 50–70 years

Crosssectional

Crosssectional

Crosssectional, populationbased

McGrath et al. (2007)

Ortega et al. (2002)

Pan et al. (2009)

Sample

Design

Study

Dietary intake of vitamin E assessed using 5-day weighed food record and serum levels of vitamin E (α-tocopherol) and cholesterol Plasma 25(OH)D

Serum 25(OH)D (vitamin D)

Nutritional status measures

CESD

PMSQ

Children – N/A Adults: (From NES): RT, DSST, serial digit learning Elderly: Memory of a story

Cognition and mood outcome measures

Methods

Other vitamins and vitamin combinations

Association between serum 25(OH)D and performance only observed in elderly group (age 60–90 years) with highest serum levels associated with largest learning and memory impairment Association between serum vitamin E concentration and cognitive function as assessed by errors on the PMSQ No association between CESD and plasma 25(OH)D concentration

Results

95.2 % had intake lower than recommended

Comments

© Woodhead Publishing Limited, 2011

25(OH)D

N = 1604 males, age ≥ 65 years

Longitudinal (follow-up 4.6 years)

Slinin et al. (2009)

Modified MMSE, TMT-B

Memory: free recall, recognition, measures of vocabulary, priming and working memory

Cognition and mood outcome measures Memory and vocabulary associated with vitamin C and vitamin A (β-carotene) at both time points No significant associations between 25(OH)D and cognitive impairment or decline

Results

From Osteoporotic Fractures in Men study

Comments

Abbreviations: 25(OH)D = 25 hydroxyvitamin D; AR = Abstract Reasoning; BD = Block design; BDS = Backward Digit Span; CESD = Centre for Epidemiological Studies–Depression; CTRM = Camden Topographical Recognition Memory; DSST = Digit Symbol Substitution Test; EBMT = East Boston Memory Test; FFQ = Food Frequency Questionnaire; kcal = calorie intake; MMSE = Mini Mental State Exam; NAART = North American Adult Reading Test; NES = Neurobehavioural Evaluation System; PMSQ = Pfeiffer’s Mental Status Questionnaire; ROCF = Rey–Osterrieth Complex Figure; RT = Reaction Time; TICS = Telephone Interview for Cognitive Status; TMT–A and B = Trail-making Test parts A and B; WAIS-R = Wisconsin Adult Intelligence Scale-Revised; WMS-III = Wisconsin Adult Intelligence Scale-Revised.

Plasma vitamin E (α-tocopherol), C (ascorbic acid) and A (β-carotene) measured in 1971 and 1993

Nutritional status measures

N = 442, age = 65–94 years (male [n = 312] and female [n = 132])

Sample

Methods

Other vitamins and vitamin combinations

Longitudinal (follow-up 22 years) and crosssectional

Design

Continued

Perrig et al. (1997)

Study

Table 9.3

Vitamin status, cognition and mood in cognitively intact adults

221

of homocysteine (Morris et al., 2001, 2003; Duthie et al., 2002; Bjelland et al., 2003; Dufouil et al., 2003; Miller et al., 2003; Ravaglia et al., 2003; Teunissen et al., 2003; Garcia et al., 2004; Kado et al., 2005; Mooijaart et al., 2005; Sachdev et al., 2005; Tucker et al., 2005; Clarke et al., 2007; Budge et al., 2008; Krieg Jr and Butler, 2009). Six additional cross-sectional studies also investigated the relationship between homocysteine and cognitive performance in sizeable cohorts independently of circulating vitamin levels (Kalmijn et al., 1999; Prins et al., 2002; Wright et al., 2004; Elias et al., 2005, 2008; Schafer, 2005). All but three of these 22 studies (Schäfer, 2005; Morris et al., 2003; Krieg Jr and Butler, 2009) reported that higher homocysteine levels were associated in some way with aspects of poorer cognitive function, cognitive decline or depression/depressive symptoms. Interestingly, several studies that assessed both homocysteine and vitamin levels demonstrated that cognitive function was related to homocysteine but not blood analyte levels of vitamins (Dufouil et al., 2003; Garcia et al., 2004; Clarke et al., 2007; Budge et al., 2008), and two studies also suggested that their observation of a relationship between homocysteine and cognition was statistically independent of vitamin levels (Morris et al., 2001; Ravaglia et al., 2003). In terms of mood, one study demonstrated that low folic acid or high homocysteine, but not B12, correlated with depressive symptoms (Sachdev et al., 2005) and another indicated a significant association of homocysteine, but not B12, with the depression sub-scale of the Hospital Anxiety and Depression Scale (HADS-D). Moreover, low folate was only related to depression in a subgroup of middle-aged female participants (Bjelland et al., 2003). Several studies have also shown that the apolipoprotein E-ε4 genotype, which represents a genetic risk factor for cardiovascular disease and Alzheimer’s disease, strengthens the relationship between homocysteine levels and cognitive function (Bunce et al., 2004; Schäfer, 2005). It is notable that the majority of the evidence outlined above as regards both vitamins and homocysteine has been collected in older cohorts, and a wide variety of cognitive measures have been employed. In contrast, where effects were not observed, populations were young (e.g. Krieg Jr and Butler, 2009) or limited cognitive testing was employed. As an example of the latter, Ravaglia et al. (2003) administered the Mini-Mental State Examination (MMSE), a verbally administered test usually used as a diagnostic measure for dementia that may not be sufficiently sensitive to detect subtle changes in cognitively intact individuals. As regards homocysteine, where it has been possible to make a comparison between older and younger participants, the evidence suggests that homocysteine has a stronger negative relationship with cognition in older participants (age >60 years). For instance, Elias et al. (2005) and Wright et al. (2004) observed negative associations between homocysteine and cognition only in older participants (60+ and 65+ years, respectively) but not in younger adults. Moreover, Krieg Jr and Butler (2009) observed a positive association between homocysteine and digit learning in 20–39 year-olds but no association in 40–59 year-olds. The

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authors of this last study suggested that young adults may benefit from increased homocysteine via a beneficial effect on N-methyl-D-aspartic acid (NMDA) receptor functions, with neurotoxic effects only becoming apparent with longer exposure, later in life. The individual study details and results are presented in Table 9.1. Dietary intake Reference to the dietary intake studies presented in Table 9.2 shows that several cross-sectional studies have included an examination of the associations between dietary intake of B vitamins and cognitive performance or mood (usually depression scales). The study with the largest sample (Bryan and Calvaresi, 2004) found that intake of vitamins B6, B12 and folate, as assessed by a food frequency questionnaire, was associated with subjective perceptions of memory. However, no objective measures of cognitive performance were employed in the study. One further study, with a relatively small sample size of N = 260, demonstrated that diets with higher levels of a number of vitamins, including folate and vitamin C, were associated with improved MMSE scores (Ortega et al., 1997). One cross-sectional study also included measures of mood (Merete et al., 2008) and indicated that increased intake of B6 from dietary sources was associated with lower depression scores. This effect was abolished when B6 from supplementation was included in the analysis. In a prospective study, La Rue et al. (1997) reported that abstract reasoning was associated with concurrent dietary intake of vitamins B1, B2, B3 and folate, and that past intake of a number of vitamins (including B6 and B12) was associated with better recall and abstract reasoning. La Rue et al. (1997) also reported a positive association between use of dietary supplements (particularly B vitamins) and visuospatial performance and abstract reasoning. In addition, one prospective study (Mishra et al., 2009) examined associations between long-term B vitamin intake and subjective mental health (General health Questionnaire [GHQ]-28) in a group (N = 636) of 53 yearold women, who had been followed up since birth. The authors found that low B12 intake at 53 years of age was associated with increased psychological distress, and that those with low, as opposed to high, B12 intake throughout adulthood had poorer subjective perceptions of their overall mental health as assessed by the GHQ-28. 9.4.2

Vitamins A, C, D and E

Biochemical status A small number of studies have assessed the circulating levels of analytes for vitamins A, C, D and E in cohorts that are assumed to be cognitively intact at the time of initial testing, or representative of the population (see Table 9.3). In prospective studies with follow-ups of ten and 22 years,

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Vitamin status, cognition and mood in cognitively intact adults

223

respectively, both Kang and Grodstein (2008) and Perrig et al. (1997) assessed levels of vitamin A (carotenoids) and E (tocopherols), with the latter study also assessing vitamin C. Whilst Kang and Grodstein (2008) found no association between vitamins A or E and cognitive performance, Perrig et al. (1997) demonstrated a relationship between both vitamins A and C and memory and vocabulary task performance at both their initial assessment and the 22 year follow-up. Similarly, in cross-sectional studies involving participants over 65 years of age, Ortega et al. (2002), in a small cohort (N = 120) of elderly participants, found an association between levels of vitamin E and cognitive function as assessed by the number of errors made on a mental status questionnaire. Similarly, Cherubini et al. (2005) in a larger (N = 1033) study using the ‘InCHIANTI’ cohort, demonstrated that the risk of cognitive decline and dementia was greater for the lowest tertile as regards vitamin E status. Perrig et al.’s (1997) finding with regard to vitamin C is also largely supported by a relatively small prospective study that primarily investigated B vitamins (reported above) but included data on vitamin C. In this study, La Rue et al. (1997) reported visuospatial performance was associated with vitamin C intake. Several sizeable cross-sectional studies (McGrath et al., 2007; Buell et al., 2009; Lee et al., 2009), with samples of N = 1080, N = 11 232 and N = 3133 respectively, and one prospective study (Slinin et al., 2009) with a sample size of 1604 have also examined the relationship between levels of vitamin D (25(OH)D) and cognitive function and/or mood. Lee et al. (2009) reported a beneficial relationship between vitamin D levels and performance, with low levels of 25(OH)D being associated with reduced digit symbol substitution task (DSST) performance in 40–79 year-olds. This is broadly in agreement with a previous study (Buell et al., 2009) that had demonstrated a relationship between vitamin D levels and performance on the DSST, the trail making test and the matrix reasoning and block design tasks from the WAIS-III. However, Slinin et al. (2009) reported no such association, and McGrath et al. (2007) reported a negative association between vitamin D and learning and memory, but only in their oldest group of participants (60–90 year-olds). In terms of mood, only one study has demonstrated a relationship with 25(OH)D (Hoogendijk et al., 2008), with lower 25(OH)D levels being associated with increasing scores on the Center for Epidemiologic Studies Depression Scale (CESD). However, other studies have demonstrated no association of 25(OH)D and mood (Buell et al., 2009; Lee et al., 2009; Pan et al., 2009). Dietary intake In terms of dietary intake, Paleologos et al. (1998) assessed the relationship between vitamin C intake and cognitive function in a small cohort (N = 117) of elderly participants using a food frequency questionnaire, finding

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that high intake was associated with better performance on the MMSE, but not a selection of other tasks. This finding is in line with data from another study (Ortega et al., 1997), that analysed dietary intake data collected alongside biochemical samples, and showed that intake of vitamin C, vitamin E and folic acid was associated with aspects of cognitive function. However, La Rue et al. (1997) took the same approach and found that similar associations were restricted to B vitamin intake. Morris et al. (2002), in a longitudinal study involving an elderly cohort (N = 2889, >65 years) assessing the effects of dietary intake of vitamins A, C and E, showed a protective effect of vitamin E on cognitive decline, as assessed by a global cognitive score derived from their study outcomes. However, one prospective study undertaken in a small cohort (N = 110) reported no relationship between vitamin (C, E, D, B6, B9, B12) intake and cognitive function (Velho et al., 2008). In terms of supplementation, one prospective study (N = 2082, mean age = 76.6) with follow-ups at three and seven years found that those who habitually consumed micronutrient supplements containing vitamins A, C, or E had a reduced risk of cognitive decline (Gray et al., 2003). In addition, a cross-sectional study examining the influence of multi-vitamin supplementation observed no influence on cognitive function or mood (Lindeman et al., 2000). It is of interest to note that all of the dietary intake studies noted above have utilised samples of older (>65 year-old) adults (see Table 9.2 for individual study details).

9.5 Evidence from intervention studies Recent randomised controlled trials examining the effect of vitamin supplementation on cognitive function and mood in cognitively intact cohorts are shown in Tables 9.4, 9.5 and 9.6. Studies were included that: were published after 1994; were undertaken in an adult population who were reported to be cognitively intact at the start of the study; had a minimum of 30 participants per treatment arm; and employed appropriate placebo and doubleblind methodology. Findings are summarised below. 9.5.1 B vitamins Seven trials of B vitamin supplementation were identified that conformed to the inclusion criteria (see Table 9.4). The overall pattern of results across the studies was mixed. Improvements in psychological functioning were seen in only three of the seven studies (Benton et al., 1997; Bryan et al., 2002; Durga et al., 2007), with the remaining studies all showing decrements of one form or another when comparing the vitamin treatment to placebo (Hvas et al., 2004; Lewerin et al., 2005; Eussen et al., 2006; McMahon et al., 2006). In terms of the studies that showed improvements, Benton et al.

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Sample

117 females, mean age 20.3 years

Women: 20–30 years (n = 56); 45–55 years (n = 80); 65–92 years (n = 75)

818 men and women 50–70 years with Hcy levels between 13 and 26 μmol/l

Benton et al. (1997)

Bryan et al. (2002)

Durga et al. (2007)

800 μg folic acid; or placebo for 3 years

750 μg folic acid, 15 μg B12, 75 mg B6; or placebo for 5 weeks

50 mg thiamine (B1); or placebo for 2 mo

Manipulation Vitamin supplementation improved thiamine status, mood (POMS) and decision times Older folic acid group significantly better on RAVLT recognition list B than placebo. B6 and placebo groups out-performed B12 and folate groups in initial letter fluency

Blood: B1, B2, B6. SRT, CRT, familiar faces test, word recall, POMS, GHQ-30, assessed at 3, 6/9 and 12 months FFQ, boxes test, digit symbolcoding, symbol search, digit span-backwards, letternumber sequencing (WAISIII), RAVLT, recall of symbols from digit symbolcoding, activity recall, Stroop, self-ordered pointing test, uses for common objects, trail making test, initial letter fluency, excluded letter fluency, vocabulary (WAISIII), spot-the-word, CESD, POMS Serum: folate, erythrocyte folate, B12, creatinine and lipids. Plasma: tHcy, B6. C67TT polymorphism, apoE genotype, blood pressure, FFQ Word learning, concept shifting, Stroop, verbal fluency, letter digit substitution Folic acid significantly decreased serum folate and tHcy at years 1, 2 and 3 and decreased folate at year 3 vs placebo. Folic acid significantly improved global cognition, word learning and letter digit substitution at 3 years vs placebo

Results

Measures

Education controlled for

Comments

Randomised controlled trials assessing the effects of B vitamins on psychological functioning in cognitively intact samples

Reference

Table 9.4

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Plasma: MMA, tHcy assessed 3 months after randomisation CAMCOG, MMSE, 12-words learning test, MDI

Injection of 1 mg cyanocobalamin (B12); or placebo for 4 weeks

134 men and women mean age 74.5 years with elevated plasma MMA (0.4–2 μmol/l)

Hvas et al. (2004)

Plasma: MMA, tHcy, holoTC at baseline, 12 and 24 weeks. Serum: B12 and creatinine at baseline, 12 and 24 weeks. RBC folate. Finger tapping, motor planning_2, trail making A, figure of rey – copy, memory (figure of rey – immediate and delayed recall, 15 word learning – immediate and delayed recall and delayed recognition, digit span backward), digit span forward, motor planning_3, trail making B, Raven, Stroop, similarities – WAIS, verbal fluency – letter and animal

1000 μg B12 (cyanocobalamin); 1000 μg B12 plus 400 μg folic acid; or placebo for 24 weeks

162 men and women ≥ 70 years with mild B12 deficiency* and with no, mild or moderate cognitive impairment

Eussen et al. (2006)

Measures

Sample

Reference

Manipulation

Continued

Table 9.4

Vitamin B12 with and without folic acid significantly raised B12 and holoTC at 12 weeks compared to placebo; and reduced MMA at 12 and 24 weeks compared to placebo. The combination also significantly decreased tHcy and increased RBC folate at 12 and 24 weeks as compared to B12 alone and placebo. Significant improvement in placebo vs B12 in memory domain Placebo improved 12-word learning test score vs vitamin

Results

No improvement even in subgroups with cognitive impairment or high MMA

*Serum cobalamin between 100 and 200 pmol/l or between 200 and 300 pmol/l, plasma MMA ≥0.32 μmol/l, serum creatinine ≤120 μmol/l.

Comments

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Serum MMA, plasma Hcy (1 and 4 months) PLM (N = 162). Digit span backward/ forward, identical forms, visual reproduction, synonyms, block design, DSS, Thurstone’s picture memory test, figure classification Plasma: Hcy, folate, B12 (6, 12, 18 and 24 months) MMSE, RAVLT, paragraph-recall tests (Weschler), verbal fluency (letter), category word fluency, reitan trail making test (part B), raven’s progressive matrices, NART (12 and 24 months)

500 μg B12 (cyanocobalamin), 800 μg folic acid and 3 mg B6; or placebo for 4 months

1000 μg folate, 500 μg B12 and 10 mg of B6; or placebo for 2 years

Measures

Manipulation Significant decreases in Hcy and MMA in vitamin group. Significant improvements in identical forms and synonyms in placebo vs vitamin group Reitan trail making time to complete was significantly slower in vitamin group. Vitamin supplementation significantly reduced Hcy and increased folate and B12 levels as compared to placebo

Results

Cholesterol and sex significantly different between groups. Results adjusted for sex and education

Comments

Abbreviations: apoE = apolipoprotein E; CAMCOG = Cambridge Cognitive Examination; CESD = Centre for Epidemiological Studies Depression Scale; CRT = Choice Reaction Time; DSS = Digit-Symbol Substitution; FFQ = Food Frequency Questionnaire; GHQ = General Health Questionnaire; Hcy = homocysteine; holoTC = holotranscobalamin; MDI = Major Depression Inventory; MMA = methylmalonic acid; MMSE = Mini Mental State Examination; NART = National Adult Reading Test; PLM = Postural Locomotor Manual; POMS = Profile of Mood States questionnaire; RAVLT = Rey Auditory Verbal Learning Test; RBC = Red Blood Count; SRT = Simple Reaction Time; tHcy = total Homocysteine; WAIS-III = Weschler Adult Intelligence Scale-Revised.

253 men and women ≥ 65 years with Hcy levels ≥ 13 μmol/l

179 men and women mean age 76 years 5 months

Lewerin et al. (2005)

McMahon et al. (2006)

Sample

Reference

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Telephone interviews: see Kang et al. (2006a) at mean 3.5 years after randomisation and 3 follow-ups every 2 years

500 mg/d vitamin C; 600 IU vitamin E q.o.d; 50 mg β-carotene q.o.d; 500 mg/d vitamin C plus 600 IU vitamin E q.o.d; 500 mg/d vitamin C plus 50 mg

2894 female health professionals ≥ 65 years with either ≥ 3 coronary risk factors or CVD

Kang et al. (2009)

Telephone interview [general cognition (TICS), verbal memory (immediate and delayed East Boston memory test, delayed recall of TICS 10-word list), category fluency (animals)] at mean 5.6 years, 7.6 and 9.6 years after randomisation

600 IU vitamin E; or placebo every other day for mean 9.6 years

5073 women ≥ 65 years

Kang et al. (2006a)

Measures

Manipulation

Sample No overall effect of supplementation. Secondary analyses: significantly less cognitive decline in vitamin E group for those reporting low dietary intake, in those with diabetes and in those who exercised <1 per week. Exclusion of non-compliant led to improved global score and verbal memory in Vitamin E group Significant improvement in global score, verbal memory and general cognition (TICS) at final assessment following vitamin C. Secondary analyses: significantly better global score in

Results

Comments

Randomised controlled trials assessing the effects of vitamins A, C and E on psychological functioning in cognitively intact

Reference

Table 9.5 samples

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185 men and women aged 60–80 years

Assessed at 4, 8 and 12 months Blood: vitamin A, E, carotene and cholesterol levels. Plasma: vitamin C. Health behaviours and status, FFQ, POMS, NART, CFQ, free word recall, delayed word recognition, logical reasoning, SRT, repeateddigits vigilance, focused attention, categoric search

Considerable increases in plasma antioxidant levels following vitamin supplementation, statistics not reported

vitamin C group in those who developed new cardiovascular events during the study; benefit of β-carotene in those reporting low dietary intake Controlled for age, education, gender, vegetable/fruit consumption, alcohol consumption, smoking, somatic symptoms, levels of other antioxidants

Abbreviations: CFQ = Cognitive Failures Questionnaire; CVD = Cardiovascular Disease; FFQ = Food Frequency Questionnaire; NART = National Adult Reading Test; POMS = Profile of Mood States questionnaire; q.o.d = every other day; SRT = Simple Reaction Time; TICS = Telephone Interview of Cognitive Status.

Smith et al. (1999a,b)

β-carotene q.o.d; 600 IU vitamin E plus 50 mg β-carotene q.o.d; 500 mg/d vitamin C plus 600 IU and 50 mg β-carotene q.o.d; placebo for mean 8.9 years 12 mg β-carotene, 400 mg vitamin E and 500 mg vitamin C; or placebo for 12 months

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119 men and women aged 17–27 years

80 males aged 18–42 years

Carroll et al. (2000)

127 men and women aged 17–27 years

Benton et al. (1995a)

Benton et al. (1995b)

Sample

Reference

3334 IE vitamin A, 14 mg thiamine (B1), 16 mg riboflavin (B2), 22 mg pyridoxine (B6), 0.03 mg B12, 600 mg vitamin C, 100 mg vitamin E, 4 mg folic acid (B9), 2 mg biotin (B7) and 180 mg nicotinamide; or placebo for 12 months 3334 IE vitamin A, 14 mg thiamine (B1), 16 mg riboflavin (B2), 22 mg pyridoxine (B6), 0.03 mg B12, 600 mg vitamin C, 100 mg vitamin E, 4 mg folic acid (B9), 2 mg biotin (B7) and 180 mg nicotinamide; or placebo for 12 months 15 mg B1, 15 mg B2, 50 mg niacin (B3), 23 mg pantothenic acid (B5), 10 mg B6, 150 μg biotin (B7), 400 μg folic acid, 10 μg B12, 500 mg vitamin C, 100 mg calcium, 100 mg magnesium, 10 mg zinc; or placebo for 28 days

Manipulation Vitamin supplementation decreased the intercept of the regression line in females after 12 months administration, indicating improved attentional processing

Vitamin supplementation increased agreeable scores, levels of B1, B2, B6 and plasma: vitamin C, B12, folic acid, biotin, vitamin E. In females vitamins significantly improved mental health (GHQ) and ‘composed’ ratings at 12 months vs placebo Vitamin supplementation improved GHQ scores, reduced anxiety (HADS), stress (PSS) and physical symptoms vs placebo

Blood: B1, B2, B6. Plasma: vitamin C, B12, folic acid, biotin, vitamin A, vitamin E, β-carotene. SRT, CRT, DSS, CAT assessed at 3, 6/9 and 12 months

Blood: B1, B2, B6. Plasma: vitamin C, B12, folic acid, biotin, vitamin A, vitamin E, β-carotene. POMS, GHQ-30, assessed at 3, 6/9 and 12 months

Plasma zinc GHQ-28, HADS, PSS, rating scales, physical symptom checklist

Results

Measures

Comments

Table 9.6 Randomised controlled trials assessing the effects of multivitamins (plus minerals in some cases) on psychological functioning in cognitively intact samples

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16 treatment condition combinations comprising those from Kang et al. (2009) plus 500 mg/d vitamin C plus B-vitamins (2.5 mg/d folic acid, 50 mg B6, 1 mg/d B12); 600 IU vitamin E q.o.d plus B-vitamins; 50 mg β-carotene q.o.d plus B-vitamins; 500 mg/d vitamin C plus 600 IU vitamin E q.o.d plus B-vitamins; 500 mg/d vitamin C plus 50 mg β-carotene q.o.d plus B-vitamins; 600 IU vitamin E plus 50 mg β-carotene q.o.d plus B-vitamins; 500 mg/d

2009 female health professionals ≥ 65 years with either ≥ 3 coronary risk factors or CVD

Kang et al. (2008)

3334 IU vitamin A, 14 mg thiamine (B1), 16 mg riboflavin (B2), 22 mg pyridoxine (B6), 0.03 mg B12, 600 mg vitamin C, 100 mg vitamin E, 4 mg folic acid (B9), 2 mg biotin (B7) and 180 mg nicotinamide; or placebo for 12/24 weeks

127 men and women aged 60–83 years

Cockle et al. (2000)

Manipulation

Sample

Reference Vitamin supplementation led to significantly increased B2, B6, B12, ATK, vitamin E, biotin, vitamin C and B1, with significantly greater increases in vitamin C and B1 in females. Vitamins led to significant improvements in CRT (TRT) and in CFF males, with the opposite effect in females Secondary analyses: significantly better global cognition after B vitamins in those reporting low dietary intake of folic acid. Significantly better category fluency in those reporting low dietary intake of B12. Low intake of at least one B vitamin led to a decrease in decline of TICS following B vitamin supplementation

Blood: B1, B2, B6. Plasma: vitamin C, B12, folic acid, biotin, vitamin A, vitamin E, β-carotene. Assessed at end of treatment: CFF, CRT, STM, WST, POMS. Assessed at week 48: MMSE, SKT, NART, AH4, AH5, GDS Semi-quantative FFQ to assess baseline diet. Telephone interview (see Kang et al. 2009) at mean 1.2 years after randomisation and 3 follow-ups every 2 years (mean final assessment 6.6 years)

Results

Measures

Allowed to take vitamin supplements if not exceeding RDA

Inconsistent dosing duration due to drop-out

Comments

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Continued

Sample

210 males aged 30–55 years

910 men and women ≥ 65 years

Table 9.6

Reference

Kennedy et al. (2010)

McNeill et al. (2007)

vitamin C plus 600 IU and 50 mg β-carotene q.o.d plus B-vitamins; or placebo 15 mg B1, 15 mg B2, 50 mg niacin (B3), 23 mg pantothenic acid (B5), 10 mg B6, 150 μg biotin (B7), 400 μg folic acid, 10 μg B12, 500 mg vitamin C, 100 mg calcium, 100 mg magnesium, 10 mg zinc; or placebo for 33 days 800 μg vitamin A, 60 mg vitamin C, 5 μg vitamin D, 10 mg vitamin E, 1.4 mg thiamine (B1), 1.6 mg riboflavin (B2), 18 mg niacin (B3), 6 mg panthothenic acid (B5), 2 mg pyridoxine (B6), 1 μg B12, 200 μg folic acid, 14 mg iron, 150 μg iodine, 0.75 mg copper, 15 mg zinc and 1 mg manganese; or placebo for 12 months

Manipulation

Vitamins improved GHQ-12, PSS, POMS vigour, correct serial 3s, mental tiredness VAS

Weak evidence for beneficial effect of supplement on verbal fluency in ≥ 75 year olds (95 % CI −0.6, 6.2), and trend for same in those at increased risk of nutritional deficiency as assessed by the nutrition risk questionnaire (95 % CI −1.0, 6.1)

Digit span-forward, verbal fluency (letter)

Results

GHQ-12, PSS, POMS, Bond-Lader mood scales, energy VAS, serial 3 subtractions, serials 7s, RVIP, mental fatigue VAS, Stroop, peg-andball, WCS

Measures

Corrected for reported fruit/ vegetable intake

Comments

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15 mg B1, 15 mg B2, 50 mg niacin (B3), 23 mg pantothenic acid (B5), 10 mg B6, 150 μg biotin (B7), 10 μg B12, 1000 mg vitamin C, 100 mg calcium, 100 mg magnesium; or placebo for 30 days 150 mg vitamin C, 50 mg magnesium, 36 mg vitamin E, 34 mg niacin (B3), 16 mg panthothenic acid (B5), 9 mg β-carotene, 3.4 mg pyridoxine (B6), 3.2 mg riboflavin (B2), 2.4 mg thiamine (B1), 400 μg folic acid (B9), 200 μg biotin (B7), 60 μg selenium and 9 μg B12; or placebo for 6 months

Manipulation

Serum: folate, B6, vitamin C, vitamin E, β-carotene, ubiquinol-10, MMA. Plasma tHcy WAIS-III plus symbol search subtest, KAI, BAT

HARS, PGWS, stress VAS, BSI

Measures

Multivitamin/mineral supplementation significantly increased concentrations of all vitamins and decreased tHcy as compared to placebo

Vitamin supplementation led to significant improvements in BSI, HARS, PGWS and VAS vs placebo

Results

Comments

Abbreviations: AH = Alice Heim; BAT = Berliner Amnesie Test; BSI = Berocca Stress Index; CAT = Continuous Attention Test; CFF = Critical Flicker Fusion; CRT = Choice Reaction Time; CVD = Cardiovascular Disease; DSS = Digit–Symbol Substitution; FFQ = Food Frequency Questionnaire; GDS = Geriatric Depression Scale; GHQ = General Health Questionnaire; HADS = Hospital Anxiety Depression Scale; HARS = Hamilton Anxiety rating Scale; KAI = Kurztest fuer Allgemeine Intelligenz; MMA = Methylmalonic Acid; MMSE = Mini Mental State Examination; NART = National Adult Reading Test; PGWS = Psychological General Well-Being Schedule; POMS = Profile of Mood States questionnaire; PSS = Perceived Stress Scale; q.o.d = every other day; RDA = recommended daily allowance; RVIP = Rapid Visual Information Processing; SKT = Syndrom Kurtz Task; SRT = Simple Reaction Time; STM = Sternberg Memory Scanning Task; tHcy = total Homocysteine; TICS = Telephone Interview of Cognitive Status; TRT = Total Reaction Time; VAS = Visual Analogue Scale; WAIS-III = Weschler Adult Intelligence Scale–Revised; WCS = Wisconsin Card Sort; WST = Word Scan Task.

220 women ≥ 60 years

300 men and women aged 18–65 with predetermined high stress scores

Schlebusch et al. (2000)

Wolters et al. (2005)

Sample

Reference

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(1997) administered vitamin B1 (50 mg thiamine) to young females for two months and found improvements in total Profile Of Mood States (POMS) score, and faster decision times on two, four and eight choice reaction time tasks. Two studies also demonstrated improved function following folic acid alone, with Durga et al. (2007), in the largest (N = 818) and longest (three years) study reported here, demonstrating improvements across cognitive domains in a cohort of 50–70 year-old participants with raised homocysteine levels at the outset. Bryan et al. (2002) also found improvements on a single task (Rey Auditory Verbal Learning Test recognition list B) from within a large selection of tasks in an older sub-section of their female cohort that were administered folic acid for five weeks. However, they found decrements on a letter fluency task, in comparison to placebo, in the same group and another group administered B12 alone. This latter finding of worse performance following B12 monotreatment was also seen in two other studies with treatment periods of four (Hvas et al., 2004) and 24 weeks (Eussen et al., 2006). The decrements in the latter study were abolished in a group co-administered folic acid. Two studies in which the treatment comprised folic acid, B6 and B12 also found no benefit of treatment and recorded decrements in the performance of at least one task (Lewerin et al., 2005; McMahon et al., 2006). Four of the studies, all of which involved administration of folic acid, measured homocysteine and reported a decrease in levels (Lewerin et al., 2005; Eussen et al., 2006; McMahon et al., 2006; Durga et al., 2007). However, given the mixed results of these studies as regards performance, no consistent relationship is evident between homocysteine and cognitive function in these studies.

9.5.2 Vitamins A, C, D and E Three studies that involved the administration of vitamins E or combinations of C, E and A (as β-carotene) to cognitively intact cohorts were identified (see Table 9.5). In the largest of these (Kang et al., 2006a), 5073 female participants over 65 years of age, drawn from the larger ‘Women’s Health Study’, took vitamin E and were assessed using a telephone cognitive battery measuring general cognition, verbal memory and category fluency 5.6 years, 7.6 years and 9.6 years after the start of the study. No overall effect of vitamin treatment was evident. Secondary analyses assessed the modification of the effects of vitamin E by 15 separate health and lifestyle factors and found significantly less cognitive decline as a consequence of vitamin E supplementation in those that had lower dietary intakes of vitamin E, those that exercised less than once per week and those who had diabetes. Kang et al. (2009) used the same methodology in an assessment of the effects of vitamin A, C and E (single vitamins and all possible combinations of the three, versus comparative placebos) in 2894 females over 65 years old with risk of cardiovascular disease. Telephone cognitive

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assessments took place at 3.5 years, with three further assessments at two-year intervals. As with the previous study, there were no significant effects of treatment with any of the micronutrients on the primary study outcome of decline in overall cognitive function, but secondary analyses showed ‘suggestive’ evidence of significant improvements following vitamin C on general cognition, verbal memory and a global composite score at the very last assessment. A final, smaller study, reported in two papers (Smith et al., 1999a,b), involved administration of vitamins A, C and E to 185, 60 to 80 year-old males and females for 12 months. There were no significant differences in performance of the wide range of cognitive tasks reported. No intervention studies assessing the effects of vitamin D on psychological functioning were identified.

9.5.3 Multivitamins For the purposes of the following ‘multivitamin’ is defined as a treatment containing multiple vitamins, including, but not restricted to, B vitamins. Eight studies assessing the cognitive/mood effects of multivitamins (plus minerals in several cases) are presented in Table 9.6. Three studies reported unambiguous improvements in psychological functioning (Carroll et al., 2000; Schlebusch et al., 2000; Kennedy et al., 2010) across their cohorts and four further studies described improvements that were seen in sub-samples, either as a function of gender (Benton et al., 1995a,b; Cockle et al., 2000) or nutritional status at the outset of the study (Kang et al., 2008). The three studies demonstrating effects across the cohorts all administered a similar B vitamin complex plus vitamin C, calcium and magnesium. In the first two of these studies (Carroll et al., 2000; Schlebusch et al., 2000), supplementation for ∼30 days led to improved wellbeing (Psychological General Wellbeing Schedule and GHQ-28, respectively), reduced stress (Perceived Stress Scale [PSS] and Berocca Stress Index) and anxiety (HADS and Hamilton Anxiety Rating Scale) on validated psychometric measures in non-elderly participants. Kennedy et al. (2010) included computerised cognitive testing and replicated the findings as regards stress (PSS) and general psychological functioning (GHQ-12), and additionally reported increased vigour (POMS), reduced mental tiredness and improved serial subtraction task performance in non-elderly males. In terms of the studies that saw differential effects according to gender, Benton et al. found improved mood (Benton et al., 1995b) and improved attentional processing (Benton et al., 1995a) in the females within their young adult cohort, with these effects only becoming apparent following 12 months administration of their high-dose multivitamin. Cockle et al. (2000), on the other hand, saw opposite significant effects on attention task performance and critical flicker fusion in their male (improvements) and female (decrements) participants during 24 weeks administration of multivitamins

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to older (60–80 year-old) adults. Two further studies (Kang et al., 2008; McNeill et al., 2007) also reported modest performance improvements that were dependent on being classified as having poorer nutritional status at the outset. Only one study examined homocysteine levels (Wolters et al., 2005) and found a significant decrease with no effects on cognition.

9.6 Conclusions In simple terms, the rationale for the current review was that vitamins are intrinsically involved in every aspect of brain function, and that our modern, micronutrient-poor diets predispose us to consume less than the optimal levels of vitamins, therefore raising the possibility that, first, intake/levels of vitamins might be related to cognitive function, and, second, supplementation with vitamins might improve psychological functioning. The epidemiological evidence relating biochemical levels and dietary intake of vitamins to psychological functioning in cognitively intact cohorts would seem to support, at least in part, this rationale. By far the most research in this area has concentrated on the B vitamins, most notably folate, and vitamins B6 and B12, for which the evidence summarised above would seem to suggest a relationship with cognitive functioning. At the very simplest level, 14 out of the 22 studies investigating B vitamins included in Table 9.1 showed some degree of a positive relationship between biochemical levels of one or more B vitamins and cognitive function, with no instances of a negative relationship. However, it should be noted that in most cases these effects were restricted to one, or few, of the cognitive outcomes of the study. In comparison, the relationship between cognitive function and homocysteine levels, itself linked inextricably to B vitamin status, is more consistent. Nineteen out of 22 studies that included an assessment of homocysteine levels, including five studies that assessed homocysteine without reference to vitamin status, demonstrated a negative relationship between cognitive function and/or mood and homocysteine levels. One of the remaining studies (Krieg Jr and Butler, 2009) showed the opposite effect, but only in younger adults, and two studies reported no effects (Kalmijn et al., 1999; Morris et al., 2003). As regards the other vitamins (A, C, D and E), the evidence is strongest for both vitamin E, for which a relationship has been found in both biochemical analyte studies (Ortega et al., 2002; Cherubini et al., 2005) and dietary intake studies (Morris et al., 2002; Ortega et al., 2002), and vitamin C, which similarly has been shown to have an association in both biochemical (La Rue et al., 1997; Perrig et al., 1997) and dietary intake (Paleologos et al., 1998; Ortega et al., 2002) studies. Vitamin D has also been the subject of six large, epidemiological, biochemical status studies, three of which reported associations with cognitive function (McGrath et al., 2007;

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Buell et al., 2009; Lee et al., 2009) and one reported a relationship between circulating vitamin D and depression scores (Hoogendijk et al., 2008). However, for all of these vitamins the evidence here is far from unequivocal, with similar numbers of studies reporting no relationship. Naturally, any interpretation of epidemiological evidence is also complicated by the inability either to attribute cause and effect, or rule out the influence of a plethora of other potential factors that might co-vary with vitamin status, that may not have been identified in the statistical models employed. Examples of the latter may include, for instance, aspects of socioeconomic status, education or healthy living practices. One particular weakness across studies here is also the predominant use of elderly cohorts. Whilst the cognitive decline associated with old age may provide a sensitive backdrop for examining the effects of dietary habits in the context of a large part of the lifespan, investigations in these age groups are also complicated by a number of factors. These include age-related changes in the ability to absorb and metabolise vitamins (Wolters et al., 2004), which may render the results of analyte studies less meaningful, and a relationship between age, declining health and cognitive function (Payette and Shatenstein, 2005; Shatenstein et al., 2007) that suggests that the elderly develop atypical diets, and may well predispose the less cognitively able individual to seek and consume a poorer diet. In comparison to the epidemiological evidence, the research investigating the effects of vitamin supplementation in cognitively intact cohorts is even less consistent. For the B vitamins approximately equal numbers of studies show improvements and decrements in this population. Studies with negative findings include all three studies that included a vitamin B12 mono-treatment. It is also notable that no discernible relationship was evident between instances of treatment-related reductions in homocysteine levels and cognitive performance, with evidence of both decrements and improvements in performance seen in these studies. Evidence is particularly sparse for the non-B vitamins. Two studies were identified that included large cohorts who received vitamin E (Kang et al., 2006a) and combinations of vitamins A, C and E (Kang et al., 2009), respectively, for over nine years. However, supplementation had no significant effect on the primary study outcomes in either case, with suggestive evidence of benefits seen only in secondary analyses. Naturally, while attractive from the point of view of attributing any treatment-related effects, the focus of these studies on one, or occasionally two, vitamins lowers the likelihood of targeting a cohort with a specific requirement for increased levels of the vitamin being supplemented, or alternatively raises the possibility of failing to increase the reduced levels of other micronutrients that might co-exist in the individual as a consequence of poor general diet. Similarly, a good argument could be made that undertaking intervention research in the elderly, as is the case in most of the above studies, is a case of ‘locking the stable door after the horse has

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bolted’ in terms of systemic damage due to poor dietary status. A more effective strategy, which is also considerably less practical, would be to conduct intervention studies over considerably longer periods of time, commencing when the sample is not elderly, in the hope of attenuating systemic damage across larger portions of the lifespan. Having said this, the evidence as regards multivitamins might offer some hope with regard to supplementation. Across the eight studies identified in Table 9.6 three reported straightforward benefits to psychological functioning across their non-elderly cohorts, and four of the remaining studies reported benefits in sub-sections of their sample. Interestingly, the multivitamins studies included equal numbers of studies conducted in older and younger cohorts, and the results show benefits that are more pronounced in the younger samples. This pattern of results may reflect a combination of the intactness of the cohorts in terms of the physiological mechanisms that might be modulated, and the broad nature of the treatments, in that the use of multiple vitamins should be more likely to bolster an individual’s requirement for one or more vitamins. It is interesting to note in this respect that there are marked inter-individual differences in the absorption and excretion of vitamins (Shibata et al., 2005, 2009) as a consequence of a number of factors, including genetic makeup, gender and ethnicity (Kauwell et al., 2000; Caudill, 2009). In this respect, it should be noted that RDAs are merely population statistics and of very little use in identifying the required minimum daily intake of a nutrient for any individual. Overall, it is notable that both the epidemiological investigations and intervention studies employed a heterogeneous range of cognitive measures, generally employed pencil and paper, as opposed to computerised, testing, and in many cases included measures, such as the MMSE, that lack the sensitivity to detect subtle differences in performance. There was also a lack of any measure of mood or subjective psychological functioning reported in most studies. The pattern of results from the epidemiological studies is therefore largely in agreement with Raman et al. (2007), who included studies assessing cohorts suffering cognitive decrements and Alzheimer’s disease in their review of B vitamins, and concluded that the majority of studies demonstrated a relationship between B vitamin status/ homocysteine/cognitive function, but that no conclusions could be drawn due to methodological shortcomings across the entire literature. The findings as regards the small number of intervention studies included here also agree with systematic reviews of the efficacy of vitamin B6, B9 and B12 (Malouf and Grimley Evans, 2003, 2008; Balk et al., 2007) and vitamin E (Isaac et al., 2008) in attenuating the cognitive declines associates with age and dementia. These reviews concluded that there is no consistent evidence for efficacy on the basis of the small number of studies that met their inclusion criteria, and questioned the methodologies employed across research in this area.

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This raises the question of how to reduce these methodological inconsistencies to a point where a more focused picture of the effects of vitamins on brain function emerges. Given the insensitivity of many of the paper and pencil outcomes employed in much of this research, and the ubiquity of computers, it would firstly seem appropriate in future to take advantage of the sensitivity of measurement, both in terms of accuracy and speed of performance, that computerised cognitive assessments allow across cognitive domains, and in terms of concomitant assessment of mood and psychological state. In terms of intervention studies, one of the obvious methodological shortcomings is the focus on one, or possibly two, vitamins. A more sensible approach might be to supplement with a broad range of vitamins in the hope of satisfying the unmet needs of a larger proportion of the sample. Whilst this may create complications in terms of attributing any demonstrated effects, analyte data taken before and after treatment should go some way towards addressing mechanistic questions. Interestingly, while the strongest relationship seen in the studies reviewed above is that between circulating levels of homocysteine and cognitive function, direct modulation of homocysteine levels in the intervention studies bore no discernible relationship to any changes in cognitive function. These findings might be taken as support for the suggestion that the interrelationships between B vitamins and homocysteine levels, and the causality of the relationships with brain function are far from clear (Elias et al., 2006; Krieg Jr and Butler, 2009). It remains a possibility that homocysteine levels represent an epiphenomenon reflecting other, as yet un-delineated factors. One striking pattern across the studies reviewed here is that they have overwhelmingly been conducted in cohorts of older adults (>65 years), with very little information available as to the epidemiological relationships, or the effects of vitamin supplementation, in younger groups of adults. However, deficiencies, as defined by our current criteria, exist across age groups. Given that the optimum level of vitamin consumption must reside some way above deficiency levels, it is possible that a large sub-section of the general, non-elderly population must have less than optimal micronutrient status. More research might therefore be usefully directed towards delineating the optimal levels of vitamins and their relationships with brain function in non-elderly humans. As outlined above, this research should take advantage of the many sensitive computerised measures of cognitive function that are now readily available. The one area where the preponderance of studies has been conducted in younger samples is that assessing the effects of multivitamins. The literature here suggests that non-elderly healthy adults might derive benefits from supplementation in terms of psychological functioning. This in itself supports the notion of less than optimal nutritional status in the population, but also suggests that broad multivitamin treatments, which might provide different benefits to individuals on the basis of their personal nutritional status, might be more useful than single/several vitamin supplements.

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9.7 Implications for the food industry, nutritionists and policy-makers At the present time, our knowledge about the relationship between brain function and vitamin status is limited. Whilst we have a good understanding of the minimum levels of vitamins required to protect us from a number of specific and more general disease states, there is no consensus on the level of micronutrients required for optimum brain function in healthy humans. The epidemiological evidence suggests a number of relationships between vitamins and brain function, but the data have largely been collected in older cohorts and those already suffering from significant levels of cognitive decline or dementia. It could be suggested that research in these populations has limited applicability to the majority of the population. The evidence from supplementation trials is particularly weak, and this might be attributable both to the nature of the populations under investigation and the appropriateness of the behavioural measures employed. A future priority in this area of research should be an examination of the relationships between micronutrient status and brain function in samples that are representative of the whole population across the entire lifespan, using some of the more sophisticated assessment techniques that can be readily operationalised in an age when access to computers is ubiquitous.

9.8 Future trends The above reviewed research suggests that future investigations into the relationship between vitamins and brain function should clearly shift its focus more towards non-elderly populations. Similarly, intervention studies might usefully target non-elderly populations and administer broad multivitamin treatments, preferably for extended periods of time. This latter suggestion would also have the beneficial effect of providing information on the efficacy of vitamin treatments that are those, or similar to those, most often purchased and consumed by the population. As this research, should it prove successful, would clearly benefit the food supplement industry, it would seem appropriate that vitamin manufacturers and retailers should bear a large part of the financial cost. Given the generic nature of micronutrients this might be accomplished by an industry wide collaboration in terms of funding, with additional product-specific ‘claims’ trials being funded by the relevant retailer/manufacturer.

9.9 Sources of further information and advice • The International Food Information Council Foundation provides ‘science-based information on health, food safety and nutrition for the public good’. Go to: www.foodinsight.org

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• The Linus Pauling Institute’s Micronutrient Information Center’s stated aim is to be ‘a source for scientifically accurate information regarding the roles of vitamins, minerals, other nutrients, dietary phytochemicals (plant chemicals that may affect health), and some foods in preventing disease and promoting health’. Go to: www.lpi.oregonstate.edu/ infocenter • The Food Standards Authority in the UK is an independent Government department whose function is to protect the public’s health and consumer interests in relation to food. Their website includes access to information on many aspects of nutrition, including food and dietary surveys, and advice on healthy eating. Go to: www.food.gov.uk • In the USA the Centres for Disease Control and Prevention has a wide range of information both for health professionals and a ‘Nutrition for Everyone’ section that includes advice and fact sheets on individual micronutrients www.cdc.gov/nutrition

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semi-purified diet based on the Japanese dietary reference intakes. Journal of Nutritional Science and Vitaminology, 51, 319–328. shibata k, fukuwatari t, watanabe t and nishimuta m (2009) Intra- and interindividual variations of blood and urinary water-soluble vitamins in Japanese young adults consuming a semi-purified diet for 7 days. Journal of Nutritional Science and Vitaminology, 55, 459–470. slinin y, paudel m l, taylor b c, fink h a, ishani a, canales m t, yaffe k, barrettconnor e, orwoll e s, shikany j m, leblanc e s, cauley j a, ensrud k e and for the osteoporotic fractures in men study research group (2009) 25-Hydroxyvitamin D levels and cognitive performance and decline in elderly men. Neurology, 74, 33–41. smith a d, kim y-i and refsum h (2008) Is folic acid good for everyone?. American Journal of Clinical Nutrition, 87, 517–533. smith a, clark r, nutt d, haller j, hayward s and perry k (1999a) Anti-oxidant vitamins and mental performance of the elderly. Human Psychopharmacology – Clinical and Experimental, 14, 459–471. smith a p, clark r e, nutt d j, haller j, hayward s g and perry k (1999b) Vitamin C, mood and cognitive functioning in the elderly. Nutritional Neuroscience: An International Journal on Nutrition, Diet and Nervous System, 2, 249– 256. teunissen c e, blom a h, van boxtel m p, bosma h, de bruijn c, jolles j, wauters b a, steinbusch h w and de vente j (2003) Homocysteine: a marker for cognitive performance? A longitudinal follow-up study. The Journal of Nutrition, Health and Aging, 7, 153–159. tucker k l, qiao n, scott t, rosenberg i and spiro a, iii (2005) High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. American Journal of Clinical Nutrition, 82, 627–635. valdenaire o, vernier p, maus m, dumas milne edwards j b and mallet j (1994) Transcription of the rat dopamine-D2-receptor gene from two promoters. European Journal of Biochemistry, 220, 577–584. valdenaire o, maus-moatti m, vincent j d, mallet j and vernier p (1998) Retinoic acid regulates the developmental expression of dopamine D2 receptor in rat striatal primary cultures. Journal of Neurochemistry, 71, 929–936. velho s, marques-vidal p, baptista f and camilo m e (2008) Dietary intake adequacy and cognitive function in free-living active elderly: a cross-sectional and shortterm prospective study. Clinical Nutrition, 27, 77–86. wahlin å, hill r d, winblad b and bäckman l (1996) Effects of serum vitamin B12 and folate status on episodic memory performance in very old age: a populationbased study. Psychology and Aging, 11, 487–496. wahlin t-b, wahlin å, winblad b and bäckman l (2001) The influence of serum vitamin B12 and folate status on cognitive functioning in very old age. Biological Psychology, 56, 247–265. wietrzych m, meziane h, sutter a, ghyselinck n, chapman p f, chambon p and krezel w (2005) Working memory deficits in retinoid X receptor gamma-deficient mice. Learning & Memory, 12, 318–326. wolters m, strohle a and hahn a (2004) Age-associated changes in the metabolism of vitamin B-12 and folic acid: Prevalence, etiopathogenesis and pathophysiological consequences. Zeitschrift Fur Gerontologie Und Geriatrie, 37, 109– 135. wolters m, hickstein m, flintermann a, tewes u and hahn a (2005) Cognitive performance in relation to vitamin status in healthy elderly German women – the effect of 6-month multivitamin supplementation. Preventive Medicine, 41, 253–259.

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10 Caffeine, mood and cognition P. J. Rogers and J. E. Smith, University of Bristol, UK

Abstract: Caffeine is widely consumed and has widespread physiological effects. We review evidence that the acute alerting and associated psychomotor performance effects of caffeine experienced by frequent caffeine consumers represent withdrawal reversal rather than a net benefit for functioning, and that avoidance of withdrawal is an important motive for caffeine consumption. On the other hand, tolerance develops to the anxiogenic effect of caffeine even in susceptible individuals, and while caffeine raises blood pressure, tea and coffee consumption are not associated with increased risk of vascular disease. Indeed, consumption of these drinks appears to reduce risk of cognitive decline in older age, possibly because of beneficial actions of other compounds present in tea and coffee, and the sensitization of the neuroprotective action of adenosine resulting from caffeine intake. The example of caffeine demonstrates the challenge of finding ingredients for foods or drinks that could be used effectively to acutely enhance mood, alertness and/or cognitive function. Key words: caffeine, alertness, psychomotor performance, anxiety, cognitive decline.

10.1 Introduction It is usual to begin an article on this subject by noting the worldwide popularity of caffeine-containing drinks. Indeed, globally, more people consume caffeine more often than any other drug. Per capita caffeine consumption is highest in Europe, where, like for the rest of the world, tea and coffee are the predominant sources of caffeine (Fredholm et al., 1999). Despite their increasing popularity, cola and ‘energy’ drinks account for very little of the caffeine consumed worldwide (e.g., less than 5 % of the caffeine consumed by adults in the UK (Heatherley et al., 2006a)), although cola consumption is proportionally higher in the US and among children (Frary et al., 2005). These are important statistics. Small effects of caffeine on the health and wellbeing of individual caffeine consumers could sum to large effects at a population level. Furthermore, relationships between caffeine consumption

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and health may owe much to the effects of other compounds present in tea and coffee. Below, after providing some background information, we discuss four interrelated aspects of the popularity and effects of caffeine-containing drinks; namely, caffeine reinforcement, the acute psychostimulant and anxiogenic effects of caffeine, and the possible longer term cognitive effects of tea and coffee consumption.

10.2 Background – caffeine intake and its physiological effects Accurate measurement of individuals’ daily caffeine intake is made difficult by the large variation in the caffeine content of caffeine-containing drinks. A major source of this variation is method of preparation (e.g., brewing time and amount of tea or coffee used), but data are readily available on average caffeine content that can be applied to consumption by regional or national populations. For example, in the Dietary Caffeine and Health Study we collected detailed data on consumption of caffeine-containing drinks and foods of a diverse sample of nearly 6000 adults, aged 17–100 years, living in Bristol in the UK (Heatherley et al., 2006b). To calculate caffeine intake, we used caffeine content data from various authoritative sources, including the UK’s Foods Standards Agency and manufacturers. The values per serving (i.e., cup, glass, can or 50 g bar) included the following: instant coffee 54 mg, ground coffee 105 mg, tea (bags, loose leaf, instant and green) 40 mg, branded cola 30 mg, supermarket brand cola 16 mg, energy drinks (e.g., Red Bull) 80 mg, and chocolate 8–27 mg. We found that caffeine intakes were higher in men than women (263 vs 226 mg/d), and increased up to age 65 years, declining somewhat thereafter. Caffeine intake from tea (119 mg/d) and coffee (107 mg/d) accounted for 94 % of total caffeine intake. Only 2.9 % of the sample reported consuming no products containing caffeine, and 91 % consumed at least 40 mg of caffeine per day (Heatherley et al., 2006a). After drinking tea, coffee or other caffeine-containing drink, caffeine is distributed rapidly throughout the body, reaching its highest concentration in the bloodstream and in the brain within 30–40 minutes. Caffeine and its metabolites, including the psychoactive metabolite paraxanthine, are then gradually eliminated from the body, mainly in the urine. For adults, the elimination half-life of caffeine (i.e., the time it takes for half of the caffeine consumed to be eliminated from the body) is around three to six hours, and is, for example, longer during pregnancy and shorter in smokers (James, 1997). In the amounts consumed in tea, coffee, cola, etc. the physiological and behavioural effects of caffeine occur primarily via antagonism of the neuromodulator adenosine at adenosine A1 and A2A receptors (Fredholm et al., 2005). These cell-surface receptors are distributed throughout the body, including the brain, and by blocking the action of endogenous adenosine,

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caffeine has significant cardiovascular, cerebrovascular, renal, gastrointestinal and metabolic effects. Adenosine is also closely involved in the regulation of sleep and wakefulness (Basheer et al., 2004), and it plays an important role in preventing cell damage during hypoxia and ischaemia (see Section 10.6). In response to regular caffeine consumption, however, there are changes in adenosine signalling that serve to counter the effects of caffeine and, at least in part, maintain normal functioning. For example, caffeine causes vasoconstriction, and vasodilation leading to increased cerebral blood flow appears to be the cause of headache that occurs on withdrawal of caffeine in frequent caffeine consumers (Couturier et al., 1997).

10.3 Caffeine reinforcement So why are caffeine-containing drinks so popular? One motive for consumption may be to quench thirst. This may be especially true for tea, which is rated as more ‘refreshing’ than coffee (unpublished data from the Dietary Caffeine and Health Study, Heatherley et al., 2006b), and indeed, contrary to a common view, consumption of caffeine-containing drinks has a net positive effect on fluid balance (Graham, 2001). This is notwithstanding the small diuretic effect of caffeine, to which frequent caffeine consumers appear to develop partial tolerance. A more obvious and explicit motive for consuming caffeine-containing drinks is the recognition of their potential beneficial psychostimulant properties – ‘I can’t start the day without a coffee,’ and ‘caffeine keeps me going when I begin to flag.’ Specific claims for performance-enhancing effects abound; for example, ‘The good news about coffee and health is its beneficial effects in improving attention and performance. Coffee also helps you think more quickly, have a better memory and improved reasoning’ (Coffee Science Information Centre), and ‘Study aid in a can – Red Bull increases concentration and endurance.’ We examine the evidence concerning the alerting and cognitive performance effects of caffeine below. Clearly, though, belief in such effects, whether or not directly linked to caffeine, encourages use of caffeine-containing products. Despite the widely known psychostimulant effects of caffeine, when people are asked about tea, coffee and cola the single most frequently stated determinant of their consumption is their liking for the taste of the drink (unpublished results from the Dietary Caffeine and Health Study (Heatherley et al., 2006b)). This liking, which is often very individual (i.e., specific brand of tea or coffee, particular brewing method, addition of milk and/or sugar, etc.), is acquired. We are not born with a liking for the taste of, for example, black coffee. In part, this is because coffee contains bitter tasting compounds, including caffeine, and humans have an inborn dislike of bitter tastes. Most likely this is because bitterness signals the presence of possibly harmful constituents in the potential food or drink. (Many bitter

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tasting compounds in nature are toxic, and caffeine, for example, may function as a pesticide in the plants that produce it (Nathanson, 1984).) Liking, however, can be modified through association of the taste and flavour of the food or drink with the after-effects of its ingestion (Brunstrom, 2005). The most dramatic example of this is the strong and specific aversion, including dislike, that can develop for a food or drink when its consumption is followed by nausea and vomiting. Such aversions are especially likely to develop if the food or drink is relatively novel for the individual. Similarly, association of a taste and flavour paired with positive consequences can result in increased liking for that taste and flavour. That is, our perception of the taste, flavour and identity of the item is the same, but our hedonic (affective) response is altered. Accordingly, how good a food or drink tastes will, to a significant extent, correspond to the benefit or harm experienced on previous exposures to that specific, or very similar, food or drink. As with the inborn aversion to bitter tastes, learned aversions and preferences help guide adaptive dietary choices. It may be that our liking for the taste and flavour of tea and coffee is reinforced by the psychostimulant effects of caffeine that occur following their consumption. We tested this hypothesis in experiments in which participants were given a novel-flavoured, and initially only moderately pleasant, fruit juice to drink either with or without caffeine. In one experiment the caffeine and placebo (starch) were given in capsules swallowed with the drink. Even though there was generally equal liking for the two drinks on the first occasion they were tasted, there was, as predicted, a greater increase in preference for the caffeine-containing drink (caffeine-paired flavour) on re-exposure (Rogers et al., 1995; Richardson et al., 1996). This learning was found to occur rather quickly; for example, clear differences in favour of liking for a caffeine-containing drink have been observed after just a very few exposures to the drink (Yeomans et al., 1998); and at doses (70–100 mg) of caffeine relevant to the consumption of typical caffeine-containing products (see also Smit and Blackburn, 2005). A further result from this research was that the presence or absence of caffeine in the drink only had a clear effect on preference or liking if the participants usually included caffeine in their diet and if they were acutely deprived of caffeine (overnight caffeine abstinence) before taking the experimental drink (Rogers et al., 1995; Tinley et al., 2003). More specifically, these frequent caffeine consumers developed an aversion for the drink if it did not contain caffeine, and an increase in preference if it did (Rogers et al., 1995). We interpreted this as evidence for negative reinforcement. That is, aversion developed for the drink without caffeine because its consumption was associated with the negative effects of overnight caffeine withdrawal, and an increase in preference occurred because the caffeinecontaining drink removed these effects (Rogers et al., 1995). This, in turn, is supported by extensive evidence for caffeine withdrawal effects in relation to alertness and psychomotor performance (see below).

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Negative reinforcement of liking helps to explain how caffeine consumption is maintained – we consume coffee, at least in part because we like it, and not just as an unpleasant tasting medicine for increasing alertness and concentration. But what gets us started on caffeine? That is, what reinforces initial consumption? One possibility, as mentioned above, is a reduction in thirst. The sociability and even peer-pressure associated with drinking tea and coffee will perhaps also encourage consumption. Additionally, these drinks can be made more acceptable by adding milk and/or sugar, and consuming weaker (more dilute) tea or coffee may further improve initial acceptability. Then with daily intake of even moderate amounts of caffeine, reversal of withdrawal effects will perhaps play the dominant role in influencing consumption of tea and coffee, both via reinforcement of liking and explicit recognition of improvement in mood and functioning. Note that individually on a daily basis we are not able to distinguish between a net beneficial effect of caffeine and withdrawal relief, as our experience, of for example a change from a less to a more alert state, is the same.

10.4 The alerting and psychomotor effects of caffeine – net benefit or withdrawal reversal? There are many published studies measuring the mood and cognitive performance effects of caffeine, and a clear result is that caffeine compared with placebo increases alertness, reduces fatigue and sleepiness, and improves performance, especially on vigilance and psychomotor tasks. Although most studies have used doses of caffeine in the range of 100–300 mg, these effects occur at even the relatively low amounts of caffeine found in, for example, a 50 g portion of dark chocolate (20 mg) or a can of cola (30 mg) (Lieberman et al., 1987; Smit and Rogers, 2000). Furthermore, within the range of doses present in typical caffeine-containing products, there seems to be a relatively flat relationship between dose and effects on alertness and task performance. For example, the peak effect of caffeine versus placebo on psychomotor performance is similar after 12.5 and 100 mg caffeine (Smit and Rogers, 2000), and a second dose of a cupof-coffee equivalent amount of caffeine does not affect alertness or performance unless this is taken at least six to eight hours after the previous dose (Robelin and Rogers, 1998; Heatherley et al., 2005). It seems likely, however, that after higher doses of caffeine there may be a more rapid onset of effects, and the effects will be sustained for longer. Effects of caffeine have also been observed for cognitively demanding tasks, but less consistently so, and the extent to which any enhancement is due merely to increased alertness (and perhaps a faster motor response – see below) or to a more specific effect on, for example memory processes, is uncertain. Unfortunately, though, as suggested in the previous section, it appears that the effects of caffeine on alertness and cognitive performance do not

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represent a net benefit for functioning but merely withdrawal reversal. Specifically, what is occurring is that acute (e.g., overnight) caffeine withdrawal lowers alertness and degrades performance, and caffeine consumption restores functioning to, but not above, ‘normal’ levels (Rogers and Richardson, 1993). Counter-regulatory changes in adenosine receptors and/ or increased levels of endogenous adenosine resulting from chronic exposure to caffeine (Fredholm et al., 1999) would be a plausible mechanism underlying such withdrawal effects. The extent to which the effects of caffeine measured in the laboratory are of practical significance is rarely considered. One way to investigate this would be to compare the magnitude of the effects of caffeine and caffeine withdrawal on alertness with the magnitude of changes in alertness occurring in caffeine non-consumers from, say, mid-morning (peak alertness) to early or mid-afternoon (post-lunch dip in alertness). However, arguably, even small changes in alertness or sleepiness (see below) could be critical for safety, for example in relation to driving. It is also certainly the case that fatigue, headache and other symptoms associated with caffeine withdrawal can be quite debilitating (Juliano and Griffiths, 2004). Because a vast majority of studies test only frequent caffeine consumers, they cannot distinguish between net benefit and withdrawal reversal. Evidence for withdrawal reversal comes from studies that have attempted to take into account the negative effects of acute caffeine withdrawal (reviewed by James and Rogers, 2005). Specifically, these studies test the effects of caffeine in individuals who are free from the acute effects of caffeine withdrawal. These are people who either consume very little or no caffeine in their diet, or frequent caffeine consumers who have undergone long-term withdrawal from caffeine. The rationale for long-term withdrawal is that during long-term abstinence from caffeine the body’s adenosine system re-establishes its normal level of functioning (five to ten days appears to be sufficient time). Consistent with withdrawal reversal, a variety of such studies have found that alertness is lower and mood and psychomotor performance are worse in overnight caffeine abstinent caffeine consumers than in both non-consumers of caffeine and long-term withdrawn consumers (reviewed by James and Rogers, 2005). Furthermore, giving caffeine to overnight withdrawn participants is found to largely reverse these deficits; that is, their level of functioning is restored to that displayed by placebotreated non-consumers and placebo-treated long-term withdrawn participants. What is more surprising is that caffeine is also often found to have little, or no, effect on alertness and performance in non-consumers and long-term withdrawn consumers, in one study even when participants were sleep restricted (Rogers et al., 2005). Indeed, all these results – lower alertness after overnight caffeine withdrawal, restoration of alertness by caffeine to, but not above, the level of non-consumers, and no effect on alertness in non-consumers – were observed in a relatively little cited study published

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over 40 years ago (Goldstein et al., 1969). We have recently replicated and extended this result (Rogers et al., 2010), finding a clear withdrawal effect (lowered alertness) in a group of participants with an average daily caffeine intake of only 130 mg, and a more severe effect in higher consumers (350 mg/d). Again, like Goldstein et al. (1969) we found no increase in alertness in non-consumers ( <2 mg/d) after caffeine, or indeed in low consumers (20 mg/d). On the other hand, some studies, including one of ours, have apparently detected alerting effects of caffeine in non-consumers (e.g., Rogers et al., 2003; Haskell et al., 2005; Childs and de Wit, 2006). One of the critical differences between these studies would seem to be the assignment of caffeine consumer status. In two of the studies, participants who were described as ‘non-consumers’ (Haskell et al., 2005) or ‘light, nondependent caffeine users’ (Childs and de Wit, 2006), based on their self-reported intake of caffeine-containing drinks and foodstuffs, nonetheless appeared to be consuming significant amounts of caffeine. The evidence for this is the levels of caffeine in their saliva prior to testing. These were 0.11 μg/ml (Childs and de Wit, 2006) and 0.36 μg/ml (Haskell et al., 2005), which is close to the concentration (0.18 μg/ml) we found for our group above who consumed on average 130 mg caffeine daily, and much higher than the concentrations for our very low and non-consumer groups (0.024 and 0.014 μg/ml, respectively) (Rogers et al., 2010). These results on salivary caffeine concentrations are revealing, but rather few studies collect such data (these analyses are fairly expensive). It is worth noting that, as well as providing information on likely level of habitual caffeine consumption, measurement of salivary caffeine concentration prior to testing can be used to verify compliance with intake restrictions (e.g., to be overnight caffeine abstinent) in frequent consumers. This is important for accurate determination of the effects of acute caffeine withdrawal, as the effects will be underestimated if even a small minority of participants do not abstain as instructed. Another difference between studies may be in the measurement of selfreported alertness. The results reported by Goldstein et al. (1969) described above were responses made on the following cluster of descriptors: ‘alert,’ ‘attentive,’ ‘observant’ and ‘able to concentrate.’ While caffeine failed to affect ratings on this cluster in non-consumers, it did increase their ratings on a cluster consisting of the descriptors ‘active,’ ‘stimulated’ and ‘energetic.’ In other words, unsurprisingly, caffeine is not without effect in nonconsumers. We have observed similar results. Caffeine did not increase mental alertness (‘I feel mentally alert / attentive / able to concentrate / observant’) measured on our Mood and Physical Symptoms Scales, but it did decrease sleepiness (‘I feel sleepy / drowsy / half-awake’) (Fig. 10.1). Furthermore, we have found that caffeine also increases non-consumers’ ratings of ‘stimulated’ and ‘I feel weird / unusual’, etc. (unpublished data). It may be that this stimulant effect is confused in some studies or by some participants as an increase in alertness (cf Rogers et al., 2003); however, it

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Alertness rating (9-point scale)

Alertness: ‘I feel mentally alert/attentive/ able to concentrate/observant’ P < 0.00001

5

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Sleepiness: ‘I feel sleepy/drowsy/half awake’ P < 0.00001

4 P = 0.006 3

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Fig. 10.1 Contrasting effects of caffeine, consumed at 11.15 h (100 mg) and 12.45 h (150 mg), on daytime alertness and sleepiness in ‘non-consumers’ of caffeine and frequent caffeine consumers. Mean habitual caffeine intakes of these two groups were 10 and 240 mg/d. The ‘non-consumer’ group includes very low consumers (≤39 mg/d). All consumers had caffeine intakes ≥40 mg/d. Participants were required to be overnight caffeine abstinent (i.e., not to consume any caffeine-containing products from 19.00 h on the evening before the test day). Full details of the methods for this study are described in Rogers et al. (2010).

does not seem to be associated with improved psychomotor performance (Rogers et al., 2003). The differential effect of caffeine on alertness and sleepiness in non-consumers is consistent with other evidence that subjective alertness cannot be reduced simply to the absence of sleepiness (Shapiro et al., 2006). Although Goldstein et al. (1969) found no effect of caffeine on sleepiness in non-consumers, their participants’ baseline level of sleepiness

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over the two-hour morning test period was very low. In contrast, our study (Rogers et al., 2010) included the post-lunch period during which baseline sleepiness increased. In this situation, caffeine reduced sleepiness (Fig. 10.1), as it did in another study, again in the absence of an increase in mental alertness, when participants were tested during the late afternoon and early evening (J. E. Smith, unpublished). Consistent with the results for mental alertness shown in Fig. 10.1, we found a very marked slowing of psychomotor performance in frequent caffeine consumers deprived of caffeine overnight (e.g., performance on a simple reaction time task compared with that of non-consumers receiving placebo was 53 ms slower). Caffeine reversed this deficit, and these effects were correlated with the effects of caffeine withdrawal and caffeine on alertness (in preparation). Caffeine also had a small, but statistically significant, effect on simple reaction time in non-consumers (16 ms faster), which was unrelated to any subjective effect of caffeine we measured. In this computer-based simple reaction time task, participants were required to respond as quickly as possible to the presentation of a star on the computer screen by pressing the keyboard spacebar. The interval between each stimulus presentation varied between 1 and 16 s, and the full task comprised a total of 96 presentations (cf Heatherley et al., 2005). We interpret the small enhancement of performance on this task by caffeine in caffeine ‘nonconsumers’ as a motor effect (in preparation). Whether this is a central or peripheral effect of caffeine is uncertain. Nonetheless, there is good evidence that caffeine can enhance physical performance, albeit not directly akin to the physical demands of a reaction time task. Most of the evidence is from studies conducted on athletes, and a consistent finding is that caffeine increases endurance (Graham, 2001). These studies have tended to test the effects of fairly high doses (≥300 mg) of caffeine, but within the acceptable limit set by the International Olympic Committee. Significantly, though, it seems that, in contrast to its effects on mental performance, caffeine use in this context does provide a net benefit. This is based on the observation that caffeine enhances physical performance to a similar extent in caffeine consumers and non-consumers (Rogers, 2000; Graham, 2001). Although we found no evidence of caffeine reinforcement in the absence of frequent dietary caffeine intake (see previous section), it is conceivable that the stimulant effects of caffeine in non-consumers, whilst not necessarily particularly pleasant, may encourage repeat consumption. This would then provide another motive for initiation of caffeine intake of sufficient frequency for subsequent consumption to be sustained primarily by withdrawal reversal. The most compelling support for the withdrawal reversal hypothesis is provided by the results for long-term withdrawn participants, because these results are unconfounded by individual differences related to past caffeine consumption – that is, individuals are randomised to withdrawn or not withdrawn (maintained on caffeine) groups, or the same individuals are

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tested when long-term withdrawn and when not withdrawn. Such studies also model the effects that would be achieved by giving up caffeine (e.g., by switching to decaffeinated products), the initial effects of which are very clearly negative. These effects have been characterised extensively, and include lowered alertness, fatigue, slowed psychomotor performance, reduced concentration and increased headache, peaking in intensity after around 24–48 hours without caffeine (Juliano and Griffiths, 2004). What is less clear is how levels of functioning after longer periods of withdrawal compare with functioning during periods of regular caffeine intake. This is a crucial question in assessing whether caffeine consumption is or is not beneficial. Are, for example, alertness, work performance, sleep and mood better, and blood pressure lower (see below) without caffeine as part of our diet? Or are they worse or the same? The research to date suggests better functioning without caffeine (James and Rogers, 2005), although further studies with even more comprehensive assessment of physiology and behaviour, ideally in real-life settings and perhaps targeting key times of the day (e.g., when alertness is low), are needed. Although highly informative, unlike studies of long-term withdrawn caffeine consumers, studies on non-consumers do not provide a definitive test of withdrawal reversal versus net beneficial effects of caffeine. This is because, first, the effects of caffeine observed in non-consumers might be modified by frequent dietary intake of caffeine (e.g., due to tolerance). Thus, even if caffeine were found, say, to acutely enhance memory performance in non-consumers, it could not be concluded that this benefit would persist with frequent consumption. Second, it may be that there are pre-existing differences between frequent caffeine consumers’ and non-consumers’ responses to caffeine. Specifically, it may be that many non-consumers avoid caffeine because they have experienced little benefit from it and/or because they already function very well without it (e.g., their level of alertness on waking in the morning is high). Another possibility is that non-consumers experience adverse effects of caffeine, which outweigh any benefits. A good example of the latter may be the tendency of caffeine to increase feelings of anxiety and ‘jitteriness’, which is the subject of the next section.

10.5 Caffeine and anxiety In contrast to the absence of an effect of caffeine on alertness in caffeine non-consumers, Goldstein et al. (1969) observed a marked increase in ratings of jitteriness (cluster comprising the descriptors: ‘jittery,’ ‘nervous,’ ‘shaky’) of these non-consumers, especially at the highest dose of caffeine given (300 mg). Again, we found a similar result. Even 100 mg caffeine increased jitteriness (‘I feel jittery / shaky’) and anxiety (‘I feel tense / anxious / nervous / on edge’) in non-consumers, but not in frequent consumers (Rogers et al., 2010). The very reliable effect which is often described

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spontaneously by participants as ‘jitteriness,’ may be a combination of mental (anxiety) and somatic effects, of which the latter may include muscular tremor and perception of cardiovascular changes. Thus caffeine worsens performance on tests of hand steadiness (Heatherley et al., 2005), and increases ratings of ‘heart pounding’ (Rogers et al., 2008). (Note though that caffeine does not increase heart rate, although it does raise blood pressure (Rogers et al., 2008, and see below)). Why do caffeine non-consumers show an increase in jitteriness/anxiety in response to caffeine, whereas frequent consumers do not? One possibility is that non-consumers are predisposed to this effect, and this is why they largely avoid caffeine. Consistent with this, recent studies have discovered an association between caffeine-induced anxiety and variation (a single nucleotide polymorphism – SNP) in the gene coding for the adenosine A2A receptor (ADORA2A). Specifically, it was found that 150 mg of caffeine increased anxiety in individuals carrying the TT genotype of the ADORA2A SNP rs5751876, but not in the CT and CC genotype groups (Alsene et al., 2003; Childs et al., 2008). The participants in these studies were reported to be infrequent caffeine consumers (no individual reported consuming more than three cups of coffee or equivalent per week, and many were recorded as consuming no caffeine). This SNP has also been found to be associated with panic disorder (Deckert et al., 1998), a condition characterised by recurrent episodes of panic and fear. People with panic disorder typically consume little caffeine, and if they are given caffeine it is likely to precipitate a panic attack. The significance of this vulnerability to caffeine-induced anxiety for caffeine intake in the wider population is, however, unclear. Although one study found that individuals with the rs5751876 TT genotype were less likely to be heavier (>200 mg per day) caffeine consumers than CC and CT individuals (Cornelis et al., 2007), this genotype is relatively uncommon (20–30 %) even among caffeine non-consumers. Furthermore, in contrast to Cornelis et al. (2007), we recently found that the ADORA2A rs5751876 TT genotype was not associated with lower dietary caffeine intake – indeed, among frequent caffeine consumers TT individuals consumed more coffee than their CC and CT counterparts (Rogers et al., 2010). This might seem puzzling, especially as coffee contains higher amounts of caffeine than other dietary sources. However, it should be noted that a cup-of-coffee equivalent dose of caffeine generally induces only a modest increase in rated anxiety in caffeine non-consumers and in susceptible individuals (e.g., an average of about two thirds of a point on an eight-point scale in our study (Rogers et al., 2010)). And rather than being appraised wholly negatively, perhaps this is experienced as stimulation or excitement. This would be consistent with Thayer’s conceptualisation of mood and arousal that sees a modest level of tense arousal, resulting from an external threat or challenge, or drug, as pleasant (Thayer, 1989). Although caffeine avoidance, predicted by caffeine-induced anxiety, has been observed in some experimental studies

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Adjusted mean ± SE DASS sub-scale score

(Stern et al., 1989; Evans and Griffiths, 1992), this was found to occur only at doses much higher (300 mg) than the amounts consumed in a single cup of tea, coffee or other caffeine-containing drink. The main reason, though, to doubt the relevance of caffeine-induced anxiety as a deterrent of dietary caffeine consumption is that substantial tolerance appears to develop to this effect of caffeine, even at rather modest levels of daily caffeine intake. For example, we found, irrespective of ADORA2A rs5751876 genotype, very much smaller increases in anxiety after caffeine in frequent than in non-/very low caffeine consumers (mean caffeine intakes of 240 and 10 mg/d, respectively) (Rogers et al., 2010). Further evidence on caffeine and anxiety comes from the Dietary Caffeine and Health Study (Heatherley et al., 2006b). We found positive associations between caffeine intake and depressed mood, anxiety and stress (Rogers et al., 2006). However, as Fig. 10.2 shows, the levels of depressed

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Fig. 10.2 Association between level of caffeine consumption and levels of depressed mood, anxiety and stress (all Ps < 0.0001), after controlling for gender, age, level of social and economic deprivation (based on postcode), alcohol intake and smoking. The data are from 5868 respondents in the Dietary Caffeine and Health Study (Heatherley et al., 2006b) and are based on an analysis reported in Rogers et al. (2006). Mean daily caffeine intakes for the five groups were as follows: n (‘nonconsumers’) = 12 mg, l (low) = 103 mg, m (medium) = 231 mg, h (high) = 380 mg, vh (very high) = 651 mg. Depressed mood, anxiety and stress were measured by the Depression, Anxiety and Stress Scales (DASS) (Lovibond and Lovibond, 1995). Participants rated how they had been feeling over the past week in response to 21 questions (e.g., ‘I found it hard to wind down’). The maximum possible score for each scale on the DASS is 42 and, based on normative data, ‘normal’ scores for depressed mood, anxiety and stress are ≤9.5, ≤7 and ≤14, respectively, and scores indicating ‘moderate’ (87–95th percentile) depression, anxiety and stress are 13–20, 9.5–14.5 and 18–26, respectively (Lovibond and Lovibond, 1995).

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mood, anxiety and stress were well within the normal range even for the group with the very highest level of caffeine intake. Furthermore, in the same study we found that less than 5 % of non-coffee and/or non-tea consumers reported they avoided these drinks because they made them feel anxious, tense or jittery. And very few gave one or more of these effects as their sole reason for avoiding the drink (0.4 % for coffee and 0.1 % for tea). Among the small percentage (4 %) of non- or extremely low caffeineconsuming respondents, reports of one or more of these adverse effects as a cause of caffeine avoidance was higher (14.5 %, 4 % and 7 %, for coffee, tea and cola, respectively), but other reasons, including ‘I don’t like the taste’ and ‘I prefer other drinks’ (68 % for coffee), ‘It’s not good for my health’ (42 %), and ‘It interferes with my sleep’ (29 %), predominated (note that respondents could select more than one reason). At least 92 % of these various respondents had tried tea, coffee and/or cola (unpublished). Despite the limitations inherent in questionnaire surveys, these results show good agreement with the evidence from laboratory studies, which overall indicates little cause for concern in relation to caffeine’s potential to increase anxiety.

10.6 Caffeine (tea and coffee) consumption and risk of cognitive decline Observational (correlational) studies also provide information on caffeine intake and cognitive function, of which an example is the Health and Lifestyle Survey of British Adults. In an analysis of data from this study, Jarvis (1993) found positive associations between levels of tea and coffee consumption and cognitive function assessed by various tasks completed in in-home tests. These associations were significant after controlling for at least some potential confounding factors, including level of education and overall health. This benefit of caffeine appears to contradict the withdrawal reversal hypothesis – for example, tea/coffee (caffeine) nonconsumers performed more poorly on the tasks than tea/coffee consumers. In addition there was a dose-related improvement in cognitive function, and memory scores as well as performance on reaction time and sustained attention tasks were positively associated with caffeine intake. And these relationships were much stronger in older people. In fact, there were no statistically significant relationships between caffeine intake and cognitive performance in the youngest age group (16–34 years). In contrast, laboratory studies of the acute effects of caffeine administration in caffeinewithdrawn participants have found a flat dose–response relationship for caffeine and task performance (Lieberman et al., 1987; Robelin and Rogers, 1998; Smit and Rogers, 2000). They have also found that caffeine (relative to placebo) improves performance on cognitively undemanding, sustained attention tasks equally in younger and older participants, but tends not to

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affect memory performance, even though memory worsens with age (Rogers, 2007). Jarvis’s (1993) finding of a relationship between higher habitual tea/coffee consumption and better cognitive function in older age has been confirmed in other populations (e.g., Johnson-Kozlow et al., 2002; Ritchie et al., 2007), and it has been suggested that this cognitive benefit is due largely to caffeine’s psychostimulant effect. However, in view of the evidence supporting withdrawal reversal, and the other differences between the results of intervention and observational studies of the cognitive effects of caffeine, this would seem unlikely. What then can explain the relationship between habitual caffeine consumption and cognitive function in older people? One possibility is that, rather than an acute effect, this is due to a chronic protective effect of caffeine and/or other constituents of tea and coffee – caffeine is only one of thousands of compounds present in tea and coffee. Against this, though, caffeine increases blood pressure, and raised blood pressure in middle age increases risk of cognitive impairment later in life (Stewart, 1999). Indeed, the blood pressure effect of caffeine is potentially very important for health. For example, it has been argued that by increasing blood pressure (due its vasoconstrictive effect) caffeine consumption may contribute substantially to the prevalence of cardiovascular disease and stroke (James, 2004), and by implication to an increased risk of cognitive decline in older age (see below). It is reassuring, however, that tea and coffee consumption have not generally been found to be associated with these adverse effects. Indeed, some studies even suggest that consumption of tea may reduce the risk of cardiovascular and cerebrovascular disease (Arts et al., 2005). The risks of cardiovascular disease associated with coffee consumption are also less than might be expected from its caffeine content (Cornelis and El-Sohemy, 2005). These findings suggest that other effects of tea and coffee must outweigh the consequences of the blood pressure raising effect of caffeine. For example, polyphenols present in tea, including catechin, may reduce risk via vasorelaxant effects, and effects on blood cholesterol, blood coagulation and inflammatory processes (Hodgson, 2006). Certain compounds such as cafestol (the concentration of which is affected by brewing method) in coffee may increase risk, but again, balancing this, chlorogenic acid and other phenols are thought to have beneficial effects (Cornelis and ElSohemy, 2005). Furthermore, another risk factor for cognitive decline, Type 2 diabetes (Stewart and Liolitsa, 1999), appears to be lowered by caffeine (or coffee) intake (Tuomilehto et al., 2004). It may also be that the blood pressure raising effect of caffeine is opposed by other compounds present in tea and coffee. We have found exactly this for theanine (Rogers et al., 2008). Theanine is a non-proteinic amino acid which is structurally similar to glutamate, and its only significant dietary source is tea, including black and green tea (Balentine et al., 1997). Theanine is not present in coffee; nonetheless, coffee consumption does not appear to increase risk of

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hypertension as might be predicted from its high caffeine content (Winkelmayer et al., 2005). On the other hand, cola intake, whether sugar-containing or low calorie, and after controlling for body mass index, has been found to be associated with greater risk of hypertension (Winkelmayer et al., 2005). Perhaps, therefore, protective constituents are present in coffee but not in cola. Finally, caffeine itself may exert a positive effect by enhancing the neuroprotective actions of adenosine. A significant cause of cognitive decline and dementia in older age is transient ischaemic episodes linked to underlying vascular disease (atherosclerosis) (O’Brien et al., 2004). Brain ischaemia is the loss of glucose and oxygen supply to the brain, and can lead to cell death. During ischaemia, there is a large increase in extracellular adenosine which, acting via adenosine A1 and A2a receptors, helps to counter some of the key pathophysiological processes, including excitatory neurotransmitter release, that lead to ischaemic cell death (Fredholm et al., 2005). Because caffeine blocks adenosine A1 and A2a receptors, caffeine should exacerbate ischaemic damage, and indeed this is what has been found in animal studies when caffeine is administered acutely prior to the ischaemic insult (Jacobson et al., 1996). However, chronic pre-treatment with caffeine reduces ischaemic brain damage (Jacobson et al., 1996), suggesting that a protective effect is gained through upregulation of adenosine receptors or other related adaptive change. In other words, frequent exposure to caffeine may modify the adenosine system to increase its neuroprotective function. Indeed, it could be that maximum protection occurs when the ischaemic insult coincides with caffeine withdrawal. Thus while caffeine withdrawal acutely slows performance, it may help to preserve cognition over the longer term for people at increased risk of brain ischaemia.

10.7 Conclusions and future trends: implications for the food industry, nutritionists and policy-makers The public and the food industry are interested in products that offer the possibility of increased alertness and enhanced mental performance, and caffeine’s reputation as a relatively harmless psychostimulant makes it the most popular, and currently perhaps the only, functionally significant ingredient for such products. Only a small minority of people appear to avoid caffeine because of concerns about possible adverse effects on their health. However, caffeine’s usefulness as a ‘functional’ ingredient is undermined by findings that show that the acute cognitive performance enhancing and alerting effects of caffeine experienced by caffeine consumers represent only withdrawal reversal. Even so, the presence of caffeine will motivate the choice and consumption of products, both through the intention to gain a benefit and via more implicit and indirect effects, including caffeinereinforced flavour preference. It has been claimed that the caffeine added

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to cola drinks functions primarily as a flavour enhancer. However, even though the amounts of caffeine are fairly modest, the evidence would seem to indicate that its psychoactive and dependence-producing effects are more important than any direct effect on taste acceptability (Griffiths and Vernotica, 2000). The evidence for caffeine dependence is, of course, withdrawal reversal. Frequent caffeine consumers need to consume caffeine regularly in order to maintain normal functioning – ‘dependence refers to the state of needing the drug in order to function within normal limits’ (Altman et al., 1996, p. 287). At the same time, caffeine appears to have low addictive potential, in that caffeine use very rarely escalates out of control to cause severe psychological distress or physical harm. In part, this is because caffeine has rather weak reinforcing and psychoactive effects. Caffeine does not strongly activate brain systems thought to be critically associated with the effects of substances, such as cocaine, amphetamines and alcohol, which pose a much higher risk of abuse than caffeine (Nehlig, 1999). Indeed, frequent caffeine consumers generally do not appear to find it particularly difficult to abstain from caffeine either when experiencing the adverse effects of caffeine withdrawal or in the longer term, especially perhaps when they do this by replacing their usual tea, coffee and/or other caffeine-containing with equivalent decaffeinated products (cf Heatherey et al., 2005). Additionally, behaviour towards caffeine is undoubtedly also shaped by its context of use – it is socially accepted, legal and inexpensive. The example of caffeine demonstrates the challenge of finding ingredients for foods or drinks that could be used to acutely enhance mood, alertness and cognitive performance. Frequent intake may to lead to physiological changes opposing the ingredient’s effects, resulting in tolerance and impaired function on withdrawal. It is also quite likely that desired effects of ingredients with significant activity would be accompanied by unwanted (side) effects. Nevertheless, as indicated in the previous section, there is ample evidence showing that diet affects cognitive health, a major mechanism being avoidance of vascular disease. We have discussed this (‘a healthy body, a healthy mind’), together with evidence on longer term dietary influences on mood, in more detail elsewhere (Rogers, 2001). In view of the contributions of cerebrovascular disease and depression to the global burden of disease (Murray and Lopez, 1996), these areas should be given high priority in future nutrition and behaviour research. Returning specifically to caffeine, it would appear that there may be little immediate gain from frequent consumption. Nonetheless, it possibly provides a means for reducing sleepiness, especially for infrequent consumers (Fig. 10.1), and so it may be useful when taken very occasionally, for example to aid driving long distances under monotonous conditions. Caffeine also appears to aid physical, including athletic, performance. Various concerns such as that caffeine exacerbates tinnitus appear to be misplaced (St Claire et al., 2010), and with frequent consumption, tolerance develops to the

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modest anxiogenic effect of caffeine. On the other hand, there is at most partial tolerance to its blood pressure raising effect. The risks of frequent consumption are disruption of sleep, and reduced alertness and impaired cognitive performance and headache when caffeine is withdrawn, but it would appear that frequent caffeine consumers adopt a pattern of consumption that mostly avoids these adverse effects – they cease consumption late afternoon or early evening and resume it very soon after awakening (Smit and Rogers, 2007). Research over the past 20 years has greatly increased our knowledge about caffeine and human performance, health and wellbeing, though there is much still to learn. Tea, coffee and cola are commercially important and, through their widespread consumption, together with caffeine’s varied physiological and psychoactive effects, they potentially have a significant impact on population health and wellbeing. Other constituents of caffeine-containing drinks may also have significant health effects. However, when taking either an individual or a population perspective on health it is important to place such effects in the context of the broad range of modifiable risk factors. Thus the balance of positive and negative effects of typical consumption of caffeinecontaining products probably sums to a small impact on health compared with, for example, smoking, overeating or physical inactivity.

10.8 Sources of further information and advice • Fredholm B B, Bättig K, Holmén J, Nehlig A and Zvartan E E (1999) ‘Actions of caffeine in the brain with special reference to factors that contribute to its widespread use’. Pharmacological Reviews, 51, 83–133. • James J E (1997) Understanding Caffeine: A Biobehavioral Analysis. Thousand Oaks, CA: Sage. • Smith B D, Gupta U and Gupta B S (2007) Caffeine Activation Theory: Effects on Health and Behavior. Boca Raton, FL: CRC Press.

10.9 Acknowledgements Dr Sue Heatherley and Emma Mullings contributed to the previously unpublished research described in this chapter. That research was supported by a grant (BBS/B/01855) from the BBSRC.

10.10 References alsene k, deckert j, sand p and de wit h (2003) ‘Association between A2a receptor gene polymorphisms and caffeine-induced anxiety’. Neuropsychopharmacology, 28, 1694–1702.

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11 Neurocognitive effects of herbal extracts A. Scholey and C. Stough, Swinburne University, Australia

Abstract: The chapter summarises the evidence pertaining to the biobehavioural effects of selected herbal extracts, concentrating on evidence from well-controlled human trials. The focus is on cognition enhancement but will include some relevant material on modulation of mood. There is good evidence that certain extracts have cognition-enhancing properties. These include extracts of Ginkgo, Ginseng, Salvia, Guaraná, Lemon balm, Bacopa and others. In the domain of mood Lemon balm has consistently been shown to have a calming effect. Evidence for other herbals is less clear although cocoa polyphenols may have anti-fatigue effects. One constant challenge for the psychopharmacology of herbal extracts is the use of standardised extracts and the use of multiple extracts in some medicinal systems. New technologies used to meet these challenges will be discussed briefly. Key words: herbal extracts, polypharmacology, neurocognitive change, mood.

11.1 Introduction 11.1.1 History of use of herbal products for neurocognition Improving mental performance is often cited as one of the key motivations to take herbal remedies amongst the so-called ‘baby boomer’ generation (Cardello and Schutz, 2006; Cox et al., 2004; Marinac et al., 2007). However, the use of herbal extracts for cognition enhancement has a long history. Homer’s Odyssey tells of an antidote that Odysseus and his men take in order to protect themselves from a drug that Circe has poisoned them with. The drug may well have been Datura stramonium, a plant known variously as jimson weed, angel’s trumpet, devil’s weed and stinkweed, and which contains the anticholinergic agent atropine (Doaigey, 1991). The antidote, described as ‘a black root, but milk-like flower’, allowed Odysseus to rescue his crew from Circe and to recover their memories. It is thought by some to have been the snowdrop (Galanthus nivalis), the original source of the currently licensed anti-dementia drug and cholinesterase inhibitor (ChEI) galantamine. In the late twentieth century researchers in Western Europe

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began examining galantamine for its potential ability to slow the progressive behavioural decline typical of Alzheimer’s Disease (AD). This decline is underpinned, in part (but by no means exclusively), by degeneration of the cholinergic system. The first patent on the synthetic processing of galantamine was lodged in 1996 and, following large international Phase III clinical trials, the product was licensed for AD treatment in many European countries, the US, Australia and some Asian countries. The case of galantamine illustrates ‘classical’ drug development (the isolation and subsequent synthesis of an active agent) from a traditional neurocognitive use of a plant. Galantamine is by no means unique as an ancient cognition enhancer: the Greeks considered garden sage (‘elelisphakon’ – Salvia officinalis) to be ‘good for helping diminution of senses and loss of memory’, and Ayurvedic medicine prescribes the use of sage to ‘clear emotional obstructions from the mind and for promoting calmness and clarity’. Sage differs from galantamine in that its behavioural effects do not seem to rely on a single component but rather on the synergistic interactions between various compounds. In the case of Melissa officinalis (Lemon balm), an early recommendation by Paracelsus (1493–1541) suggested that it could be used for ‘all complaints supposed to proceed from a disordered state of the nervous system’. In other cases, the use of herbal extracts for enhancing cognition emerged from an understanding of their specific properties. For example, possibly the most widely researched botanical for brain function, Ginkgo biloba, was originally used for other, non-cognitive, indications in Traditional Chinese Medicine.

11.1.2 Evolution of psychoactives in plants There are probably various reasons for the evolution of components with psychoactive properties within plants. Of course it is possible that such effects have arisen by chance. However, it is possible that nervous system effects of plant components have arisen through evolution, that is that certain advantages have been imparted on plants containing components which influence brain activity, the effects of which are largely noxious and serve to protect from predators but, especially at lower levels, may have serendipitous advantageous effects on neurocognitive function. This possibility relates to the notion of ‘hormesis’ – that exposure to lower amounts of plant toxins can evoke adaptive responses which are beneficial to the organism (but note this refers to physiological levels rather than the nonexistent dilutions in homeopathy). Such effects are well characterised in the cancer literature where the phenomenon of cancer prevention following exposure to low levels of potentially carcinogenic chemicals is fairly well established (Calabrese, 2005). Mattson and Cheng present a compelling argument for similar effects occurring in the neurocognitive domain, where the process has been termed ‘neurohormesis’ (Mattson and Cheng, 2006).

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Unlike ‘fight-or-flight’ responses in animals, plants cannot flee from danger and their ‘fight’ capacity is largely restricted to the production of noxious substances in leaves, roots and flowers. Over the course of millions of years, plants have evolved metabolic pathways which produce substances (often secondary metabolites) that influence cellular targets in predators. These secondary metabolites include various alkaloids, cardenolides, flavonoids, indoles and terpenoids (Koul, 2008). One obvious example of neurohormesis relates to anti-oxidant effects in neuroprotection. Much has been made of the anti-oxidant properties of certain plant secondary metabolites. It is noteworthy that many plant components, for example the flavonoids, exhibit anti-oxidant capacity at micromolar levels which are physiologically unrealistic following oral ingestion. On the other hand, much lower doses clearly exhibit neuroprotective capacity, an effect which may be attributable to neurohormesis-like effects (Mattson and Cheng, 2006). There appear to be many such effects when considering chronic administration of plant extracts. On the other hand, it is worth noting that certain acute benefits of herbal extracts are due to direct physiological effects.

11.1.3 Monotherapy versus polypharmacology Plant extracts may contain numerous potentially psychoactive components. While ‘classical’ dose–response curves are rare even in mainstream psychopharmacology, with herbal extracts the dose–response relationship can be even more complex. Mainstream drug development and, to some degree, traditional pharmacognosy aims to isolate active principles from plant material. In some cases, this is highly effective, leading for example to the development of aspirin, opiate anaesthetics, digitoxin and taxol. However, in certain cases attempts to isolate and refine active principles from plant extracts may be self-defeating since overall biological effects rely on synergistic interactions between plant components. For example, individual components of sage had far less cholinesterase inhibiting properties than the whole extract (Savelev et al., 2003). Figure 11.1 shows the theoretical effects of isolating an active component as opposed to reducing synergy. A more relevant issue might be the extent to which botanical extracts used in behavioural research are (or have the potential to be) standardised. Translating the findings of one study to another without knowledge of any standardisation remains difficult, if not impossible, even when results appear consistent between studies. Even standardisation based on concentrations of one or several components does not guarantee that there is batch-tobatch consistency or ‘phytoequivalence’. Herbal extracts may contain many active components and whole plant extracts may exert multiple subtle effects, i.e. they exhibit ‘polyvalence’. Individual plant components may act individually either positively or negatively, and in concert may affect multiple systems. For example, there is established effects of certain herbal extracts on neuronal systems (e.g., sage

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…...

Components in plant material

…...

Extraction process enriches active

Extraction process reduces sy e gy synergy

Effect (a)

275

Effect

(b)

Fig. 11.1 Schematic representation of (a) classic drug development from plant extracts where isolating a component enriches the effect on a physiological process – here illustrated as binding to one key receptor. However, some physiological processes are less straightforward (b) here illustrated simply by requiring the action of binding several receptors. In this case isolation of individual components will reduce the effectiveness of the extract compared with a polypharmacological approach.

and lemon balm on cholinergic activity); metabolic activity (e.g., ginseng on blood glucose, polyphenols on cerebral blood flow); and hormonal systems (e.g., soy isoflavones on oestrogen). Since these same systems themselves underpin behavioural processes, it is perhaps not surprising that certain herbal extracts can influence behaviour. Given that there are approximately 350 000 plant species, it is also unsurprising that certain extracts can confer behavioural benefits. The effects of herbal extracts may particularly depend upon complex interactions between them and physiological systems. Additionally, the interactions between active components in plant extracts may be synergistic, resulting in complex dose- and time-dependent effects. These factors are challenging for the cognitive science of nutrition and behaviour. On the other hand, cognitive performance and decline are themselves complex and multidimensional. The idea of an effective cognitive enhancer which targets only a single neurotransmitter system seems at odds with our understanding of the complexity of brain function – neurocognitive decline and dementia even more so. For example, AD is a form of dementia characterised by the loss of cholinergic neurons and the progressive deterioration of cognitive function and memory. Treatments such as the cholinesterase inhibitor (ChEI) Donepezil (Aricept®), or the analogue of plant-derived galantamine (Reminyl) may slow the progression of AD but do not cure the disease. Moreover, side-effects are common and include diarrhoea, muscle cramps, fatigue, nausea, rhinitis, vomiting, anorexia and insomnia.

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Brain atrophy

Risk factors

Ageing

ApoE phenotype

Cholinergic degeneration*

Hormonal status

Plaques and tangles

Head trauma

Alzheimer’s disease

Abnormal amyloid processing*

Aluminium exposure Socioeconomic status

Inflammation*

Oxidative stress*

Diet* Compromised glucose metabolism*

Alcohol consumption Viral exposure

Nicotine intake

Fig. 11.2 Schematic diagram of influences on the progression of Alzheimer’s disease illustrates the multi-faceted nature of the disorder including disease processes on the left and risk factors on the right (of which age is the single more important). Processes marked with * indicate known influence of herbal extracts.

Like other degenerative diseases, AD can be considered to be product of a pathological cascade involving progressively accelerating neurotoxic interactions between oxidative stress, inflammatory responses, neurohormonal pathology, compromised cerebral metabolism, neurofibrillary tangle generation, β-amyloid deposition, amongst other processes which include damage to the cholinergic system (see Fig. 11.2). Current monotherapy focusing only on cholinesterase represents just one of several candidate targets for dementia treatment. Cholinesterase therapy emerges within weeks in responders and rarely delays the course of the disorder by more than a year. Damage associated with processes such as oxidative stress may develop over many years, even decades, and its effective treatment may involve appropriate dietary or supplementation measures over similar timescales. It therefore seems pertinent to explore the possibility of a polypharmacological approach to AD. Herbal medicines often possess multiple components with different pharmacological targets, and some of these are extremely relevant to AD disease processes. The development of well-characterised and standardised herbal extracts, supported by empirically robust mechanistic and proof-of-concept neurocognitive trial data, will facilitate this endeavour.

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It is beyond the scope of this chapter to document the effects of all herbal extracts with cognition-enhancing properties (some of these are included in Table 11.1). Instead we will concentrate on leading herbal extracts and the evidence for their efficacy as neurocognitive enhancers and/or modulators of mood.

11.2

Ginkgo biloba

Ginkgo biloba has been reviewed extensively elsewhere, including recently Brown et al. (2010) and Weinmann et al. (2010), so only key points are considered here. The Ginkgo biloba tree is one of the oldest surviving tree species on earth (McKenna et al., 2001). Extracts and infusions made from its leaves have been used in Traditional Chinese Medicine for millennia. Standardised extracts of Ginkgo biloba have been available since the late 1960s when Schwabe developed extract EGb761. This extract is concentrated in a ratio of 1 part extract to 50 parts dried leaves and contains an invariant 24 % flavone glycosides (primarily quercetin, kaempferol and isorhamnetin, all powerful anti-oxidants) and 6 % terpene lactones (2.8– 3.4 % ginkgolides A, B and C, and 2.6–3.2 % bilobalide). Ginkgo biloba extract is prescribed in France and Germany for the treatment of conditions including problems with memory and concentration, confusion, depression, anxiety, dizziness, tinnitus and headache (Mahady, 2002; Smith and Luo, 2004). In the early 1990s Ginkgo became one of the most popular supplements for memory enhancement in the US (Smith and Luo, 2004). Currently Ginkgo is marketed as a treatment for age-associated cognitive decline, as well as a treatment for slowing the progression of neurodegenerative diseases such as AD. However, despite relatively intense research on the cognitive effects of Ginkgo, there is still no conclusive evidence as to its efficacy in the treatment or prevention of dementia (Birks and Grimley Evans, 2009). The peak plasma levels of various components of Ginkgo occurs within the hours following administration. For example ginkgolide B peaks around 2.25 ± 0.45 hours following oral administration with an elimination half-life 4.31 ± 0.49 hours (Drago et al., 2002). It follows that there may be acute benefits of Ginkgo administration (Kennedy et al., 2000, 2002a; Elsabagh et al., 2005). An early well-controlled, double-blind, placebo-controlled, balanced cross-over study involving 20 healthy young participants investigated the cognitive effects of single doses (120 mg, 240 mg, 360 mg) of standardised Ginkgo biloba extract (GBE) over six hours (Kennedy et al., 2000). There was a clear, linear, dose-dependent increase in performance of a ‘speed of attention’ factor – an aggregate of reaction time scores from three separate attention tasks from a computerised assessment battery. This effect was significant for the two higher doses, with the lower 120 mg dose enhancing performance on a different measure – the ‘quality of memory’ factor

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Table 11.1 Selection of herbs with known neurocognitive effects not included in this chapter Name (Alternative/ common name)

Recommended dose

Acute/ chronic

Caffeine Theanine

40–250 mg 250 mg

Acute Acute

Rosmarinus officinalis (Rosemary) Eleutherococcus senticosus

aromatherapy

Acute

4 ml (aqueous)

Acute & chronic

Rhodiola rosea

100–400 mg / day (chronic) 370–555 mg (acute) N/A

Chronic & acute

Huperzine

300–500 μg/ day

Chronic

Pycnogenol (French maritime pine bark extract) Phosphatidylserine

150 mg/day

Chronic

200–300 mg/ day

Chronic

Vinpocetine (derived from snowdrop)

10–60 mg/day

Chronic

Curcumin

Chronic

Purported mechanism Blocking adenosine receptor Increases serotonin and dopamine levels acutely, and modulates neurotransmitter pool of glutamate in neurons with chronic use Cholinesterase inhibitor due to Rosmarinic acid. Neuroprotective Enhances ACh release and acts as an anti-oxidant and anti-inflammatory Inhibitors of monoamine oxidase and catechol-Omethyltransferase activity. Antioxidant. Cholinesterase inhibitor Clears amyloid plaques, antiinflammatory, decreases the activity of cytokines. Antioxidant. Metal chelator Cholinesterase inhibitor, antioxidant, reduces glutamate-induced cell death through NMDA receptor antagonism Powerful anti-oxidant, anti-inflammatory Enhances biosynthesis and release of neurotransmitters. Enhances cholinergic function, improves membrane fluidity. Antioxidant and anti-inflammatory Increases blood flow to the brain. Improves the uptake and release of glucose in the brain. Anti-oxidant

NMDA = N-methyl-D-aspartic acid.

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(comprising scores from six memory tasks). More recently, we published a re-analysis incorporating the data from that study and two others using similar methodology in which 120 mg Ginkgo was included as one arm (Kennedy et al., 2007a). This revealed that the attentional effects may be fragile and indeed suggested that 120 mg may impair attentional speed. On the other hand, the memory effects appear to be robust with 120 mg Ginkgo improving memory for one to four hours following administration. In relation to the long-term neuroprotective effects of Ginkgo, a number of mechanisms have been proposed, including: anti-oxidant, antiinflammatory, preservation of mitochondria function / increased adenosine triphosphate (ATP) production, inhibition of β-amyloid formation, reduction in neuron apoptosis and enhancement of cholinergic transmission (Ramassamy et al., 2007; Mahadevan and Park, 2008). A recent Cochrane review of Ginkgo biloba in the treatment of dementia and mild cognitive impairment (MCI) concluded that there is currently inconsistent and unreliable evidence to suggest a clinically significant benefit (Birks and Grimley Evans, 2009). The review’s meta-analysis included 36 randomised, double-blind studies to September 2007. Out of the four most recent trials, all with large samples (N > 150 dementia patients), three reported no significant difference between active and placebo. A study by Mazza and colleagues (2006) also reported a positive treatment effect of Ginkgo over placebo, but used a smaller sample size n = 76. Since the completion of the Cochrane review, the results of a large-scale community-based longitudinal study have been published (DeKosky et al., 2008). The Ginkgo Evaluation of Memory (GEM) was the first multi-centre study to investigate the effect of Ginkgo on dementia incidence over an eight-year period (DeKosky et al., 2008). The study compared a 240 mg daily dose of EGb 761 to placebo in 3069 elderly participants (2587 with normal cognition and 482 with amnestic MCI). Participants were assessed at six-monthly intervals over the course of the study and 523 developed dementia, with a numerically larger number from the Ginkgo group developing dementia than placebo (277 vs 246), although this difference was not statistically significant. Further, Ginkgo was also found to have no effect on the rate of progression to dementia from MCI. The authors concluded that there was no evidence to suggest that Ginkgo was effective in reducing the overall incidence rate of dementia in elderly individuals with either normal cognition or those with MCI. These findings were supported, though only to a degree, by a smaller scale feasibility study investigating the efficacy of Ginkgo Biloba in the primary prevention of dementia (Dodge et al., 2008). In the primary analysis no reduced risk of progression to MCI and no protection of memory function were observed for the Ginkgo group. However, in a secondary analysis controlling for medication adherence level, the Ginkgo group exhibited a lower risk of progression to MCI and a smaller decline in memory scores. There were however more adverse events (ischemic strokes and transient

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ischemic events in the Ginkgo group). At the time of writing this chapter the results of GuidAge, a large (N = 2854) 5-year Alzheimer’s disease prevention trial, have been released. These show that 1.6 % of patients treated with EGb 761 for at least four years developed AD compared to 3.0 % of those on placebo. If confirmed these statistically significance findings suggests that long-term Ginkgo supplementation may have striking cognitive benefits. In summary, Ginkgo may have robust acute effects on memory in healthy individuals which may be evident from one hour following a single dose. However, despite the considerable research focus on Ginkgo biloba in the prevention of cognitive decline and dementia, current evidence for its efficacy in chronic trials targeted at neurocognitive decline remains inconclusive, though the most recent findings appear positive.

11.3 Ginseng Ginseng refers to species of the Panax genus of the Araliaceae plant family. Extracts of Ginseng have been used for millennia in Traditional Chinese Medicine, its role in the pharmacopoeia being that of a ‘tonic’ to provide energy and to aid convalescence in the ill and elderly (Fulder, 1993). For example, it has been noted that the effects of Ginseng became apparent ‘when the resistance of the organism was diminished or the organism was taxed with extra demands’ (Brekhman and Dardymov, 1969). This role is supported by both anecdotal and empirical evidence. For example, individual ginsenosides have been shown to have anti-inflammatory effects in vivo (Matsuda et al., 1990) and in vitro to possess anti-mutagenic and DNA protective properties (Ong and Yong, 2000). The constituents of the Panax genus which are thought to contribute to its bioactivity are the ginsenoside saponins. Ginsenosides can be classified into three groups on the basis of their chemical structure; the Panaxadiol group (Rb1, Rb2, Rb3, Rc, etc.), Panaxatriol group (Re, Rf, Rg1, Rg2, Rh1) and the oleanolic acid group (e.g., Ro) (Tachikawa et al., 1999). Of the few standardised extracts, G115 contains an invariant 4 % ginsenosides while GinsenipureTM comes in two forms, standardised to 4 % and 15 % ginsenosides, respectively. The ginsenosides have been reported to exert effects on the cholinergic system, which is critically involved in attention and memory. Isolated Rb1 stimulates choline acetyltransferase activity (Salim et al., 1997) and acetylcholine release (Benishin et al., 1991). Ginsenosides Rg1 and Rb1 have also been found to elicit marked alterations in brain serotonin concentrations, which may influence mood and sleep patterns. Other targets include nerve growth factor (Chu and Zhang, 2009). Rb1 was capable of in vivo modulation of long-term potentiation (LTP), a putative analogue of memory formation (Abe et al., 1994). Other ginsenosides have also been reported

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to effect specific cognition-relevant mechanisms. For example, Rd influences corticosterone secretion (Hiai et al., 1983) and ginsenosides Rd and Re may increase levels of the norepinephrine, dopamine, serotonin and γ-aminobutyric acid (GABA) (Tsang et al., 1985; Chu and Zhang, 2009). In rodents, Ginseng administration results in attenuation of learning deficits associated with ageing (Nitta et al., 1995; Wen et al., 1995; Zhao and McDaniel, 1998) or forebrain ischaemia (Nitta et al., 1995) where Ginseng was also neuroprotective, rescuing hippocampal neurons. In young rodents, Ginseng-related improvements may follow an inverted-U dose–response. Mice administered 3, 10, 30, 100 and 300 mg/kg Panax Ginseng (extract G115) improved performance following 10 mg/kg in an inverted-U dose– response manner. However, this effect was observed for a selection of tasks only (Petkov and Mosharrof, 1987). Animal studies have observed cognitive benefits over a range of doses, ranging from 10 mg/kg to 150 mg/kg (Petkov and Mosharrof, 1987; Petkov et al., 1993), with some doses also appearing to impair aspects of cognitive function (Petkov and Mosharrof, 1987). The behavioural profile of Ginseng is further complicated by variations in methods of assessment, age and dosage (Kennedy and Scholey, 2003). A series of double-blind, placebo-controlled studies has assessed the mood and cognitive effects of acute administration of Ginseng in healthy young adults. These have found that enhancement by Ginseng was observed largely for secondary memory (i.e when material is learned, stored and later retrieved). In the first study (Kennedy et al., 2001b) doses of 200, 400 and 600 mg of Ginseng (G115) were administered. Enhancement of ‘secondary memory’ was found following 400 mg at four post-dose testing sessions, while the lower and higher dosage reduced performance for ‘speed of attention’. In a further study assessing combinations of Ginseng and Ginkgo (ratio 100:60) at dosages of 320, 640, 960 mg, a similar pattern was observed (Kennedy et al., 2001a), with performance of secondary memory being improved by 960 mg, and reduced performance on speed of attention for the other doses (320 and 640 mg). A later study (Kennedy et al., 2002a) replicated the finding that a 400 mg dosage improved ‘secondary memory’. A further study assessed the effect of 200, 400 and 600 mg Ginseng on mental arithmetic performance, where cognitive demand was manipulated. Again, this task was improved by a 400 mg dosage, but only for the most demanding (Serial Sevens) task (Scholey and Kennedy, 2002). Further work showed that 200 mg of G115 significantly shortened latency of the P300 component of auditory evoked potentials, an electrophysiological index of working memory (Kennedy et al., 2003a). One further study has reported faster responses on an attentional task 90 minutes following 400 mg G115 (Sünram-Lea et al., 2004). A more recent report found better performance on a deliberately demanding cognitive battery, coupled with reduced capillary blood glucose (Reay et al., 2005), suggesting that the effects may be modulated by processes involving cellular glucose uptake or disposal. However, a follow-up study did not find that the effect was further

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enhanced by co-administration of glucose with G115 (Reay et al., 2006). It appears to be the case that Panax ginseng or its constituents are capable of producing tangible cognitive-enhancing effects and that for Panax ginseng a dose equivalent to 200 mg or 400 mg of a 4 % ginsenoside extract may be the optimal dose for young healthy adults when administered acutely prior to a cognitive test. There are few behavioural studies addressing the potential cognitionenhancing effects of chronic administration of Ginseng in humans. One study reported the effects of 12 weeks administration of Panax ginseng (200 mg G115 per day) on healthy young volunteers’ cognitive and psychomotor performance (D’angelo et al., 1986). Cognitive and psychomotor assessments were conducted at a pre-treatment baseline and then during the 12th week of treatment. Ginseng administration led to significantly more correct responses on a mental arithmetic task. However, no differences between the Ginseng and placebo groups were found on a cancellation task. Another study investigated the effects of eight to nine weeks of Ginseng ingestion (400 mg standardised GerimaxTM Ginseng extract) on cognitive performance in healthy middle-aged participants (Sørensen and Sonne, 1996). Ginseng led to significantly faster performance in only the most rapid auditory reaction times test (10th percentile). A third empirical investigation (Labadorf et al., 2004) examined the mood, memory and attentional effects following 14 days of 200 mg G115 in 18 healthy young volunteers. Cognitive assessment was conducted using a computerised assessment battery at a pre-dose baseline, and thereafter at one, three and six hours post-treatment on days 1, 7 and 14. Results revealed that Ginseng led to better performance on all four factors – speed of attention, quality of attention, speed of memory and quality of memory – derived from the cognitive drug research (CDR) research battery. It should be noted that this study is only available as a conference abstract so has not undergone rigorous peer review. One small study (N = 16) has reported positive effects of eight weeks Ginseng on working memory performance coupled with reduced self-rated calmness (Kennedy et al., 2007b). A further investigation, involving analysis of data from a small cohort of self-reported users of Ginseng products drawn from a large prospective study, analysed the results/responses from 3500 self-reporting participants. Eighty-six participants reported that they were currently using, and had been using, Ginseng regularly. Of these, 51 had been using Ginseng for more than two years, and the mean intake time for the remaining 35 participants was 5.6 months. Episodic and semantic memory was assessed using eight memory tests, but no effect of Ginseng compared to control groups was observed on these parameters (Persson et al., 2004). However, this study has been criticised for numerous methodological shortcomings that could account for null findings (Scholey et al., 2005). For example, no attempt was made to assess the level or frequency of dose, there was a huge variability in the period of herbal use (potentially from two weeks to many years),

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there was no pre-treatment cognitive performance data reported, the study was not double-blinded, and people who took the herb may have done so because of pre-existing memory problems. Few conclusive interpretations can be made from these chronic studies as they have investigated different cohorts (i.e. healthy young and middleaged), administered different Ginseng extracts (e.g., G115 or Gerimax) and doses (200 mg and 400 mg), for different durations (two to 12 weeks) and implemented different assessment tools designed to assess different aspects/ domains of cognitive functioning. Further research is required to examine the chronic use of Ginseng on neurocognitive outcome measures.

11.4

Bacopa monnieri

Bacopa monniera (BM) is a member of the Scrophulariaceae family. It is sometimes referred to as Brahmi which is derived from the name of the Hindu ‘Brama’ or creator. Since the brain is believed to be the creative centre in the Hindu religion, this name is given to any compound which improved brain function (examples include Centella asiatica and others). Bacopa has been used in Ayurvedic medicine for millennia as a memory enhancer, sedative, analgesic, anti-inflammatory and anti-epileptic treatment (Jain, 1994; Stough et al., 2001). It is classified as a ‘medhyarasayana’, i.e. it improves ‘medhya’ – memory and intellectual functioning. Saponins (specifically bacosides A and B) are the active ingredients that are believed to underlie the memory-enhancing effects of Bacopa. Suggested mechanisms of action include pro-cholinergic effects, GABA-ergic modulation, anti-oxidant effects, brain protein synthesis, serotonin agonist, modulation of brain stress hormones and reduction of β-amyloid (Calabrese et al., 2008). A recent study by Hota and colleagues (2009) investigated the effects of Bacopa on ameliorating the effects of hypobaric anoxia (reduced delivery of oxygen to brain tissue at altitude) on spatial memory function. Bacopa administration enhanced learning ability, increased memory retrieval and prevented dendritic atrophy following hypoxic exposure in rats. Further evidence was also provided for the role of glutamatergic transmission in the memory-enhancing effects of Bacopa, suggesting that it has an ability to modulate positive synaptic plasticity through augmentation of glutamatergic transmission, as well as the amelioration of cell death associated with glutamate-mediated excitotoxicity. Bacopa was also found to decrease oxidative stress, plasma corticosterone levels and neuronal degeneration, to increase cytochrome c oxidase activity and ATP levels, suggesting a positive effect on mitochondrial function and possibly brain energy metabolism. An early placebo-controlled randomised trial investigated the effects of 300 mg Bacopa monnieri on 46 healthy volunteers aged 18–60 on a battery of cognitive tests after five weeks and 12 weeks (Stough et al., 2001). A

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standardized extract (CDR08) from the Central Drug Research Institute in Lucknow India was used for the study which was standardised for Bacosides A and B, with no less than 55 % of combined bacosides. Each capsule contained 150 mg of Bacopa, equivalent to 3 g of dried herbs, with two capsules administered per day. Bacopa was found to significantly improve performance on the Rey Auditory Verbal Learning Test (AVLT) as well as State Anxiety at 12 weeks. Further three-month clinical trials of Bacopa monnieri in elderly adults have reported similar improvements in a number of measures, including the retention of new information in delayed recall of word pairs (Roodenrys et al., 2002), improvements in sub-sets of the Wechsler Memory Scale (Raghav et al., 2006) and improvements on the Stroop task assessing the ability to ignore irrelevant information (Calabrese et al., 2008). In a follow-up randomized controlled trial (RCT) in 2008, 300 mg CDR08 Bacopa extract was administered to 62 healthy volunteers aged 18–60 years over a 90-day period. Significant improvements in the working memory factor from the cognitive drug research battery were observed in the group receiving Bacopa. Greater accuracy on the rapid visual information processing test was also observed in this group following treatment. These findings corroborated the results of the previous study, providing further evidence for the cognitive-enhancing effects of Bacopa (Stough et al., 2008). Bacopa is a nutraceutical that holds great promise for the amelioration of age-related cognitive decline as well as cognitive enhancement in the young. The few clinical studies to date provide preliminary evidence of improvements to working memory function associated with chronic supplementation. However, further clinical trials are needed in order to examine potential acute effects, determine optimal dosage levels and further investigate efficacy associated with chronic supplementation.

11.5 Salvia The salvia genus consists of around 900 species. Whilst the genus was recognised and named by both Egyptian and Greek civilisations, it owes its name to the Romans (from the Latin salvage meaning ‘to save’). The most common European members of the genus are Salvia officinalis (garden sage) and Salvia lavandulaefolia (Spanish sage). The proposed mechanisms of action for S. Officinalis include acting as a cholinesterase inhibitor (AChEI) as well as acting via anti-oxidant, antiinflammatory and oestrogenic effects (Perry et al., 1999; Kennedy and Scholey, 2006). Several RCTs have been conducted to assess the acute memoryenhancing effects of S. officinalis. One study examined the acute effects of S. officinalis on mood and cognition in 30 healthy participants, who completed a test battery at baseline as well as one hour and four hours post-dose

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on three separate testing occasions (Kennedy et al., 2005). On each occasion, they received either placebo, 300 mg or 600 mg of dried sage leaf. The higher dose was found to be associated with improved performance on the Stroop test as well as an aggregate score obtained from a simultaneously performed, multi-tasking battery of tests including tasks of mathematical processing and memory search tasks at both post-dose time points. In a more recent study, the acute effect of S. officinalis on memory was examined using 20 elderly volunteers (over 65) administered 167, 333, 666 and 1332 mg of dried sage and tested 1, 2.5, 4 and 6 hours post-dose (Scholey et al., 2008). Significant improvements in secondary memory performance (aggregate percentage accuracy in word recognition, picture recognition, immediate and delayed word recall from the Cognitive Drug Research (CDR) computerised battery) were noted for the 333 mg dose in comparison to placebo at all post-dose time points. The extracts used in the study were subjected to in vitro analysis, confirming cholinesterase-inhibiting properties in comparison to an ethanol control sample (Scholey et al., 2008). These findings supported earlier data from studies of the acute effects of S. lavandulaefolia essential oil, another ChEI of the sage family containing similar components to S. officinalis. A significant improvement in immediate and delayed word recall post-dose was found using a 50 μl dose of the oil in 20 young healthy volunteers (Tildesley et al., 2003). A second study by the same group using the same methodology reported improvements in Speed of Memory at four and six hours post-dose associated with 50 μl S. lavandulaefolia as well as an improvement in secondary memory performance at one hour post-dose and Speed of Memory at 2.5 hours post-dose with the 25 μl dose (Tildesley et al., 2005). Regarding studies of the chronic effects of S. officinalis amongst clinical populations, one study examined the effects of S. officinalis on memory in 39 AD patients (Akhondzadeh et al., 2003). Significantly improved scores on the Alzheimer’s Disease Assessment Scale-cognitive sub-scale (ADAScog) were reported for those in the sage group in comparison to placebo at 16 weeks. However, this study was not without criticism, with reviewers drawing attention to the unexpectedly large effect size, an ill-defined herbal extract and no description of the placebo (Kennedy and Scholey, 2006). On the other hand, the data are largely consistent with an open label trial using the S. lavandulaefolia essential oil from the sage family (Perry et al., 2003) which reported a significant improvement in the accuracy of performing a vigilance task at the six-week end-point amongst 11 AD patients. To date, the findings from the relatively few studies that have been conducted using S. officinalis and S. lavandulaefolia are promising, suggesting efficacy associated with both acute and chronic supplementation. Further RCTs, as well as longitudinal studies, using larger samples from both the non-clinical population as well as MCI and AD patients are warranted in order to properly establish the efficacy of sage as a cognitive enhancer.

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Melissa officinalis

Melissa officinalis (lemon balm) is a cultivated perennial lemon scented herb. Records concerning its use date back over 2000 years with entries in the Historia Plantarum (approximately 300 bc) and the Materia Medica (approximately 50–80 bc). Following its introduction into Spain in the seventh century, its use spread throughout Europe by the middle ages. Medicinal use throughout this early epoch include a recommendation by Paracelsus (1493–1541) that balm would completely revivify a man and should be used for ‘all complaints supposed to proceed from a disordered state of the nervous system’. Traditionally, lemon balm was used as a mild sedative and anxiolytic, though several herbal apothecaries of the time created balm with general beneficial effects upon the brain and in particular with specific improvements to memory (Kennedy et al., 2002b). The putative biologically active compounds in Melissa officinalis include monoterpenoid aldehydes (including citronellal, neral and geranial), flavonoids and polyphenolic compounds such as rosmarinic acid and monoterpene glycosides (Mulkens et al., 1985; Carnat et al., 1998; Sadraei et al., 2003). There is evidence to suggest that Melissa officinalis enhances cholinergic transmission, based on the fact that it binds to both nicotinic and muscarinic acetylcholine receptors within the central nervous system (Perry et al., 1996; Wake et al., 2000). However, large variation in receptor binding affinities have been noted between varying strains and preparations of Melissa officinalis, with the more reliable action of the plant across samples being its calming effects (Kennedy et al., 2003b). A number of possible active components of the dried leaf and essential oil of the herb have been identified. Constituents that may have pharmacological effects include a number of monoterpenoid aldehydes (including citronellal, neral and geranial), (Carnat et al., 1998a; Sadraei et al., 2003), flavonoids and polyphenolic compounds (most notably rosmarinic acid) (Petersen and Simmonds, 2003) and monoterpene glycosides (Mulkens et al., 1985), with further new compounds being identified (Mencherini et al., 2007). These components are absorbed readily following oral ingestion of Melissa. Mantle et al. demonstrated that Melissa leaf had modest but ‘appreciable’ levels of anti-oxidant activity in comparison to recognised anti-oxidants such as Panax ginseng (Mantle et al., 2000). The anti-oxidant properties of a whole extract of Melissa are probably mainly attributable to its flavonoid content (Hohmann et al., 1999). Any cognition-modulating effects of Melissa officinalis are likely due to its actions in the cholinergic system (nicotinic and muscarinic receptors). Nicotinic and muscarinic receptor binding in human brain homogenates varied considerably across strains of Melissa (Wake et al., 2000). An extract with negligible cholinergic receptor binding produced behavioural results consistent with its long traditional use as a mild sedative/anxiolytic but did

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not enhance memory (Kennedy et al., 2003b, 2004b), whereas an extract specifically chosen for its high muscarinic and nicotinic binding properties in human brain tissue had the same mood effects but also improved memory performance (Kennedy et al., 2003b). This last example also suggests that, in the case of Melissa officinalis, the robust calming/anxyolitic effects of the plant (Kennedy et al., 2004b) are dependent on an, as yet unidentified, noncholinergic mechanism. One study examined a chemically-validated essential oil derived from Melissa and found that Melissa inhibited binding of GABAA to receptor channel in the rat forebrain, but had no effect on or nicotinic acetylcholine receptors (Abuhamdah et al., 2008). They also found that Melissa elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission. Another mechanisms to increase GABA levels in the brain, and potentially to control anxiety, is to inhibit the enzyme GABA transaminase (GABA-T) (Ashton and Young, 2003). A survey of ten anxiolytic botanicals was reported recently and an extract of Melissa officinalis was found to be the best inhibitor of in vitro GABA-T activity from rat brain (Awad et al., 2007). The action of Melissa on GABA-T was confirmed by a further study along with bioassay fractionation which led to the identification and isolation of rosmarinic acid and the triterpenoids, ursolic acid and oleanolic acid as active principles. It was determined that rosmarinic acid was the major compound responsible for activity, but the authors noted that synergistic effects may also play a role (Awad et al., 2009). There is good evidence for Melissa having acute anxiolytic (anti-anxiety) effects. In human studies, Melissa can increase self-rated ‘calmness’ using established mood scales (Kennedy et al., 2003b, 2004b, 2006). Additionally, when subjects were subjected to laboratory stressor Melissa increased calmness (Kennedy et al., 2004b) and in combination with Valerian, lemon balm decreased state anxiety (Kennedy et al., 2006) at a lower dose but increased it at a higher level. Six hundred mg/day of Valerian for seven days was also capable of decreasing heart rate responses to a laboratory stressor (Cropley et al., 2002). There is also some evidence that 50 mg of isolated valepriates of Valerian having an anxiolytic effect (in generalised anxiety disorder (GAD) patients) with four weeks treatment (Andreatini et al., 2002). Thus the empirical evidence for lemon balm administration is largely in keeping with its traditional use as a calming agent.

11.7 Guaraná The plant species guaraná originates from the central Amazonian Basin, and has a long history of local usage, initially as a stimulant by indigenous tribes people (Henman, 1982) and more latterly as a ubiquitous ingredient in Brazilian soft drinks. An extensive range of products that include guaraná (Paullinia cupana) seed extracts as ingredients are commercially available.

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Examples include confections (e.g., chocolate products), fruit juice based drinks, ‘energy’ drinks, dietary and herbal supplements and, most controversially, natural weight loss products. The putative stimulant properties are generally taken to reflect the presence of caffeine, which comprises 2.5–5 % of the extract’s dry weight, although other purine alkaloids (theophylline and theobromine) are present in smaller quantities (Weckerle et al., 2003). The psychoactive properties of guaraná have also been attributed to a high content of both saponins and tannins (Espinola et al., 1997), the latter of which may well underlie the demonstrated anti-oxidant properties of the plant (Mattei et al., 1998). Two studies in rodents have included behavioural measures. In one (Mattei et al., 1998), both acute and chronic administration of guaraná was found to have no toxic effects, but also failed to modulate motor activity or pentobarbital-induced sleep parameters. A further study demonstrated both that chronic (nine months) administration of a lower (0.3 mg/ml) but not a higher (3.0 mg/ml) dose of guaraná improved swimming time in mice, and reversed memory deficits in rats on a passive avoidance task (Espinola et al., 1997). A similar effect was also found following acute administration of 3 mg/kg guaraná, 30 mg/kg guaraná and 1 mg/kg of caffeine (Espinola et al., 1997). An early investigation into potential effects of guaraná in normal young volunteers failed to find any effects of guaraná using tests of digit span, free recall, digit symbol, cancellation tests and the mosaic test (Galduróz and Carlini, 1994). The same study also evaluated sleep interference and anxiety and again found no effects. The authors present possible explanations for their lack of positive results such as task insensitivity – they also failed to find effects of 25 mg caffeine in the same study, a dose twice that of the lowest known psychoactive dose (Smit and Rogers, 2000). In this first investigation in humans, 1000 mg guaraná was tested, containing only 2.1 % caffeine. Given the lack of data in this area, it is quite possible that any effects could have been missed simply as a result of inappropriate dose selection. Finally, the time course of testing may not have been sufficient, acute testing only being carried out at one hour post-treatment and chronic testing following three days of treatment administration. In a follow-up study (Galduróz and Carlini, 1994), the same doses and tasks were used to assess chronic (five months) effects in an elderly population. They found only one improvement, a significant effect of guaraná on mosaic performance at five months. A very few studies have examined guaraná’s acute behavioural effects. In one randomised, double-blind, placebo-controlled, counter-balanced study, 75 g of a proprietary extract of guaraná (Pharmaton extract PC-102), Ginseng and their combination were compared with placebo over the course of six hours using a battery of computerised assessments (Kennedy et al., 2004a). Guaraná speeded responses on attentional tasks and a heavily loaded Serial Subtraction task (Serial 7s) – although there was evidence of

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a speed–accuracy trade-off on the latter measure. There was also evidence of secondary memory improvements. In another similarly controlled study from our group, the cognitive and mood effects of different doses of guaraná were assessed. The doses used were 37.5 mg, 75 mg, 150 mg and 300 mg, and their effects were assessed using the same outcomes in 30 healthy participants. Testing took place predose and at one hour, three hours and six hours thereafter with a seven-day ‘wash out’. The data confirm the positive effects on secondary memory which in this case was evident following 37.5 mg and 75 mg of extract. There was a significant positive effect on ‘alert’ following the highest dose only and significant improvements of ‘content’ ratings associated with all doses (Haskell et al., 2007). The data suggest that guaraná scan positively modulate cognitive performance and mood. An unpublished study from Scholey’s group has directly compared the neurocognitive effects of guaraná with caffeine administered at the same dose contained within guaraná treatment. The data showed that the cognitive and mood profile of guaraná is distinct from that of its caffeine content. Guaraná extracts appear to show positive effects on cognitive performance which may be robust in the secondary memory domain. These effects are probably not underpinned by caffeine alone and may be attributable to modulation of caffeine by other guaraná components or by direct effects of non-caffeine constituents. Examination of the behavioural effects of decaffeinated guaraná may resolve this issue. The effects of chronic guaraná administration are not known.

11.8 Flavonoids Flavonoids are a diverse class of natural compounds, found within many plants; they are a class of polyphenols and at least 4000 have been identified. Several sub-categories of flavonoids exist in the human diet, including flavanols (flavan-3-ols), flavonols, isoflavones, flavones, flavanones and anthocyanidins. Much research has focused on the potential health benefits of flavanols which are found in numerous common foodstuffs including grapes, red wine, apples, green and black teas and cocoa (Gu et al., 2004). The potential health benefits associated with the consumption of flavanolcontaining foods are likely to have ramifications for cognitive function. Here, we use cocoa flavonols as an example since they have been used in several studies examining neurocognitive effects. Consumption of flavanol-containing cocoa products can reduce platelet aggregation (Holt et al., 2006) and improve insulin sensitivity (Grassi et al., 2008) and blood pressure. There is also increasing evidence that consumption of cocoa flavanols (CF) can improve a host of parameters reflecting improved peripheral and central blood flow (Grassi et al., 2008). While the mechanisms

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underlying these effects remain to be elucidated, they may be related to increased nitric oxide synthesis within blood vessels. Crews et al. (2008) evaluated the cognitive effects of cocoa in over-60 year-olds. Participants were administered 37 g dark chocolate and a 273 ml cocoa drink or matching placebo products daily for six weeks. There were no treatment-related changes in cognitive function, nor in numerous physiological or other biomarkers measured during mid-point or end-point assessments. While these findings might suggest no efficacy for cocoa flavanols on cognition, the lack of effects may be due to either a flavonoid-rich habitual diet or the fact that these were cognitively high-functioning individuals. Pulse rate was significantly elevated in the cocoa consumers, suggesting that the treatment was having some physiological effect over and above diet. The possibility that participants were approaching ceiling performance, thereby minimising any CF effects on cognition, cannot be ruled out. Interestingly, cocoa flavonol ingestion is associated with increased cerebral blood flow and brain activation. In one study, subjects received a daily cocoa or control drink for five days and on day five they underwent cognitive testing and functional magnetic resonance imaging (fMRI) (Francis et al., 2006). The cocoa condition was associated with greater activation of task-relevant brain loci (dorsolateral prefrontal cortex, anterior cingulate and parietal cortex) but no cognitive enhancement. Prior to the intervention phase, participants were trained to a high performance criterion (greater than 95 % accuracy); therefore, it is possible that performance was approaching ceiling, minimising the possibility of enhancement through CF ingestion. As the participants had received cocoa on the assessment day (day 5 of the sub-chronic trial), the authors examined the potential acute effects of cocoa flavanols on cerebral blood flow (CBF). They found increased CBF which within two hours of cocoa consumption which returned to baseline by six hours. This timeframe is consistent with a study finding dose-dependent improvements in cognitive performance following ingestion of cocoa polyphenols during a heavily loaded cognitive demand battery (Scholey et al., 2010). The peak improvements in cognitive performance and reduced mental fatigue roughly coincided with peak CBF and serum flavonol levels. This suggests that such processing is sensitive to changes in blood flow mediated by cocoa polyphenols via the mechanism described above. On the other hand, a recent study using the same cognitive paradigm following ingestion of the red wine polyphenol resveratrol found no cognitive effects, although there was evidence of increased CBF (Kennedy et al., 2010). These data suggest that, for polyphenols, the cognitive and physiological effects can be dissociated. They clearly illustrate that one cannot generalise from the effects of one plant extract, or even class of extract, to another. This also suggests that other flavanols may well impart cognitive benefits. For example, there is epidemiological evidence linking tea consumption with better cognitive performance, and

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individual tea flavanols are known to influence blood flow both acutely and chronically.

11.9 Conclusions and future trends The concentrations of the active components in herbal extracts and preparations vary with the specific extraction method. Similarly, the levels of active components in plant material depend on growth conditions, such as climate, soil composition, light levels and time of harvest. Contemporary agricultural techniques, including highly controlled hydroponic environments, now offer the opportunity to tightly control the growing environment, including the introduction of stressors that provoke specific changes in levels of active components. It may be feasible to grow ‘standardised’ plants which retain any positive properties of whole extract. From both a methodological perspective and theoretical standpoint, the psychopharmacology of plant extracts offers unique challenges. From a methodological standpoint, it is of paramount importance to perform replicable experiments using standardised extracts to allow meaningful comparison across studies (Scholey et al., 2005). It is also worth noting that one approach to addressing the role of individual components within botanicals might be to compare the effects of extracts with differing profiles of putative actives. For example the ginsenoside profile of American Ginseng (Panax quinquefolius) differs from that of Asian Ginseng (Panax ginseng) largely through the profile of two key ginsenosides. It would clearly offer some insight into the roles of these ginsenosides to compare the behavioural effects of the two. Another means of assessing the effects of individual components would be to assess the effects of the whole extract without the component of interest. For example, one might assess the role of caffeine in coffee by comparing caffeinated and decaffeinated coffee. It is currently expensive and technologically difficult to extract single components from plant material while leaving the other components intact. However, as such technology becomes more sophisticated the possibility of ‘knockout psychopharmacology’ may become a reality. One further issue is that, like for other functional foods and nutraceuticals, the legal landscape differs across the world, with different legislation governing what claims can be made about herbal medicines in different countries. A more harmonised global legislation would help to increase the rigour of clinical trials using herbal extracts enormously.

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kennedy d, jackson p, haskell c and scholey a (2007a) Modulation of cognitive performance following single doses of 120 mg Ginkgo biloba extract administered to healthy young volunteers. Human Psychopharmacology: Clinical and Experimental, 22, 559–566. kennedy d, reay j and scholey a (2007b) Effects of 8 weeks administration of Korean Panax ginseng extract on the mood and cognitive performance of healthy individuals. Journal of Ginseng Research, 31, 34–43. kennedy d, wightman e, reay j and haskell c (2010) Effects of resveratrol on cerebral blood flow parameters and cognitive performance in humans: a doubleblind, placebo-controlled, crossover investigation. American Journal of Clinical Nutrition, 91, 1590–1597. koul o (2008) Phytochemicals and insect control: an antifeedant approach. Critical Reviews in Plant Sciences, 27, 1–24. labadorf c m t, labadorf s et al. (2004) The global cognitive effects of ginseng taken by healthy volunteers over a 21 day period. Journal of Pharmacology, 18 (Suppl 1), A46. mahadevan s and park y (2008) Multifaceted therapeutic benefits of Ginkgo biloba L.: chemistry, efficacy, safety, and uses. Journal of Food Science, 73, R14–19. mahady gb (2002) Ginkgo biloba for the prevention and treatment of cardiovascular disease: a review of the literature. The Journal of Cardiovascular Nursing, 16, 21–32. mantle d, eddeb f and pickering a (2000) Comparison of relative antioxidant activities of British medicinal plant species in vitro. Journal of Ethnopharmacology, 72, 47–51. marinac j, buchinger c, godfrey l, wooten j, sun c and willsie s (2007) Herbal products and dietary supplements: a survey of use, attitudes, and knowledge among older adults. JAOA: Journal of the American Osteopathic Association, 107, 13–20. matsuda h, samukawa k and kubo m (1990) Anti-inflammatory activity of ginsenoside ro1. Planta Medica, 56, 19–23. mattei r, dias r, espínola e, carlini e and barros s (1998) Guaraná (Paullinia cupana): toxic behavioral effects in laboratory animals and antioxidant activity in vitro. Journal of Ethnopharmacology, 60, 111–116. mattson m and cheng a (2006) Neurohormetic phytochemicals: Low-dose toxins that induce adaptive neuronal stress responses. TRENDS in Neurosciences, 29, 632–639. mazza m, capuano a, bria p and mazza s (2006) Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer’s dementia in a randomized placebo-controlled double-blind study. European Journal of Neurology, 13, 981–985. mckenna d j, jones k and hughes k (2001) Efficacy, safety, and use of ginkgo biloga in clinical and preclinical applications. Alternative Therapies in Health and Medicine, 7, 70–90. mencherini t, picerno p, scesa c and aquino r (2007) Triterpene, antioxidant, and antimicrobial compounds from Melissa officinalis. Journal of Natural Products, 70, 1889–1894. mulkens a, stephanou e and kapetanidis i (1985) Glycosides with volatile genins in leaves of Melissa officinalis. Heterosides a genines volatiles dans les feuilles de Melissa officinalis L. (Lamiaceae), 60, 276–278. nitta h, matsumoto k, shimizu m, ni x and watanabe h (1995) Panax ginseng extract improves the scopolamine-induced disruption of 8-arm radial maze performance in rats. Biological & Pharmaceutical Bulletin, 18, 1439–1442.

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ong y and yong e (2000) Panax (ginseng)-panacea or placebo? Molecular and cellular basis of its pharmacological activity. Annals-Academy of Medicine Singapore, 29, 42–46. perry n, court g, bidet n, court j and perry e (1996) European herbs with cholinergic activities: Potential in dementia therapy. International Journal of Geriatric Psychiatry, 11, 1063–1069. perry e k, pickering a t, wang w w, houghton p j and perry n s l (1999) Medicinal plants and Alzheimer’s disease: from ethnobotany to phytotherapy. Journal of Pharmacy and Pharmacology, 51, 527–534. perry n, bollen c, perry e and ballard c (2003) Salvia for dementia therapy: review of pharmacological activity and pilot tolerability clinical trial. Pharmacology Biochemistry and Behavior, 75, 651–660. persson j, bringlöv e, nilsson l and nyberg l (2004) The memory-enhancing effects of Ginseng and Ginkgo biloba in healthy volunteers. Psychopharmacology, 172, 430–434. petersen m and simmonds m (2003) Rosmarinic acid. Phytochemistry, 62, 121–125. petkov v and mosharrof a (1987) Effects of standardized ginseng extract on learning, memory and physical capabilities. American Journal of Chinese Medicine, 15, 19–29. petkov v, kehayov r, belcheva s, konstantinova e, petkov v, getova d and markovska v (1993) Memory effects of standardized extracts of Panax ginseng (G115), Ginkgo biloba (GK 501) and their combination Gincosan (PHL-00701). Planta Medica, 59, 106–114. raghav s, singh h and dalal p (2006) Randomized controlled trial of standardized bacopa monniera in age-associated memory impairment. Indian Journal of Psychiatry, 48, 238–242. ramassamy c, longpre f and christen y (2007) Ginkgo biloba extract (EGb 761) in Alzheimer’s disease: is there any evidence? Current Alzheimer Research, 4, 253–262. reay j, kennedy d and scholey a (2005) Single doses of Panax ginseng (G115) reduce blood glucose levels and improve cognitive performance during sustained mental activity. Journal of Psychopharmacology, 19, 357–365. reay j, kennedy d and scholey a (2006) Effects of Panax ginseng, consumed with and without glucose, on blood glucose levels and cognitive performance during sustained mentally demanding tasks. Journal of Psychopharmacology, 20, 771–781. roodenrys s, booth d, bulzomi s, phipps a, micallef c and smoker j (2002) Chronic effects of Brahmi (Bacopa monnieri) on human memory. Neuropsychopharmacology, 27, 279–281. sadraei h, ghannadi a and malekshahi k (2003) Relaxant effect of essential oil of Melissa officinalis and citral on rat ileum contractions. Fitoterapia, 74, 445–452. salim k, mcewen b and chao h (1997) Ginsenoside Rb1 regulates ChAT, NGF and trkA mRNA expression in the rat brain. Molecular Brain Research, 47, 177–182. savelev s, okello e, perry n, wilkins r and perry e (2003) Synergistic and antagonistic interactions of anticholinesterase terpenoids in Salvia lavandulaefolia essential oil. Pharmacology, Biochemistry, and Behavior, 75, 661–668. scholey a and kennedy d (2002) Acute, dose-dependent cognitive effects of Ginkgo biloba, Panax ginseng and their combination in healthy young volunteers: differential interactions with cognitive demand. Human Psychopharmacology: Clinical and Experimental, 17, 35–44. scholey a, kennedy d and wesnes k (2005) The psychopharmacology of herbal extracts: issues and challenges. Psychopharmacology, 179, 705–707. scholey a, tildesley n, ballard c, wesnes k, tasker a, perry e and kennedy d (2008) An extract of Salvia (sage) with anticholinesterase properties improves

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12 Malnutrition and externalizing behaviour J. Liu and A. Raine, University of Pennsylvania, USA

Abstract: Malnutrition, particularly the deficiencies of zinc, iron, and omega-3 fatty acids and the excessive consumption of food additives, is increasingly recognized as a risk factor for childhood externalizing behaviour, including aggression, hyperactivity, delinquency, conduct disorder, and antisocial personality disorder. It is hypothesized that malnutrition can interfere with brain functioning by diminishing neuronal growth and development of the brain, altering neurotransmitter functioning, increasing neurotoxicity, and impairing cognitive functioning. These mechanisms present significant implications for malnutrition during childhood, when the brain is growing most rapidly and therefore vulnerable and sensitive to insults. The food industry, policy makers, and health care professionals will have an important role in changing practice and strengthening education and research to prevent malnutrition for current and future generations. Key words: externalizing behaviour, childhood malnutrition, micronutrient deficiencies, food additives.

12.1 Introduction This chapter is concerned with the impact of malnutrition on externalizing behaviour. Externalizing behaviour often refers to problems manifested in outward behaviour and is considered a negative reaction to one’s environment. These problem behaviours can include aggression, hyperactivity, delinquency, conduct disorder, and anti-social personality disorder. While externalizing behaviour problems can be seen in both children and adults, it is especially important to recognize these behaviours in a developing child because childhood externalizing behaviour is a major predisposition to adolescent delinquency and adult violence later in life (Raine, 2002; Tremblay et al., 2004). Understanding the causes of externalizing behaviour during childhood may help diminish adult violence. Early nutritional factors are increasingly viewed among other health risk factors as contributing to the development of these behaviours (Liu and Raine, 2006). For years, great

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effort, both from research and clinical communities, has been made to reduce the occurrence of externalizing behaviour in children and adolescents. For example, psychoanalytic, behaviour modification, and experimental drug therapy approaches have been implemented. However, these approaches have not been successful in decreasing externalizing behaviour. One possible explanation lies in the fact that biological factors, including malnutrition, were not considered as possible factors influencing behavioural development. What is malnutrition? The World Health Organization defines malnutrition as ‘the cellular imbalance between the supply of nutrients and energy and the body’s demand for them to ensure growth, maintenance, and specific functions’ (WHO, 2000). Normally malnutrition refers to a deficiency of macronutrients (i.e. protein–energy malnutrition) and/or micronutrients (i.e. iron, zinc, or vitamin deficiency). While macronutrients are required by the human body in larger quantities, micronutrients are only needed in very small amounts (milligrams or micrograms per day depending on the micronutrient). Studies have suggested that both macro- and micronutrient deficiencies are linked to increased behaviour problems in both children and adults (Liu et al., 2004; Neugebauer et al., 2006). Millions of children worldwide are malnourished (WHO, 2001; Muller and Krawinkel, 2005; Liu et al., 2006). More specifically, approximately one third of African children and 10–25 % of children in other developing countries are malnourished (Lopez, 2004). Regarding micronutrition, it is estimated that up to half of all the children in the world are deficient in iron and/or zinc (WHO, 2001). In developing countries in particular, micronutrient deficiencies are still prevalent. For example, iron deficiency anaemia is the most prevalent nutritional deficiency worldwide, and it is estimated that up to half of all the children in the world are deficient in iron (WHO, 2001), approximately 90 % of whom are living in developing countries (Lopez, 2004). In addition, although much progress has been made in industrialized countries, iron deficiency is still relatively common, especially in minority vulnerable populations (Ramakrishnan and Yip, 2002). For example, in a study of 1641 toddlers in the US, 12 % of Hispanic children were irondeficient compared to 6 % each in whites and blacks (Brotanek et al., 2007). Zinc deficiency also continues to be a nutritional problem in children in both developing and developed countries (Werbach, 1992; Breakey, 1997; Penland, 2000; Hambidge and Krebs, 2007). Longitudinal studies show that malnutrition during infancy is associated with increased childhood behavioural problems including attention deficits and aggressive behaviour (Galler et al., 1983, 2005; Galler and Ramsey, 1989). Early childhood malnutrition has also been related to externalizing behaviour in both childhood and adolescence (Liu et al., 2004, 2005). Past research studying the effects of diet and nutrition on behaviour has primarily focused on hyperactivity and attention deficit disorder. However, since the late 1990s studies have begun to recognize the roles that diet and

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nutrition play in the development of human aggressive, violent, anti-social, and criminal behaviour (Neugebauer et al., 1999; Fishbein 2001; Gesch et al., 2002; Liu et al., 2004). Recently, a study was conducted that found fewer incidents among prisoners who were given a nutritional supplement (Zaalberg et al., 2010). The study looked at 221 young Dutch prisoners who received either a placebo or a nutritional supplement containing vitamins, minerals, essential fatty acids over a period of one to three months (Zaalberg et al., 2010). Compared to the placebo group, reported incidents and rule-breaking behaviour were significantly lower, although other assessments found no significant reductions in aggressiveness or psychiatric symptoms (Zaalberg et al., 2010). Overall, this chapter outlines recent empirical findings regarding malnutrition as a risk factor for childhood externalizing behaviour, and highlights possible brain mechanisms that could explain the malnutrition– externalizing behaviour link. Following this, we propose implications that this link has for food industries, nutritionists, and policy-makers. Finally, we will briefly address future trends in the prevention and intervention of malnutrition from an education, practical, and research standpoint. This exploration will hopefully shed light on the true meaning behind the ancient dictum ‘you are what you eat,’ which emphasizes the importance of nutritional factors on negative externalizing behaviours. More specifically, we will focus on micronutrients (zinc and iron) and omega-3 fatty acids, in addition to certain food additives, all of which have been implicated in children’s externalizing behaviours.

12.2 Dietary influences on externalizing behaviour 12.2.1 Iron and zinc micronutrient deficiencies Both iron and zinc are important trace metals that are minerals essential for good nutrition and for maintaining brain homeostasis. Iron has significant involvement in oxygen transport, and zinc plays a crucial role in growth and development, both physically and neurobehaviourally. With a balanced diet, one will typically not be at risk for nutritional deficiency. However, environmental influence and individual lifestyle can impact one’s micronutrient status, leading to deficiency and thereby dysfunction of both the body and the brain. There is evidence that micronutrients including iron and zinc affect both brain and behavioural functioning (Rosen et al., 1985; Watts, 1990; Tu, 1994; Sever et al., 1997; Konofal et al., 2005). Observational studies have reported iron deficiency in aggressive and conduct disordered children (Rosen et al., 1985; Werbach, 1992; Corapci et al., 2010). In a US study, a third of juvenile delinquents were found to have iron deficiency (Rosen et al., 1985). In one clinical trial, Sever et al. (1997) found that children with attention deficit hyperactivity disorder (ADHD) who were not iron-deficient showed both

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cognitive and behavioural improvements after treatment with iron supplements. In terms of zinc, several studies assessed the role of zinc deficiency in externalizing behaviour (Halas et al., 1977; Brophy, 1986; Watts, 1990; Arnold and DiSilvestro, 2005). In animals, the offspring of rats deprived of zinc during pregnancy were significantly more aggressive than controls (Halas et al., 1977). In humans, zinc deficiency has been correlated with hyperactivity and ADHD (Yorbik et al., 2008). In this correlation study, Yorbik and colleagues measured the plasma zinc levels of 28 boys and reviewed the event-related potentials (ERPs) of the boys. In the low-zinc group compared to zinc non-deficient group, the latencies of the N2 ERP in frontal and parietal region were significantly shorter (Yorbik et al., 2008). This suggests that plasma zinc levels may affect information processing in ADHD children (Yorbik et al., 2008). In a review of existing literature, it was found that lower zinc tissue levels (serum, red cells, hair, urine, nails) were found in children with ADHD (Arnold and DiSilvestro, 2005). In addition, the review reported the results of two zinc supplementation studies, which showed significant benefit (Arnold and DiSilvestro, 2005). However, the study cautions that both intervention studies and all but one of the correlation studies occurred outside of the US, in countries with different diets and socioeconomic conditions (Arnold and DiSilvestro, 2005). Overall, the paper recommends further study of zinc supplementation, which could be a more cost-effective treatment for children with ADHD (Arnold and DiSilvestro, 2005). An example of micronutrient deficiency was seen in a longitudinal study conducted by Liu et al. (2004) in children from the island of Mauritius, which is populated by an ethnically diverse community. Children were assessed for signs of malnutrition at the age of 3 years. Other than protein malnutrition, iron and zinc deficiency were identified, as indicated by anaemia (low haemoglobin), thin, sparse hair (zinc or iron deficiency), and hair dyspigmentation (zinc deficiency). Cognitive ability was assessed at age 3 using the Boehm Test of Basic Concepts – Preschool version. Cognitive ability was also re-assessed with seven sub-tests of the Wechsler Intelligence Scale for Children (WISC) at age 11 years. An index of psychosocial adversity was developed, based on 14 variables assessed by social workers. Externalizing behaviour problems were measured with three independent instruments at ages 8, 11, and 17 years. Externalizing behaviour at age 8 was measured with the Children’s Behaviour Questionnaire completed by the child’s teachers. At ages 11 and 17 years, the child’s behaviour was assessed by the parents’ and teachers’ ratings on externalizing sub-scales (aggression, delinquency, hyperactivity) of the Child Behaviour Checklist and the Revised Behaviour Problem Checklist. The results of this longitudinal study showed three key findings. First, there is a direct effect of early malnutrition (age 3) on later childhood externalizing behaviour. Specifically, those with signs of malnutrition at the age of 3 were shown to be more aggressive or hyperactive at 8 years of age,

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exhibited more externalizing problems at age 11, and had greater conduct disorder and excessive motor activity at age 17. Interestingly, there was a dose–response relationship between the degree of malnutrition (i.e. the number of signs of malnutrition) and degree of externalizing behaviour at ages 8 and 17. It was found that the greater the number of signs of malnutrition present, the greater the degree of externalizing behaviour problems. Social adversity is often related to negative behavioural outcomes in children. Also, as Benton (2008) points out, malnutrition is typically associated with social and cultural deprivation. In this study, Liu et al. controlled for up to 14 variables of social adversity in order to tease out the direct influence of malnutrition on behaviour, independent of social deprivation. The results confirmed that the effect of malnutrition on externalizing behaviour is not confounded by psychosocial adversity, indicating that regardless of the children’s background, they were equally susceptible to the effects of malnutrition on behaviour problems. Lastly, and importantly, malnutrition and externalizing behaviour were mediated by poor cognitive functioning both at ages 3 and 11 years. This finding indicates that malnutrition predisposes to neurocognitive deficits, which in turn predispose to persistent externalizing behaviour problems throughout childhood and adolescence. The findings suggest that reducing early malnutrition may help reduce later anti-social and aggressive behaviour. While the above example was a longitudinal observational study, clinical trials and intervention studies also show a similar effect of malnutrition on behaviour. In his extensive review of the impact of diet on anti-social, violent, and criminal behaviour, Benton (2007) summarized three welldesigned trials in which micronutrient supplementation resulted in a significant reduction in violent and non-violent anti-social behaviour (Schoenthaler et al., 1997; Schoenthaler and Bier, 2000; Gesch et al., 2002). In another double-blind clinical trial, 400 children with a primary diagnosis of ADHD were randomly assigned to take either placebo or 150 mg of zinc sulfate per day for 12 weeks (Bilici et al., 2004). Behaviour was assessed with a clinical ADHD scale and a parent rating scale. Children who took the zinc supplements showed significant reductions in hyperactivity and impulsivity, although the treatment did not affect the children’s attention deficits. Older children with a higher body mass, those with low zinc levels, and those with low levels of free fatty acids responded best to the intervention. A randomized, double-blind, placebo-controlled trial in working-class children in two primarily Hispanic elementary schools in the US was also conducted by Schoenthaler and Bier (2000). Half of the enrolled 486 schoolchildren were given daily vitamin and mineral supplementation at 50 % of the US recommended daily allowance for four months, and the other half were given a placebo. A 47 % reduction in anti-social behaviour was reported in children taking the supplements compared with children who received a placebo. Intervention studies like this one add weight to the

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findings from correlation studies by suggesting a causal relationship between micronutrient deficiency and behaviour problems. However, an important caveat is that studies in this field are not always consistent and the results have been mixed (Kordas et al., 2005). Studies suggest that mineral deficits alone may not be entirely responsible for behaviour problems, but instead low mineral levels may exacerbate the effects of environmental toxicity (Walsh et al., 1997; Hubbs-Tait et al., 2005). Neurotoxicity caused by detrimental environmental factors, such as lead exposure, has been linked to increased behaviour problems in children and adults. Studies illustrate how iron deficiency can increase the metabolic toxicity of lead poisoning (Warrier et al., 1985). More specifically, irondeficient animals have been shown to absorb a greater percentage of ingested lead compared to iron-replete animals (Mahaffey-Six and Goyer, 1972; Barton et al., 1978). This is due to the fact that both iron and lead bind competitively to the same absorptive receptor, and iron deficiency therefore implies increased lead retention. However, adding calcium to the diet has been shown to decrease the toxic effects produced by lead exposure (Bogden et al., 1997; Woolf et al., 2007). Along these same lines, it has been reported that animals fed a diet high in manganese, a toxic heavy metal, do not have high levels of blood manganese when such diets contained an adequate amount of calcium (Masters et al., 1998). In contrast, when the diet was deficient in calcium, manganese uptake was high. Lead exposure has been linked with externalizing behaviour problems in children. Needleman et al. (1996) reported that increased bone lead concentrations in school children correlated with increased aggression, attention problems, and delinquency. Children are particularly vulnerable to neurotoxic substances such as lead. Their small bodies absorb more lead than adult bodies do. Their hand–mouth behaviour and their proximity to the floor significantly expose children to polluted dust and dirt. Due to the developing nature of the brain and nervous system, their brains are more susceptible to injury from exposure to chemicals and poisoning.

12.2.2 Omega-3 fatty acids Omega-3 fatty acids, also known as polyunsaturated fatty acids (PUFAs), are considered to be essential fatty acids (EFAs) because, while they are necessary for good health, they cannot be produced by the body and therefore must be consumed. While the benefits of omega-3 on cardiovascular health, such as a decreased risk of coronary heart disease or sudden cardiac death, have been well-established (Albert et al., 1998; Hu et al., 2002), its effects on neurodevelopment and growth, cognition (memory and performance), and behaviour have been receiving an increasing amount of attention. There are three varieties of omega-3 fatty acids: alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA is a short-chain fatty acid while EPA and DHA are long-chain fatty

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acids. ALA is found in plant sources such as walnuts, flax seed, canola oil, and soybean oil. EPA and DHA are found in fish and can be obtained through fish oil supplements. The short-chained ALA consumed can be converted by the body into the long-chained EPA and DHA, but only on a limited basis (Harper et al., 2006). DHA deficiency is associated with declines in cognition (Lukiw et al., 2005). In addition, low levels of DHA in the cerebral cortex are found in depressed patients (McNamara et al., 2007). Omega-3 fatty acid deficiency has been hypothesized as an agent in depression, memory problems, mood swings, and many other conditions. In addition, children lacking sufficient amounts of omega-3 fatty acid are hypothesized to be especially likely to exhibit hyperactivity, learning disorders, and behavioural problems. This evidence has its basis in animal studies, epidemiological observational studies, and intervention studies. Taken together, these studies all provide preliminary support for the claim that omega-3 fatty acid intake can help regulate our behaviour. In terms of animal studies, omega-3 fatty acid deprivation has been shown to increase aggression in different animals in controlled experimental laboratories. In a study conducted by DeMar et al. (2006), researchers strove to investigate whether dietary omega-3 fatty acid deprivation would increase behavioural disturbances. Rats were assigned to diets either deficient or adequate in omega-3 fatty acid for 15 weeks. Flaxseed oil supplied the omega-3 fatty acids in the adequate diet condition. During the subsequent three weeks, data were obtained via locomotor activity, depression, and aggression tests. The results showed that the omega-3 fatty aciddeprived rats had significantly higher depression and aggression scores in an isolation-induced resident–intruder test. The measure for depression was a Porsolt forced-swim test. In this test, a rat is forced to swim in a pool of water with no escape (Porsolt et al., 1977). After an initial burst of activity, the rat will stop moving, which is interpreted as a sign of despair. Rats in a state of lowered mood will have shorter time periods between activity and cessation of activity. In the test of aggression, the omega-3 deprived ‘resident’ rats frequently shoved and pinned the ‘intruder’ rats against the cage walls, in addition to vigorously preening the fur of the ‘intruder’ along its back, sides, and face. More recently, Re et al. (2008) investigated the effects of omega-3 fatty acid deprivation on aggressive behavioural alterations in dogs. In this study, researchers investigated 18 healthy, adult male German Shepherd dogs that exhibited aggressive behaviour. Compared to the control group of non-aggressive dogs, aggressive dogs showed lower omega-3 fatty acid plasma concentrations. Nevertheless, the later study is cross-sectional and therefore cannot determine a causal effect of omega-3 fatty acid status on aggression. Human studies also verify that omega-3 fatty acid deficiencies are linked to aggression, depression, and impulsive behaviour (Hibbeln et al., 2006). Behaviour problems (including temper tantrums) occur more often in boys

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with lower total fatty acid concentrations in the plasma phospholipid fraction (Stevens et al., 1996). In a study conducted by Hibbeln et al. (2007), 11 875 pregnant women filled out a food frequency questionnaire that aimed to assess seafood consumption at 32 weeks’ gestation. The researchers compared the behavioural and cognitive outcomes of children aged 6 months to 8 years, whose mothers consumed none, 1–340 g per week, or >340 g of seafood per week. Among these pregnant women, low maternal seafood intake was found to be associated with sub-optimum outcomes for children’s pro-social behaviour, fine motor activity, communication, and social development (Hibbeln et al., 2007). In contrast, higher maternal intakes of seafood, a valuable source of essential fatty acids, have been associated with greater pro-social behaviour and social development in children (Hibbeln et al., 2007). In intervention studies, omega-3 fatty acid supplementation has been shown to have positive behavioural benefits. In the US, a randomized trial of EPA supplementation for two months in women with borderline personality disorder showed significantly reduced aggression compared to a mineral oil placebo (Zanarini and Frankenburg, 2003). In a pilot intervention study in 50 children with ADHD, children who received DHA/EFA supplementation showed reduced oppositional defiant behaviour compared with controls (Stevens et al., 2003). However, a randomized, double-blind, placebo-controlled trial of fish oil fortification of foods conducted on 9–12 year-old children was found to reduce impulsivity and physical aggression in girls, but not in boys (Itomura et al., 2005). Supplementation with DHA (345 mg/day) for four months increased plasma phospholipid DHA concentrations 2.6-fold compared with a placebo group, but did not improve any objective or subjective measures of symptoms related to ADHD (Itomura et al., 2005). Finally, omega-3 fatty acid supplementation in patients with mild to moderate Alzheimer’s disease decreased depressive and symptoms of agitation (Freund-Levi et al., 2007). In a double-blind, randomized controlled clinical trial, Gesch et al. supplied 231 volunteer prisoners with either a supplement or a vegetable oilbased placebo of identical appearance (Gesch et al., 2002). The aim of this study was to determine the influence of supplementary vitamins, minerals, and essential fatty acids on the anti-social behaviour of young adult prisoners. The outcome measures in this study consisted of prison reports of violence and rule infractions. Gesch et al. found that supplementing prisoners’ diets with vitamins, minerals, and essential fatty acids for a minimum of two weeks resulted in a 35.1 % reduction in anti-social behaviour (Gesch et al., 2002). However, it is not clear whether this change was due to the presence of the fatty acids or the vitamins/minerals in the supplement. For example, Schoenthaler found comparable results with only a vitamin and mineral supplement, so perhaps these gains were due to the presence of the vitamins and minerals (Schoenthaler et al., 1997). Nevertheless, fatty acids are believed to play a role in the regulation of mood and behaviour.

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It should be noted, however, that research on the role of DHA and omega-3 long-chain EFAs has produced somewhat equivocal results. For example, some studies have found the effects of omega-3 fatty acid intake to be confounded by sociodemographic factors (Wavlen et al., 2009). Additionally, while most studies have found that children with ADHD consume less omega-3 (Antalis et al., 2006), some studies have found that ADHD children consume equivalent amounts of omega-3 to controls, but display abnormal essential fatty acid profiles and have significantly lower levels of DHA than control subjects (Colter et al., 2008). Nonetheless, research on omega-3 fatty acid has already highlighted the importance of this nutrient’s contribution to the development of externalizing behaviour. However, future research is still needed to further expand on such findings in order to draw a stronger causal conclusion.

12.2.3 Food additives There has been significant controversy associated with the risks and benefits of food additives. Generally speaking, food additives are artificial colours (e.g. tartrazine), flavours (e.g. vanillin), preservatives (e.g. butylated hydroxyanisole – BHA, butylated hydroxytoluene – BHT, tertiary butylhydroquinone – TBHQ), or sweeteners (e.g. aspartame) added to food in order to enhance its taste and appearance. In addition, additives are often used as aids in the manufacturing or processing of the foods (e.g. to prevent food products from clogging machines). Despite their many aesthetic and functional purposes, food additives have been shown to contribute to negative behavioural and physiological changes in consumers. The association between food additive-intolerance and behavioural and learning disorders in susceptible individuals was first explored by Feingold et al. in 1973, who looked at the impact of a particular additive, salicylates. Feingold believed that foods with salicylates were a contributor to hyperactivity. Some foods high in salicylates include vegetables, herbs, fruits, spices, nuts, and many processed foods. Foods naturally low in salicylates include meat, fish, cheese, eggs, and grains. The Feingold diet, which emphasized consumption of food with low levels of salicylates and minimized foods with higher levels of salicylates, was developed. However, it was found that children responded negatively, rather than positively, to the diet (Egger et al., 1985; Carter et al., 1993). Regarding the effect of food additives on behavioural disorders, studies suggest that the consumption of certain food additives and preservatives can contribute to the development of ADHD and to both the duration and frequency of hyperactivity in children (Rose, 1978; Boris and Mandel, 1994; McCann et al., 2007). Specifically, the ingestion of synthetic food colourings such as tartrazine has been shown to induce irritability, restlessness, and sleep disturbances in children (Rowe and Rowe, 1994). The landmark study of Boris and Mandel showed that 73 % of children diagnosed with ADHD

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responded well to a diet that eliminated all artificial food colours (Boris and Mandel, 1994). In addition, it was found that supplementation with artificial food colouring and sodium benzoate resulted in increased hyperactivity and adverse behaviour (Bateman et al., 2004; McCann et al., 2007). In the study by McCann and colleagues, 297 children were given either a placebo or a drink containing sodium benzoate and artificial food colouring additives (McCann et al., 2007). Children given the additives exhibited more hyperactive behaviour according to assessments from their parents and teachers (McCann et al., 2007). In light of their apparent impact on behaviour, research suggests that food additives specifically found in sweetened foods can contribute to childhood aggression and later adult violence (Benton, 2007; Moore et al., 2009).The experiment by Bateman and colleagues looked at 1873 children and found that hyperactivity decreased (compared to the placebo group) when sodium benzoate and artificial food colouring additives were removed (Bateman et al., 2004). In addition, it was found that hyperactivity levels were increased (compared to the control group) when the children were supplemented with sodium benzoate and food colourings (Bateman et al., 2004). Behaviour assessments were performed by parents and a tester who did not know the dietary status of the children (Bateman et al., 2004). Some food additives have also been shown to influence the neurophysiology of its consumers. For instance, monosodium glutamate (MSG) is a popular flavour-enhancing food additive that is added to foods to increase palatability and thereby consumption. Studies involving an early administration of MSG to mice show a degeneration of neurons in the inner layer of the retina and in the brain, convulsions, altered lipid metabolism, and an increased incidence of adulthood obesity (Olney, 1969; Maga 1995). The detrimental effects of some food additives on the brain and cognition pose a significant threat to consumers, particularly children whose brains are still in stages of development. Efforts to avoid childhood consumption of specific food additives have been made, and the introduction low food additive diets to schools has been shown to result in increases in academic performance, as evidenced by a 16 % rise in national academic ranking and a 7 % decrease in learning of disabled children in 803 New York City public schools (Schoenthaler et al., 1986). However, as discussed by Benton, it can be difficult to attribute these effects to the addition/removal of a single ingredient when other potential factors could account for the observed effects (Benton, 2007).

12.2.4

Possible brain mechanisms underlying the malnutrition – externalizing behaviour relationship A significant question that arises involves the mechanism by which malnutrition predisposes to externalizing behaviour problems. While this exact

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mechanism is unknown, we hypothesize that the answer lies within brain dysfunction. More specifically, malnutrition can interfere with brain functioning by diminishing neuronal growth and development of the brain, altering neurotransmitter functioning, and increasing neurotoxicity. These various forms of brain dysfunction can, in turn, predispose the individual to persistent externalizing behavioural problems (Liu and Raine, 2006). First, regarding diminished neuronal growth and development, both protein and micronutrients such as zinc and iron are known to be essential elements in maintaining the normal structure and function of the central nervous system (Young and Leyton, 2002; Gallagher et al., 2005; Liu et al., 2006; Nakagawasai et al., 2006). It is known that iron and zinc are essential for the synthesis and maintenance of myelin in the brain which, in turn, increases the speed of transmission of electrical impulses down the axon of a neuron. Consequently, inadequate amounts of iron and zinc can cause impaired brain growth, development, and functioning. Furthermore, DHA, an omega-3 fatty acid, is a key component of the brain. The brain is composed of 60 % fat, and DHA is the richest fatty acid in the brain. In the brain, DHA functions as a critical building block for the formation of grey matter. An increasing amount of data demonstrates that low levels of polyunsaturated fatty acids play a role in the pathophysiology of aggressive disorders (Buydens-Branchey et al., 2003). Second, micronutrients play an important role in influencing neurotransmitter functioning. Neurotransmitter metabolism involves a chain of biochemical reactions that rely on vitamins and minerals, such as zinc and iron, which function as important co-enzymes in the production, release, inhibition, transmission, and receptor formation aspects of neurotransmission. In addition to micronutrients, DHA also plays a role in the synthesis of serotonin and dopamine. Dopamine is a major neurotransmitter in the brain, and iron is highly concentrated in dopamine pathways. Animal studies show that a prenatal deficiency of omega-3 fatty acid in rats results in a decreased density of synaptic vesicles at the terminal ends of neurons, the storage site of neurotransmitters (Yoshida et al., 1997). Kodas et al. (2004) found that omega-3 deficiency can negatively impact serotonin neurotransmission in rats. Similarly, Zimmer et al. (2000) found that rats deficient in omega-3 fatty acids exhibited altered dopamine neurotransmission. Neurotransmitters are important regulators of emotion and behaviour, and the lack of such biochemicals has been associated with externalizing behaviour problems. Benton (2007) believes that a range of micronutrients is a possible key in the metabolism of neurotransmitters which in turn regulate aggressive behaviour. Aggressive offenders have repeatedly been found to have lower levels of the neurotransmitter serotonin (Halperin et al., 1994; Virkkunen et al., 1995). Similarly, aggressive monkeys have also been found to have low levels of serotonin (Kyes et al., 1995). Drug research also suggests that the relationship may be causal. Prozac, which increases

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serotonin, has been found to reduce aggression in humans (Coccaro and Kavoussi, 1997). Third, neurotoxicity needs to be considered. As discussed earlier, micronutrient deficiency interacts with heavy metals such as lead in predisposing to behaviour problems. Lidsky and Schneider (2003) argue that foetal lead exposure can prevent synapse formation and cell differentiation. They point out that the direct neurotoxic action of lead includes impaired neurotransmitter functioning and damage to the growth of the brain cell. Lead’s ability to substitute for calcium and perhaps zinc is believed to be a factor common to many of its toxic actions. Consequently, malnutrition-induced neurotoxicity can cause brain dysfunction and can further impact behaviour problems. Malnutrition can also predispose to externalizing behaviour problems through impairment in cognitive functioning (Liu et al., 2003). Low intelligence (IQ) has been found to mediate the relationship between malnutrition and increased externalizing behaviour throughout childhood and adolescence (Liu et al., 2004, 2005). Poor cognitive ability is consistently found to predispose to externalizing behaviour problems (Liu et al., 2006). A low IQ could predispose a child to failure in school, resulting in increased frustration and low self-esteem, in turn resulting in anti-social behaviour. Despite evidence that protein malnutrition and micronutrient deficiency affects behaviour, it is unknown whether the effects of early malnutrition on later behaviour are permanent or reversible, or if the effects on behaviour begin before birth. Malnutrition during the prenatal period is believed not only to produce permanent alterations in brain structure (Gressens et al., 1997; Duran et al., 2005; Gallagher et al., 2005), but also to cause enduring behavioural changes (Smart, 1986; Duran et al., 2005). Animal research has shown that prenatal supplementation with choline (which itself is not a B vitamin but part of the vitamin B family) in rats advances hippocampal development (Mellott et al., 2004). Studies suggest that choline supplementation is also beneficial in humans (Zeisel et al., 1991; Zeisel, 2000). A reduction in the area of the hippocampus is linked to aggression in male mice (Sluyter et al., 1994). The mossy fibre system of the hippocampal formation in rats is decreased by chronic postnatal protein malnutrition, but not prenatal protein malnutrition. Consequently, both prenatal and postnatal nutritional influences are likely to be significant influences on brain development and behaviour. It is generally believed that the brain is most vulnerable and sensitive to insults when it is growing most rapidly. Supporting this argument, Neugebauer et al. (1999; Neugebauer, 2006) showed that the male offspring of nutritionally-deprived pregnant women had 2.5 times the normal rate of anti-social personality disorders in adulthood when the severe malnutrition occurred during the time when the brain is developing rapidly, in first and second trimesters of pregnancy. Whether the effect of malnutrition on the brain and behaviour is permanent or reversible continues to be an area of

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ambiguity in nutrition research. Although it was believed that early malnutrition caused irreversible cognitive impairments, the effects on some parts of the brain, such as the cerebellum, that are impacted by prenatal malnutrition appear to be reversible with nutritional rehabilitation (Levitsky and Strupp, 1995). In particular, a review found that if iron deficiency occurred in the first two years of life, short-term trials of iron treatment generally failed to help development (Grantham-McGregor and Ani, 2001). But if the iron deficiency occurred after the first two years of life, some benefit from iron treatment was found (Grantham-McGregor and Ani, 2001). Although the results were convincing, they were not conclusive (GranthamMcGregor and Ani, 2001). More research is needed to determine whether the effects are reversible or not.

12.3 Implications for the food industry, nutritionists, and policy-makers The food industry can combat malnutrition by first changing the composition of its food products. Many current practices, such as blanching, milling, and extrusion, result in a significant loss of vitamins and minerals (Reddy and Love, 1999). To compensate for this, the overall nutritional value of foods can be enhanced by fortifying foods with micronutrients and omega-3 fatty acid (de Pee and Bloem, 2009). Additionally, the food industry can utilize new methods of processing to increase the nutritional value of foods. Indeed, there are cases where processed foods are not harmful but relatively healthy. For example, dried foods have the advantageous attributes of being convenient, nutritious, and flavourful. However, it may not feasible to remove all food additives as some (such as preservatives) are necessary to prevent spoilage and disease. However, the food industry can work to minimize the addition of food additives wherever possible. Nutritionists should focus on the prevention of malnutrition via nutritional education and early identification of individuals at risk for malnutrition. The efforts of nutritionists should be targeted at high-risk groups such as infants and pregnant women, because nutritional intervention in these populations can offer the greatest potential benefit (Schroeder, 2001). For example, studies show that the prenatal availability of omega-3 in the mother’s overall diet is important to child development (Strain et al., 2008). Indeed, as noted earlier, a greater intake of omega-3-rich seafood during the prenatal period has been associated with more pro-social behaviour and better social development scores in later childhood (Hibbeln et al., 2007). Furthermore, maternal diets that lack omega-3 during the first two trimesters of pregnancy have been shown to greatly increase the likelihood of a preterm birth (Olsen et al., 2006), and therefore subsequent childhood behavioural problems such as ADHD (Johnson, 2007). The results from Hibbeln and colleagues were that consumption of fish greater than

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recommended was beneficial. However, there is a concern that some fish consumption can potentially lead to exposure to mercury, which has a high toxicity. Although nearly all types of fish contain some mercury, certain types have mercury levels much higher than others. For example, the Food and Drug Administration (FDA) and Environmental Protection Agency (EPA) advise women who may become pregnant, pregnant women, nursing mothers, and young children to avoid some types of fish (such as shark, swordfish, king mackerel, and tilefish) and eat fish and shellfish that are lower in mercury (shrimp, canned light – not albacore – tuna, salmon, pollock, and catfish) (US FDA, 2009). In addition, results in animals have found that selenium present in the fish may provide a protective effect to mercury exposure and prevent harm (Lindh et al., 1996; Wang et al., 2001). Nutritionists as well as health professionals (physicians and nurses) could give advice and counselling to pregnant women during prenatal visits to help them make appropriate choices. Nevertheless, pregnant women must also consult with their own physicians for nutrition plans that meet their specific needs. Given the multifactorial causes of malnutrition, nutritionists must utilize a conceptual framework for the diagnosis of malnutrition, involving an analysis of the individual, the household, the community, and the economic/ political/physical environment (Hay, 1979). For an individual who already suffers from malnutrition, a nutritionist’s treatment strategy should effectively address its many causes and involve instruction on how to modify the individual’s diet and/or food environment. Primary prevention programmes focused on the prenatal and perinatal periods could focus on providing pregnant women with nutritional counselling. A landmark study by Olds et al. (1998), which showed that pre- and postnatal home visitations by nurses significantly reduced juvenile delinquency 15 years later, sets an excellent example for nutritional intervention during prenatal and postnatal periods for violence prevention. Nurses and midwifes are ideally positioned to conduct nutritional assessment and offer nutrition educational for pregnant women during their prenatal visit. Nutrition education programmes can include video presentations, reading materials, one-on-one teaching, or group teaching. Teaching strategies need to focus on practical learning and giving food lists that contain micronutrients, including calcium, zinc, and iron, all of which are essential for foetal brain development (Liu and Wuerker, 2005). When children begin to grow, their daycare centres and school lunchrooms can provide them with healthy snacks (such as fruits and vegetables among other things), taking into consideration the protein, micronutrient, omega-3 fatty acid, and food additive content. In addition, an age-appropriate nutrition class can be added to the school curriculum to educate students scientifically on the importance of nutrition as well as its physiological and behavioural impact on the body (Manios and Kafatos, 1999; Anderson et al., 2005). Finally, better education

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of school administrators and parents could lead to better awareness of the problem and ultimately to better nutrition for the children. Malnutrition also holds powerful implications for policy-makers. In order to reduce the prevalence of malnutrition, both diets and living conditions need be improved, particularly in developing countries. Therefore, increased attention to health (infection, disease), education, and socioeconomic status can allow for a multidimensional awareness of an individual’s nutritional status.

12.4 Future trends Poor nutrition at the prenatal and postnatal levels may contribute to the development of childhood externalizing behaviour. However, externalizing behaviour problems caused by poor nutritional status is amenable to change. Therefore, greater attention to nutrition has implications not only in treating and preventing conduct disorder in children, but also for cognitive development and school performance. However, this research area has important limitations. More studies of the hypothesized relationship are needed, particularly prospective studies of the effects of early malnutrition on later externalizing behaviour at different ages. Because research findings have not always been consistent, better study designs and better comparisons between studies should be facilitated, and other risk factors in addition to nutrition need to be included. Future research needs to place greater emphasis on investigating more specific macro/ micro nutritional deficiencies in relation to the development of antisocial behaviour, and adequate dosage of omega-3 in conducting experimental manipulations in both humans and animals to establish causality more effectively. Furthermore, Benton (2007) points out that, in terms of future studies of omega-3 fatty acid supplements, consideration needs to be placed on an understanding of how omega-3 interacts with individual differences in the pre-existing diet and the ability to metabolize fatty acids. However, although diet can play an important role in the development of behavioural problems and disorders, it is only a part of the problem. Diet and malnutrition cannot lead to behavioural problems by themselves, but only increase the likelihood and potential of developing those problems. Other factors such as genetics, birth complications, environment exposure, family/neighbourhood influence, parenting style, peer relationship, and life events can contribute to development of negative behavior outcomes. However, despite the contribution of other components, diet and nutrition can play a part and therefore steps must be taken to minimize their impact, particularly since malnutrition can be prevented or addressed more cost-effectively.

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12.5 Sources of further information and advice There is a great deal of nutrition information online that provides advice on how one can obtain sufficient quantities of omega-3 in one’s diet. The American Heart Association (AHA) advocates the health benefits of omega-3 and recommends eating fish at least two times a week. The AHA has posted information on their website regarding dietary recommendations as well as rich sources of omega-3 (AHA, 2010). The Food and Drug Administration (FDA) website also contains an advisory on the mercury levels of specific types of seafood (US Food and Drug Administration, 2009).

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13 The role of nutrition and diet in learning and behaviour of children with symptoms of attention deficit hyperactivity disorder N. Sinn, University of South Australia, Australia and J. Rucklidge, University of Canterbury, New Zealand

Abstract: Symptoms of hyperactivity, impulsivity and inattention, associated with attention deficit hyperactivity disorder (ADHD), can constitute a chronic, often debilitating psychiatric condition. Despite abundant research, there is no clear consensus on causes and treatments. The most commonly prescribed treatment is stimulant medication; however, there are concerns regarding safety, tolerability and long-term use. We provide an overview of published evidence for nutritional and dietary approaches to addressing ADHD symptoms. Although more research is needed, there is support for a role of food sensitivities with varying support for some nutrients, particularly omega-3 fatty acids, and there may be promise for a multi-ingredient approach. Key words: learning, behaviour, ADHD, children, nutrition, diet, omega-3 fatty acids, additives.

13.1 Overview of attention deficit/hyperactivity disorder (ADHD) Attention deficit hyperactivity disorder (ADHD) is the most prevalent childhood disorder, estimated to affect 2–18% of children (Rowland et al., 2002) depending largely on diagnostic criteria used. Core symptoms associated with ADHD are developmentally inappropriate levels of hyperactivity, impulsivity and inattention, with an inattentive subtype (ADD) that does not include hyperactive behaviour. ADHD has a high co-morbidity rate with other mental health problems such as anxiety and mood disorders, including depression, suicidal ideation (Birleson et al., 2000; Root and

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Resnick, 2003) and bipolar disorder (Biederman et al., 1996) and is often particularly associated with anti-social problems such as conduct disorder and oppositional defiant disorder (Crowley et al., 1998; Colledge and Blair, 2001; Root and Resnick, 2003). It is now accepted that ADHD can be a chronic condition across the lifespan (Gittelman et al., 1985) and can lead to anti-social behaviour, substance abuse and borderline personality disorder in late adolescence and adulthood (Biederman, 1997, Ingram et al., 1999; Rey et al., 1995; Fossati et al., 2002). In addition, ADHD is associated with cognitive deficits; it has been estimated that a quarter of these children have a specific learning disability in maths, reading or spelling (Pliszka, 1998). Attention difficulties are associated with delays in general cognitive functioning, weak language skills and poor adjustment in the classroom (Warner-Rogers et al., 2000). The disruptive behaviour, poor self-discipline, distractibility and problems with response inhibition, self-regulation and emotional control that are associated with ADHD can impact adversely on families, relationships, social interactions and children’s self-esteem and school performance, presenting substantial personal, social and economic burden for afflicted children, families, schools and the broader community. The aetiology of ADHD is complex and is associated with both genetic and environmental factors (Root and Resnick, 2003). Twin studies have provided strong evidence for a genetic component to the disorder which, in combination with other biological factors, is likely to underlie the neurological deficits that are exacerbated over time by environmental influences (Bradley and Golden, 2001). Psychophysiological research has identified neurological abnormalities, particularly in the frontal lobes, in children with ADHD compared with controls (Mann et al., 1992; Riccio et al., 1993). Similarly, a number of studies have identified reduced blood flow to the frontal lobes in children with ADHD (Bradley and Golden, 2001). This is consistent with hypotheses that symptoms of ADHD are related to abnormalities in frontal lobe systems that are thought to be regulated by neurotransmitters noradrenaline and dopamine (Biederman, 1997). The high co-morbidity of ADHD with a variety of other psychopathologies suggests that these mental health problems share similar underlying neurological mechanisms. This notion is supported by the fact that children with ADHD often have family histories of neurodevelopmental and psychiatric disorders (Richardson, 2003). Biological influences that have been associated with ADHD, via their impact on brain development and neurological functioning, include exposure to lead, mercury and pesticides and prenatal exposure to tobacco (Braun et al., 2006; Curtis and Patel, 2008).

13.1.1 Treatment Stimulant medications, such as methylphenidate (Ritalin®), pemoline (Cylert®) and dextroamphetamine (Dexedrine®), with or without cognitive-behavioural therapy, are the most common and most studied © Woodhead Publishing Limited, 2011

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treatments for childhood ADHD (MTA Cooperative Group, 1999; AntaiOtong, 2008). Response rates vary from 30 % to 70 % for these types of interventions (Adler et al., 2005; Antai-Otong, 2008). Additionally, many trials exclude patients with co-occurring disorders, so even less is known about medication treatment in these individuals. These limitations make it difficult to establish who would benefit from drug treatment given that trial participants are often quite different from those seen in the community. Side-effects associated with pharmacological treatments for ADHD can also be concerning, for instance cardiovascular risks associated with methylphenidate (Wilens et al., 2005; Antai-Otong, 2008) and suicide attempts (FDA warning on Strattera/atomoxetine). A recent long-term follow-up of the Multimodal Treatment Study of Children with ADHD (MTA) study (MTA Cooperative Group, 2004), a 14-month randomised controlled trial (RCT), found that children in their pre-teens who had been medicated with methylphenidate had stunted growth (Swanson et al., 2007) as well as increased risk of juvenile delinquency and possibly substance abuse (Molina et al., 2007) compared with those who had been, and remained, unmedicated.

13.1.2 Alternative treatments Complementary and alternative methods (CAM) of treating ADHD are often sought by families wanting treatments with fewer side-effects or remedies they consider ‘safer’ than medication (Sinha and Efron, 2005). The term ‘alternative and complimentary’ is misleading given the essentiality of nutrients as building blocks of our bodies and brains, and indeed for life itself. It is important, however, for clinicians to ask patients and their families whether they are using any supplements, given that these can influence medication treatment. Bussing et al. (2002) found in a sample of 822 families that 12 % of children diagnosed with ADHD used CAM, and 7 % of parents who suspected ADHD in their child used them. Other studies confirm the high rate of CAM use with children and lack of disclosure to medical practitioners (Chan, 2002; Bussing et al., 2003). Stubberfield and colleagues (1999) found that 65 % of their sample of children with ADHD was using some form of alternative therapy. Although there are data showing that children are not receiving the recommended daily allowances of nutrients (Munoz et al., 1997), it appears that the negative trials on megavitamins (doses 100 times the recommended daily intake) in the 1970s that found that these doses were no better than a placebo (e.g., Arnold et al., 1978) may have resulted in a loss of scientific interest on multi-ingredient nutritional approaches for the treatment of ADHD given the dearth of studies performed over the next two decades. Although there is much research on medication, there has been very little on nutrient interventions. The lack of funds available for that type of study may also have contributed to the lack of research (Baime, 2002). The lack of scientific data makes treatment decisions difficult for families, who may © Woodhead Publishing Limited, 2011

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then resort to trial and error. What is more concerning, families often do not inform their medical practitioners of alternative treatments being used, placing children at unnecessary risk from potential interactions between conventional treatments and alternatives (Bussing et al., 2003; Sinha and Efron, 2005). While families are trying many alternative treatments for ADHD, including regulation of diet, biofeedback and massage, this review focuses specifically on nutrient and dietary approaches (see also Rucklidge et al., 20091; Sinn, 20082). Despite poor methodologies in some studies, we attempt to be inclusive given the overall dearth of studies conducted in the area. However, it is cautioned that cross-comparisons cannot be done given that doubleblind, randomised, placebo-controlled trials have a different methodological rigour compared with open-labelled trials. Therefore, following a brief overview of nutrition in brain development and function, this chapter will review the current state of evidence for the role of single nutrients, botanicals, multi-ingredient approaches and food intolerances in ADHD.

13.2 Nutrition and the brain The brain’s critical need for adequate nutrition is demonstrated by effects of malnourishment on the developing brain, including reduced DNA synthesis, cell division, myelination, glial cell proliferation and dendritic branching. The pathological manifestation of malnourishment will depend on the stage of brain development at the time of nutritional insult (Lecours et al., 2001). Effects of some nutrient deficiencies on development have become widely well-known and accepted; for instance perinatal deficiencies in iodine, now considered the world’s most preventable cause of mental retardation (Hetzel, 2000), folate (Lumley et al., 2001), related to spinabifida, and iron-related anaemia (Lozoff et al., 2006). Severe deficiencies in omega-3 polyunsaturated fatty acids (n-3 PUFA), particularly docosahexaenoic acid (DHA), can result in profound mental retardation associated with peroxisomal disorders (Martinez, 1996; Uauy et al., 1996). A long-term impact of famine on cognitive and behavioural development was demonstrated by a longitudinal follow-up of children who had been malnourished compared to a healthy comparison group from the same classroom after controlling for confounders such as socioeconomic status (Galler and Barrett, 2001) 1 Reproduced from Expert Rev. Neurother]apeutics 9(4), 461–476 (2009) with permission of Expert Reviews Ltd. 2 Reproduced from Nutr Rev 66(10), 558–568 (2008) with permission of International Life Sciences Institute (ILSI).

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Less extreme effects of sub-optimal nutrient levels on brain development and ongoing function are not as well recognised. Given the essentiality of an intricate interplay of macro- and micronutrients for optimal brain function, this could result in cognitive and behavioural problems for which the role of nutrition may be overlooked. Although the brain only accounts for 2–2.7 % of body weight, it requires 25 % of the body’s glucose supply and 19 % of the blood supply at rest, increasing by 50 % and 51 %, respectively, in response to cerebral activity (Haller, 2005). Glucose is required for the brain’s metabolic activities and is its primary source of energy. The brain has very limited capacity for storing glucose, hence the essentiality of a continuous reliable supply of blood. A number of nutrients appear to be involved in maintaining cerebral blood flow and the integrity of the blood– brain barrier, including folic acid, pyridoxine, colabamin, thiamine (Haller, 2005) and n-3 PUFA (Sinn and Howe, 2008). Neurotransmitters such as serotonin and dopamine are also an integral component of the brain’s communication system; various nutrients are required for monoamine metabolic pathways and act as essential co-factors for the enzymes involved in neurotransmitter synthesis (Haller, 2005).

13.3 Nutrients and ADHD 13.3.1 Pyridoxine (vitamin B6) Pyridoxine is essential for neurotransmitter synthesis and normal brain development. Only one study has investigated its effect on hyperactivity, and apparently has not been replicated or extended. Coleman et al. (1979) conducted a small 21-week double-blind cross-over RCT comparing low/ high dose of pyridoxine (10 and 15 mg/kg) with low/high dose of methylphenidate with placebo in six hyperactive children: non-significant trends suggested that pyridoxine and methylphenidate were more effective than placebo in suppressing symptoms of hyperkinesis. Although the evidence does not support therapeutic benefit from pyridoxine supplementation alone, it has not been adequately tested.

13.3.2 Zinc As well as important roles in immune function, growth, development and reproduction, zinc is required for the developing brain. It plays numerous roles in ongoing brain function via protein binding, enzyme activity and neurotransmission. As an essential co-factor for over 100 enzymes, zinc is required for the conversion of pyridoxine (B6) to its active form which is needed to modulate the conversion of tryptophan to serotonin. Zinc is involved in the production and modulation of melatonin, which is required for dopamine metabolism and is a co-factor for δ6 desaturase, which in turn

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is involved in essential fatty acid conversion pathways (Arnold and DiSilvestro, 2005). A number of researchers have reported that zinc deficiencies can lead to cognitive impairment and slowed information processing (Toren et al., 1996; Yorbik et al., 2008). A comprehensive review on the role of zinc in brain function and in ADHD includes nine published studies around the world that report lower zinc levels in children with ADHD as well as correlations between lower zinc levels and severity of symptoms (Arnold and DiSilvestro, 2005). One avenue of zinc depletion in these children may be via reactions to synthetic chemicals found in food additives. Twenty hyperactive males who reacted to the orange food dye tartrazine were challenged in a double-blind placebo-controlled trial with 50 mg of the food additive. Following the challenge, serum zinc levels decreased and urine levels increased in the hyperactive group compared with controls, suggesting metabolic wastage of zinc under chemical stress. Behavioural and emotional symptoms also deteriorated in hyperactive children in association with changes in zinc levels (Ward et al., 1990). Two clinical zinc supplementation trials have been conducted in children with ADHD and one trial investigated the effect more broadly on ADHD symptoms in a sample of low socioeconomic status (SES). All zinc trials have been conducted in the Middle East. One controlled study found significant improvements in hyperactivity, impulsivity and socialisation scores, but not inattention, after 12 weeks of supplementation with 150 mg zinc per day in children with ADHD compared with controls. It should be noted that this is a particularly high dose of zinc, and there was a high dropout rate in the study (52.9 % and 50.5 % in the zinc and placebo groups, respectively), although not significantly different between active and placebo groups (Bilici et al., 2004). Most of the dropouts were due to protocol violation and adverse events. The other study allocated 44 children who were diagnosed with ADHD to methylphenidate along with either 55 mg zinc sulfate or placebo over six weeks to investigate adjunctive benefits of zinc. Scores on parent and teacher rating scales improved in both groups, and these improvements were significantly greater in the zinc group (Akhondzadeh et al., 2004). The third double-blind RCT investigated the effect of 15 mg/day of elemental zinc syrup as compared with a placebo group receiving the syrup without the zinc (Uckardes et al., 2009). The trial was 10 weeks and the sample consisted of 252 third grade students (218 finished the trial) in a low SES primary school in Turkey. Based on Conners’ Parent and Teacher Rating Scales as measures of outcome, there were significant changes in both groups on parent-rated symptoms of inattention and hyperactivity; however, the prevalence of children with clinically significant scores for attention and hyperactivity only decreased significantly in the zinc-supplemented group. There were no changes in teacher ratings. Overall, the differences between the two groups were small to negligible.

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It is interesting to note that both zinc and free serum fatty acid levels were found to be lower in a group of 48 children with ADHD compared with 45 controls, and that these levels were strongly correlated in the ADHD group (Bekaroglu et al., 1996). In light of these studies and other nutritional deficiencies in ADHD, a RCT, described later, focused on n-3 PUFA and investigated additive benefits of a multivitamin/mineral (MVM) tablet in conjunction with the PUFA supplement (Sinn and Bryan, 2007). No additional benefits were found with the MVM supplement over and above the PUFA supplement; however, the supplement contained <2 mg zinc, which when compared to the above studies is likely to have provided inconclusive results regarding potentially additive benefits of zinc combined with PUFA. With only three studies investigating zinc supplementation for ADHD, definitive conclusions are not possible, although these initial results suggest more research is warranted. Low zinc could be an effect, a cause, or could simply co-occur with ADHD. For those considering zinc supplementation, it is important to note that excessively high doses can be harmful and that high doses can interfere with copper and iron absorption. For example, at 50–150 mg/day, zinc can cause gastrointestinal problems and headaches and doses of 300 mg/day can suppress immune function (Arnold et al., 2005).

13.3.3 Iron Anaemia is estimated to affect around a quarter of the world’s population and is most prevalent in preschool aged children (47 %; WHO, 2008). Around 50 % of cases are thought to be caused by iron deficiency; other contributors include blood loss, infections and deficiencies in other micronutrients such as vitamins A, B12, folate and riboflavin. Anaemia carries a profound risk for delayed or impaired childhood development. Iron is important for the structure and function of the central nervous system and it plays a number of roles in neurotransmission. Iron deficiency has been associated with poor cognitive development and it has been proposed that iron deficiency may affect cognition and behaviour via its role as a co-factor for tyrosine hydroxylase, the rate-limiting enzyme involved in dopamine synthesis (Black, 2003; Konofal et al., 2004). Iron levels were found to be twice as low in 53 non-anaemic children with ADHD compared to 27 controls with no other evidence of malnutrition; specifically, serum ferritin (a protein that stores iron and releases it in a controlled fashion) levels were abnormal (<30 ng/mL) in 84 % of children with ADHD and 18 % of controls (p < 0.001). Furthermore, low serum ferritin levels were correlated with more severe ADHD symptoms measured with Conners’ Parent Rating Scales (CPRS), particularly with cognitive problems and hyperactivity (Konofal et al., 2004) as well as sleep disturbance (Cortese et al., 2009). A recent study also found low iron levels in 52

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non-anaemic children with ADHD, and these were correlated with hyperactivity scores on CPRS, although not with a range of cognitive assessments (Oner et al., 2008). It has been suggested that a role of iron in ADHD may be attributed to its neuroprotective effect against lead exposure (Konofal and Cortese, 2007). Iron deficiency is also associated with restless legs syndrome, which has a high co-morbidity with ADHD symptoms and therefore may account for a greater variance of symptoms in this sub-group of children (Konofal et al., 2007). Indeed, a recent study found that children with ADHD who suffered from restless legs had lower iron levels than those without restless legs (Oner et al., 2007). An early uncontrolled pilot study investigated effects of iron supplementation on ADHD symptoms in 14 non-anaemic 7–11 year-old boys. After 30 days of daily supplementation with 5 mg/kg ferrous-calcium citrate (active elemental iron, 0.05 mg/kg daily), blood samples showed increases in serum ferritin levels, and significant decreases were found on parent ratings of symptoms on Conners’ Rating Scales. However, these improvements were not correlated with increased iron levels and no significant improvements were found on teacher ratings. It was concluded that iron supplementation may not be effective in non-iron deficient children and that it should be investigated in iron-deficient children with ADHD (Sever et al., 1997). It is also possible that 30 days may not have been long enough to observe any effects. A case study report outlined effects of iron supplementation on a 3 year-old boy with diagnosed ADHD. This boy did have an iron deficiency and also displayed sleep problems: delayed sleep onset and excessive motility in sleep. Mild improvements in symptoms were reported by parents and teachers after four months of iron supplementation, and marked improvements were reported after eight months. He also showed enhanced quality of sleep (Konofal et al., 2005). These studies were followed up by a double-blind, placebo-controlled study with 23 non-anaemic, iron-deficient children (serum ferritin levels <30 ng/mL) aged 5–8 with ADHD. Following 12 weeks of supplementation with 80 mg ferrous sulfate per day or placebo, symptoms tended to improve in the treatment group on all ADHD scales and were significant on two outcome measures. Seventy-five per cent of children in the treatment group had diagnosed or possible restless leg syndrome and this improved in 12 out of those 14 children following iron supplementation. These improvements were not seen in the placebo group (n = 5) (Konofal et al., 2008). A minority of participants reported gastrointestinal symptoms such as abdominal pain. This study supports indications that children with low iron levels, and suffering both ADHD and restless legs, may be more likely to benefit from iron supplementation. It is not known, however, whether long-term supplementation could induce haemosiderosis, an iron overload disorder.

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13.3.4 Magnesium Sub-optimal magnesium (Mg) levels may impact on brain function via a number of mechanisms including reduced energy metabolism, synaptic nerve cell signalling and cerebral blood flow, and it has been suggested that its suppressive influence on the nervous system helps to regulate nervous and muscular excitability (Kozielec and Starobrat-Hermelin, 1997). Low Mg levels have been reported in children with ADHD. In 116 children with diagnosed ADHD, 95 % were found to have Mg deficiency (77.6 % in hair; 33.6 % in blood serum) and these occurred significantly more frequently than in a control group. Mg levels also correlated highly with a quotient of freedom from distractibility (Kozielec and Starobrat-Hermelin, 1997). In 50 children aged 7–12 years with ADHD, Mg supplementation (200 mg/day) over six months resulted in significant reductions in hyperactivity and improved freedom from distractibility compared with both pre-test scores and a control group of 25 children with ADHD who were not treated with Mg (Starobrat-Hermelin and Kozielec, 1997). Another open study also found lower Mg levels in 30 out of 52 hyperactive children compared with controls, and improvements in symptoms of hyperexcitability following one to six months of supplementation with combined Mg/vitamin B6 (100 mg/day) (Mousain-Bosc et al., 2004). A similar study by the same researchers two years later found lower Mg levels in 40 children with clinical symptoms of ADHD than in 36 healthy controls. Decreased Mg levels were also associated with increased hyperactivity and sleep disturbance and poorer school attention. After two months of Mg/ vitamin B6 supplementation for the 40 children with ADHD, hyperactive symptoms were reduced and school performance improved (Mousain-Bosc et al., 2006). A more recent study investigated the effect of supplementing ADHD children (6–11 years) with Mg–B6 (48 mg of magnesium lactate and 5 mg of pyridoxine HCl) for 30 days as compared with a group of children receiving a multivitamin for 30 days. It was unclear whether the control group had ADHD. Significant changes were noted in the Mg–B6 treated group in anxiety, inattention and hyperactivity and some neurological tests, but not in the control group (Nogovitsina and Levitina, 2007). This work indicates the need for more controlled studies in children with ADHD and magnesium deficiency, and elucidation of individual versus additive benefits of Mg and B6.

13.3.5

Amino acids

Phenylalanine Amino acid precursors have been the subject of clinical interest given that they form the building blocks of some neurotransmitters. For instance,

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phenylalanine is the initial precursor of dopamine. Over 20 years ago (Wood et al., 1985), adults with ADHD were randomised in a two-week doubleblind cross-over study of DL-phenylalanine (50–400 mg three times daily) versus placebo. In the 13 participants who completed the study, mood improved significantly; however, during a subsequent three-month openlabel extension, all improvements were lost. The authors reported that another open-label trial with L-phenylalanine produced no effect. L-tyrosine and tryptophan Tyrosine is an amino acid precursor for catecholamine synthesis and tryptophan is a precursor for indoleamine synthesis. We found two studies on L-tyrosine, both reported more than 20 years ago. Nemzer et al. (1986) conducted a double-blind study comparing L-tyrosine (140 mg/kg), tryptophan (100 mg/kg), dextroamphetamine (5/10 mg) and placebo in 14 ADHD children over a one-week period for each condition. Parent and teacher ratings and measures of attention were obtained at baseline and at the end of each condition. Tyrosine did not differ from placebo on any of the variables measured. However, tryptophan, while not significantly different from placebo on teachers’ ratings, was significantly better on parent ratings, suggesting it could be of benefit for those children with more home-based difficulties. Those on amphetamine improved on all measures compared with placebo. Reimherr et al. (1987) conducted an eight-week open-label trial of L-tyrosine (50–150 mg/kg) in 12 adults with ADHD residual type. Although eight of them showed an initial positive response (within two weeks) with marked to moderate changes, after six weeks they developed tolerance and the authors concluded that L-tyrosine was not effective in the treatment of ADHD. S-adenosyl-methionine (SAM-e) SAM-e is a methyl donor, and therefore plays an important role in many metabolic pathways through the process of methylation; e.g., it participates in the synthesis and catabolism of biogenic amines. Shekim et al. (1990) conducted a four-week open-label trial in eight adults with ADHD, using oral SAM-e titrated up to a maximum of 2400 mg per day. Reduced problems with concentration, restlessness, self-control and impulsivity were reported by 75 % of the participants. Although these researchers indicated that they were planning to conduct an RCT, we were unable to locate such a study. Carnitine Acetyl-L-carnitine is a small water soluble molecule that plays an important role in the metabolism of fatty acids and is biosynthesised from the amino acids lysine and methionine. It binds fatty acids (such as arachidonic acid (AA) and docosahexanoic acid (DHA)) to assist with mitochondrial oxidation, thereby generating metabolic energy, and it can also remove

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potentially toxic metabolic intermediates like carboxylic acids. It is suspected of influencing cholinergic and dopaminergic neurochemical pathways, both implicated in ADHD. Humans synthesise about a quarter of their carnitine and then obtain the rest from their diet (Abikoff et al., 2002). Several RCTs of carnitine have been reported in childhood ADHD. Van Oudheusden and Scholte (2002) used a randomised, double-blind, placebocontrolled double cross-over trial with 26 ADHD boys (22 of whom completed the trial). The active ingredient was a maximum of 4 g of carnitine. The trial consisted of three eight-week phases, balanced for order: either carnitine–placebo–carnitine or placebo–carnitine–placebo. Carnitine was well tolerated and associated with significantly better scores on both Conners’ Parent and Teacher Rating Scales. Despite the significant difference, only 54 % of those taking carnitine were considered ‘responders’ based on the Parent Scale and only 50 % based on the Teacher Scale (in contrast to 13 % and 17 % of those on placebo respectively). Overall, carnitine showed promise in this study for improving attention and reducing aggression in boys with ADHD. In contrast, Arnold and colleagues (2007) conducted a 16-week doubleblind multisite placebo-controlled trial with 112 children with ADHD using a soluble strawberry flavoured powder of acetyl-L-carnitine (ALC) in doses ranging from 500–1500 mg b.i.d (an amount up to 25 % less than the Van Oudheusden and Scholte study) or a matching placebo. Although no safety problems were identified, the main analyses revealed no group differences and, indeed, the mean changes on ADHD rating scales by both parents and teachers were small for both groups. In addition to administering lower doses of ALC, this study differed from the previous in that the ALC contained an additive (strawberry flavouring) that may exacerbate ADHD symptoms in some children. However, two interesting secondary findings were noted: superiority of ALC over placebo in those children with the inattentive subtype of ADHD, and an unexplainable geographical effect in that response to the active ingredient varied depending on location of the site. Finally, Torrioli et al. (2008), using a sample of 63 (51 completed) boys with both ADHD and fragile X syndrome, conducted a double-blind, parallel, multicentre comparison of ALC (20–50 mg/kg) with placebo. The children were not taking stimulants during the trial. Although the authors concluded that ALC improved hyperactivity over the one-year period, their reports of statistical analyses directly comparing the placebo and the active ingredient were inconsistently reported. The means on the hyperactivity symptom were lower after 12 months, but only for parent ratings, and it is unclear whether the change is clinically meaningful. Although more clinically significant changes were noted on measures of adaptive behaviour, the conclusions need to be cautiously interpreted. Further, the only data they provided on ADHD symptoms were a global measure of both hyperactivity

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and inattention and it is, therefore, impossible to assess which specific ADHD symptoms improved. In summary, the findings for carnitine are mixed, with two positive trials (but one with some methodological problems) and one negative trial using an ALC supplement containing an additive that may have contributed to the negative outcome. There has been an overall lack of adverse effects reported. Melatonin Although melatonin is not an amino acid, it is naturally synthesized from the amino acid tryptophan (via synthesis of serotonin). It is a hormone produced naturally by the pinealocytes in the pineal gland. Melatonin is not used to directly affect ADHD symptoms, but rather has been used in the treatment of sleep problems common in this population (Cohen-Zion and Ancoli-Israel, 2004). Two randomized placebo-controlled trials have shown that melatonin, while it does not improve ADHD behaviours, does improve initial insomnia and advances circadian rhythms of sleep–wake as well as enhancing total time asleep (Weiss et al., 2006; Van der Heijden et al., 2007).

13.3.6 Polyunsaturated fatty acids (PUFAs) Sixty per cent of the dry weight of the brain is composed of fats, and the largest concentration of long-chain omega-3 polyunsaturated fatty acid (n-3 PUFA), docosahexaenoic acid (DHA) in the body is found in the retina, brain and nervous system (Salem et al., 2001). There is evidence that DHA is required for nerve cell myelination and is thus critical for neural transmission (Youdim et al., 2000). Importantly, DHA levels in neural membranes vary according to dietary PUFA intake (Yehuda et al., 2000; Youdim et al., 2000). DHA precursor eicosapentaenoic acid (EPA) is also thought to have important functions in the brain (Hibbeln et al., 2006), possibly via its role in synthesis of eicosanoids with anti-inflammatory, anti-thrombotic and vasodilatory properties. Animal studies have associated lower n-3 levels with lower levels of neurotransmitters dopamine and serotonin and some restoration of neurotransmitter levels with n-3 PUFA supplementation (Chalon et al., 2001; Chalon, 2006); one of their primary influences on mental health may also be via improved cerebral vascular function (Sinn and Howe, 2008). Researchers observed signs of fatty acid deficiency in hyperactive children in the 1980s (Colquhoun and Bunday, 1981), following which a number of studies reported lower n-3 PUFA levels in children with ADHD compared with controls (Mitchell et al., 1983, 1987; Stevens et al., 1995; Burgess et al., 2000; Chen et al., 2004). Randomised controlled trials have found equivocal results, which may be explained by variations in selection criteria, sample size, dosage and nature of the n-3 PUFA supplement and length of supplementation. An American study supplemented 6–12 year-old medi-

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cated boys with a ‘pure’ ADHD diagnosis (without co-morbidities) with 345 mg algae-derived DHA per day for 16 weeks and found no significant improvements on outcome measures (Voigt et al., 2001). However, the children were taking stimulant medication and closer inspection of parent ratings reveals that children’s t-scores (scores standardised by age and gender for comparability) were already in the normal range at baseline, which would have masked the detection of any changes following the DHA supplement. Another American study gave 50 children (43 completed) aged 6–13 with ADHD symptoms and skin and thirst problems 480 mg DHA and 80 mg EPA with 40 mg arachidonic acid (AA; n-6 PUFA) daily over 4 months. Significant improvements were only found on conduct problems rated by parents and attention problems rated by teachers – importantly, the latter improvements were correlated with increases in erythrocyte DHA levels (Stevens et al., 2003). A Japanese study using both DHA and EPA found no significant treatment effects of fish oil-enriched bread (supplying 3600 mg DHA and 700 g EPA per week) on symptoms of ADHD in a two-month placebo-controlled, double-blind trial with 40 children aged 6–12 who were mostly drug-free (34/40). The placebo bread contained olive oil (Hirayama et al., 2004). Blood samples were not taken so it is not clear whether this sample had a baseline deficiency in fatty acids. Given that the study was conducted in Japan, known to have high fish consumption, it is possible that they did not. It is also possible that two months may not have been a sufficient length of time for effects to become observable. Another pilot study in the UK supplemented 41 unmedicated children aged 8–12 with literacy problems (mainly dyslexia) and ADHD symptoms above the population average with 186 mg EPA and 480 mg DHA with 42 mg AA per day over 12 weeks and reported improvements in ADHD symptoms on Conners’ Rating Scales and literacy (Richardson and Puri, 2002). Since these small trials, two large randomised placebo-controlled, double-blind interventions have been published. The first was conducted in the UK with 117 unmedicated children aged 5–12 with Developmental Coordination Disorder; a third of these children had ADHD symptoms >90th percentile, placing them in the clinical range for a probable diagnosis. On average, these children were functioning a year behind their chronological age on reading and spelling. Following three months of daily supplementation with 552 mg EPA and 168 mg DHA with 60 mg gamma linolenic acid (GLA; n-6 PUFA) from evening primrose oil, children in the treatment group showed significant improvements in core ADHD symptoms rated by teachers on Conners’ Rating Scales. The treatment groups also increased their reading age by 9.5 months, compared to 3.3 months in the placebo group, and their spelling age by 6.6 months compared to 1.2 months in the placebo group (Richardson and Montgomery, 2005). A review of the abovementioned studies was published following the latter trial (Richardson, 2006).

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The next study investigated treatment with the same supplement in 132 unmedicated Australian children aged 7–12 who all had parent-reported ADHD symptoms in the clinical range for a probable diagnosis. This study also investigated additive benefits of a MVM supplement. There were no differences between the PUFA groups with and without the MVM supplement. However, both PUFA groups showed significant improvements compared to placebo in core ADHD symptoms rated by parents on Conners’ Rating Scales over 15 weeks (Sinn and Bryan, 2007). Cognitive assessments found significant improvements in children’s ability to switch and control their attention, and in their vocabulary. Importantly, the latter improvements mediated parent-reported improvements in inattention, hyperactivity and impulsivity (Sinn et al., 2008). The effect sizes of the UK and Australian studies are similar to those reported in a meta-analysis of stimulant medication trials (Schachter et al., 2001). A Swedish study then investigated the same supplement as the previous two studies in 8–18 year-olds with ADHD over three months (N = 75). They did not find improvements in the treatment group compared with placebo overall; however, when they investigated sub-groups according to comorbidities, those children with the inattentive subtype and co-morbid neurodevelopmental disorders, including learning difficulties, had more than 50 % reduction in symptoms (Johnson et al., 2009). A group in Israel published in the same year a RCT with 7–13 year-old unmedicated children with ADHD (Raz et al., 2009). They reported no treatment effects on parent and teacher questionnaires or a computerised continuous performance task. However, the PUFA supplement contained relatively small amounts of LA (480 mg) and ALA (120 mg), the latter of which is likely to have had minimal conversion to EPA and DHA, and they were only supplemented for seven weeks whereas indications are that at least eight and preferably a minimum of 12 weeks are required to show any improvements overall and with larger doses of long-chain n-3 PUFAs. Interestingly, they did report some improvements in both groups which could be a placebo effect although the placebo contained vitamin C and was therefore not a nonactive compound. These studies were followed up by a recently completed 12-month randomised controlled 3 × 3 cross-over trial that compared EPA-rich and DHA-rich oils (without evening primrose oil) versus a safflower oil placebo. The study focused on children with ADHD and learning difficulties and took erythrocyte (red blood cell) blood samples to try and gain a clearer picture of responders (Sinn et al., 2009; Milte et al., in press). At baseline, higher n-6 PUFA levels predicted poorer literacy (word reading, vocabulary and spelling) and attention, and higher DHA predicted improved word reading after controlling for co-variates (N = 75). When comparing children with learning difficulties (age-scaled literacy scores below age level) and without learning difficulties, DHA was lower in those with learning difficulties after controlling for differences in age and health. Preliminary four

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month parallel results did not find significant differences in outcome measures between groups. However, increased erythrocyte DHA levels were associated with improved parent-rated symptoms and literacy, particularly in the sub-group with learning difficulties. It should be noted that the studies outlined here were not all focusing primarily on children with ADHD (e.g. Durham trial included one third of children with ADHD symptoms). Therefore these findings, taken together with previous studies, indicate that children with learning difficulties as part of a constellation of symptoms associated with developmental disorders, with or without ADHD, may be more likely responders. They may be a different group or their symptoms may occur further along a continuum of developmental problems associated with poor attention. Children’s fish and n-3 PUFA intake is generally poor so parents are advised in any event to ensure that their children consume adequate levels. The International Society for the Study of Fatty Acids and Lipids (ISSFAL) recommends 500 mg per day (n-3 PUFAs DHA + EPA) and the safe upper limit for children and adults in Australia is recommended as 3 g per day. It may be that in some children with developmental disorders including ADHD and learning difficulties, low n-3 PUFA levels are contributing to their symptoms. Note that there have been concerns about methylmercury in fish. Well refined, concentrated fish oil preparations contain essentially no methyl mercury and very low levels of organochoride contaminants. For further information on safety of eating fish, refer to the section ‘safety of omega-3 fatty acids’ and references cited by Kris-Etherton and colleagues (2002).

13.4 Botanicals The use of plants as remedies for mental health concerns is not new. For centuries, native peoples around the globe have utilised plants and plant extracts to improve mood, facilitate concentration and alleviate stress (Rohdewald, 2002; Bussmann and Sharon, 2006). Today, the wisdom of traditional healing practices is beginning to be understood in light of scientific knowledge of how certain botanicals may aid in the treatment of health conditions.

13.4.1 Pinus pinaster bark extract (Pycnogenol®) Anti-oxidants are receiving growing interest for their potential to reduce oxidative stress in the brain, which may contribute to a variety of psychiatric disorders including autism and ADHD (Ng et al., 2008). Pycnogenol is the registered trademark for a potent antioxidant derived from maritime pine bark. It contains concentrated polyphenolic compounds, primarily procyanidins and phenolic acids (for a review of its pharmacology see

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Rohdewald, 2002). Pycnogenol may also increase nitric oxide production and has been reported to improve blood circulation (Fitzpatrick et al., 1998; Nishioka et al., 2007). Therefore it may assist with cerebral blood flow which is also thought to be impaired in ADHD (Bradley and Golden, 2001). Several anecdotal reports indicate successful treatment of ADHD symptoms with Pycnogenol (Greenblatt, 1999; Heimann, 1999). In one case report, parents gave Pycnogenol to their 10 year-old boy with ADHD following unsuccessful response to stimulant medication. They noted significant improvements in target symptoms over two weeks. When they agreed to try him on stimulant medication without the Pycnogenol again, he reportedly became significantly more hyperactive and impulsive and received numerous demerits at school. When Pycnogenol supplementation was reinstated, he again improved within three weeks (Tenenbaum et al., 2002). Only two controlled studies have been conducted. One compared Pycnogenol with methylphenidate and placebo in a three-way cross-over trial with 24 adults aged 24–50 who met the criteria for ADHD. They were all given 1 mg/lb body weight Pycnogenol per day, methylphenidate (increased gradually from 10 mg to 45 mg per day) and placebo for three weeks, each separated by a one week washout. No significant improvements were observed in the methylphenidate or the Pycnogenol groups compared with placebo. It is possible that there wasn’t a treatment effect in this group or alternatively that three weeks was not long enough and/or the sample was too heterogeneous and the sample size too small (Tenenbaum et al., 2002). In the other study, 61 children aged 9–14 with ADHD symptoms [diagnosed as Hyperkinetic Disorder (n = 44), Hyperkinetic Conduct Disorder (n = 11) or ADD (n = 6)] were randomly allocated to receive 1 mg/kg body weight of Pycnogenol or placebo daily for one month and assessed again following an additional month of treatment washout. Significant improvements were observed in the treatment groups after one month on teacher ratings of hyperactivity and inattention, parent ratings of hyperactivity and visual–motoric coordination and concentration. Symptoms tended to relapse following the one month washout (Trebatická et al., 2006). Importantly, biomarkers of oxidative damage decreased in the treatment group compared with placebo, and this was associated with improvement in symptoms (Chovanová et al., 2006; Dvorˇáková et al., 2006, 2007). No significant side-effects have been reported. Further controlled studies are clearly warranted to investigate effects of Pycnogenol /anti-oxidants on ADHD symptoms in children. Note that many fruits, vegetables and nuts/legumes (lacking in many children’s diets) contain a wide variety of anti-oxidants, particularly small red beans, blueberries, red kidney beans, pinto beans, cranberries, artichoke hearts, prunes, raspberries, strawberries, apples, cherries, black plums and pecan nuts (Wu et al., 2004).

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13.4.2 Panax quinquefolium (American ginseng) and Ginkgo biloba Both of these extracts have been shown to increase cerebral dopaminergic activity in animal studies (Itoh et al., 1989; Ramassamy et al., 1992), an area of suspected deficit in people with ADHD (Barkley, 1997). In a four-week open study, 36 children with ADHD were given a product containing ginseng (200 mg) and Ginkgo biloba (50 mg) extracts twice daily (Lyon et al., 2001). Children on medication such as stimulants were included (n = 25) if symptoms of ADHD were poorly controlled in spite of the medication. Five participants reported adverse events during the course of the study but completed anyway. In two cases, the adversity experienced was attributed to the treatment itself: greater emotionality and impulsivity in one and increased hyperactive behaviour in another, though both of these participants reported symptom improvement in other areas. Improvement was defined as a change in individual symptom or global scores of at least five points in the direction of normal range, based on age and gender. To a varying degree (31–47%), improvement was reported in all seven ADHD indices measured at weeks two and four on the Revised Connors Parent Rating Scale (CPRS-R) (L) (Lyon et al., 2001). There are a few limitations to these findings, including: a number of the children who improved were taking stimulant medication as well, so any potential benefit of the botanical supplement must be considered with this in mind, and 3–15 % of the children had a negative outcome, as measured by an increase in T-score on aspects of the CPRS-R (L) by five points (half a standard deviation). Finally, the findings are limited by the uncontrolled nature of an open trial of such short duration. Salehi and colleagues (2010) conducted a double-blind randomised parallel group comparison of Ginkgo biloba (80–120 mg) and methylphenidate (20–30 mg) over a 6 week period. Participants were 50 outpatients with ADHD (6 to 14 years) and outcome measures included the Parent and Teacher ADHD Rating Scales. Although fewer side effects were noted in the Ginkgo biloba group and both groups improved significantly, the group treated with methylphenidate benefited significantly more from the treatment than the Ginkgo biloba treated group. Approximately a third of the Ginkgo biloba group benefited from the treatment compared with 88 % of those in the methylphenidate group. This trial indicates limited benefit of Ginkgo biloba as a treatment for ADHD.

13.4.3 Hypericum perforatum (St John’s wort) One RCT using Hypericum perforatum or St John’s wort for ADHD was found (Weber et al., 2008). St John’s wort has been noted to increase the levels of serotonin, dopamine and noradrenaline in the brain (Muller et al., 1997; Neary and Bu, 1999). Deficiencies in these neurotransmitters, particularly dopamine and noradrenaline, have been implicated in ADHD

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symptoms such as inattention and impulsivity (Kratochvil et al., 2002). Based on this knowledge, a noradrenaline reuptake inhibitor, atomoxetine, has been developed and approved for ADHD treatment in the US (Kratochvil et al., 2002). In an eight-week RCT, 54 children with ADHD were randomised to 300 mg St John’s wort extract standardised to 0.3 % hypericin or a placebo three times daily. Participants were included if scores were >1.5 SDs above age and gender norms on the ADHD Rating Scale-IV and were free of other ADHD medications during the trial. Concurrent use of multivitamins and essential fatty acids was allowed as long as the treatment had been consistent for the previous three months and was expected to remain at the same levels. One participant in the placebo group dropped out due to an adverse event. No significant difference was found in either of the two measures used: the ADHD Rating Scale-IV or the Clinical Global Impression Improvement Scale, indicating that St John’s wort did not improve ADHD symptoms in this study.

13.4.4 Passiflora incarnata Passiflora incarnata is a herb that has been used for the relief of mild symptoms of mental stress and to aid sleep. One study has investigated its use in the treatment of ADHD. In a randomised, double-blind study in 34 children with ADHD (6 and 13 years of age), the efficacy of passion flower tablets was compared with methylphenidate (Akhondzadeh et al., 2005). Seventeen children were treated with passion flower tablets (0.04 mg/kg/ day) for eight weeks. A control group of 17 children received methylphenidate (1 mg/kg/day). Outcome measures included the Parent and Teacher ADHD Rating Scales. Both groups improved significantly over the eightweek trial compared to baseline; there was no statistically significant difference in treatment result between the two groups. Given the small sample size and the lack of a placebo group, these results need to be viewed as preliminary.

13.5 Multi-ingredient formulations Research with multi-ingredient formulae in the treatment of ADHD is relatively rare, despite positive findings for combination therapies in other fields of research such as in the treatment of cognitive deficits, anti-social and disruptive behaviours (Benton, 1992; Schoenthaler and Bier, 2000; Gesch et al., 2002). This may in part be due to earlier studies which found that vitamins, given in ‘mega’ doses (100 times the recommended daily intake) were not effective in the treatment of ADHD (Arnold et al., 1978; Haslam et al., 1984). It has since been suggested that these doses could have

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been toxic, and/or the trials were too short and that the number of trials was too few to draw any specific conclusions about the efficacy of multinutritional approaches in the treatment of ADHD. However, due to these preliminary negative studies, interest in this line of research waned, as demonstrated by the small number of studies published over the following two decades. A number of studies were reported in the individual supplementation section of this review, which added ingredients to the treatment approach initially studied. It is important to consider these in our overall interpretation of the studies and, more generally, in our appreciation of the multinutritional approach to the treatment of ADHD. For example, one of the first reports on PUFA supplementation (Colquhoun and Bunday, 1981) used a combination of ingredients for at least one of their participants (PUFA with zinc, vitamin C, pyridoxine and niacin). Sinn and Bryan (2007) had a third arm in their study on PUFAs which consisted of a multivitamin/ mineral tablet plus fatty acids but found no additive benefit over the PUFAonly arm; however, they acknowledged that the dose may have been too low to reach any conclusions about specific ingredients in the tablet. The majority of studies with PUFA used an oil with added vitamin E to prevent oxidation, although potential antioxidant benefits cannot be discounted; gingko and ginseng were used in combination in Lyon et al.’s open-label trial (2001). A recent trial followed 40 children with clinical symptoms of ADHD over an eight week period during which time they received 6 mg/kg magnesium plus 0.6 mg/kg vitamin B6 (Mousain-Bosc et al., 2006). They were compared to 36 control children not receiving supplementation. Intraerythrocyte magnesium (Erc–Mg) and blood ionised calcium were measured, as well as behaviour. During the supplementation, symptoms of hyperactivity and aggressiveness were significantly reduced and school attention improved. The therapy was then stopped and clinical symptoms returned together with a decrease in Erc–Mg values. Although this ABA (on–off–on) study highlights the therapeutic effect of Mg–B6 supplementation, it was done in children who had low intraerythrocyte Mg values and therefore may not generalise to a larger ADHD population. Further, the children were young (mean age of the sample was 6 years) and the impact of other co-occurring behaviours was not considered. Another three-month open-label trial which combined 200 mg flax oil and an anti-oxidant (25 mg vitamin C twice daily), studied 30 unmedicated children with ADHD and 30 normal controls (Joshi et al., 2006). The controls did not receive any treatment but served as a comparison group for blood work. Fasting venous blood showed that pre-supplementation, children with ADHD had significantly lower red blood cell membrane lipid levels compared with the controls. At post-supplementation, there was a significant increase in n-3 PUFAs EPA and DHA and a decrease in AA (n-6 PUFA) in the children with ADHD. Scores on a parent-rated measure

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of ADHD behaviours showed a significant drop in inattention, impulsivity, hyperactivity, restlessness and self-control. Kaplan and colleagues (2004) conducted an open-label trial with children with a variety of psychiatric disorders, including ADHD, bipolar disorder, anxiety, oppositional behaviours and Asperger’s disorder. Six of the 11 children in the trial had ADHD although one of these dropped out. After 16 weeks of taking a micronutrient supplement (distributed under the name of EMPowerplus3), consisting mainly of minerals, vitamins and amino acids, some of which are given at levels higher than RDA, the children were rated as significantly improved in attention, anxiety, aggression, delinquency and mood. Few adverse effects were reported and those that did occur were mild for all except two who were concurrently taking psychiatric medications. Indeed, Popper (2001) has warned against taking such supplements concurrently with medications due to the hypothesised potentiating effect these combination formulas can have on the medication. The latter trial is limited by observer and placebo/expectancy effects. Pilot data on an open-label trial using EMPowerplus with 14 adults with ADHD and mood instability showed significant improvement in all ADHD symptoms (although problems with inattention were less well controlled than hyperactivity and impulsivity) as well as stabilisation of mood for all patients in the trial (Rucklidge et al., 2011). For those who stayed on the supplement, the changes were sustained and further improved at four months whereas for those who came off it, regression in symptoms typically occurred. Effects were larger than what would be expected for a placebo effect. A case study has shown that these improvements can be sustained to at least a year and that stopping the formula resulted in a return in symptoms (Rucklidge and Harrison, 2010). Side-effects have been mild (gastrointestinal upset or headaches) and transient. More trials, including an RCT, are currently underway with individuals with ADHD to better evaluate the effect this multi-ingredient supplementation approach has on symptoms of ADHD. Harding and colleagues (2003) compared methylphenidate with dietary supplements in the treatment of ADHD symptoms in 20 children over a four-week period. Co-occurring diagnoses and use of other medications served as exclusion criteria. The dietary supplement consisted of many nutrients (taurine, glutathione, α-lipoic acid, garlic extract, glycine, five amino acids, 13 minerals), presumed gastrointestinal and immune support (lactobacillus acidophilus and bifidus, lactoferrin, silymarin), PUFAs and phospholipids, iodine and tyrosine, all the B vitamins and some phytonutrients. Their rationale for such a broad-based approach was that they were attempting to address all the nutritional deficits associated with ADHD. 3

EMPowerplus is distributed by Truehope Nutritional Support. It consists of 36 ingredients: 14 vitamins, 16 minerals, 3 amino acids and 3 antioxidants. A list of the ingredients and their doses can be found on the company’s website, Truehope.com.

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With 10 children per group (based on parental choice), both groups showed significant improvement on neurocognitive tests that measure auditory response control, auditory attention, visual attention and visual response control. The nutrient group did as well as the methylphenidate group. Although there were no measures of behavioural change in ADHD symptoms, this study adds to indications that a dietary approach may be preferable to medication as it does not incur side-effects and indeed may be, at least to some extent, rectifying an underlying problem. Patel et al. (2007) reported an open-label pilot observational study with an even more comprehensive approach. Ten children with both autism and ADHD were treated for three to six months with vitamins (A, B-complex), seven minerals, coenzyme Q10, amino acids and peptides, some PUFAs, milk thistle, α-lipoic acid, digestive enzymes and probiotic bacteria. In addition, the parents of these children received instructions on controlling environmental factors (i.e., mites, exposure to pesticides, toxins, cleaners), an organic diet, gastrointestinal support, antigen injection therapy (to address dust mite allergens, moulds, foods and chemicals), chelation therapy and injection one to three times per week with glutathione and methylcobalamin (vitamin B12). They also continued their usual therapies (e.g., speech, occupational therapy). Although significant changes were observed in urinary lead levels, no other heavy metals were significantly different from baseline (although near significant drops (p < 0.1) were noted in cadmium and mercury). The researchers reported that on parental questionnaires, there was an ‘average’ improvement in concentration and attentional problems (range 40–100 % improvement) and an ‘average’ decrease of hyperactivity-related problems (range 0–95 % improvement); however, they did not report the actual tests used to measure behaviour change, how they defined improvement or any statistical tests. Based on the extensive and varied therapies the children received (ranging from psychosocial to supplementation), it is impossible to evaluate the specific effect of the nutritional supplements on behaviour change. Further, the ecological validity of the programme would make it very difficult to replicate. These types of studies raise the possibility that a multimodal treatment can most effectively address all the symptoms associated with this heterogeneous disorder, but the current research has many methodological limitations and requires more extensive investigation. Most scientific methodology alters a single variable at a time, so it is worth briefly considering the justification for multi-nutrient supplementation. Every neurotransmitter goes through many metabolic steps to ensure its synthesis, uptake and breakdown. Every one of those steps requires enzymes, and every enzyme is dependent upon multiple co-enzymes (co-factors). A variety of vitamins and minerals are required as co-factors in most if not all of those steps. Consequently, as discussed elsewhere (Ames et al., 2002; Kaplan et al., 2007), one possible mechanism underlying psychiatric symptoms is inborn metabolic dysfunction associated with

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slowed metabolic activity due to sub-optimal availability of vitamin and mineral co-factors (Ames et al., 2002). Impaired brain metabolic activity associated with other disorders has already been shown to be correctable through nutrient supplementation (Ames et al., 2002). One can thus envision multi-nutrient supplementation as providing sufficient cofactor that even enzymes with drastically reduced activity become so supersaturated that near-normal function is restored (Ames et al., 2002). Other mechanisms have been hypothesised as explanations for the effect of nutrients on brain function, such as improved energy metabolism (Arnold et al., 2007).

13.6 Food intolerance In addition to nutritional influences, there is evidence that many children with ADHD react to certain foods and/or food additives. Suggestions of links between diet and behaviour go back to the 1920s; they became wellknown in the 1970s with the Feingold diet which focused on eliminating naturally occurring salicylates, artificial food colours, artificial flavours and the preservative butylated hydroxytoluene (BHT) (Feingold, 1975). Behavioural reactions to food substances are associated with pharmacological rather than allergic mechanisms, although it is possible that these reactions co-exist (Swaine et al., 1985). Underlying mechanisms for behavioural food reactions are not entirely clear. Increased motor activity was identified in neonatal rats following red food colour ingestion (Shaywitz et al., 1979); other early animal studies linked reactions to the nervous system, e.g. similar hyperactive response was identified to dopamine depletion as well as administration of sulfanilic acid, an azo food dye metabolite, in developing rats (Goldenring et al., 1982); dose-dependent increase in red food colour may increase the release of acetylcholine into neuromuscular synapses; and colours may affect uptake of neurotransmitters (Kaplita and Triggle, 1982). In support of animal studies, EEG readings were reported to normalise in nearly 50 % of children (N = 20) with behaviour disorders after starting an elimination diet (Kittler and Baldwin, 1970). Behavioural food reactions may be attributable to the presence of metals, including lead, mercury and arsenic, in food colourings (FDA, 2007). Feingold reported that more than half of children who adhered to his elimination diet responded favourably, and that many children’s symptoms reached the normal range of behaviour. It has since been discovered, however, that many of the foods in his diet contained salicylates, and that many of these children also react to other food components such as food colouring (Swaine et al., 1985). The complexities of dietary intervention, most notably the large variety of potentially suspect food substances and individual differences in the nature and dosage of the food intolerance,

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resulted in inconsistencies in subsequent research trials. Many of these studies also had interpretational issues (Weiss, 1982) and methodological limitations involving the formulation of the intervention diet and the placebo diet and washout periods between them. A discussion of these complexities and subsequent research is provided by Breakey et al. (2002). Dietary intervention for ADHD and inconsistent findings have generated a great deal of controversy and titles such as ‘Diet and child behaviour problems: fact or fiction?’ (Cormier, 2007). However, despite methodological difficulties of measuring dietary complexities and individual variation, a recent review cited eight controlled studies that found either significant improvement following a ‘few-food’ (oligoantigenic) diet compared with placebo or worsening of symptoms in placebo-controlled challenges of offending substances following an open challenge to identify the substance (Arnold, 1999). A subsequent meta-analysis confirmed a consistently significant effect of oligoantigenic diets on hyperactivity and related symptoms (Benton, 2007). This paper also notes that food intolerances do not appear to be unique or consistent; i.e. there are individual variations to offending foods and children who react to food substances typically react to more than one item. The most common ones that are noted are dairy products, wheat and chocolate. A meta-analysis of 15 double-blind placebo-controlled trials focusing specifically on artificial food colours found that these food additives promoted hyperactive behaviour in hyperactive children (Schab and Trinh, 2004). Following this meta-analysis, a randomised, double-blinded, placebocontrolled cross-over challenge trial with 153 children aged 3 years and 144 children aged 8/9 years from a general population of British children reported significant effects of artificial colours and sodium benzoate preservative on hyperactive behaviour (McCann et al., 2007). It might be noted that the food colourings and preservative (or placebo) were delivered in fruit juice containing salicylates, which could have confounded effects for the more hyperactive children at risk for salicylate sensitivity. It is notable that this study demonstrated hyperactive effects of food colourings on healthy children from a general population, therefore expanding effects of food colourings beyond children with sensitivities. Finally, there has been a great deal of interest in the role of sugar in hyperactive behaviour, largely through anecdotal observations by parents. For information on research in this area refer to Benton (2007).

13.7 Conclusions Research to date indicates a role for nutritional and dietary influences on hyperactivity and concentration/attention problems associated with ADHD in children. There is some support for sub-optimal iron, zinc and

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magnesium levels and improvements with supplementation in children with low levels of these nutrients. There are also indications that supplementation with antioxidant Pycnogenol might assist with symptoms. However, more well-controlled clinical trials are required. The strongest support so far is for contributing influences of n-3 PUFA, behavioural reactions to food colourings and individual reactions to a variety of food substances. Research still needs to determine optimal levels of these nutrients for this group of children and markers of food sensitivity (currently requiring time-intensive dietary challenges) in order to inform clinical practice in the identification of potential deficiencies and/or behavioural food reactions. There are also suggestions that these children often react to inhaled environmental substances such as petrol fumes, perfumes, fly sprays and felt pens, which requires investigation (Breakey et al., 2002). The multiingredient approaches require more rigorous studies in order to better assess the impact of a broader supplementation approach to the symptoms of ADHD. There are clearly multiple influences on ADHD, including genetic, environmental and psychosocial factors, and it is unlikely that children with symptoms associated with ADHD represent a homogeneous population although there may be a similar underlying biological component that predisposes children to nutritional deficiency or reaction to environmental substances. It is of note that a longitudinal study of children who suffered moderate to severe malnutrition during their first year of life had 60 % frequency of ADHD compared with 15 % in healthy controls from the same classrooms, and these were not accounted for by differences in socioeconomic factors (Galler and Barrett, 2001). It is also possible that a genetic problem with enzyme production or absorption of nutrients may predispose children to nutrient deficiencies and/or excessive oxidation and contribute concurrently to food sensitivities; these may all exacerbate psychosocial factors (e.g., it is easier to parent a child with an easy-going, undemanding personality). These possibilities need to be explored in multidisciplinary, multimodal research models that take all potential factors into consideration in order to provide optimal treatment for these children.

13.8 Implications for the food industry, nutritionists and policy-makers Converging evidence indicates that a healthy diet with adequate nutrient intake is important not only for children’s physical health and development but also brain development and function – and therefore children’s learning and behaviour. There is also evidence now that some children have neurological reactions to certain foods and food additives. Although more research needs to be invested in this critical area of children’s health and

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development, increasing awareness by parents of dietary influences on their children’s mental health, along with adverse effects of prescription medications that do not address underlying causes, implies that expectations from the food industry for safe, healthy, nutritious food are likely to grow. To respond to this demand and to pursue responsible, ethical practices, the food industry would be well-advised to invest in production and marketing of nutritious food free of artificial colourings and additives for children. Production and marketing of whole foods – including most importantly vegetables, fruit, nuts and oily fish – to children and supporting government policies for media, food manufacturers and schools would assist in promoting increased consumption of essential nutrients outlined herein. It is possible that some children have higher requirements for some nutrients, e.g. n-3 PUFAs, which also has implications for food and supplement manufacturers, although this remains to be established. As a society we are all responsible for investing in our future human capital – our children – and therefore need to take a responsible, multifaceted approach to supporting them in optimal growth and development.

13.9 Future trends Although many RCTs on nutritional supplementation have been conducted, far more studies are open-label trials which makes it more difficult to comment on the efficacy of many of the individual supplements being studied. Given the lack of controls generally in this field, products do not have to be rigorously tested, and therefore consumers must be sophisticated when considering these treatments in order to make informed decisions based on variable data. One should be sceptical of a treatment if manufacturers claim the product works for everyone with ADHD or other health problems, uses only case histories or testimonials as proof or cites only studies with no control (comparison) groups. While testing a treatment without a control group is a necessary first step in investigating a new treatment, subsequent studies with appropriate control groups are needed to clearly establish effectiveness and to ensure that any effect found using an open-label method is not simply a result of the powerful placebo effect. Many of the studies meet this first criterion, but far fewer, the second. Mainstream medicine has accepted the notion that pharmaceuticals are the preferred approach to the treatment of ADHD. This review reveals that there is potential benefit from nutritional approaches, but much more research is required. One major issue here is the lack of research funding for effects of nutrition on behaviour compared to the extensive funds provided for pharmaceutical trials. An interesting theme that has emerged is the focus taken by many researchers in studying individual nutrients (with varying success) rather than a broad-spectrum approach investigating

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multi-ingredient formulae. Given that physiological function is best optimised by having all systems in balance, with different vitamin and mineral levels affecting the absorption and effectiveness of each other, one needs to question the efficacy of ingredients that are studied individually. Perhaps the single ingredient approach, although easier to test scientifically, is too narrow. Given the heterogeneous nature of ADHD, it is unlikely that a single universal treatment will be effective. As scientists become better at identifying subtypes of this disorder (Nigg, 2005), identification of treatments specific to ADHD subtypes may become more viable. The success of a treatment is influenced by several factors including an individual’s expectations and response, the side-effects experienced, a person’s preconceived ideas and the burden placed on the patient by the treatment. For these reasons, the availability of a variety of empirically-supported treatment options will be beneficial to patients and their families in the long term.

13.10 Sources of further information and advice A reference list for research referred to in this chapter is provided below. There are many books and online resources which need to be accessed with some discretion; some are listed below – we hope these are helpful however please note that the authors and editor take no responsibility for their content: • Food and Behaviour (FAB) Research: www.fabresearch.org. • They are what you feed them: how food affects your child’s behaviour, mood and learning by Dr Alexandra Richardson (Harper Thorsons, 2010). • Twelve effective ways to help your ADD/ADHD child: drug-free alternatives for attention-deficit disorders by Laura J Stevens (Avery, 2009). • Online ADD/ADHD Newsletter (Laura Stevens): www.youradhdnewsletter.com • Nutrition and ADHD: Omega-3 fatty acids, micronutrients and attention deficit hyperactivity disorder by Natalie Sinn, Janet Bryan and Carlene Wilson (VDM Verlag Dr Müller, 2009). • Feingold Association of the United States website provides a resource for scientific studies on food intolerance: http://www.feingold.org/ research.php. • The Royal Prince Alfred Hospital Allergy Unit also provides information on research into food intolerances and behaviour: http://www. sswahs.nsw.gov.au/rpa/allergy/. • Doris Rapp MD provides an extensive resource for information on children’s allergies to food and environment: www.drrapp.com.

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14 Vitamin status and psychiatric disorders D. Benton, Swansea University, UK

Abstract: It is well accepted that a clinical deficiency of vitamin B1 and niacin results in problems of mood and cognition. However, there has been interest in the possibility that a sub-clinical intake of other B vitamins may influence the incidence of both dementia and depression. Attention has been directed to the level of homocysteine in the blood as it is a risk factor for both dementia and depression. Although there is good evidence that homocysteine levels can be reduced by supplementation with folate, vitamin B6 and vitamin B12, we await evidence that this translates to changes in the risk of either dementia or depression. The free radical theory of ageing suggests that DNA, protein and lipids are damaged by free radicals. Vitamins A, C and E have anti-oxidant properties and it has been proposed that increasing their intake will reduce the rate of cognitive decline. There is general agreement that oxidative stress is associated with the development of dementia and that cognitive decline is greater in those with less anti-oxidant capacity. There is, however, little evidence that supplementation with anti-oxidant vitamins reduces cognitive decline. We need to establish the relative extent to which oxidative stress is involved in the aetiology of dementia. Key words: Alzheimer’s disease; anti-oxidants; autism; dementia; depression; folate; homocysteine; niacin; oxidative-stress; schizophrenia; vitamin B1; vitamin B6; vitamin B12.

14.1 Introduction In recent years there has been growing interest in the possibility that the intake of B vitamins may influence the incidence of both dementia and depression. Although problems of mood and memory are symptoms of a clinical deficiency of a number of vitamins, for example vitamin B1 and niacin, more recently there has been considerable interest in the level of homocysteine in the blood. Homocysteine (tHcy, plasma total homocysteine) is a sulphur-containing amino acid that when present in the blood in high levels is a risk factor for mental retardation, cardiovascular disease, dementia and depression. As the level of tHcy in the blood can be

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influenced by dietary factors, it has generated considerable attention. Supplementing with vitamin B6, vitamin B12 and folic acid will all decrease the level of tHcy. The question is whether such changes bring with them a decreased risk of depression and dementia? If the manipulation of diet can reduce the risk of depression and dementia then this will be a major prize. The Alzheimer’s Society in the UK estimated that one in 50 of those between 65 and 70 have the disease, but the rate amongst those in their eighties is one in five. In an ageing society this represents an enormous burden, psychologically, socially and financially. It has been estimated that there will be 4.6 million new cases of dementia throughout the world each year. As the world’s population ages the incidence of dementia will inevitably increase markedly over the coming decades. Although the largest risk factor for dementia is age, it does not occur inevitably as we grow older. A view current at one time was that cognitive ageing was largely unavoidable as it reflected an age-related loss of brain cells. Today attention is being directed to the factors that prevent mental decline, with the nature of the diet being increasingly explored as one such factor. Waraich et al. (2004) pooled studies of the rate at which depressive illness occurs. In the general population the prevalence for major depressive disorder was 4.1 per 100 people per year. The rate is higher in women rather than men. In developed countries the World Health Organization has estimated that depression will be the greatest cause of disease burden by the year 2020. In the UK depression is the third most common reason for approaching a medical practitioner. Again, the possibility that aspects of diet may decrease the incidence of depression or facilitate the response to drug therapy is being explored.

14.2 Homocysteine There are suggestions that tHcy may be a risk factor for both dementia and depression and that the nature of the diet may influence its level. Homocysteine as such does not come from the diet, rather it is formed by the demethylation of the dietary amino acid methionine (Fig. 14.1). Subsequently, with the involvement of several B vitamins it can be broken down into methionine or alternatively converted into cysteine. The enzyme methionine synthase, that has vitamin B12 as a co-factor and methyltetrahydrofolate (part of the folate cycle) as a substrate, reforms methionine. As such, blood levels of homocysteine are a sensitive marker of folate and vitamin B12 deficiency. The alternative breakdown pathway involves cystathionine β-synthase that synthesizes the amino acid cysteine from homocysteine using vitamin B6 (pyridoxine) as a co-factor (Stehouwer and van Guldener, 2001). Thus a high level of tHcy can reflect a deficiency of folate, vitamin B6 or vitamin B12 that can be reduced by supplementation or a change in

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FOLATE CYCLE Tetrahydrofolate

Methionine

Serine

Methyl Acceptor

S-Adenosylmethonine

Glycine DMG

Betaine Methylated S-Adenosylhomocysteine Acceptor

Vitamin B12

Methionine Synthetase

5.10 Methyl Tetrahydrofolate NADPH NADP+

HOMOCYSTEINE

5 Methyl Tetrahydrofolate

Cystathionine β synthetase Vitamin B6 Cystathionine TRANS-SULPHURATION PATHWAY

Cysteine Sulphate + H2O

Urine

Fig. 14.1 The remethylation of homocysteine.

diet. An increased folate intake is particularly effective in this respect (Ntaios et al., 2009). The toxicity of tHcy reflects a number of mechanisms that result in particular from its chemical reaction with many molecules, in particular proteins. It also activates the N-methyl-D-aspartic acid (NMDA) receptor (glutamate receptor) and increases the level of reactive oxygen species and ionized calcium. Thus cell death can follow exposure to homocysteine. Improving folate status results in a decline in tHcy. Folate is absorbed in the upper jejunum where it is metabolized to methyltetrahydrofolate, in which form it is mainly found in the blood. Various polymorphisms of the genes responsible for producing the enzyme methylenetetrahydrofolate reductase (MTHFR) influence the absorption of folate. Folate status can be improved by supplementation with the artificial compounds either folic acid or folinic acid. The latter is more stable, has a longer half-life in the body and crosses the blood–brain barrier where it is cleared more slowly from the brain than folic acid (Smith, 2008).

14.2.1 Homocysteine and depression Given the association between depression and tHcy, and that improving folate status decreases tHcy, attention has been attracted to the influence

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of folate status on mood and more specifically depression. The homocysteine hypothesis proposes that the levels of this amino acid in the blood are raised by genetics and diet, resulting in depression caused by vascular disease of the brain and changes in neurotransmitters (Coppen and Bolander-Gouaille, 2005; Folstein et al., 2007). Almeida et al. (2007, 2008) considered the association between various cardiovascular risk factors and depression and found that those with higher plasma tHcy were more likely to be depressed. The use of logistic regression found that tHcy levels accounted for the greatest amount of variance: about 15 % of the incidence of depression in this sample of older men. In fact there are several observational studies that have related tHcy to the incidence of depression. The largest study of this topic was carried out by Bjelland et al. (2003). In a sample of nearly 6000, those who were depressed were nearly twice as likely to have a high level of tHcy, although low levels of folate or vitamin B12 were not predictive. A Finnish study related symptoms of depression to tHcy (Tolmunen et al., 2004). Those whose tHcy values were in the top third of the distribution had a more than two-fold increase in the risk of being depressed. In Japan, higher tHcy and lower folate status predicted depression in men but not women (Nanri et al., 2010). In the Rotterdam Study high levels of tHcy and a deficiency of vitamin B12 and folate were all associated with depression (Tiemeier et al., 2002). With both folate status and tHcy the relationship to depression was reduced after accounting for functional disability and cardiovascular disease, although the relationship with a low vitamin B12 status remained. It was suggested that vitamin B12 may be causally associated with depression, whereas folate status may reflect co-morbidity. The findings were similar to those reported by Penninx et al. (2000) in older women living in the community. Those with vitamin B12 deficiency were twice as likely to report symptoms of depression, a finding not observed with either tHcy or folate status. Thus several studies have associated tHcy with an increased incidence of depression although on occasions the relationship has not been found (Penninx et al., 2000). There are, however, various problems in interpreting such data. It is unclear whether an association between depression and vitamin deficiency was caused by depression or preceded it. As a lack of appetite and a lack of concern about diet is characteristic of depression, it is reasonable to suggest that in part at least micronutrient deficiency might result from rather than being caused by the disorder. However, although such correlational data do not demonstrate causality, the possibility arises that the management of this risk factor might decrease the instance of depression. Although such data are limited, the use of randomized controlled trials in which changes in depression are monitored after the level of tHcy has been manipulated can establish a causal relationship.

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14.2.2 Micronutrient supplementation Taylor et al. (2004) after a review of the effect of folate supplementation concluded that: ‘. . . folate may have a potential role as a supplement to other treatment for depression. It is currently unclear if this is the case both for people with normal folate levels and for those with folate deficiency’. For example Passeri et al. (1993) gave 5′-methyltetrahydrofolic acid or a placebo in addition to standard psychotropic medication and found over four weeks that it significantly reduced depression. Godfrey et al. (1990) considered patients with a diagnosis of major depression or schizophrenia and offered methylfolate or a placebo in addition to standard medication. In both groups of patients, taking methylfolate significantly improved recovery. Similarly Coppen and Bailey (2000) gave folic acid or a placebo to patients with major depression who were in addition taking fluoxetine. The levels of plasma folate increased and tHcy was significantly reduced in women but not men. The combination of fluoxetine and folic acid resulted in greater improvement. Although the data are preliminary, they are sufficient to recommend that larger scale trials are needed to consider whether a better folate status improves the response to anti-depressant drugs. Factors that need to be considered include the pre-existing folate status, the genetic makeup and the dose and form of the supplement supplied.

14.2.3 Folic acid and mood The role of folate status in the general population, in those without a history of clinical depression, has also been considered. Shorvon et al. (1980) contrasted the consequences of megaloblastic anaemia that had resulted from either folate or vitamin B12 deficiency. Although in total around a quarter displayed cognitive decline, peripheral nerve damage was more likely with vitamin B12 deficiency and the incidence of depression was double in those with folate deficiency. The suggestion that a deficiency of folate is associated with depression, whereas a deficiency of vitamin B12 induces cognitive impairment, has been made (Reynolds, 2006). This association between folate deficiency and depression has led to the suggestion that the ability of folate to facilitate changes in tHcy might be the underlying mechanism. There have been few studies of the effect of micronutrient supplement on the mood of healthy individuals. Benton et al. (1995) gave ten times the recommended daily dose of nine vitamins, or a placebo. After a year males reported themselves as feeling more ‘agreeable’ and females taking the vitamin supplement were more ‘agreeable’ and ‘composed’ and had generally better mental health. These changes in mood after a year occurred even though the blood status of nine vitamins reached a plateau after three months. The improvement in mood correlated with improved vitamin B2

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and vitamin B6 status over the year but not changes in folate or vitamin B12 status. However, Bryan et al. (2002) for five weeks gave folate, vitamin B12 and vitamin B6 to healthy adult women of a wide age range and found that supplementation had no effect on mood. The only study of folate by itself was carried out by Williams et al. (2005) in a sample of healthy community living males. In a placebo-controlled trial folic acid supplements were consumed for three months. Although blood levels of folate increased and tHcy declined, neither mood nor serotonin levels changed. The study was, however, on a small scale and those with the TT polymorphism (see below) were excluded from taking part. Ford et al. (2008) randomly allocated men 75 years and older, who were not depressed, to a supplement of vitamin B12, folic acid and vitamin B6 or alternatively a placebo. Over a period of two years the incidence of depression did not differ in these two groups. Thus, in samples of the general population there is little evidence that the use of supplements to improve folate status has a general impact on mood. It may be, however, relevant that previous reports of a positive mood enhancement following folate supplementation have tended to study those who were either, or both, folate deficient and clinically depressed.

14.2.4 Genetic variation – The MTHFR gene An interesting approach has been to use genetic variation to try to demonstrate causality. The enzyme MTHFR reductase is encoded by the MTHFR gene that is found on chromosome one. Of a number of polymorphisms, the one at position 677 has been particularly studied as the nucleotide at this position can occur as two possibilities, cytosine (C) or thymine (T). Those with two copies of 677C (677CC) have the ‘normal’ genotype and metabolize folate well. In contrast, those with 677TT individuals are characterized by a mild reduction in enzyme activity. In the US, about 10 % of population have the 677TT variant (Schneider et al., 1998). Those with the 677TT genotype are more susceptible to a low intake of folate and thus are more likely to have higher tHcy levels (Jacques et al., 1996). In the present context, the argument is that polymorphisms of the 5,10 MTHFR reductase gene are important as they create the methyl donor, 5 MTHFR necessary for the remethylation of tHcy (Fig. 14.1).The TT polymorphism is associated with a lower production of the methyl donor and therefore increases the level of plasma tHcy in a similar manner to a low consumption of folate. The advantage of using such an approach is that the genetic form acquired by an individual reflects the random assortment of alleles, and therefore should not be associated systematically with other variables that predispose to depression. Thus individuals can be viewed as having been randomly allocated to conditions resulting in high (TT) or low (CC) levels of tHcy.

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Some have reported a greater incidence of depression in those with the TT polymorphism (Bjelland et al., 2003; Lewis et al., 2006). Others, however, have failed to find such an association (Almeida et al., 2005; Chen et al., 2006). For example Gaysina et al. (2008) examined over 1000 patients with unipolar depression and found no differences between the genotype of depressive patients and controls. This study had the necessary statistical power to find an effect of the size reported by Bjelland et al. (2003). It is perhaps not surprising that there are inconsistencies as many factors influence the incidence of depression and many genes are known to be involved. As such, an undifferentiated sample could potentially hide subgroups for which folate status is important.

14.3 Dementia and homocysteine Smith (2008) noted that there were ‘Seventy-seven cross-sectional studies on more than 34 000 subjects and 33 prospective studies on more than 12 000 subjects that have shown associations between cognitive deficit or dementia and homocysteine and/or B vitamins’. He concluded that raised tHcy was a strong predictor of future cognitive decline. He pointed out that largescale trials of homocysteine-lowering vitamins are required to establish whether dementia can be in part prevented. Although in cross-sectional studies raised levels of tHcy have been found to be associated with dementia, stronger evidence comes from intervention studies where the level of tHcy is manipulated and the rate at which dementia occurs is recorded. In the Framingham study, Seshadri et al. (2002) over an eight-year period related the initial level of tHcy to the development of dementia. The relative risk of developing dementia was 1.4 for each increase of one standard deviation in tHcy. Similarly, in an Italian study, those with a tHcy level greater than 14 μmol per litre had double the risk of developing Alzheimer’s disease. In addition, low folate status independently predicted dementia over a four-year period (Ravaglia et al., 2005). However, the Washington Heights–Inwood Columbia Ageing Project did not find that high tHcy levels were associated with the development of dementia or a decrease in memory scores over time (Luchsinger et al., 2004). Oulhaj et al. (2010) measured tHcy and used this to predict the rate of cognitive decline in patients with Alzheimer’s disease for periods of at least a year and a half and for up to nine and a half years. The higher the tHcy values the faster was cognitive decline, particularly in patients who initially were less than 75 years and had not suffered a stroke. Given there is an association between high tHcy, dementia and arterial disease, the possibility has been considered that when folic acid supplementation decreases the level of the amino acid, cognitive benefits might result. However, as both a deficiency of folate and vitamin B12 can result in a similar type of anaemia, a concern is that folate supplementation may mask

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a deficiency of vitamin B12. This is particularly a concern as vitamin B12 deficiency can result in irreversible brain damage. For this reason, folic acid supplements sometimes also include vitamin B12 to prevent such a possibility. However, where a combination of these two vitamins has been administered, it is necessary to consider the effect of giving vitamin B12 alone so that a role for folic acid supplementation can be established. Randomized, controlled trials of older adults who received folic acid supplementation either with or without vitamin B12 have been collated in a Cochrane review (Malouf and Grimley Evans, 2008). Of the eight trials considered, four involved a healthy sample and four recruited those with either cognitive impairment or dementia. The limited nature of the evidence resulted in the conclusion that there was as yet no consistent evidence that these vitamins have a beneficial influence on cognition. The consumption of folic acid and vitamin B12 did, however, decrease the levels of tHcy. In a study of healthy subjects to whom folic acid and vitamin B12 were administered, cognition did not benefit, irrespective of whether folic acid was administered with or without vitamin B12 (Bryan et al., 2002). There are, however, reports of a positive response. Fioravanti et al. (1998) gave folic acid to older subjects with cognitive impairment and a low folate status. Over a two-month period there was an improvement in both memory and attention, a response that correlated with the initial severity of folate deficiency. Similarly Durga et al. (2007) examined a sample of those aged 50–70 years who had raised tHcy but normal vitamin B12 levels at baseline. Randomly they received either folic acid or a placebo. Supplementation for three years improved aspects of cognitive functioning that decline with age. In those with Alzheimer’s disease, the response to cholinesterase inhibitors was reported to be increased by taking 1 mg / day of folic acid (Connelly et al., 2008). Not all studies, however, have found a beneficial response. Eussen et al. (2006) gave a group aged more than 70 years, with a mild vitamin B12 deficiency, a supplement of vitamin B12 either with or without folic acid. After six months, cognition did not differ as judged by neuropsychological tests. In a small-scale study, Pathansali et al. (2006) gave folic acid for a month to those over 70 years but found no effect on a range of psychological tests. The study of Kang et al. (2008) is of interest as it gave a supplement of folic acid, vitamin B12 and vitamin B6 to a sample of women at risk of cardiovascular disease, rather than being preselected on the basis of their mood. By telephone, cognitive functioning was assessed over a five-year period; however, those taking the B vitamins did not differ from the placebo group. Similarly, van Uffelen et al. (2007) gave these three B vitamins for a year to adults living in the community but found that they did not affect measures of the quality of life. For a year and a half in a randomized trial, Aisen et al. (2008) gave a supplement of folate, vitamin B6 and vitamin B12 to those with mild to moderate Alzheimer’s disease. The vitamin supplements did not slow cognitive decline.

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Balk et al. (2007) systematically reviewed trials in which vitamin B6, vitamin B12 or folic acid were administered while monitoring changes in cognitive functioning. They found 14 trials, although most were described as being of low quality. The conclusion was that ‘supplementation with vitamins B6 or B12 or folic acid among either elderly cognitively intact individuals or those with dementia or cognitive impairment does not improve cognitive function’. The data were, however, limited by the short duration of most trials and a failure for clinical outcomes to be considered. The data were said to be ‘sparse, and firm conclusions are not possible’. Malouf and Grimley Evans (2008) similarly considered the influence of folic acid supplementation, with or without vitamin B12, and found no evidence that it helped either healthy or cognitively impaired older individuals. The obvious conclusion was that there was a need for large-scale and long-term, randomized controlled trials, as ultimately only intervention studies will establish a causal relationship between tHcy and dementia. Such data are likely to become available. Importantly, Clarke (2008) reported that there were 12 large Hcy-lowering trials that should in total have data from 30 000 participants. The investigators have agreed to combine these data, allowing a reliable conclusion to be drawn. These data are likely to greatly influence our understanding of this topic.

14.4 Vitamin B1 Vitamin B1 or thiamine is found widely in foods, including unrefined cereals, fresh meat, green vegetables, milk and fruit. However, as it is readily destroyed by boiling, and as it is stored in the body in only small amounts, there is a risk of deficiency if the level of intake is reduced for only a few weeks. The first signs of vitamin B1 deficiency are likely to be psychological, including confusion, problems of concentration and memory, irritability and depression. A prolonged and severe deficiency can result in brain damage, with consequence implications for cognitive functioning. A primary role for vitamin B1 is its involvement in releasing energy from carbohydrate, where its acts as a co-enzyme for several enzymes.

14.4.1 Beri-beri amnesia Beri-beri is a disorder of the nervous system caused by vitamin B1 deficiency. Symptoms include cardiovascular and nervous system problems. Beri-beri is rare in industrialized countries, particularly as some foods, for example breakfast cereals, are fortified. An exception is when there is alcohol abuse, where the diet is likely to be poor and the absorption and storage of vitamin B1 is adversely influenced by the inflammation of the stomach lining.

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When the eating of polished rice became widespread in the Far East, severe memory problems appeared and were labelled ‘beri-beri amnesia’. During the Second World War, de Wardener and Lennox (1947) studied prisoners of the Japanese who were suddenly subjected to a diet low in vitamin B1. Within six weeks the first symptoms were noticed, loss of appetite was followed by uncontrolled eye movements, sleeplessness and anxiety. Loss of memory occurred in 62 % of subjects: it was the ability to store new information that was disrupted, rather than the ability to retrieve information from long-term stores. That vitamin B1 was important was demonstrated on the occasions when supplies of the vitamin were available. The response to the administration of the vitamin was dramatic; in most cases, the symptoms improved within 48 hours. These workers equated the symptoms of beri-beri with Wernicke’s encephalopathy.

14.4.2 Wernicke–Korsakoff syndrome Wernicke’s encephalopathy reflects an acute yet severe vitamin B1 deficiency. In contrast, Korsakoff’s syndrome or psychosis results from a chronic deficiency, the sequela of Wernicke’s encephalopathy. Thus Wernicke’s encephalopathy and Korsakoff’s syndrome represent different stages of the same deficiency process, the Wernicke–Korsakoff syndrome or the related Alcohol Amnesic Syndrome. In susceptible individuals, a vitamin B1 deficiency follows a characteristic pattern that starts with a Wernicke’s state, that if untreated results in Korsakoff’s amnesicconfabulation. Wernicke’s encephalopathy involves by definition brain damage, paralysis of the eyes and a loss of coordination. The disorder results from a lack of vitamin B1 due to gastrointestinal problems or under-nutrition, or as a response secondary to chronic alcoholism. A genetic predisposition has been suggested as only a minority of alcoholics and the malnourished develop these symptoms and it is more commonly seen in Europeans (Bliss and Gibson, 1977). The symptoms of Wernicke’s encephalopathy have been also described in patients fed for extended periods by intravenous drips that lack a source of thiamine (Nadel and Burger, 1976). The symptoms of Korsakoff’s syndrome include problems of memory, confabulation (inventing memories to take the place of those that have been forgotten), a lack of insight and general apathy. Treatment involves administering vitamin B1 supplements by an intravenous or intramuscular route. It has been reported that 25 % of patients completely recover when treated with vitamin B1, whereas 50 % partially recover (Editorial, 1990). Although the administration of vitamin B1 is clinically recommended, a Cochrane review (Day et al., 2004) concluded that there was insufficient evidence, based on well-designed trials, to suggest the optimum dose, frequency and duration of treatment. However, when treated, recovery can take from days to over a month. The condition specifically responds to

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vitamin B1 and not niacin, pyridoxine, folic acid, ascorbic acid, riboflavin or vitamin B12 (Phillips et al., 1952). Victor et al. (1971) examined the postmortem brains of those with the Wernicke–Korsakoff syndrome. About half had damage to the periaqueductal grey matter, the mamillary bodies and medial thalamus. Sullivan and Pfefferbaum (2009) used structural magnetic resonance imaging (MRI) to produce images of the brains of those with Korsakoff’s syndrome and similarly found atrophy of the mammillary bodies and thalamus, associated with larger ventricles. Sechi and Serra (2007) noted that, based on postmortem examination, there was evidence that Wernicke’s encephalopathy is greatly underdiagnosed in both adults and children. When the characteristic neural lesions are looked for at postmortem, there is an impression that the incidence of the syndrome is increasing, being present in as many as 2.8 % of the population (Victor et al., 1971). Harper (1983) concluded that only 20 % with the disorder were diagnosed during their life, despite early treatment being associated with complete recovery. Harper (2009) found that heavy social drinkers, without noticeable neurological or liver problems, can have brain damage with an associated decline in cognitive functioning. In Australia concern about the frequent association between the intake of alcohol and vitamin B1 deficiency has led to a call for the fortification of beer with vitamin B1 (Price et al., 1987).

14.4.3 Restricted vitamin B1 intake Although studies that grossly limit intake have not been carried out recently, the feeding of a restricted diet offers a way of examining the short-term implications of deficiency. The US Recommended Daily Allowance for vitamin B1 is 1.2 mg/day for adult males and 1.1 mg/day for females (Dietary Reference Intakes, 1998). Wilder (1943) maintained four patients on a diet offering 0.075 mg vitamin B1 / 1000 calories. After ten days to five weeks there was an inability to concentrate, confusion of thought, uncertainty of memory, while the subjects became irritable, fearful and depressed. As such, a severe limitation of intake is unlikely to occur in normal diets. A study was also run offering 0.45 mg vitamin B1 / day (Williams et al., 1942). Similar changes resulted although after a longer period of deprivation. Vitamin B1 deficiency seems to particularly influence cognitive functioning as Keys et al. (1943) found that psychomotor performance was not influenced. Tuttle et al. (1949) similarly fed a group of young women a diet offering either 0.14 or 1.34 mg vitamin B1/day for six weeks. The low vitamin B1 diet was associated with poorer reaction times. An interesting conclusion of this study was that it was doubtful whether a minimum vitamin B1 requirement can be meaningfully established as there are such wide individual differences in need. Brozek (1957) fed young men diets that provided 0.61, 1.01 or 1.81 mg of vitamin B1/day and found that anorexia, muscular weakness, increased

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irritability and depression were the first signs of deprivation. A personality test established that depression and anxiety had increased. Thus, as well as cognitive problems, depression is amongst the first reactions to vitamin B1 deficiency. The re-administration of vitamin B1 produced dramatic changes; in particular, appetite was rapidly restored and personality changed for the better (Brozek, 1957).

14.4.4 Sub-clinical deficiencies of vitamin B1 Although there is strong evidence that a clinical deficiency of vitamin B1 is associated with psychological problems, the question of sub-clinical deficiencies has been addressed to only a limited extent. Irritability, aggressive behaviour and personality changes have, however, been described in vitamin B1-deficient adolescents whose diet consisted largely of high-calorie ‘junk’ foods (Lonsdale and Shamburger, 1980). Treatment with vitamin B1 resulted in the improvements of the symptoms, although they had previously failed to respond to drugs or psychotherapy. Smidt et al. (1991) found that healthy elderly Irish women responded to vitamin B1 supplementation with reports of feeling brighter, cheerier and less fatigued: a finding that perhaps reflects the lack of a vitamin B1 food enrichment policy in Ireland. About half the sample had vitamin B1 status, judged by biochemical assay, that placed them in the marginal category. Heseker et al. (1990) used biochemical indices of vitamin status to distinguish young adult males with an adequate status from those towards the bottom of the normal range. They found that low vitamin B1, ascorbic acid and folate status was associated with poor mood. Supplementation with thiamine for two months, under a double-blind procedure, resulted in increased sociability and sensitivity. Benton et al. (1995) gave young healthy adults either ten times the recommended daily dose of nine vitamins, or a placebo, for a year. In females, baseline thiamine status was associated with poor mood and an improvement in vitamin B1 status after three months was associated with feeling more composed and happier. Benton et al. (1997) followed up this finding and gave either vitamin B1 or a placebo for two months to young adult females. An improvement in thiamine status was associated with a better mood. Again, this response took place in subjects whose thiamine status, based on a biochemical criterion, was adequate before supplementation. The possibility that mood responds to thiamine supplementation was thus suggested by the findings of four well-controlled trials, although we need larger scale trials before any general recommendation can be offered. That an improvement in vitamin B1 status improved mood in individuals whose status was ‘adequate’ prior to supplementation (Benton et al., 1995, 1997) questions the ability of the biochemical assay of peripheral tissue to predict the needs of the brain. These findings are similar to those of Harrell (1946) who examined 120 children living together on a farm that was used

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as an orphanage. They ate the same diet that was estimated to supply 1 mg of vitamin B1/day, so a priori the diet would have been thought to be adequate in this respect. Under a double-blind procedure the children took either a placebo, or 2 mg vitamin B1, on a daily basis. Various tests were taken before and after taking the tablets for a year. There were remarkable improvements in those taking the vitamin B1 rather than the placebo: they were significantly taller, had better eye-sight and quicker reaction times, and scored better on tests of memory and intelligence. Thus, again, in a well designed trial there was a response to thiamine supplementation in those whose diets as judged by traditional criteria would be said to be adequate.

14.5 Niacin Niacin, also known as vitamin B3 or nicotinic acid, is found in liver, beef, chicken, fish, cereals and legumes and can be synthesized by the body from the amino acid tryptophan, that in turn is found in meat, dairy products and eggs. In the body niacin is converted to nicotinamide, then to nicotinamide adenine dinucleotide and subsequently to nicotinamide adenine dinucleotide phosphate, important for the synthesis of lipids and nucleic acids. Niacin deficiency is rare in developed countries; rather, it is usually associated with malnutrition, poverty and alcoholism. Deficiency is frequently associated with eating maize (corn) as the staple food as it is the only grain low in niacin. It has, however, been suggested that the incidence of niacin deficiency is increasing in the US, associated with excessive slimming and infection with the human immunodeficiency virus (Delgado-Sanchez et al., 2008). Where a serious deficiency of niacin occurs it leads to pellagra, characterized by the three Ds; diarrhoea, dermatitis and dementia. A major symptom is a problem with memory although this can be reversed by administering the vitamin. Amongst the earlier occurring symptoms are irritability, anxiety, depression and apathy (Dickerson and Wiryanti, 1978).

14.5.1 Schizophrenia In the 1950s Abram Hoffer and others developed the idea that schizophrenia could be treated by gram doses of niacin. For example, Hoffer et al. (1957) gave schizophrenics either a placebo, niacin or nicotinamide (3 g / day) under double-blind conditions for 33 days. Over the following two years, those receiving the vitamin were reported to show better adjustment and fewer relapses. Hoffer and Osmond (1964) presented follow-up data after 10 years: 75 % of those receiving the vitamins had not required readmission to hospital, whereas this was true for 36 % of those who received a placebo.

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When the American Psychiatric Association reviewed the topic their conclusions reflected many negative findings. They pointed out methodological flaws in the early work and reviewed later studies that had failed to find any benefit. The conclusions were notable for the strength of the language used: ‘. . . the credibility of the megavitamin proponents is low. Their credibility is further diminished by a consistent refusal over the past decade to perform controlled experiments and to report their new results in a scientifically acceptable fashion. Under these circumstances this Task Force considers the massive publicity which they promulgate . . . using catch phrases which are really misnomers like “megavitamin therapy” and “orthomolecular treatment,” to be deplorable’ (Lipton, 1973). Hoffer and Osmond (1976), however, claimed that the report was biased and contained many errors and misrepresentations. The conclusion that niacin is not widely recommended for the treatment of schizophrenia is unavoidable. Yet some have argued that the possibility that megadoses may be of value should not be finally discounted. Dickenson and Wiryanti (1978) argued that schizophrenia reflects several aetiologies and that not everybody responds to niacin. In fact, The American Psychiatric Association had previously discussed this possibility and concluded that ‘. . . the possibility of a small subgroup that is responsive . . . appears to be miminal . . .’ (Lipton, 1973).

14.6 Vitamin B6 Vitamin B6, that occurs in three forms, pyridoxal, pyridoxine and pyridoxamine, is found in many foods including meat, grains and vegetables and is absorbed by the jejunum and ileum. It occurs in various forms including pyridoxine that is used as a supplement. The metabolically active form pyridoxal 5′-phosphate is a co-factor for many aspects of amino acid metabolism, being involved, for example, in the metabolism of all amino acid neurotransmitters. It is also implicated in the release of glucose from glycogen, gene expression and the synthesis of haemoglobin and histamine.

14.6.1 Vitamin B6 and autism The use of vitamin B6 as a treatment of autism began when Heeley and Roberts (1966) found that 11 out of 19 autistic children given tryptophan excreted abnormal metabolites in their urine, although no behavioural studies were carried out. In the 1960s there was a climate that encouraged the taking of large doses of vitamins for a range of disorders. Rimland (1974) obtained detailed case reports from parents who reported, or did not report, an improvement in the autistic symptoms of their children. He looked for statistical clusters and found that the giving of vitamin B6 seemed to be a common factor when an improvement was reported. Rimland et al.

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(1978) followed up this initial observation using a double-blind procedure to examine children who had previously reacted favourably to vitamin B6. The hypothesis was supported that behaviour would respond to vitamin B6 supplementation. The doses of vitamin B6 varied from child to child (100– 3000 mg / day), and children were also receiving a variety of other drugs, vitamins and minerals. The conclusion that some autistic children respond to vitamin B6 was supported in a series of often small-scale studies by teams in Tours, France, and the Langley Porter Institute in San Francisco. Usually magnesium was also administered to decrease side-effects such as irritability, sound sensitivity and enuresis. Kleijnen and Knipschild (1991) reviewed 53 controlled trials of the effects of niacin, vitamin B6 and multivitamins. They concluded that most had methodological shortcomings but ‘only in autistic children are some positive results found with very high dosages of vitamin B6 combined with magnesium, but further evidence is needed before more definitive conclusions can be drawn’. Subsequently, Nye and Brice (2005) produced a Cochrane review and concluded that ‘due to the small number of studies, the methodological quality of studies, and small sample sizes, no recommendation can be advanced regarding the use of B6–Mg as a treatment for autism’. There are, however, some positive reports, although the small body of evidence precludes any general recommendations. For example Kuriyama et al. (2002) considered children with pervasive developmental disorders similar to those with vitamin B6-dependent epilepsy. In this sample of eight children, there was a significant benefit when treated with vitamin B6. Pfeiffer et al. (1995) noted that although the majority of studies report a favourable response to vitamin treatment, interpretation was limited by the use of imprecise outcome measures, small samples and the use of the same subjects in several studies. A concern is that the large doses used have been reported to cause peripheral nerve damage. Cohen and Bendich (1986) concluded that doses greater than 500 mg/day can produce sensory nerve damage although lower doses appeared to be safe. More generally, Malouf and Grimley Evans (2003) reviewed the influence of vitamin B6 supplementation on the cognition of older adults, particularly in the context of the ability of supplementation to reduce tHcy. They were unable to find any trial that had administered vitamin B6 to those with dementia or pre-existing memory problems. However, there were two trials that had considered healthy older samples. Bryan et al. (2002) for five weeks gave different groups of women over 65 years of age folic acid, vitamin B12 or vitamin B6. The 12 who received vitamin B6 did not differ from those who were allocated the placebo on measures of mood and cognition. Deijen et al. (1992) matched pairs of males between 70 and 79 years of age. For 12 weeks they received either vitamin B6 or a placebo. Again, supplementation did not influence either cognition

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or mood although vitamin status was improved in the sample taking the active tablet. Although tHcy status was not measured, such supplementation might be expected to decrease levels in the blood. Thus to date, there is no evidence that short-term vitamin B6 supplements benefit either mood or cognition. However, the possibility that longer-term supplementation might be beneficial cannot be excluded. Benton et al. (1995) gave a multivitamin supplement or a placebo to a sample of 129 young healthy adults for a year. Although the blood levels of these vitamins had peaked by three months, mood continued to improve up to 12 months. The degree to which mood improved correlated with the improvement in vitamin B6 status. It is clearly possible to use supplementation to improve the vitamin B6 status of older people and such supplementation is known to reduce tHcy. However, without larger scale and long trials we cannot conclude that such supplementation is beneficial.

14.7 Vitamin B12 Although vitamin B12 (also called cobalamin) supplementation can reduce tHcy, this vitamin has tended to be more often considered in the context of cognitive decline and the development of dementia. Vitamin B12 or cobalamin is absorbed by the ileum after being bound to intrinsic factor, a glycoprotein produced by the parietal cells of the gastric mucosa. Cyanobalamin is a form that does not occur naturally but, due to its stability, is used in supplements. Vitamin B12 is involved in the metabolism of every cell, and plays important roles in the production of red blood cells, nerve cells and genetic material, fatty acid synthesis and the production of energy. The vitamin is obtained almost entirely from meat, meat products and fish, as vegetables offer an inadequate source. A loss of parietal cells will lead to an inability to absorb the vitamin. Although the most common cause of deficiency is the lack of intrinsic factor, a diet lacking in vitamin B12, particularly associated with being vegetarian or vegan, can be a problem. Other causes of a deficiency are an inadequate absorption due to problems such as coeliac disease, gastritis, Crohns disease or a disorder of the pancreas. Heavy alcohol consumption or some therapeutic drugs can also cause a problem.

14.7.1 Dementia and vitamin B12 About 40 % of those who are vitamin B12-deficient have symptoms associated with damage to the spinal cord, peripheral nerves or brain. The duration of the deficiency tends to correlate with the severity of the abnormalities. The first abnormality is usually sensory numbness and tingling, particularly

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in the arms and legs. In more advanced cases, reflexes are abnormal and there is motor impairment. In a minority of cases, psychiatric disturbances occur, although rarely without other neurological changes (Savage and Lindenbaum, 1995). Among the many symptoms of deficiency are fatigue, depression and a poor memory. A colloquial description is that ‘brain fog’ results; problems of concentration, a failure to think clearly and poor memory. A risk is that if diagnosis is delayed then irreversible damage to the brain may result. Vogiatzoglou et al. (2008) followed up a group aged between 61 and 87 years of age. In this group, none of whom were vitamin B12-deficient, those with the lower levels of vitamin were more likely to show signs of brain shrinkage after five years. In fact, those with higher vitamin levels were six times less likely to have brain shrinkage compared with those who had lower levels of the vitamin. The correlational nature of these data, however, prevented the conclusion that the association reflected a causal relationship. Seal et al. (2002) considered those with low or borderline levels of serum vitamin B12 concentrations in a group with a mean age of 81.4 years. Although vitamin status improved and tHcy values fell, but not to a statistically significant extent, cognition did not improve. In fact, studies of supplementation with this vitamin have produced mixed findings and there are few studies that have used brain scans in this context. Hvas et al. (2004) considered those with vitamin B12 deficiency. In this sample of the elderly, supplementation for three months did not improve cognitive functioning or reduce depression. Martin et al. (1992) gave vitamin B12 to elderly subjects with low serum vitamin B12 who displayed cognitive impairment. After at least six months of supplementation, 11 out of 18 patients showed cognitive improvement, a response that correlated with the duration of the cognitive problems. The more recently the problems had first occurred, the better was the response to supplementation. They concluded that ‘there may be a time-limited window of opportunity for effective intervention in patients with cognitive dysfunction and low serum cobalamin’. Malouf and Grimley Evans (2003) systematically reviewed the association between vitamin B12 and cognitive impairment. They noted that low blood levels of vitamin B12 have been found in more than 10 % of older adults. In particular, those with Alzheimer’s disease are particularly likely to have low vitamin B12 status. They looked at randomized double-blind trials in which supplements of vitamin B12 were consumed. Two studies of those with cognitive impairment were found (Fourniere et al., 1997; Seal et al., 2002), although there was no study of those not cognitively impaired. They concluded that there was no evidence that vitamin B12 supplementation improved cognitive functioning, although the existing studies used small samples and there had been no examination of those without preexisting cognitive impairment.

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14.7.2 The interaction between folate and vitamin B12 metabolism When Herbert (1962) used himself as a subject and consumed a diet deficient in folate, he experienced insomnia, irritability, fatigue and forgetfulness; symptoms that disappeared when folic acid was subsequently consumed. The importance of an adequate intake of folate for psychological functioning had become apparent. The metabolism of folate and vitamin B12 are closely connected, such that some consequences of vitamin B12 deficiency can be masked by a high folate status. Figure 14.1 illlustrates that both folate and vitamin B12 act as co-enzymes in one-carbon metabolism. If a high intake of folic acid results in a failure to recognize vitamin B12 deficiency then permanent brain damage can result. Smith (2007) noted that we do not let a drug onto the market without assessing safety and possible side-effects, yet in 1998 the US Food and Drug Administration fortified flour with folic acid. He suggested that there are grounds for concern. In older adults, who took supplements of more than 400 μg/day folic acid, there was an increased risk of cognitive decline (Morris et al., 2007), although the effect was less marked if, in addition, vitamin B12-containing supplements were consumed. Morris et al. (2007) had considered healthy individuals over 60 years of age. As might be expected, low vitamin B12 status was associated with macrocytosis, anaemia and cognitive impairment. However, the effects of folate status were two-fold, depending on the level of vitamin B12. If vitamin B12 was in the normal range, a high level of serum folate (> 59 nmol/L) reduced the probability of cognitive impairment. This observation was the more remarkable as it was observed in a population whose levels had been raised by folate fortification. Similarly, in a sample of Latinos living in California, higher levels of red blood cell folate had previously been found to be associated with a lower incidence of cognitive impairment and dementia (Ramos et al., 2005). It seems that in those with a good vitamin B12 status, supplementation with folic acid benefited cognitive functioning. However, the other message from Morris et al. (2007) was that higher levels of serum folate were associated with cognitive impairment in those with low vitamin B12 status. The straightforward interpretation is that the cognitive problems resulting from low vitamin B12 status are worse when the levels of folate are high. That many participants in these studies reported the use of folic acid-containing supplements, in addition to that in fortified foods, raises questions about their use. A concern is that Morris et al. (2007) found about 4 % of their sample of the elderly had a combination of a low vitamin B12 and high folate status. They suggested that if such data extrapolate to the entire American population then about 1.8 million might be at increased risk of cognitive impairment and anaemia because of an imbalance between folate and vitamin B12. As it is clearly unethical to give folic acid to those with a poor vitamin B12 status, Selhub et al. (2009) examined data from the US National Health and Nutrition Examination Survey (NHANES), using as a natural experi-

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ment a comparison of the time before and after the fortification of flour with folic acid. Compared to those with normal folate and vitamin B12 status, the incidence of impaired cognitive function was twice as great in those with low vitamin B12 status but normal serum folate. However, in those with a low vitamin B12 but high level of folate status, the incidence of cognitive problems was five times that associated with normal folate and vitamin B12 values. Importantly, the adverse interaction between high levels of folate and low vitamin B12 status was seen only in participants after the fortification of flour with folic acid. Smith (2007) raised a series of questions. Is it the balance between these two vitamins rather than the concentrations that is important? Should there also be fortification with vitamin B12? What mechanisms lead to cognitive impairment in those with a high folate / low vitamin B12 status? Does unmetabolized folic acid cause problems? Are sectors of the population, for example vegetarians, being harmed by folic acid fortification and supplements? He summarized a dilemma: ‘is it ethical to save one infant from developing a NTD (neural tube disorder) and hopefully provide that child a high-quality life but increase the risk of poorer health in over 1000 elderly persons?’

14.8 Anti-oxidants, micronutrients and the oxidative stress hypothesis of ageing Harman (1956) proposed the free radical theory of ageing that relates the ageing process to damage caused to DNA, protein and lipids by free radicals. Free radicals are a by-product of metabolism but are also formed by smoking, alcohol consumption, stress, sunlight and pollution. Free radicals are highly unstable molecules that, as they possess an unshared single electron, are highly reactive and cause damage when they react with other molecules. Oxidative stress is said to occur if the production of reactive oxygen is greater than the body’s ability to deal with it, or if the body is unable to repair any damage that has resulted. The reduction–oxidation reaction is driven by enzymes that attempt to maintain a reduced state: if not successful, the production of peroxides and free radicals will damage many aspects of the cells’ functioning. A role for oxidative stress has been suggested in many human diseases including heart disease, Parkinson’s disease and Alzheimer’s disease. In particular the brain is susceptible to oxidative stress as it is rich in polyunsaturated fatty acids and has a high metabolic rate, the antioxidant systems are poorer than with other organs and high levels of transition metals such as iron can act as pro-oxidants. Diet, however, can be viewed as having the potential to offer antioxidants that either inhibit the oxidation of target molecules or block the generation of free radicals or the chain reaction they generate. One goal is

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to consume sufficient anti-oxidants nutrients to deal with free radicals generated by the body. Various micronutrients have anti-oxidant properties: vitamin A, β-carotene that can be metabolized into vitamin A, vitamin C, vitamin E and selenium. Selenoproteins by definition have selenium as part of their structure and include glutathione peroxidise, an enzyme family whose main role is to protect the body from oxidative damage. Vitamin E is the collective name for eight related tocopherols and tocotrienols. It has attracted particular attention as it is the most important lipid soluble anti-oxidant and the brain is a fatty organ and therefore highly susceptible to damage from free radicals. Vitamin E protects cell membranes from oxidation by reacting with lipid radicals produced in the lipid peroxidation chain reaction. Concerns have, however, been raised about the consumption of high levels of vitamin E, although Pavlik et al. (2009) analysed the survival rate of patients with Alzheimer’s disease who took high levels of vitamin E and failed to find an increased rate of mortality. The carotenoids, the main pigments that create the red, orange, yellow and green colours of vegetables and fruits, also have anti-oxidant properties. There are over 600 types of carotenoids that split into two groups, the xanthophylls that are yellow pigments and carotenes that are orange. Lycopene is a bright red carotene that is responsible for the red colour of tomatoes, other fruits and vegetables. Polyphenols are found in many foods, including legumes, fruits, vegetables, red wine, green tea and chocolate. The flavonoids, also called bioflavonids, are a type of polyphenol found in many berries, tea and coffee. They occur widely as pigments in flowers and vegetables and, although now they are not thought to be essential nutrients, at one time they were called vitamin P. It is, however, difficult to establish a role for a particular structure as, for example, red wine has more than 60 different flavonoids, in fact in total as much as 3 g per litre.

14.8.1 Postmortem studies of those with dementia In addition to the classical pathological characteristics of Alzheimer’s disease, amyloid plaques and neurofibrillary tangles, damage mediated by reactive oxygen species and reactive nitrogen species is typically observed. There have been consistent reports that lipid peroxidation, the way in which lipids are attacked by reactive oxygen species, is greater in the brains of those with Alzheimer’s disease. For example Subbarao et al. (1990) studied those with Alzheimer’s disease at postmortem and found that an index of peroxidation was higher in the frontal cortex but not the cerebellum, an area typically without senile plaques. Similarly, Lovell et al. (1995) found evidence of greater lipid peroxidation in eight out of nine areas of the brain, differences that were statistically significant in the pyriform cortex, and the hippocampus that plays an important role in memory. Markesbery and Carney (1999) reviewed the topic and concluded that: ‘There is increasing

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evidence that free radical damage to brain lipids, carbohydrates, proteins, and DNA is involved in neuron death in neurodegenerative disorders’. They also found evidence for a decline in polyunsaturated fatty acids and that markers of lipid peroxidation are greater in the cerebrospinal fluid of those with Alzheimer’s disease. In addition, increased levels of markers for inflammation have been found in the brains of those with Alzheimer’s disease. Oxidation and inflammation have been described as being twinned as they occur together.

14.8.2 Cross-sectional studies Perkins et al. (1999) related the level of serum antioxidant (vitamins A, C, E, carotenoids, selenium) to poor memory in a sample from the US Third National Health and Nutrition Examination Survey. Lower levels of vitamin E were associated with poorer memory, although the other anti-oxidants were not. The Honolulu–Asia Aging Study considered those who used vitamin E and vitamin C supplements (Masaki et al., 2000). The taking of both supplements together was found to protect against the development of vascular dementia. In those without dementia, the use of either vitamin resulted in a better performance on cognitive tests. The data are not, however, totally consistent. Mendelsohn et al. (1998) examined the use of anti-oxidant supplements among older community living adults in Pennsylvania with an average age of 74.5 years. About a third reported the use of supplements containing vitamin A, C, or E, β-carotene, zinc or selenium, a phenomenon more common in women and those with a period of higher education. After accounting for potentially confounding factors, the taking of an anti-oxidant supplement was not associated with better cognitive functioning. Thus, some but not all cross-sectional studies have found a relationship between anti-oxidant intake and better cognitive functioning. Although such data can be viewed as consistent with anti-oxidants helping to prevent cognitive decline, these are not well-controlled studies and causality cannot be established. Although typically attempts were made to control statistically for confounding variables, the decision to consume anti-oxidant vitamins is associated with a range of variables that themselves predict successful ageing. Ultimately it is only intervention studies that will allow the role of vitamin supplementation to be established.

14.8.3 Prospective studies The findings from prospective studies are confusing. The Honolulu–Asia Aging Study related the level of dietary vitamin E to the development of dementia over a 30-year period and found no relationship (Laurin et al., 2004). Similarly, over four years the Washington Heights–Inwood Columbia Aging Project found that the level of vitamin E, carotenes and vitamin C

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in the diet, or the taking of supplements, did not influence the incidence of Alzheimer’s disease (Luchsinger et al., 2003). Over a ten-year period, Fillenbaum et al. (2005) considered the use of vitamin C and/or vitamin E supplements in a community sample and found that they did not influence the incidence of dementia. Gray et al. (2008) found that the use of vitamin E and C supplements, alone or in combination, did not reduce risk dementia over a period of five and a half years. However, the Nurses’ Health Study (Grodstein et al., 2003) considered nearly 15 000 women between 70 and 79 years, and found the long-term use of vitamin C and vitamin E supplements was associated with better cognition as judged by telephone-based tests. The association was greater in women with a low dietary intake of α-tocopherol and was less consistent when vitamin E was taken by itself. Similarly, the taking of vitamin C by itself did not influence cognition. Morris et al. (2002) examined a sample living in the community who were at least 65 years of age and over an average of 3.9 years related diet at baseline to the development of dementia. Those consuming lower levels of vitamin E were more likely to develop Alzheimer’s disease, although this occurred only in those without the apolipoprotein ε 4 genotype (APOE ε 4, a risk factor for the disease). The intake level of vitamin C or β-carotene was not associated with the risk of Alzheimer’s disease. Interestingly, they found that vitamin E from supplements, rather than food sources, did not reduce the risk of dementia. It may be relevant that supplements usually contain α-tocopherol, whereas food contains other forms of vitamin E. Therefore, Morris et al. (2005) over a fouryear period related the level and type of tocopherol level to the incidence of Alzheimer’s disease. They found that various forms of tocopherol, rather than α-tocopherol alone, may be protective. The Rotterdam study also produced a positive finding. Over a six-year period, a high intake of vitamin C and vitamin E was associated with lower risk of Alzheimer’s disease, a relationship that was stronger amongst smokers (Engelhart et al., 2002). This relationship was not influenced by APOE ε 4. Others have found that, although vitamin E was not effective alone, there was a lower incidence of dementia when it was combined with vitamin C (Zandi et al., 2004; Maxwell et al., 2005).

14.8.4 Intervention studies By far the most weight can be placed on the results of double-blind, placebo-controlled, randomized trials. An early open trial for a year gave both vitamin C and vitamin E to those in a home for the elderly. An improvement in verbal memory was reported (Srám et al., 1993). Sano et al. (1997) gave patients with moderate Alzheimer’s disease either vitamin E or a placebo for two years. The time before they were forced to enter an institution was significantly longer when vitamin E was administered; 670 days compared with 440 days for the placebo group.

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However, Petersen et al. (2005) studied subjects with mild cognitive impairment (MCI) but found that over two years vitamin E supplementation was not beneficial, irrespective of the presence of APOE ε 4. Similarly, when Yaffe et al. (2004) gave vitamin C, vitamin E and β-carotene supplements for a median of 6.9 years, those taking these anti-oxidants did not differ on six cognitive tests from a group taking a placebo. Again, Kang et al. (2006) gave healthy women over 65 years of age vitamin E for 5.6 years, but again it did not significantly change various cognitive measures. These last two studies are important as they were ancillary parts of studies with other major objectives and they give information concerning individuals who were not preselected for problems of memory and thus give information concerning the ability to generally prevent cognitive decline. Smith et al. (1999) was similarly also unable to find in a community sample of older adults that the consumption of vitamin C, vitamin E and β-carotene for a year influenced the performance of tests of memory. An approach with some potential is the use of brain imaging as a marker of brain degeneration. In a multicentre trial, Jack et al. (2008) considered the taking of vitamin E and donepezil as a treatment of MCI. The percent change in the size of various areas of the brain was established. Brain atrophy was greater in those who developed Alzheimer’s disease and the rate of brain atrophy correlated with changes in the scores of various cognitive tests. The annual decline in brain volume did not differ in those consuming vitamin E rather than the placebo. The study does, however, suggest that brain imaging may prove to be a useful outcome measure when considering cognitive decline.

14.8.5 Status of the oxidative stress hypothesis Thus clinical trials with anti-oxidants have produced only limited evidence that supplementation is beneficial. As ultimately the deciding evidence will come from randomized clinical trials, this failure has created doubts about the oxidative stress hypothesis. Dangour et al. (2004) reviewed studies of micronutrient supplementation on a range of disorders including cognitive decline. They concluded that ‘while observational data suggest the presence of a link between dietary micronutrient intake and health outcomes, evidence from large randomized controlled trials does not support the use of antioxidant vitamin or mineral supplements among well-nourished older populations’. This failure to respond to supplementation raises serious questions concerning about the oxidative stress hypothesis. Is it possible that oxidative stress is secondary to the complex underlying pathology of dementia? Praticò (2008) concluded that oxidative stress occurred early in the development of dementia and that general epidemiology has found that cognitive decline was greater in those with less anti-oxidant capacity. Thus there is considerable evidence that Alzheimer’s disease is associated with

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oxidative stress, although the essential question is whether it is a cause or a consequence of disease? It looks as if there is a need for some rethinking, as the simplest conception of the hypothesis would predict that anything that reduces oxidative stress should decrease the incidence of dementia. Praticò (2008) noted that we do not know what dose of an anti-oxidant is sufficient to reduce the level of oxidative stress that characterizes the development of the disease. In addition, we need to know the anti-oxidant status of subjects so that those in need of additional capacity can be distinguished. The form of the vitamin administered, whether there are synergistic actions between nutrients, the duration of administration and the age of the subjects are other matters that have attracted little attention. The body of data is not sufficient to consider these factors, making a synthesis and full evaluation of the topic impossible. Benton (2010) discussed the timescale of cognitive decline. He concluded that it was a life-long process. The concept of ‘cognitive reserve’ has been discussed; that is, the capacity of the brain to resist the effects of disease without manifesting clinical symptoms. For example, higher levels of intelligence in younger life reduce the risk of subsequent dementia. As such, when considering dementia we may need to examine the diet of the mother before birth and of the child throughout their formative years. Thus, as well as trying to slow cognitive decline, perhaps we should consider trying to create a brain with as much surplus capacity as possible? Subsequently, the size of the brain shrinks throughout adult life, beginning in the twenties. Benton (2010) noted that attempts to examine the impact of diet on cognitive decline have failed to address the time scale over which changes occur. For example, the study of those with mild cognitive impairment (MCI) is a common strategy: that is, the examination of those who are beginning to display the early signs of memory impairment. If such people are displaying the early stages of dementia then there has already been brain damage. It is possible, if not probable, that the influence of diet takes place over many years, so that an intervention may need to begin when a young adult and continue over several decades. It is therefore reasonable to suggest that the findings in this area are to date inconclusive. There are very good reasons to expect that anti-oxidant vitamins should prove beneficial, but to date there is little evidence that when anti-oxidant vitamins are supplied they decrease the incidence of dementia. As there are many factors that influence the development of dementia, it is optimistic to expect that changing the level of one vitamin in the diet, for a relatively short period, is going to have a dramatic impact. There is, however, considerable evidence at a biochemical level that oxidative stress plays a role in cognitive decline. A working hypothesis could be that vitamin status when considered using a sufficiently complex theoretical framework may in the future be shown to play a role.

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14.9 Future trends It is probable that in the future the underlying theoretical model will need to be more sophisticated. To date, the approach taken has been rather simple in its conception; anti-oxidants should slow ageing; as various vitamins reduce tHcy, they should prevent cognitive decline. It is arguably unreasonable to expect such universal and straightforward responses. There are obvious factors that should be added to such underlying ideas in the hope that they will help to improve our ability to understand the ageing process. Rather than expecting everybody to react in a similar manner, we will need to consider their existing diet, biochemical status and genotype. If the anti-oxidant or folate status is already excellent then supplementation would not be expected to be beneficial. We require measures of pre-existing biological status and evidence of the extent to which any intervention has been influential. There are wide-ranging individual differences in the needs for micronutrients, depending on genetics and lifestyle. At the very least, those with different relevant genotypes need to be distinguished. The timescale of the ageing process needs to be acknowledged such that it influences the design of studies. Diet during in the formative years helps to develop a ‘cognitive reserve’ that slows the decline in cognitive functioning in later life (Richards and Sacker, 2003). The decline in size of the brain (Hommer et al., 2001) and also the decline in cognition functioning begins when in your twenties (Nilsson, 2003). The possibility that the nature of diet influences the brain throughout life should be considered. To date, studies have tended to recruit those where brain damage has already occurred such as those with MCI or actual dementia. If the damage is taking place over many decades then it may be too late to observe the effect of changes in diet. Such a long timescale brings with it problems as you cannot randomly allocate people to a diet and expect them to eat it for decades. We need to establish biomarkers that can act as surrogate measures of cognitive decline in short-term studies. Brain imaging offers one possibility, for example looking for changes in the volume of areas of the brain such as the hippocampus. Although future evidence is required to firmly establish such associations, these might involve the monitoring of any of the biological mechanisms that are hypothesized to be associated with ageing, including oxidative stress, inflammation, homocysteine, advanced glycation endproducts and the provision of fatty acids. Finally, the likelihood of success in this area is likely to be increased by the use of sensitive measures of cognition (Benton et al., 2005). Memory is a multidimensional process that cannot be measured using a single test; it cannot be assayed as if it is a biochemical parameter. The most commonly used test in this area is the Mini-Mental State Examination that attracts the criticism that it is a brief and crude test that adds several unrelated aspects of cognition together to

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produce a single uninterruptable score (Benton et al., 2005). The conclusion that we need a number of large-scale, long-term, randomized trials is familiar but nevertheless accurate.

14.10 Sources of further information and advice There are many scientific and medical societies with an interest in ageing, nutrition or oxidative stress that might prove of interest to those in the area. The following should be treated as examples rather than an exclusive list. • The Oxygen Club of California is dedicated, on a worldwide basis, to facilitating discussion amongst those interested in free radicals, oxidants, anti-oxidants, micronutrients, nutrition and health. http://www. oxyclubcalifornia.org. • The American Aging Association promotes studies into ageing studies with the aim of slowing the ageing process and to inform the public of practical ways of achieving a long and healthy life. http://www. americanaging.org. • The World Society of Anti-Aging Medicine was created in Paris and promotes anti-ageing medicine by arranging educational events for physicians and the general public. http://www.wosaam.org. • The World Anti-Aging Academy of Medicine was established to coordinate organizations that at the national level advance preventive medicine. http://www.waaam.org. • The European Society of Preventive Regenerative and Anti-Aging Medicine (ESAAM) is based in Vienna and is an umbrella organization for national anti-ageing societies in Europe. www.esaam.org.eu. • The International Academy of Nutrition & Aging deals with problems concerning nutrition and ageing. http://www.healthandage.com/html/ min/iananda/.

14.11 References aisen p s, schneider l s, sano m, diaz-arrastia r, van dyck c h, weiner m f, bottiglieri t, jin s, stokes k t, thomas r g and thal l j (2008) High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. J Am Med Assoc, 300, 1774–83. almeida o p, flicker l, lautenschlager n t, leedman p, vasikaran s and van bockxmeer f m (2005) Contribution of the MTHFR gene to the causal pathway for depression, anxiety and cognitive impairment in later life. Neurobiol Aging, 26, 251–7. almeida o p, flicker l, norman p, hankey g j, vasikaran s, van bockxmeer f m and jamrozik k (2007) Association of cardiovascular risk factors and disease with depression in later life. Am J Geriatr Psychiatry, 15, 506–13. almeida o p, mccaul k, hankey g j, norman p, jamrozik k and flicker l (2008) Homocysteine and depression in later life. Arch Gen Psychiatry, 65, 1286–94.

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balk e m, raman g, tatsioni a, chung m, lau j and rosenberg i h (2007) Vitamin B6, B12, and folic acid supplementation and cognitive function. A systematic review of randomized trials. Arch Intern Med, 167, 21–30. benton d (2010) Neuro-development and neuro-degeneration. Are there critical stages for nutritional intervention? Nutr Rev, 68 (Suppl), S6–S10. benton d, haller j and fordy j (1995) Vitamin supplementation for 1 year improves mood. Neuropsychobiol, 32, 98–105. benton d, griffiths r and haller j (1997) Thiamine supplementation mood and cognitive functioning. Psychopharmacol, 129, 66–71. benton d, kallus k w and schmitt j a j (2005) How should we measure nutritioninduced improvements in memory? Eur J Nutr, 44, 485–498. bjelland i, tell g s, vollset s e, refsum h and ueland p m (2003) Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry, 60, 618–26. bliss j p and gibson g e (1977) Abnormality of a thiamine-requiring enzyme in patients with Wernicke-Korsakoff syndrome. New Eng J Med, 297, 1367–70. brozek j (1957) Psychological effects of thiamine restriction and deprivation in normal young men. Am J Clin Nutr, 5, 109–18. bryan j, calvaresi e and hughes d (2002) Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr, 132, 1345–56. chen c s, tsai j c, tsang h y, kuo y t, lin h f, chiang i c and devanand d p (2005) Homocysteine levels, MTHFR C677T genotype, and MRI Hyperintensities in late-onset major depressive disorder. Am J Geriatr Psychiatry, 13, 869–75. cohen m and bendich a (1986) Safety of pyridoxine – a review of human and animal studies. Toxicol Lett, 34, 129–39. coppen a and bailey j (2000) Enhancement of the antidepressant fluoxetine by folic acid: a randomised placebo controlled trial. J Affect Disord, 60, 121–3. coppen a and bolander-gouaille c (2005) Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol, 19, 59–65. clarke r (2008) B-vitamins and prevention of dementia. Proc Nutr Soc, 67, 75–81. connelly p j, prentice n p, cousland g and bonham j (2008) A randomised doubleblind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer’s disease. Int J Geriatr Psychiatry, 23, 155–60. dangour a d, sibson v l and fletcher a e (2004) Hormones and supplements: do they work? Micronutrient supplementation in later life: limited evidence for benefit. J Gerontol A Biol Sci Med Sci, 59, B659–73. day e, bentham p, callagham r, kuruvilla t and george s (2004) Thiamine for Wernicke–Korsakoff Syndrome in people at risk from alcohol abuse. Cochrane Database Syst Rev, CD004033. de wardener h e and lennox b (1947) Cerebral Beriberi (Wernicke’s Encephalopathy). Lancet, I, 11–17. deijen j b, van der beek e j, orlebeke j f and van den berg h (1992) Vitamin B-6 supplementation in elderly men: effects on mood, memory, performance and mental effort. Psychopharmacol, 109, 489–96. delgado-sanchez l, godkar d and niranjan s (2008) Pellagra: rekindling of an old flame. Am J Ther, 15, 173–5. dickerson j w t and wiryanti j (1978) Pellagra and mental disturbance. Proc Nutr Soc, 37, 167–71. dietary reference intakes (1998) Washington DC: National Academy Press. durga j, van boxtel m p, schouten e g, kok f j, jolles j, katan m b and verhoef p (2007) Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet, 369(9557), 208–16.

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editorial (1990) Korsakoff’s syndrome. Lancet, 336, 912–13. engelhart m j, geerlings m i, ruitenberg a, van swieten j c, hofman a, witteman j c and breteler m m (2002) Dietary intake of antioxidants and risk of Alzheimer disease. J Am Med Assoc, 287, 3223–9. eussen s j, groot l c, joosten l w, bloo r j, clarke r, ueland p m, schneede j, blom h j, hoefnagels w h, van staveren w a (2006) Effect of oral vitamin B12 with or without folic acid on cognitive function in older people with mild vitamin deficiency a randomized placebo controlled trial. Am J Clin Nutr, 84, 361–70. fillenbaum g g, kuchibhatla m n, hanlon j t, artz m b, pieper c f, schmader k e, dysken m w and gray s l (2005) Dementia and Alzheimer’s disease in communitydwelling elders taking vitamin C and/or vitamin E. Ann Pharmacother, 39, 2009–14. fioravanti m, ferrario e, massaia m, cape g, rivolta g, grossi e and buckley a e (1998) Low folate levels in the cognitive decline of elderly patients and the efficacy of folate as a treatment for improving memory deficits. Arch Gerontol Geriatr, 26, 1–13. folstein m, liu t, peter i, buel j, arsenault l, scott t and qiu w w (2007) The homocysteine hypothesis of depression. Am J Psychiatry, 164, 861–7. ford a h, flicker l, thomas j, norman p, jamrozik k and almeida o p (2008) Vitamins B12, B6, and folic acid for onset of depressive symptoms in older men: results from a 2-year placebo-controlled randomized trial. J Clin Psychiatry, 69, 1203–9. fourniere f, ferry m, cnockaert x, chahwakilian a, hugonot-diener l, baumann f, nedelec c, buronfosse d, meignan s, fauchier c, attar c, belmin j and piette f (1997) Vitamin B12 deficiency and dementia a multicenter epidemiologic and therapeutic study preliminary therapeutic trial [Deficience en vitamine B12 et etat dementiel etude epidemiologique multicentrique et therapeutique essai preliminaire]. Semaine Des Hopitaux, 73, 133–40. gaysina d, cohen s, craddock n, farmer a, hoda f, korszun a, owen m j, craig i w and mcguffin p (2008) No association with the 5,10-methylenetetrahydrofolate reductase gene and major depressive disorder: results of the depression case control (DeCC) study and a meta-analysis. Am J Med Genet B Neuropsychiatr Genet, 147B, 699–706. godfrey p s, toone b k, carney m w, flynn t g, bottiglieri t, laundy m, chanarin i, and reynolds e h (1990) Enhancement of recovery from psychiatric illness by methylfolate. Lancet, 336, 392–5. gray s l, anderson m l, crane p k, breitner j c, mccormick w, bowen j d, teri l and larson e (2008) Antioxidant vitamin supplement use and risk of dementia or Alzheimer’s disease in older adults. J Am Geriatr Soc, 56, 291–5. grodstein f, chen j and willett w c (2003) High-dose antioxidant supplements and cognitive function in community-dwelling elderly women. Am J Clin Nutr, 77, 975–84. harman d (1956) A theory based on radical and radiation chemistry. J Gerontol, 11, 298–300. harper c (1983) The incidence of Wernicke’s encephalopathy in Australia – a neuropathological study of 131 cases. J Neurol Neurosurg Psychiatry, 46, 593–8. harper c (2009) The neuropathology of alcohol-related brain damage. Alcohol Alcohol, 44, 136–40. harrell r f (1946) Mental responses to added thiamine. J Nutr, 31, 283–98. heeley a f and roberts g e (1966) A study of tryptophan metabolism in psychotic children. Dev Med Child Neurol, 3, 708–18. herbert v (1962) Experimental nutritional folate deficiency in man. Trans Assoc Am Physicians, 75, 307–20.

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heseker h, kubler w, westenhofer j and pudel v (1990) Psychische Veranderungen als Fruhzeichen einer suboptimalen Vitaminversorgung. Ernahrungs-Umschau, 37, 87–94. hoffer a and osmond h (1964) Treatment of schizophrenia with nicotinic acid. A ten year follow-up. Acta Psychiat Scand, 40, 171–89. hoffer a and osmond h (1976) Megavitamin Therapy in reply to The American Psychiatric Association Task Force Report on Megavitamin and Orthomolecular Therapy in Psychiatry. Toronto: Canadian Schizophrenia Foundation. hoffer a, osmond h, callbeck m j and kahan i (1957) Treatment of schizophrenia with nicotinic acid and nicotinamide. J Clin Exp Psychopathol, 18, 131–58. hommer d, momenan r, kaiser e and rawlings r (2001) Evidence for a genderrelated effect of alcoholism on brain volumes. Am J Psychiatry, 158, 198– 204. hvas a m, juul s, lauritzen l, nexo e and ellegaard j (2004) No effect ofvitamin B12 treatment on cognitive function and depression: a randomized placebo controlled study. J Affective Disord, 81, 269–73. jack c r jr, petersen r c, grundman m, jin s, gamst a, ward c p, sencakova d, doody r s and thal l j (2008) Longitudinal MRI findings from the vitamin E and donezepil treatment study for MCI Members of the Alzheimer’s Disease Cooperative Study (ADCS). Neurobiol Aging, 29, 1285–95. jacques p f, bostom a g, williams r r, ellison r c, eckfeldt j h, rosenberg i h, selhub j and rozen r (1996) Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation, 93, 7–9. kang j h, cook n, manson j, buring j e and grodstein f (2006) A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med, 166, 2462–8. kang j h, cook n, manson j, buring j e, albert c m and grodstein f (2008) A trial of B vitamins and cognitive function among women at high risk of cardiovascular disease. Am J Clin Nutr, 88, 1602–10. keys a, henschel a f, mickelson o and brozek j (1943) The performance of normal young men on controlled thiamine intake. J Nutr, 26, 399–415. kleijnen j and knipschild p (1991) Niacin and vitamin B6 in mental functioning: a review of controlled trials in humans. Biol Psychiatry, 29, 931–41. kuriyama s, kamiyama m, watanabe m, tamahashi s, muraguchi i, watanabe t, hozawa a, ohkubo t, nishino y, tsubono y, tsuji i and hisamichi s (2002) Pyridoxine treatment in a subgroup of children with pervasive developmental disorders. Dev Med Child Neurol, 44, 284–6. laurin d, masaki k h, foley d j, white l r and launer l j (2004) Midlife dietary intake of antioxidants and risk of late-life incident dementia: the Honolulu-Asia. Aging Study. Am J Epidemiol, 159, 959–67. lewis s j, lawlor d a, davey smith g, araya r, timpson n, day i n and ebrahim s (2006) The thermolabile variant of MTHFR is associated with depression in the British Women’s Heart and Health Study and a meta-analysis. Mol Psychiatry, 11, 352–60. lipton m (1973) Task Force Report on Megavitamin and Orthomolecular Therapy in Psychiatry. Washington, DC: American Psychiatric Association. lonsdale d and shamburger r j (1980) Red cell transketolase as an indicator of nutritional deficiency. Am J Clin Nutr, 33, 205–11. lovell m a, ehmann w d, butler s m and markesbery w r (1995) Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology, 45, 1594–601. luchsinger j a, tang m x, shea s and mayeux r (2003) Antioxidant vitamin intake and risk of Alzheimer disease. Arch Neurol, 60, 203–8.

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pathansali r, mangoni a a, creagh-brown b, lan z c, ngow g l, yuan x f, ouldred e l, sherwood r a, swift c g and jackson s h (2006) Effects of folic acid supplementation on psychomotor performance and hemorheology in healthy elderly subjects. Arch Gerontol Geriatr, 43, 127–37. pavlik v n, doody r s, rountree s d and darby e j (2009) Vitamin E use is associated with improved survival in an Alzheimer’s disease cohort. Dement Geriatr Cogn Disord, 28, 536–40. penninx b w j h, guralnik j m, ferrucci l, fried l p, allen r h and stabler s p (2000) Vitamin B12 deficiency and depression in physically disabled older women: epidemiologic evidence from the women’s health and aging study. Am J Psychiatry, 157, 715–21. perkins a j, hendrie h c, callahan c m, gao s, unverzagt f w, xu y, hall k s and hui s l (1999) Association of antioxidants with memory in a multiethnic elderly sample using the Third National Health and Nutrition Examination Survey. Am J Epidemiol, 150, 37–44. petersen r c, thomas r g, grundman m, bennett d, doody r, ferris s, galasko d, jin s, kaye j, levey a, pfeiffer e, sano m, van dyck c h and thal l j (2005) Vitamin E and donepezil for the treatment of mild cognitive impairment. New Eng J Med, 352, 2379–88. pfeiffer s i, norton j, nelson l and shott s (1995) Efficacy of vitamin B6 and magnesium in the treatment of autism: A methodology review and summary of outcomes. J Autism Dev Disorders, 25, 481–93. phillips g b, victor m, adams r d and davidson c s (1952) A study of the nutritional defect in Wernicke’s syndrome. J Clin Invest, 31, 859–71. praticò d (2008) Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal. Trends Pharmacol Sci, 29, 609–15. price j, kerr r, hicks m and nixon p f (1987) The Wernicke-Korsakoff syndrome: a reappraisal in Queensland with special reference to prevention. Med J Aust, 147, 561–5. ramos m i, allen l h, mungas d m, jagust w j, haan m n, green r and miller j w (2005) Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr, 82, 1346–52. ravaglia g, forti p, maioli f, martelli m, servadei l, brunetti n, porcellini e and licastro f (2005) Homocystine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr, 82, 636–43. reynolds e (2006) Vitamin B12, folic acid, and the nervous system. Lancet Neurol, 5, 949–60. richards m and sacker a (2003) Lifetime antecedents of cognitive reserve. J Clin Exp Neuropsychol, 25, 614–24. rimland b (1974) An orthomolecular study of psychotic children. Orthomol Psychiatry, 3, 371–7. rimland b, callaway e and dreyfus p (1978) The effect of high doses of vitamin B6 on autistic children: a double-blind crossover study. Am J Psychiatry, 135, 472–5. sano m, ernesto c, thomas r g, klauber m r, schafer k, grundman m, woodbury p, growdon j, cotman c w, pfeiffer e, schneider l s and thal l j (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. New Eng J Med, 336, 1216–22. sechi g and serra a (2007) Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol, 6, 442–55. savage d g and lindenbaum j (1995) Neurological complications of acquired cobalamin deficiency: clinical aspects. Baillieres Clin Haematol, 8, 657–78. schneider j a, rees d c, liu y t and clegg j b (1998) Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet, 62, 1258–60.

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15 Antioxidants, diet, polyphenols and dementia J. K. Sahni, INRS-Institut Armand Frappier, Canada and INRS-Énergie, Matériaux et Télécommunications, Canada, L. Letenneur, INSERM, France and Victor Segalen University, France, L. H. Dao, INRS-Énergie, Matériaux et Télécommunications, Canada and C. Ramassamy, INRS-Institut Armand Frappier, Canada and Université Laval, Canada

Abstract: In developing countries, ageing of the population leads to an increase of cases with cognitive impairment, the most dramatic form being dementia. Dementia is characterised by the alteration of superior cognitive functions such as memory, attention or executive functions. The most prevalent cause of dementia is Alzheimer’s disease (AD). At present, no treatment is available to cure AD and therefore prevention becomes an important way to reduce its prevalence. We shall review several epidemiological studies that showed an association between fruit and vegetable intake and cognition, or between anti-oxidant nutrients and dementia. Besides this, the chapter will focus on anti-oxidative, anti-amyloidogenic, anti-inflammatory properties and the activation of adaptive cellular stress responses associated with the use of numerous dietary polyphenolic compounds, in particular, curcumin, resveratrol and catechins, that have received a great deal of attention as alternative candidates for the prevention of AD or for AD therapy. Key words: antioxidants, dementia, curcumin, resveratrol, catechins.

15.1 Introduction Cognitive decline and dementia represent major clinical and socioeconomic issues in Western countries. Alzheimer’s disease (AD) is the most common form of dementia, accounting for more than half of cases of dementia with more than 24 million cases worldwide (Ferri et al., 2005). The principal risk factor for AD is advanced age. As a consequence of rapid demographic ageing, AD has become one of the most severe progressive socio-economical and medical burdens facing countries all over the world.

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At the present time, there is no cure for AD, and the disease inevitably causes a severe and progressive decline in daily activities, eventually resulting in institutionalisation and death. The incidence of the disease doubles every five years after 65 years of age (Lobo et al., 2000). Among different pathogenic hypotheses, oxidative stress is believed to be an important factor underlying the decline of cognitive function often observable with ageing (Praticò, 2008). Oxidative stress is associated with several others, such as the trace element hypothesis (iron, copper) (Rivera-Mancia et al., 2010), the mitochondrial hypothesis (Aliev et al., 2009; Rhein et al., 2009) and the β-amyloid peptide (Aβ) hypothesis (Nathalie and Jean-Noel, 2008). In recent years, numerous studies have strongly suggested that free radical-mediated oxidative damage plays an early role in the pathogenesis of AD. Multiple articles have documented increased lipid peroxidation, protein carbonylation, DNA, and RNA oxidation and glycol-oxidation with a widespread oxidative damage throughout multiple brain regions in mild cognitive impairment (MCI) and early AD (Markesbery et al., 2005). Interestingly, levels of oxidative markers increased in a disease-dependent manner and correlated with Mini-Mental State Examination (MMSE) scores (Ansari et al., 2010). In this regard, antioxidant intake, including polyphenols from fruits and vegetables, is an interesting field of research because the consumption of these nutrients throughout life holds a potential to prevent deterioration in cognitive performance. This chapter is aimed at discussing the role of some antioxidants and polyphenols from fruits, vegetables and beverages in the rate of decline of cognitive functioning and the development of dementia and the influence of some polyphenols found in fruits, vegetables and beverages on brain functioning.

15.2 Antioxidants and diet approach for cognitive functioning and dementia 15.2.1 Antioxidants, flavonoids intake and cognitive functioning Several cross-sectional studies have indicated a relationship between blood concentrations of antioxidant micronutrients and cognitive impairment. Goodwin et al. found a correlation between memory test scores and plasma levels of vitamin C in 260 healthy individuals aged 60 years and older (Goodwin et al., 1983). In a population-based sample of 885 individuals aged 74–79 years from the SENECA study, a positive, although weak, correlation was found between plasma concentrations of lycopene, α-carotene, β-carotene, total carotenes, β-cryptoxanthin, α-tocopherol (as well as folate and cobalamin) and MMSE scores (Haller et al., 1996). In a sample of 5182 subjects aged 55–95 years living in Rotterdam (the Netherlands), Jama et al. showed that lower dietary intake of β-carotene was associated with a

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lower cognitive performance, but no association was found with dietary intake of vitamin C and vitamin E (Jama et al., 1996). Cross-sectional studies have also shown an association between fruit and vegetable consumption and cognitive impairment. In a sample of 260 noninstitutionalised elderly aged 65–90 years, Ortega et al. showed that better cognitive functioning (characterised by good performance in the MMSE) was associated with higher intake of fruits (Ortega et al., 1997). Subjects with poorer performance tended to have poorer fruit intake (388 g/d (sd = 194 g/d) in men and 318 g/d (sd = 188 g/d) in women) than did those who performed better on the MMSE (398 g/d (sd = 214 g/d) in men and 331 g/d (sd = 225 g/d) in women). As expected, subject with better cognitive performance had higher intake of fiber and vitamin C. However, no association was found with β-carotene or vitamin E. The major problem in cross-sectional studies is that dietary intake and cognition are recorded at the same time. Therefore, people who have poorer cognitive functioning may have changed their dietary intake because of cognitive impairment. In such studies, it is not possible to assess whether dietary intake caused poor cognitive functioning or cognitive impairment caused bad dietary habits. Longitudinal studies are more powerful in this respect as dietary intake is recorded some time prior to the occurrence of a cognitive deficit. In Zutphen (the Netherlands), 342 men were followed for three years (Kalmijn et al., 1997). The decline of more than two points in the MMSE was not associated with dietary intake of vitamin C (p < 0.9), vitamin E (p < 0.7), β-carotene (p < 0.6) or flavonoids (p < 0.06). However, the follow-up was probably too short to capture a significant decline in cognitive performance. In the South-West of France, a sample of 1642 subjects aged 65 years and older was followed for 10 years (Letenneur et al., 2007). At the initial visit, individuals in the higher quartile of flavonoid intake had better MMSE scores than those in the lower quartiles. In addition, after 10 years of followup, subjects in the highest quartile tended to have lower decline than the others. Moreover, a gradient in cognitive decline was observed according to flavonoid intake since MMSE decline increased as dietary flavonoid intake decreased. In the US, 13 388 nurses were followed for two years and cognitive functioning was assessed using psychometric tests (Kang et al., 2005). The authors showed that vegetable intake was associated with the decline in functioning. In a dose-dependent manner, women who consumed more green leafy vegetables experienced a lower decline. Apparent benefits generally increased linearly with each level of intake. For cruciferous vegetables, significantly less memory decline was found in those at the highest quintile of intake. No linear dose–response relations were observed; instead, a threshold effect at the fourth quartile was seen.

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Association between antioxidants, fruits and vegetables intake and dementia Cross-sectional analyses, based mainly on case-control studies, showed conflicting results. Riviere et al. showed that patients with AD not only had lower plasma vitamin C concentrations (despite similar intakes) as compared to control subjects, but also their plasma concentrations of vitamin C correlated with cognitive function (Riviere et al., 1998). Interestingly, in these patients, vitamin E levels did not correlate with the degree of cognitive impairment. Rinaldi reported that the plasma concentrations of several antioxidant micronutrients, including vitamins A, C and E and carotenoids, were lower in AD patients and in individuals affected by MCI as compared to control subjects, independent of the apolipoprotein E (ApoE) genotype (Rinaldi et al., 2003). However, Sinclair et al. reported that plasma concentrations of vitamin C and β-carotene were not different in AD vs controls. Plasma vitamin E was lower in AD vs controls (Sinclair et al., 1998). Plasma lipid peroxides and total antioxidant capacity were not different across groups. The main difficulty in interpreting case-control study results lies in the fact that it is impossible to assess whether the lower plasma concentrations of antioxidant, micronutrients, including vitamins A, C and E and carotenoids in AD vs controls, are due to their lower intake or due to increased metabolic demand. Several prospective studies have examined the effect of dietary antioxidant nutrients on the risk of dementia. In Manhattan, 980 subjects were followed for four years and 242 incident cases of dementia were observed (Luchsinger et al., 2003). Luchsinger et al. found no association between developing dementia and dietary intake of β-carotene, vitamin C or vitamin E. In Rotterdam, 5395 subjects were followed for six years and 197 incident cases of dementia were diagnosed. A lower risk of dementia was observed with higher intake of vitamin C (HR = 0.82, p < 0.05) and vitamin E (HR = 0.82, p < 0.04), but no association was found with β-carotene (HR = 0.87) or flavonoids (HR = 0.99). When the analyses were stratified for smoking habits, the risk of AD associated with higher intake of vitamin C and vitamin E was lower in current smokers than in former or non-smokers (HR = 0.65 vs 0.91 and 0.83, respectively). High intake of flavonoids and β-carotene was also associated with reduced risk of AD in current smokers (HR = 0.54 and HR = 0.49, respectively). In Chicago, 815 elderly aged 65 years and older were followed for four years. Although 131 incident cases were identified (Morris et al., 2002), total vitamin E intake (from foods and supplements) did not predict the incidence of the disorder. Vitamin E intake from foods had a statistically significant dose–response protective effect in the age-adjusted model (P = 0.04). The risk for persons in the top fifth of intake was lower by 67 % compared with that of persons in the lowest fifth of intake. Among persons who were ApoE ε4 negative, vitamin E from foods showed a strong linear

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protective association with AD. Vitamin C intake from foods appeared to have an inverse relationship with AD but was statistically significant in the fourth quintile only, and no dose–response relationship was seen. Therefore, intake of vitamin E from food was inversely associated with incident AD. There was no association with the use of vitamin E as a supplement. Vitamin C and β-carotene also had no statistically significant association with AD. The linear protective association of vitamin E was found only among persons who were ApoE ε4 negative. Occurrence of dementia has also been associated with fruit and vegetable intake. In King County (US), 1589 Japanese American were followed for six years (Dai et al., 2006). During this period, 81 new cases of dementia were diagnosed. Compared to subjects with a low fruit and vegetable juice intake (less than one per week), subjects with high intake (three or more juices per week) had a lower risk of developing dementia (HR = 0.24, 95 % confidence interval (CI) [0.09; 0.61]). Subjects with moderate intake (one or two times per week) had a non-significant reduced risk (HR = 0.84, 95 %CI [0.31; 2.29]). The inverse association between fruit and vegetable juices and AD appeared in all strata of education, smoking status, tea drinking, regular physical activity, ApoE genotype and total fat intake. However, the association tended to be stronger among those who were former or current smokers, drank tea less often, were positive for the ApoE ε4 allele and were less physically active. In the Three City study, 8085 elderly were followed for four years, and 281 incident cases of dementia were diagnosed (Barberger Gateau et al., 2007). A lower risk of developing dementia was observed (HR = 0.72, p < 0.02) in subjects with frequent (every day) fruit and vegetable intake. The strength of the association remained almost unchanged after controlling for ApoE genotype, body mass index and diabetes.

15.2.3 Results from clinical trials Few clinical trials have studied the effect of antioxidant vitamins. Sano et al. treated 341 AD patients divided into four arms: vitamin E, Selegiline, both and no treatment (Sano et al., 1997). After a follow-up of two years, a moderate effect of vitamin E was observed on the progression of the disease. More recently, Petersen et al. treated 769 subjects with MCI which is considered to be a prodromal state of AD (Petersen et al., 2005). Three arms of the study were constituted, Donepezil, vitamin E (2000 IU) or placebo, and the main outcome was to delay the conversion to dementia. After three years of follow-up, no difference was observed between treatments and placebo. However, in a more recent follow-up publication, the same authors reported that brain imaging showed that changes in the volumes of some areas of the brain (hippocampus, enthorinal cortex) were less evident in the group that received vitamin E rather than placebo (Jack et al., 2008). More recently, Lloret et al. treated 57 AD patients with 800 IU of vitamin E and

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assessed responsiveness to the antioxidant treatment (Lloret et al., 2009). In responders to vitamin E, cognitive performance was maintained, whereas in non-responders, cognition decreased sharply, to levels even lower than those of patients taking placebo. Another clinical trial also showed cognitive difference according to the response to a formulation of six vitamins (including vitamin E at 30 IU) and nutraceuticals (Chan et al., 2010). Adults of both genders without dementia received the treatment or a placebo. Participants receiving treatment improved in a neuropsychometric test within three months (p < 0.03), while those receiving placebo did not improve. However, unlike younger participants, participants ≥74 years of age receiving treatment did not on an average demonstrate improvement versus placebo. The percentage of responders (i.e. subjects that showed an improvement to a specific test after three months of treatment) tended to decrease with age. Non-responders within all age groups up to 74 years of age displayed similar performance, while those ≥74 years of age displayed substantially poorer scores at three months than did all other age groups. This age-related decline may be due to decreased absorption of nutrients and/ or decreased basal vitamin levels due to sub-optimal nutrition. This result may explain why clinical trials performed on elderly individuals did not show a beneficial effect of antioxidant vitamins since it may be too late and/or the supplement may not be adapted to the physiology of the older adult.

15.2.4 Discussion Clinical trials have found that vitamin E supplementation does not delay or avoid cognitive decline. Even observational studies have produced inconsistent results with antioxidant micronutrients. In contrast, fruit and vegetable intake has tended to be more consistently associated with a lower risk of developing dementia, although the number of available studies is small. This indicates that specific antioxidant nutrients such as vitamin E are not sufficient to protect against cognitive deficit, but it may be more fruitful to invite people to eat fruits and vegetables rather than take antioxidant supplements. This is also consistent with studies that have shown that people consuming a Mediterranean diet have a lower risk of developing cognitive impairment. The traditional Mediterranean diet is characterised by high consumption of plant foods (vegetables, fruits, legumes and cereals), high intake of olive oil as the principal source of monounsaturated fat but low intake of saturated fat, moderate intake of fish, low to moderate intake of dairy products, low consumption of meat and poultry and wine consumed in low to moderate amounts, normally with meals. In a cohort study of a large community-based population without dementia in New York, higher Mediterranean diet adherence was associated with a reduced risk for mild cognitive impairment and AD (Scarmeas et al., 2006). A cohort study in

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France also showed less cognitive decline in subjects who adhered to a Mediterranean diet (Féart et al., 2009). The biological basis for the apparent health benefits of a Mediterranean diet involves a decrease in oxidative stress, inflammation and vascular disease, which also participate in the pathophysiology of neurodegenerative diseases. The Mediterranean diet pattern probably does not fully explain the better health of persons who adhere to it, but it may contribute directly. A Mediterranean diet also may indirectly constitute an indicator of a complex set of favorable social and lifestyle factors that contribute to better health. Therefore, the protective effect of fruits and vegetables may be supported not only by antioxidant properties, but also by other activities. Polyphenols are good candidates to explain such beneficial effects.

15.3 Brain targets and sources of polyphenols Polyphenolic compounds are the most abundant antioxidants in diet, and the health benefits of polyphenols depend upon the amount consumed and on their bioavailability. For a number of reasons, it is extremely difficult to estimate the daily average intake of polyphenols. Therefore, only partial information is available on the quantities of polyphenols consumed daily throughout the world. Nevertheless, it is estimated that the total dietary intake of polyphenols could be as high as 1 g/d and 12 mg of anthocyanins (Wu et al., 2006). This is 10 times higher than the intake of vitamin C and 100 times higher than the intake of vitamin E. The main dietary sources of polyphenols are fruits, vegetables and plant-derived beverages such as tea and red wine.

15.4 Summary of the classification of polyphenols The considerable diversity of the chemical structures of polyphenols makes the estimation of their content in food difficult. Their complexity has delayed research on their biological activities. Polyphenols can broadly be divided into two categories, i.e. flavonoids and non-flavonoids polyphenols. Nonflavonoids and phenolic acids are abundant in foods. The most frequent are caffeic acid and, to a lesser, extent, ferulic acid. Caffeic acid is found in the form of esters, and the most frequently encountered caffeoyl ester is chlorogenic acid, which is abundant in many fruits and vegetables and in coffee. One of the main sources of ferulic acid is wheat bran (around 5 mg/g) (Dragland et al., 2003). Other phenolic acid derivatives are hydrolysable tannins. Flavonoids, the target class of polyphenols, may be divided into different sub-classes according to the degree of oxidation of the heterocyclic ring:

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flavonols, flavanones, flavanol, flavones, isoflavones, anthocyanins and anthoxanthins. The average intake of all flavonoids was found to be around 13 mg/d (Scalbert and Williamson 2000). The main source of isoflavones is soy, which contains around 1 mg of genistein and daidzein/g dry soy bean (Mira et al., 2002). Both isoflavones have received considerable attention due to their estrogenic-like properties (Adlercreutz and Mazur 1997). Flavanones are mainly found in citrus fruits, hesperidin from oranges being the most widely consumed. Quercetin, present in many fruits, vegetables and beverages, is the main flavonol in our diet and its mean intake was estimated around 16 mg/d (Hertog et al., 1993). Flavones are less common and were identified in sweet red pepper (luteolin) and celery (apigenin) (Hertog et al., 1993). The main flavanols are catechins. These compounds are abundant in tea, and an infusion of green tea could contain 1 g/L catechins, while in black tea their content is reduced to about half of this value due to their oxidation into more complex polyphenols during fermentation (Yang et al., 1997). Other sources of catechins are red wines (Frankel et al., 1993) and chocolate (Arts et al., 1999). Anthocyanins are pigments of red fruits such as berries, grapes and strawberries, and their contents could vary from 0.15 to 4.5 mg/g in fresh fruit. Proanthocyanidins are polymeric flavanols and are usually present in plants. They are responsible for the astringency of food, common sources being apple, pear, grape and beverages such as red wine, tea and chocolates. Stilbenes are not widely expressed in food plants. Nevertheless, one of them, resveratrol, has recently received great attention for its anti-carcinogenic properties, for its neuroprotective effect and as an activator of Sirt1, a member of sirtuins family. Analysis of structure– activity relationship suggests that the hydroxylated trans-stilbene ring structure is essential for activation of sirt1. However, the very low content of resveratrol in wine (0.3–2 mg/ml) makes its contribution to some biological effects in vivo debatable. Lignans are mainly present in flaxseed and flaxseed oil. Their presence has been identified in plasma and in urine and could be metabolised by the gut microflora. Lignans are recognised as phytoestrogens due to their estrogen-like effect. Other unknown dietary polyphenols could also be generated after food fermentation, storage or cooking. These compounds receive increasing interest as several epidemiological studies have suggested associations between the consumption of polyphenol-rich foods or beverages and the prevention of some chronic diseases such as AD (Table 15.1). Research on the neuroprotective effects of dietary polyphenols has developed considerably in the past ten years. However, it becomes clear that the mechanisms of action of these polyphenols go beyond their antioxidant activity and the modulation of oxidative stress. These compounds are able to protect neuronal cells in various in vivo and in vitro models through different intracellular targets.

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1.

S.No.

Green tea Catechins including EGCG

• Antioxidant and free radical scavenging activities • Decrease translation of APP mRNA and membrane-bound holoprotein APP • Increase α-Secretase • Decrease production of Aβ peptides in APP695 over-expressing neurons • Decrease Aβ-induced caspase activity in hippocampal neuronal cells • Green tea catechins especially EGCG also modulate a number of signalling pathways such as MAPK, protein kinase C, phosphatidylinositol-3-kinase (PI-3 kinase)-Akt which may mediate some of the neuroprotective mechanisms • In neuronal cell line and primary cell culture models, EGCG prevented the decline in ERK1/2 induced by 6-hydroxydopamine or oxidised low-density lipoproteins • Possess anti-inflammatory effect • Decrease Aβ-induced neuronal cell death • Decrease lipid peroxide in the brain

Beneficial effect

Nagai et al., 2002; Tedeschi et al., 2004 Choi et al., 2001; Levites et al., 2003 Luczaj and Skrzydlewska, 2005

Levites et al., 2003; Schroeter et al., 2001

Kim et al., 2007b, Bastianetto et al., 2007; Levites et al., 2003; Koh et al., 2004

Choi et al., 2001

Guo et al., 1996 Levites et al., 2002a; Wu et al., 2006, Bickford et al., 2000 Levites et al., 2002a Rezai-Zadeh et al., 2005

Reference

Summary of beneficial effects of some important polyphenols with neuroprotective potential in AD

Polyphenol

Table 15.1

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Resveratrol

Flavanoids from blueberries

4.

Curcumin

3.

2.

• Reverse cognitive deficits in Morris water maze performance test in 19 month-old rats • Significantly lower caspase-3 activity in the ischemic hemisphere with av protection of the brain against apoptosis in rats

• Protects PC12 cells against Aβ-induced toxicity and accumulation of intracellular ROS • Protects SH-SY5Y neuroblastoma cells and primary hippocampal neuronal/glial cells from H2O2, nitric oxide and Aβ-induced toxicity • Decreases production of Aβ peptides in vitro • Activator of sirtuins

• Inhibits the formation and extension of Aβ fibrils and destabilises preformed Aβ fibrils in a dose-dependent fashion at a range between 0.1 μM and 1 μM. • Reduces Aβ levels and plaques in aged Tg2576 mice with advanced amyloid accumulation • Decreases senile plaques in the brains of Tg2576 mice • Inhibits lipid peroxidation • Decreases oxidised proteins in the brains of Tg2576 mice • Possesses anti-inflammatory effects • Brain permeable • Labels senile plaques in Tg2576 mice

Wang et al., 2005

Andres-Lacueva et al., 2005

Marambaud et al., 2005 Baur et al., 2006, Baur and Sinclair, 2006

Bastianetto et al., 2000; Savaskan et al., 2003

Jang and Surh, 2001

Lim et al., 2005; Yang et al., 2005 Wei et al., 2006 Lim et al., 2005 Sandur et al., 2007 Garcia-Alloza et al., 2007 Garcia-Alloza et al., 2007

Lim et al., 2005; Yang et al., 2005

Yang et al., 2005

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15.5 Important polyphenols with neuoroprotective potential 15.5.1 Catechins Tea is the most widely consumed beverage in the world, after water. The beneficial effects of green tea date back to 2700 BC, and their medicinal properties were recognised in the 16th century by European explorers who used tea extracts to fight fever, headache and stomachache. Green tea is rich in flavonoids (30 % of dry weight of a leaf) (Graham, 1992) and the main compounds are epigallocatechins-gallate (EGCG), (−)–epigallocatechin (EGC), (−)-epicatechin (EC) and (−)-epicatechin-3-gallate (ECG). Although these catechins are abundant in green tea, they are also found in other commonly consumed fruits and beverages. In contrast, black tea contains small amounts of catechins. Due to the fermentation process of black tea, its primary antioxidant polyphenols are theaflavins (Leung et al., 2001). Catechins intake has been associated with a wide variety of beneficial health effects in vitro and in vivo (see review by Sutherland et al., 2006). Green tea polyphenols have shown beneficial effects in animal models of stroke/cerebral ischemia, AD and Parkinson’s disease. All the catechins have a wide variety of biological actions pertaining to their chemical structure, but the different mechanisms underlying these actions have not been fully elucidated. Antioxidant properties of catechins Antioxidant and free radical scavenging activities mainly contribute to their beneficial effects. These flavonoids display antioxidant properties in the order EGCG > ECG > EGC > EC (Guo et al., 1996). Their free radical abilities relate directly to the chemical structures of each compound, namely, the gallate moiety esterified at the 3 position of the C ring, the catechol group (3,4-dihydroxyl groups) on the B ring and the hydroxyl group at the 5 and 7 positions on the A ring. The galloylated catechins are more active antioxidants due to their higher phospholipids/water partition coefficients (Caturla et al., 2003). Moreover, the free radical scavenger property increases with the number of hydroxyl groups the catechin possesses. For instance EGCG and EC possess eight and five hydroxyl groups, respectively, and the antioxidant activity of EGCG is higher than EC. Furthermore, their antioxidant ability is higher than α-tocopherol or vitamins C and E. Catechins can exert antioxidant activity through different mechanisms, such as by chelating metal ions such as copper (II) and iron (II) to form inactive complexes and prevent the generation of potentially damaging free radicals. This property may have an implication in AD. Indeed, changes in the levels of iron, ferritin and transferrin receptor have been reported in hippocampus and in cortex from AD (Honda et al., 2005). Iron could also promote deposition of Aβ or contribute to the regulation of amyloid precursor protein (APP) translation with the presence of an iron-responsive element in the 5′UTR region of APP mRNA (Rogers et al., 2002). Thus,

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reduction of the free iron pool by EGCG chelation may lead to suppression of the translation of APP mRNA. Accordingly, Levites et al. (2002a) have demonstrated that prolonged administration of EGCG to mice induced a reduction in holo-APP levels in the hippocampus (Wu et al., 2006). This mechanism will decrease the production of Aβ and thereby the generation of Reactive Oxygen Species (ROS). This result was supported by those obtained in cell culture models with a concomitant decrease in Aβ levels. Catechins could also exert their antioxidant effects through the ultrarapid electron transfer to ROS-induced radical sites on DNA or by forming stable semiquinone free radicals. Moreover, after the oxidation of catechins by free radicals, a dimerised product is formed with an increased ability to scavenge superoxide anions and iron-chelating potential. The prevention of oxidative-induced damages by catechins is very effective as catechins can inhibit the ROS-induced damage from a wide variety of initiators, including hydrogen peroxide, iron, paraquat or radiolysis. Antioxidant properties of catechins were also observed on different in vivo models. For instance, in rats receiving green tea extracts orally exhibited higher levels of different anti-oxidants such as glutathione peroxydase and reductase, superoxide dismutase and catalase (Luczaj and Skrzydlewska 2005). These effects on antioxidants levels were also investigated in humans. It has been evidenced that after 42 days of the consumption of two cups of green tea, containing approximately 250 mg of total catechins, a significant increase in plasma total antioxidant was observed while the plasma peroxides level decreased (Erba et al., 2003). Catechins could also decrease oxidative stress by inhibiting the activity of xanthine oxidase (Bickford et al., 2000), a ROS generating system. Catechins can also protect different lipid from oxidation, in the liver, serum and brain (Luczaj and Skrzydlewska, 2005). For instance, it has been demonstrated that catechins could protect against lipid peroxidation induced by 6-hydroxydopamine, hydrogen peroxide and iron (Guo et al., 1996). These antioxidant effects are observed in vitro with concentrations ranging from 1–50 μM. However, with higher concentrations (100–500 μM) and in the presence of copper (II) or iron (III), EGCG exacerbated oxidative stress, cytotoxicity and DNA damages induced by hydrogen peroxide (Furukawa et al., 2003; Oikawa et al., 2003; Elbling et al., 2005). Catechins and apoptosis EGCG could also modulate apoptosis pathways to protect cells against oxidative stress. The effects of catechins on apoptotic pathways could be divergent. For instance, on PC12 cells EGCG, with low doses (1–10 μM), could inhibit caspase-3 activity or activate PI3K/Akt pathway which promote cell survival (Koh et al., 2004). On the other hand, catechins could also modulate apoptosis by altering the expression of anti-apoptotic and pro-apoptotic genes. In SH-SY5Y cells, it has been found that EGCG prevented the expression of proapoptotic genes Bax, Bad, cell cycle inhibitor Gadd45, Fas ligand and tumour necrosis factor-mediated apoptosis ligand

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TRAIL (Levites et al., 2003; Kalfon et al., 2007) while inducing the antiapoptotic genes Bcl-2, Bcl-w and Bcl-X in 6-hydroxydopamine-induced apoptosis (Levites et al., 2002b; Weinreb et al., 2004). However, at high doses (50–500 μM), EGCG can induce proapoptotic properties by increasing Bax, Bad and caspase-6 activity while decreasing Bcl-x and Bcl2. Green tea catechins, especially EGCG, also modulate a number of signaling pathways such as MAPK (Kim et al., 2007b), protein kinase C (Levites et al., 2003; Bastianetto et al., 2007) and phosphatidylinositol-3kinase (PI-3 kinase)-Akt (Koh et al., 2004), and these modulations may mediate some of the neuroprotective mechanisms of EGCG. In neuronal cell line and primary cell culture models, EGCG prevented the decline in ERK1/2 induced by 6-hydroxydopamine or oxidised low-density lipoproteins (Schroeter et al., 2001; Levites et al., 2003). Anti-inflammatory property of catechins There is substantial evidence that catechins can exert anti-inflammatory effects. This property could be due to their abilities to scavenge NO, peroxynitrite anion or to reduce the activity of nitrous oxide (NO) synthase (Nagai et al., 2002; Tedeschi et al., 2004) with EGCG being the most effective (Paquay et al., 2000). The neuronal nNOS and the inducible iNOS isoforms could be targeted by catechins (Chan et al., 1997). This inhibitory effect of catechins likely involved the inhibition of the activation of the transcription factor NF-κB as the κB sequence is present on the promoter of the iNOS gene (Lin et al., 1997). In contrast, catechins could induce the endothelial isoform eNOS activity, a vasodilatator-inducing enzyme. This activity contributes to the anti-inflammatory effects of catechins (Lorenz et al., 2004). Another mechanism of action proposed may be the presence of the anti-oxidant response element (ARE) on the promoter of eNOS gene and catechins could bind to the ARE and activate eNOS (Yu et al., 1997). These effects of EGCG on NOS activities also contribute to the antiischemic effect of EGCG (see review by Sutherland et al., 2006). The anti-inflammatory effect of EGCG has also been studied in many cell types through the regulatory effect of EGCG on cytokine secretion. For instance, Kim et al. (2007a) have demonstrated that EGCG was able to inhibit the production of IL-1, attenuate the expression of cyclooxygenase-2 induced by IL-1 and Aβ or activate NF-κB and MAPK pathways induced by IL1 and Aβ (Heo and Lee 2005). Catechins and the Aβ-mediated pathology Although there is no significant outcome relative to tea consumption in AD case-control, there are several in vitro studies showing that green tea extract could protect neurons from Aβ-induced damages (Choi et al., 2001; Levites et al., 2002a,b). Over the past decade, intense focus has been given to investigate the processes of APP proteolysis and Aβ metabolism as possible

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targets for AD therapy. APP can be processed by two pathways: (i) a nonamyloidogenic pathway which involves cleavage of the APP to soluble APP (sAPP) by the α- and γ-secretases activities; and (ii) formation of the amyloidogenic Aβ peptides, by the β- and γ-secretases. Various synthetic and naturally-occurring compounds have been analysed for their efficacy in the modulation of these pathological events. Among them, EGCG is able to regulate the proteolytic processing of APP both in vitro and in vivo (Levites et al., 2002a). In neuronal cell cultures, it could promote the nonamyloidogenic α-secretase pathway (Levites et al., 2002a). In primary neuronal cells derived from a transgenic mice model overexpressing APP with the Swedish mutation, EGCG significantly reduced Aβ peptide generation (Aβ1-40 and Aβ1-42) by 38 % with purified EGCG being more potent than green tea (Rezai-Zadeh et al., 2005). EGCG, with doses between 1 μM and 10 μM, protected against Aβ peptide and 6-hydroxydopamine-induced cell death by activation of protein kinase C (Levites et al., 2002a,b; Levites et al., 2003) that plays a central role in neuronal cell survival. In summary, green tea and its active components EGCG exert several intracellular mechanisms relating to neuroprotection. These studies demonstrated that catechins could protect different cell type against various cytotoxic compounds independent of their free radical scavenger properties but through some emerging pathways that have attracted much attention recently. However, current epidemiological and clinical evidence correlating catchin intake and the incidence of AD is inconsistent.

15.5.2 Curcumin Curcumin is a major chemical component of turmeric (Curcuma longa) and is used as a spice to give a specific flavor and yellow color to curry. Turmeric is derived from the rhizome, or root of the plant. There are substantial in vitro results indicating that curcumin has antioxidant, anti-inflammatory and anti-amyloid activities (Menon and Sudheer 2007). Antioxidant effect of curcumin Curcumin exhibits potent antioxidant property with a much higher activity than vitamin E (Zhao et al., 1989). It could also scavenge hydroxyl radical or to bind Cu2+ and Fe2+ ions (Baum and Ng 2004) and therefore could inhibit lipid peroxidation (Wei et al., 2006). It was shown to activate glutathione S-transferase (Nishinaka et al., 2007) or induce heme-oxygenase-1, HO-1 (Motterlini et al., 2000). HO-1 induction occurs through the ARE (Hayes and McMahon 2001). Curcumin could also chelate the redox active metals iron and copper (Baum and Ng 2004). The antioxidant property of curcumin was also provided in AD transgenic mouse model with reduced brain levels of oxidised proteins (Lim et al., 2001).

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Anti-inflammatory effect of curcumin The inflammatory process is thought to be implicated in the pathophysiology of AD. Some epidemiological studies have consistently demonstrated an association between the use of non-steroidal anti-inflammatory drugs and a subsequent decreased risk for the development of AD (Andersen et al., 1995). Curcumin has been shown to have anti-inflammatory effects as it is a good inhibitor of lipoxygenase and COX-2 (Sandur et al., 2007), both enzymes responsible for the synthesis of the pro-inflammatory leukotrienes, prostaglandins and thromboxanes. Curcumin is also a suppressor of iNOS (see review by (Bengmark, 2006). Curcumin is also a potent inhibitor of NF-κB and AP-1 activation (Singh and Aggarwal 1995) (see review by Shishodia et al., 2007). This mechanism is likely involved in the inhibition of the expression of inflammatory cytokines, COX-2 and iNOS as these transcription factors are well known to regulate these inflammatory factors. All of these factors (IL-1, TNFα, COX-2, iNOS, JNK, NF-κB) are also implicated in Aβ toxicity. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin reduced Aβ levels and plaques (Lim et al., 2005). In this study, low (160 ppm) and high doses (5000 ppm) of curcumin significantly lowered IL-1β. Curcumin and Aβ pathology Aggregation of Aβ into fibrils and the subsequent formation of amyloid plaques are crucial steps in the pathogenesis of AD. It has been found that curcumin inhibited the formation and extension of Aβ fibrils and destabilised preformed Aβ fibrils in a dose-dependent fashion at a range between 0.1 and 1 μM (Yang et al., 2005). Curcumin could bind to fibrillar Aβ regardless of the specific Aβ sequence. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin reduced Aβ levels and plaques (Lim et al., 2005). In this study, a low dose of curcumin (160 ppm) significantly reduced plaque burden. Subsequent in vivo studies using multiphoton microscopy demonstrate that curcumin can cross the blood–brain barrier and labels senile plaques in Tg2576 mice (Garcia-Alloza et al., 2007). In light of the spectrum of activities, curcumin represents a hopeful approach for delaying or preventing the progression of AD (Garcia-Alloza et al., 2007). Therefore, the effects of curcumin have been tested in several animal models for AD. However, preclinical data from animal models and phase I clinical studies performed with human volunteers and patients have demonstrated low systemic bioavailability following oral intake. The absorption, distribution, metabolism and excretion of curcumin in rodents have been widely described. These studies support the notion that curcumin undergoes a rapid and efficient metabolism that severely curtails the availability of parent compound. A dietary dose (1 g/kg) administered to rats resulted in about 75 % of spices related to curcumin being detected in feces (Wahlstrom and Blennow 1978). Intestinal metabolism, particularly glucuronidation and sulfation of curcumin, might explain its poor systemic

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availability (Sharma et al., 2007). The metabolites were characterised mainly as glucuronides of tetrahydrocurcumin and hexahydrocurcumin. Altogether, curcumin, a highly lipophilic compound, can protect cells against Aβ toxicity by preventing Aβ peptide aggregation, reducing plaques burden, through its antioxidant and anti-inflammatory activities and the inhibition of cell signalling pathways at multiple levels. However, curcumin undergoes rapid metabolism, and the bioavailability of the parent compound is low.

15.5.3 Resveratrol Resveratrol is a non-flavonoid compound found in grapes and red wine. The concentration of resveratrol in red wine is in the range of 1.5–3 mg/L (see review by de la Lastra and Villegas 2005). There are two isomeric forms of resveratrol, the biological inactive cis-resveratrol and the most relevant and the main biologically active trans-resveratrol (trans-3, 4, 5-trihydroxystilbene). This compound has been the focus of a number of studies demonstrating the antioxidant, anti-inflammatory, anti-mutagenic and anti-carcinogenic effects of this compound (Jang et al., 1997; Soleas et al., 1997). Interestingly, several epidemiological studies indicate an inverse correlation with wine consumption and incidence of AD (Orgogozo et al., 1997; Truelsen et al., 2002; Lindsay et al., 2002). Resveratrol as a blocker of oxidative stress In several in vitro studies, resveratrol has been recognised for its powerful antioxidant properties. Moreover, resveratrol could upregulate cellular antioxidant including glutathione, and it induces the gene expression of phase 2 enzymes (Cao and Li 2004). At cellular levels, resveratrol could protect PC12 cells against Aβ-induced toxicity and accumulation of intracellular ROS (Jang and Surh 2001). Resveratrol can also protect SH-SY5Y neuroblastoma cells and primary hippocampal neuronal/glial cells from H2O2, nitric oxide and Aβ-induced toxicity (Bastianetto et al., 2000; Savaskan et al., 2003). Moreover, in cultured PC12 cells, resveratrol can also increase the HO-1 activity in cortical mouse neurons and upregulate HO-1 gene expression via the activation of NF-E2-related factors 2 (NRf2) (Chen et al., 2005a). Interestingly, resveratrol exhibited its neuroprotective effects when it was used in pre-treatment, in co-treatment, or in post-treatment. Resveratrol as an anti-amyloidogenic compound Resveratrol could reduce the level of secreted or intracellular Aβ peptides in two cell lines, HEK 293 and N2a, transfected with APP695 (Marambaud et al., 2005). This effect was not mediated by β- and γ-secretases activities but may be through the elevation of the degradation of Aβ peptide. However, resveratrol did not affect Aβ degrading enzymes such as

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neprilysin, endothelin-converting enzyme-1 and -2 and insulin-degrading enzyme (Marambaud et al., 2005). Resveratrol attenuates the neuroinflammatory responses Resveratrol could attenuate lipopolysaccharide (LPS) induced TNFα and NO production in microglial cell line by inhibiting p38 MAPK phosphorylation and NF-κB (Bi et al., 2005). Resveratrol has been found to reduce the expression of COX-2 and the inducible form of NO synthase (Rahman et al., 2006). Resveratrol as a sirtuins activator It is well known that reducing food intake or caloric restriction extends lifespan in a wide range of species. Recently, it has been found that resveratrol can mimic dietary restriction and trigger sirtuin proteins (see review by Baur et al., 2006a; Baur and Sinclair, 2006). The sirtuin enzymes are a phylogenitically conserved family of enzymes that catalyse NADdependent protein deacetylation. In yeast, sir2 is essential for lifespan extension by caloric restriction and a variety of other stresses, including increased temperature, amino acid restriction and osmotic shock (Swiecilo et al., 2000; Anderson et al., 2003). Activators of sirtuins can be a key to extending lifespan and overcoming a variety of stresses in higher organisms. Recently, among 18 small molecules that can increase human sirt1 activity, resveratrol induced the highest activity of sirt1 and increased the lifespan in yeast nearly by 70 % (Howitz et al., 2003). Analysis of structure–activity relationship suggests that the hydroxylated trans-stilbene ring structure is essential for activation of sirt1. However, the mechanisms that link resveratrol to the activation of sirt1 and the subsequent protection of neurons against Aβ remain unknown. Nevertheless, resveratrol-induced Sirt1 has been found to repress p53 activity and to suppress apoptotic activities of FOXO proteins, thereby preventing neurons against apoptosis-induced by Aβ. FOXO could induce neuronal death through the Fas and JNK pathways. In a recent study with mixed neuron/glial cultures from Sprague-Dawley rat, it has been demonstrated that resveratrol induced Sirt1 activation and inhibited the NF-κB signalling in microglia and astrocytes, and protected neurons against Aβ-induced toxicity (Chen et al., 2005b). NF-κB signalling controls the expression of both iNOS and cathepsin B, two factors that mediate apoptosis. In PC12 cells, Aβ induces the degradation of IκBα, the inhibitory sub-unit of NF-κB activation and increases the nuclear translocation of p65. The activation of NF-κB was reversed when cells were treated by resveratrol (25 μM) (Jang and Surh 2003). It has been recently demonstrated that Sirt1 could be activated by flavonoids and this activation is associated to the NF-κB inhibition and protection against Aβ toxicity (Longpre et al., 2006). Thus, modulation of different sirtuins by phenolic compounds could provide an important arsenal to overcome a variety of

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stresses that compromise neuronal survival in different neurodegenerative diseases such as AD. After oral administration of resveratrol, it is rapidly metabolised (within 2 h, with a peak in <30 min) into both glucuronic acid and sulfate conjugations of the phenolic groups in liver and intestinal cells (see review by de la Lastra and Villegas 2005). More than 90 % of total resveratrol, given as pure aglycone, circulates in the plasma in the conjugated form and glucuronidation predominates the metabolism of resveratrol. These results indicate that the circulating form of resveratrol is predominantly the modified metabolite and not the original aglycone form. Therefore, the antioxidant and anti-inflammatory activities and the effect on cell signalling of the original aglycone compound seem to be considerably diluted due to its extensive and rapid metabolism. However, the biological activities of the circulating form and their functions remain to be determined, particularly their implication in neuroprotective effects. In summary, it is clear that the neuroprotective effect of resveratrol implicates different pathways which may be critical to neuronal protection in AD. In addition to its antioxidant effects, the efficacy of resveratrol against Aβ toxicity also involves several transduction pathways or the modulation of glia/astrocyte functions. All of these functions may play synergistic roles in treating AD. However, pharmacokinetic studies indicated that resveratrol is rapidly metabolised in liver and intestinal epithelial cells. Therefore, the efficacy of resveratrol in the treatment of AD will also depend on the bioavailability of metabolites and their biological activities.

15.5.4 Effects of polyphenols from berries on cognitive performance Berries are rich sources of phenolic compounds such as phenolic acids as well as anthocyanins, proanthocyanidins or other flavonoids. For instance, the total phenolic acids could range from 2845 to 5418 mg/kg (Zadernowski et al., 2005) with hydroxycinnamic acids constituting from 68.9–85 % of the total phenolic acids, and more than 20 phenolic acids could be identified in berries. In blueberries (Vaccinium ashei reade), catechin is the major flavonoid. They can reach 387 mg/100 g fresh weight, epicatechin can range from 34 to 129 mg/100 g fresh weight and total anthocyanins can range from 84 to 113 mg/100 g fresh weight (Sellappan et al., 2002). It has been estimated that 1.20 g of total anthocyanins was present in human serum after a consumption of 100 g of blueberries and maximal level was reached four hours after the consumption. Interestingly, a significant positive correlation between serum anthocyanin content and postprandial antioxidant status has been observed (Mazza et al., 2002). This absorption could have some positive effects in the brain through different processes as it has been demonstrated in different animal studies. Thus, dietary supplementation for eight weeks with blueberry extracts reversed cognitive deficits in a Morris

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water maze performance test in 19 month-old rats (Andres-Lacueva et al., 2005). However, the effect of blueberry extracts on cognitive functions might involve more than their antioxidant actions. Thus aged rats with a blueberry extracts diet had significantly lower levels of NF-κB than aged rats with a control diet (Goyarzu et al., 2004). It has been described that the aged control diet group had significantly higher average of NF-κB levels than the young rats (Goyarzu et al., 2004). These results are in accordance with the known effect of flavonoids on cell signalling such as on the activity of NF-κB (Dias et al., 2005; Martinez-Florez et al., 2005; Longpre et al., 2006). Additional evidence was seen in a recent study with the double transgenic mice model of AD over-expressing APP and presenilin 1, in which genetic mutations promoted the production of the Aβ peptide and hallmark of AD-like senile plaques in several regions. When these mice were supplemented with blueberry extracts (2 % of diet) from 4 months and continued until 12 months of age, their performance in a Y-maze test, a cognitive performance test, was similar to that of non-transgenic mice and significantly better than that of non-supplemented transgenic mice (Joseph et al., 2003). However, the examination of the brain of these mice revealed that blueberry extracts supplementation did not affect the Aβ peptide production or deposition or the number of plaques. These data suggest that the impairment of cognitive functions observed in these transgenic mice may not necessarily be the result of deposition of the Aβ peptide. In these mice supplemented with blueberry extracts, the concentrations of hippocampal ERK as well as striatal and hippocampal PKCα are higher than in transgenic mice supplemented with control diet. Both protein kinase C and ERK have been shown to be involved in early and late stages of memory formation (Micheau and Riedel, 1999). These results indicate that blueberry extracts supplementation might prevent cognitive deficits through neuronal signalling pathways. Diet supplemented with blueberry extracts could also protect the brain against apoptosis as rats receiving blueberry extracts had significantly lower caspase-3 activity in the ischemic hemisphere (Wang et al., 2005). Taken together, these studies demonstrate that blueberry extracts-supplemented diets could protect neuronal loss and prevent the decrease of cognitive functions against different insults through the antioxidants, anti-apoptotic and regulation of cell signalling.

15.6 Conclusions Human observational epidemiology studies have, in general, been consistent with the hypothesis that there is an inverse relationship between antioxidant levels/intake, cognitive function and, ultimately, the risk of developing AD. However, randomised clinical trials with high doses of one

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of the most potent antioxidants in vitro, that is, vitamin E, do not support the findings of those studies. Does this observation mean that the oxidativestress hypothesis of AD is not valid anymore? First, considering the complexity of the redox system in vivo, we may probably need better antioxidant drugs and, in certain cases, a combinatory approach would be preferable to a single antioxidant. Second, before starting any antioxidant therapy trial it will be extremely important to have clear information on the endogenous antioxidant levels of the participating subjects. This aspect is important for patient selection in order to identify potential ‘responders’ (subjects with low antioxidants) versus ‘non-responders’ (subjects with high or normal antioxidant levels) to a drug with antioxidant properties. In conclusion, fruits and vegetables are associated with a better cognitive evolution. It has not been possible to demonstrate that antioxidant nutrients such as vitamin E were at the origin of the protection. Fruit and vegetable intake is more complex than the addition of specific nutrients. Dietary behaviour may also be involved, and Mediterranean diet is an illustration of a combination of several foods that may be beneficial. From a preventive point of view, rather than recommending antioxidant nutrients intake in the form of vitamins, it would be wiser to promote fruits and vegetables consumption that may bring benefit not only with regard to cognitive ageing but also other pathologies like cardiovascular diseases and cancers. Hundreds of polyphenols with potent antioxidant activity have been shown to have neuroprotective effect in vitro and in animal studies, but only a few compounds, e.g. curcumin, have progressed successfully into active clinical trials in neurodegenerative diseases. Polyphenols from fruits and vegetables seem to be invaluable potential agents in neuroprotection by virtue of their ability to influence and modulate several cellular processes such as signalling, proliferation, apoptosis, redox balance, differentiation, etc. Their neuroprotective activity in various models of neurodegenerative diseases in vitro and in vivo has been documented, but it would be unwise to extrapolate these results to the human situation without proper clinical trials in patients suffering from irreversible and extensive neuronal loss. In addition, most cell culture or animal studies have been conducted on a short-term basis. Therefore, more long-term studies should be undertaken to determine their beneficial effects in slow-developing neurodegenerative disorders such as AD. In view of their multiple biological activities, polyphenols hold great promise as potential therapeutic/prophylactic agents in neurodegenerative diseases.

15.7 Future trends Future studies should aim to enhance our knowledge of the roles and functions that polyphenolic compounds could display at the cellular and molecular levels. Moreover, the bioactivities of different metabolites, including

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glucuronidated, sulfated and methylated derivatives should be investigated. Many products are formed from the action of colonic microflora on polyphenolic components. These products may also contribute to health benefits. Therefore, the activities of these products should be analysed at the cellular levels. Finally, future research in this area should analyse the gene– nutrient interactions.

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trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med, 336, 1216–1222. savaskan e, olivieri g, meier f, seifritz e, wirz-justice a and muller-spahn f (2003) Red wine ingredient resveratrol protects from beta-amyloid neurotoxicity. Gerontology, 49, 380–383. scalbert a and williamson g (2000) Dietary intake and bioavailability of polyphenols. J Nutr, 130, 2073S–2085S. scarmeas n, stern y, tang m, mayeux r and luchsinger j a (2006) Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol, 59, 912–921. schroeter h, spencer j p, rice-evans c and williams r j (2001) Flavonoids protect neurons from oxidized low-density-lipoprotein-induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3. Biochem J, 358, 547–557. sellappan s, akoh c c and krewer g (2002) Phenolic compounds and antioxidant capacity of Georgia-grown blueberries and blackberries. J Agric Food Chem, 50, 2432–2438. sharma r a, steward w p and gescher a j (2007) Pharmacokinetics and pharmacodynamics of curcumin. Adv Exp Med Biol, 595, 453–470. shishodia s, singh t and chaturvedi m m (2007) Modulation of transcription factors by curcumin. Adv Exp Med Biol, 595, 127–148. sinclair a j, bayer a j, johnston j, warner c and maxwell s r (1998) Altered plasma antioxidant status in subjects with Alzheimer’s disease and vascular dementia. Int J Geriatr Pyschiatry, 13, 840–845. singh s and aggarwal b b (1995) Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. J Biol Chem, 270, 24995–25000. soleas g j, diamandis e p and goldberg d m (1997) Resveratrol: a molecule whose time has come? And gone? Clin Biochem, 30, 91–113. sutherland b a, rahman r m and appleton i (2006) Mechanisms of action of green tea catechins, with a focus on ischemia-induced neurodegeneration. J Nutr Biochem, 17, 291–306. swiecilo a, krawiec z, wawryn j, bartosz g and bilinski t (2000) Effect of stress on the life span of the yeast Saccharomyces cerevisiae. Acta Biochim Pol, 47, 355–364. tedeschi e, menegazzi m, yao y, suzuki h, forstermann u and kleinert h (2004) Green tea inhibits human inducible nitric-oxide synthase expression by downregulating signal transducer and activator of transcription-1alpha activation. Mol Pharmacol, 65, 111–120. truelsen t, thudium d and gronbaek m (2002) Amount and type of alcohol and risk of dementia: the Copenhagen City Heart Study. Neurology, 59, 1313–1319. wahlstrom b and blennow g (1978) A study on the fate of curcumin in the rat. Acta Pharmacol Toxicol (Copenh), 43, 86–92. wang y, chang c f, chou j, chen h l, deng x, harvey b k, cadet j l and bickford p c (2005) Dietary supplementation with blueberries, spinach, or spirulina reduces ischemic brain damage. Exp Neurol, 193, 75–84. wei q y, chen w f, zhou b, yang l and liu z l (2006) Inhibition of lipid peroxidation and protein oxidation in rat liver mitochondria by curcumin and its analogues. Biochim Biophys Acta, 1760, 70–77. weinreb o, mandel s, amit t and youdim m b (2004) Neurological mechanisms of green tea polyphenols in Alzheimer’s and Parkinson’s diseases. J Nutr Biochem, 15, 506–516. wu x, beecher g r, holden j m, haytowitz d b, gebhardt s e and prior r l (2006) Concentrations of anthocyanins in common foods in the United States and estimation of normal consumption. J Agric Food Chem, 54, 4069–4075.

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yang f, lim g p, begum a n, ubeda o j, simmons m r, ambegaokar s s, chen p p, kayed r, glabe c g, frautschy s a and cole g m (2005) Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem, 280, 5892–5901. yang g y, liu z, seril d n, liao j, ding w, kim s, bondoc f and yang c s (1997) Black tea constituents, theaflavins, inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone (NNK)-induced lung tumorigenesis in A/J mice. Carcinogenesis, 18, 2361–2365. yu r, jiao j j, duh j l, gudehithlu k, tan t h and kong a n (1997) Activation of mitogen-activated protein kinases by green tea polyphenols: potential signaling pathways in the regulation of antioxidant-responsive element-mediated phase II enzyme gene expression. Carcinogenesis, 18, 451–456. zadernowski r, naczk m and nesterowicz j (2005) Phenolic acid profiles in some small berries. J Agric Food Chem, 53, 2118–2124. zhao b l, li x j, he r g, cheng s j and xin w j (1989) Scavenging effect of extracts of green tea and natural antioxidants on active oxygen radicals. Cell Biophys, 14, 175–185.

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16 Vitamin D, cognitive function, and mental health E. P. Cherniack and B. R. Troen, University of Miami Miller School of Medicine, Miami VA Health System, USA

Abstract: Although it has long thought to be primarily involved in calcium regulation and bone metabolism, vitamin D is now believed to play an important role in the process of neural development, and insufficiency of vitamin D has been associated with pathology of cognition and mental illness. Vitamin D receptors are located in the brain, and vitamin D may protect neurons and promote neural growth. Some studies have suggested associations between basic and executive cognitive function, depressive symptoms, and serum vitamin D levels. However, causation has not been proved, and well-designed randomized, controlled clinical trials using sufficient doses of vitamin D to alleviate manifestations of mental and cognitive illness still need to be performed. It seems prudent for many reasons to detect and correct vitamin D insufficiency in all patients. Key words: vitamin D, cognition, mental illness.

16.1 Introduction Not a vitamin, but a steroid hormone, vitamin D has now been recognized to have an integral role in the process of neural development, and insufficiency of vitamin D has been associated with pathology of cognition and mental illness. Although it has long thought to be primarily involved in calcium regulation and bone metabolism, vitamin D is now believed to involved in cellular energy regulation, immune signaling, and neural and vascular integrity, all of which may have particular implications for the pathophysiology of mental illness.

16.2 The epidemic of vitamin D insufficiency – sources of vitamin D intake, epidemiology Many persons are vitamin D insufficient throughout the world (Holick, 2005). Vitamin D insufficiency (<32 ng/mL) can result in osteoporosis, an

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increased tendency to fall and sustain fractures, and the development of certain cancers (Cherniack et al., 2008a). The elderly are particularly vulnerable to vitamin D insufficiency, since they may be more likely to have an inadequate intake of dietary sources and exposure to sunlight. The prevalence of vitamin D insufficiency among the elderly from several previous published trials has been reported to be from 40–90 % (Cherniack et al., 2008a). Vitamin D is most available in fish, particularly salmon, and milk. Unless one eats at least a nine-ounce sockeye salmon fillet every day, one would have to eat rather larger quantities of other food stuffs to ingest vitamin D in sufficient amounts (USDA, 2009). Vitamin D can, however, be easily ingested through supplements in capsule form (Cherniack et al., 2008a). Vitamin D can also be obtained through the action of sunlight (Cherniack et al., 2008b). Ultraviolet light catalyzes the conversion of 7dehydrocholesterol to vitamin D3 (cholecalciferol) which is metabolized by the kidney and liver into 1,25-dihydroxycholecalciferol(calcitriol), the active form of vitamin D (Cherniack et al., 2008a). The amount of vitamin D that the skin can synthesize depends on the intensity of the sunlight, amount of skin exposed, and skin pigmentation (Hollis, 2005). Farther from the equator, the intensity of sunlight is more variable, and less intense in the winter months (Hollis, 2005). Darker skin absorbs less ultraviolet light than lighter skin. A light-skinned man in a Northern US city in a bathing suit in the mid-summer would need to receive sunlight for at least ten minutes to synthesize sufficient quantities of vitamin D (Hollis, 2005). In many parts of the world, lack of sufficient sunlight and cultural norms of dress preclude appropriate vitamin D intake from ultraviolet light, especially in darker skinned persons (Cherniack and Troen, 2008).

16.3

Vitamin D action on the brain

The 1-α-hydroxylation of 25-hydroxcholecholecalciferol into calcitriol occurs in numerous organ systems, including the brain (Cherniack et al., 2009). Neuronal support cells contain the hydroxylase enzyme that performs the final step in calcitriol synthesis (Kalueff and Tuohimaa, 2007). Brain macrophages and glial cells have been identified in the rat that can synthesize calcitriol (Neveu et al., 1994b; Naveilhan et al., 1993). 1-α-hydroxylase has been identified throughout the brains of both rats and humans in similar distributions from sections of frozen tissue (Eyles et al., 2005). Dopaminergic neurons have the highest concentrations of hydroxylase and vitamin D receptors on their nuclear membranes (Eyles et al., 2005). Vitamin D receptors (VDRs) are located in numerous sites throughout the body including the brain, and the vitamin D-VDR interaction may be

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important for neuronal development. VDRs appear throughout the brain and spinal cord in the developing rat embryo and fetus (Johnson et al., 1996; Veenstra et al., 1998). In developing animals, VDRs have been found in brain regions of increasing cell content and prevalence of dopaminergic neurons (Eyles et al., 2009). VDRs have been located in fully grown rat, hamster, and human brains in both neurons and glial cells, and have a distribution that is generally similar to that of 1-α-hydroxylase (Eyles et al., 2005). Polymorphisms of the VDR gene have been related to cognitive impairment in two studies (Gezen-Ak et al., 2007; Kuningas et al., 2009). In one investigation, 563 persons at least 85 years old who had haplotype 2(Bat), BsmI, or TaqI polymorphisms had lower scores on neuropsychological tests (Kuningas et al., 2009). Other VDR polymorphisms may reduce or increase the likelihood of dementia. In another observation, 109 elderly Alzheimer’s patients were compared with age-matched controls (Gezen-Ak et al., 2007). Those persons with an ApaI polymorphism had a 2.3 times greater probability of having Alzheimer’s, but persons with both the TaqI and the Apa polymorphisms had a 2.3 times lower probability of Alzheimer’s (GezenAk et al., 2007). Vitamin D itself has multiple actions on the nervous system. Vitamin D stimulates neuronal growth via several mechanisms. Firstly, vitamin D acts through genomic pathways (Garcion et al., 2002). The interaction of vitamin D with its receptor induces binding of other receptors, such as the retinoid X receptor, the all-trans retinoic acid receptor, thyroid hormone receptor, and Smad3, a protein which activates transforming growth factor β (Garcion et al., 2002). VDRs may mediate interactivity between the signaling pathways these receptors activate (Garcion et al., 2002). Vitamin D also has non-genomic activity (Garcion et al., 2002). Intracellular stores of calcium and external entry of calcium occurs in response to vitamin D stimulation, with the assistance of the VDR or another receptor 1,25(OH)-MARRS (Fernandes de Abreu et al., 2009). Some of effects of vitamin D on the nervous system may result from the production of neurotrophins. In the astrocyte, vitamin D stimulates neurotrophin-3 and neurotrophin-4 production (Neveu et al., 1994a). In glial cells, vitamin D induces glial-derived neurotrophic factor, which is related to transforming growth factor β (Naveilhan et al., 1996). Vitamin D promotes the expression of neural growth factor, which induces neuronal development, in mouse fibroblasts (Wion et al., 1991). Vitamin D also induces neural growth factor release and stimulates the growth of neurites in neurons cultured from the hippocampus of rat embryos (Brown et al., 2003). Vitamin D can stimulate Schwann cells in vitro to upregulate the expression of neural growth factor and VDR-responsive genes (Cornet et al., 1998). Fibroblasts treated with vitamin D also produce nerve growth factor (Saporito et al., 1994). In addition, treatment of adult rats with vitamin D stimulates neural growth factor mRNA levels in the cortex and

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hippocampus (Saporito et al., 1994). When vitamin D is withheld from pregnant rats, their young pups exhibit reduced neural growth factor levels that continue into adulthood (Eyles et al., 2003; Feron et al., 2005). Studies of vitamin D deficient maternal rats have also suggested that vitamin D is necessary for the expression of multiple proteins necessary for cytoskeletal integrity, which may be important in axonal development (Almeras et al., 2007; Fernandes de Abreu et al., 2009). Alterations in vitamin D level may influence the concentration of neurotransmitters (Garcion et al., 2002). Vitamin D also acts to protect neurons from damage. Rat hippocampal neurons grown in culture with vitamin D were more capable of withstanding injury from electrical current than those without vitamin D (Brewer et al., 2001). Rats who were injected daily with vitamin D sustained reduced chemical injury induced by injection of 6-hydroxydopamine into the brain (Wang et al., 2001). Vitamin D also protected cultured rat dopaminergic neurons from the chemotoxic agents L-buthionine sulfoximine and 1-methyl-4-phenylpyridine (Shinpo et al., 2000) and shielded fetal rat mesencephalic neurons from the chemotoxicity of glutamate and free radical damage induced by hydrogen peroxide exposure (Ibi et al., 2001). Vitamin D prevented glutamate toxicity in embryonic rat cortical neurons in culture and induced VDR mRNA expression (Taniura et al., 2006). It has been speculated that the regulation of calcium channel flux by vitamin D may protect against certain chemotoxic agents, alter neuronal excitation, and protect against excitotoxicity (Garcion et al., 2002). Vitamin D may also stimulate protective substances such as calcium-binding proteins, and the anti-oxidants glutathione, and -glutamyl transpeptidase in neurons and astrocytes while inhibiting the toxic effects of nitric oxide synthetase (Garcion et al., 1999; Garcion et al., 2002). Neurons in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, have been observed to create nitric oxide synthetase (Fernandes de Abreu et al., 2009). One source of information about the potential role of vitamin D on the developing nervous system comes from experiments on mice in which the VDR gene has been deleted (VDR knockout mice). VDR knockout mice exhibit a number of abnormal behaviors, including anxiety, deficient motor function (reduction in time to fall off a ledge, or a rotating rod, shorter maximum stride, or worse performance on a maze test), abnormal grooming and socialization, and lesser swimming ability, although they have no gross anatomical changes in Purkinje cells or cerebellar neurons (Kalueff et al., 2004, 2005, 2006; Burne et al., 2005, 2006; Keisala et al., 2009). Vitamin D exerts systemic effects that may affect nervous system development and function. Excess energy intake is stored in adipocytes, which produce inflammatory cytokines (Galic et al., 2010). These cytokines may induce vascular injury to the brain (Buell and Dawson-Hughes, 2008). In addition, elevated levels of pro-inflammatory cytokines have been associated with deficits in cognition behavioral disturbances in animal models

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(Moore et al., 2005; Eyles et al., 2009). Rats given treatments to augment levels of the pro-inflammatory cytokine1L-1β and decrease the antiinflammatory cytokine IL-10 in their hippocampi have memory impairment (Moore et al., 2005). Treatment in rats with vitamin D lowers hippocampal 1L-1β and increases IL-10 (Moore et al., 2005).

16.4 Cognition 16.4.1 Basic cognitive functions An increasing body of evidence implies a relationship between impairment in basic cognitive functions such as perception, memory, and attention, and vitamin D insufficiency (Annweiler et al., 2009; Cherniack et al., 2009). Several studies have suggested an association between vitamin D and basic cognitive functions using short global screening tests of cognition that include measurements of some basic cognitive functions. A retrospective review of the charts of 32 community-dwelling patients of a university outpatient clinic (ages 61–92 years) revealed a correlation between serum 25-hydroxyvitamin D and performance on the Mini-Mental Status Examination (MMSE) (p = 0.006) (Przybelski and Binkley, 2007). In a second, larger, study of 225 patients in a Dutch university geriatric outpatient clinic, there was also a positive correlation between the serum level of 25-hydroxyvitamin D and MMSE score (p = 0.01) (Oudshoorn et al., 2008). The relationship between vitamin D levels and cognition was studied in an even larger sample of 1766 persons aged at least 65 who were part of a larger British epidemiologic study, the Health Survey for England 2000 (Llewellyn et al., 2009). Subjects in the lowest quartile of serum 25-hydroxyvitamin D concentrations (3.2–12 ng/ml) were 2.3 times more likely to have impaired cognition, as measured by the MMSE, than those in the highest quartile (26.4–68 ng/ml). Dietary vitamin D consumption also correlated with MMSE score in 69 healthy Italian community-dwelling outpatients (r = 0.35, p < 0.01) (Rondanelli et al., 2007). There was an inverse correlation between vitamin intake and serum malondiadehyde, a measure of oxidative stress, which might imply a role for vitamin D in the reduction of oxidative stress (Rondanelli et al., 2007). The MMSE scores and serum 25-hydroxyvitamin D levels of 40 normal and 40 ‘mildly demented’ subjects who were aged at least 60 were compared in another investigation (Wilkins et al., 2006). In all participants, the mean 25-hydroxyvitamin D level was 18.58 ng/ml, and the mean MMSE score was 25.87. The subjects were then divided into three groups by vitamin D level: vitamin D deficient (<10 ng/ml), vitamin D insufficient (≥10 ng/ml but <25 ng/ml), and vitamin D sufficient (≥25 ng/ml). Lower vitamin D levels were correlated with an active mood disorder and impaired cognition as determined by a nine-item cognitive assessment test that measures basic cognitive functions, the Short Blessed Test, and a more comprehensive

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instrument, the Clinical Dementia Rating. Interestingly, there was no difference in scores on the MMSE as a function of vitamin D status. Given the low levels of vitamin D considered sufficient, it is possible a higher level defined for sufficiency (e.g. ≥32 ng/ml) would have uncovered a stronger relationship between vitamin D level and the MMSE. The same investigators did a second comparison of vitamin D levels and cognition testing results of 30 white and 30 African–American subjects, which included both normal and ‘mildly cognitively impaired’ individuals (Wilkins et al., 2009). The mean age of participants was 74.99, and the mean 25-hydroxyvitamin D level was 21.59 ng/ml (Wilkins et al., 2009). Older persons were deemed ‘vitamin D deficient’ if serum 25-hydroxyvitamin D concentrations were <20 ng/ml or ‘normal’ if concentrations were ≥20 ng/ml. Among all participants, vitamin D deficient subjects had a significantly lower score on the Short Blessed Test (p = 0.016) but not on the MMSE (p = 0.418). African–Americans had significantly lower mean 25-hydroxyvitamin D levels (17.98 ng/ml) than did whites (25.20, p < 0.001). Those African–Americans who were also vitamin D deficient did have significantly lower MMSE scores than those who did not (p = 0.008). The relationship of vitamin D deficiency to basic cognitive function was also assessed in 752 women 75 and older who were able to walk independently as part of an osteoporosis study in France (Annweiler et al., 2010). Those women whose serum vitamin D concentrations were quite low (less than 10 ng/ml) were more likely to have an abnormal score on the Pfeiffer Short Portable Mental State Questionnaire (<8) than those with higher serum vitamin D concentrations (Annweiler et al., 2010). There is generally an inverse relationship between vitamin D and the counter-regulatory parathyroid hormone (Cherniack and Troen, 2008). One study found an association between higher parathyroid hormone levels and cognitive impairment in age cohorts of 514 persons at ages 75, 80, and 85 who participated in the Helsinki Ageing Study (Bjorkman et al., 2010). Subjects whose baseline parathyroid hormone (PTH) was >62 ng/l were 2.4 times as likely (95 % CR = 1.11–4.46) to have a loss of four points over five years on the MMSE, or a worse score on the Clinical Dementia Rating.

16.4.2 Executive cognitive functions The relationship of vitamin D with executive cognitive functions is more complex (Cherniack et al., 2009). Executive functions include many different activities, such as initiating basic cognitive functions, integrating them, developing an emotional response and a working memory, planning, multitasking, and stopping activities (Roth et al., 2005). There are many tests to evaluate aspects of executive function including the Tower and Trail Making tests, verbal fluency test, Wisconsin Card Sorting tests, and the Stroop test (Roth et al., 2005). Tests of both executive function and basic cognition were performed on 1080 elderly individuals (mean age 75)

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receiving home care services in Boston (Buell et al., 2009). Over 65 % of the subjects had 25-hydroxyvitamin D levels ≤20 ng/ml. Vitamin D levels were associated with better scores on tests of global cognitive function (MMSE), attention, and processing speed, and executive function (Trails A and B, block design, digit symbol coding, and matrix reasoning). However, no correlation was found between vitamin D status and tests of memory. Serum was collected for vitamin D in a large epidemiologic cohort of 3369 men, many of whom were middle-aged but also included elderly individuals (age range 40–79, mean age 60) from several European countries (Lee et al., 2009). There was a relationship between 25-hydroxyvitamin D level and one test of executive function, the Digital Symbol Substitution Test, but not with tests of figure copying or other memory tests. One other study failed to find an association between vitamin D and cognition (McGrath et al., 2007). Among the subjects of a larger epidemiologic cohort, the participants of the National Health and Examination (NHANES III ), 4809 individuals above age 60 had a memory test in which they were required to remember the details of a story read to them. Surprisingly, those in the highest quintile of 25-hydroxyvitamin D levels did the poorest (McGrath et al., 2007). No further cognitive testing was done in these persons.

16.5

Vitamin D in dementia and Parkinson’s disease

The relationship between vitamin D level and the presence of dementia is unclear. In one investigation, 25-hydroxyvitamin D levels were noted to be lower in demented individuals than in cognitively normal elderly persons (Kipen et al., 1995). The incidence of vitamin D insufficiency was compared in three cohorts of 100 patients each: one with Alzheimer’s disease, one with Parkinson’s disease, and one control group without neurologic disease (Evatt et al., 2008). Mean vitamin D levels were significantly lower in the Parkinson’s patients (31.9 ng/ml) than in normals (37.0 ng/ml, p = 0.01) or Alzheimer’s disease patients (34.8 ng/ml, p = 0.12). A greater percentage of the Parkinson’s patients were vitamin D insufficient (defined as ≤30 ng/ml) (55.0 %) than in either the normal (36.4 %, p = 0.008) or Alzheimer’s disease patients (41.2 %, p = 0.05).

16.6 Vitamin D and depression, bipolar illness, and schizophrenia As with cognition, a growing number of investigations have delineated a role for vitamin D in the pathogenesis of depression (Cherniack et al., 2009). Although there is little direct evidence as to how vitamin D might cause

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depression, a number of suggestions have been made (Bertone-Johnson, 2009). One possibility is that vitamin D affects the levels of monamine transmitters, the lack of which is the most widely supported view of the etiology of depression. Vitamin D augments the expression of the gene that encodes for tyrosine hydroxylase, a precursor in the synthesis of the neurotransmitters serotonin and norepinephrine (Belmaker, 2008; Bertone-Johnson, 2009). Furthermore, vitamin D shields neurons against dopaminergic toxins in animal studies (Bertone-Johnson, 2009). Depression may also be the result of the result of stress on glucocorticoid function in the brain (Belmaker, 2008; Bertone-Johnson, 2009). Hippocampal neurons can hydroxylate vitamin D into its active form, possess both VDR and glucocorticoid receptors, and there may be an interaction between these two types of receptors (Bertone-Johnson, 2009). A large epidemiologic study has defined an association in the elderly between vitamin D status and depression (Hoogendijk et al., 2008). The mean 25-hydroxyvitamin D level of 1282 participants in the Longitudinal Aging Study Amsterdam (LASA) who were between 65 and 95 years old living in the community was quite low at 21 ng/ml. However, the groups with either minor or major depression exhibited a 14 % lower mean 25-hydroxyvitamin D level. There was also an inverse correlation between depression severity and 25-hydroxyvitamin D level (p < 0.03). Two other large epidemiologic studies from Asia that explored the relationship between vitamin D and depression in a predominantly middleaged population that included elderly individuals found an equivocal association between vitamin D and depression (Nanri et al., 2009; Pan et al., 2009). In one investigation of 3262 community-dwelling participants between the ages of 50 and 70 in China, depressive symptoms were inversely correlated with unadjusted vitamin D levels (Pan et al., 2009). But when adjusted for geographic location, sex, age, socioeconomic level, chronic illness, marital status, and smoking, the association no longer held. In a second study, 527 persons between the ages of 21 and 67 who worked for city governments in Japan had assessments of their serum vitamin D (Nanri et al., 2009). When the sera were obtained in a month of lesser sunlight, November, an inverse association was observed between 25hydroxyvitamin D level and severe depressive symptoms. However, there was no relationship between 25-hydroxyvitamin D levels assessed in July and depressive symptoms. Several investigations attempted to define a potential seasonal relationship between depressive symptoms and vitamin D in smaller populations of women. Nine women whose vitamin D levels were <16 ng/ml were followed for a year, and their indices of depressive symptoms varied with seasonal changes in their vitamin D levels (Shipowick et al., 2009). In a larger trial of 250 women, ages 43–72, higher symptom depression symptom scores were recorded in the winter months (Harris and Dawson-Hughes,

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1993). The investigators treated the subjects with 400 IU vitamin D, but the supplementation did not affect the results of the testing for depression (Harris and Dawson-Hughes, 1993). English women who were at least age 70 and diagnosed with seasonal affective disorder were randomized to receive 800 IU cholecalciferol or a placebo for six months (Dumville et al., 2006). A large subject population of 2117 participated, but no benefit was observed in the women who received vitamin D (Dumville et al., 2006). It should be noted that 25-hydroxyvitamin D levels were not assessed. In a small study of those with seasonal affective disorder, eight subjects were given a single dose of 100 000 IU cholecalciferol, seven were treated with phototherapy (Gloth et al., 1999). Both groups of subjects had significant improvements in depression scale scores (74 % response in subjects who took vitamin D, p < 0.005, and 36 % of subjects who received phototherapy, p < 0.01). Mean 25-hydroxyvitamin D levels rose in supplemented subjects from 11.0 ng/mL at baseline to 19.1 ng/mL (p < 0.003) and in the individuals who were treated with phototherapy from 13.7 ng/mL to 18.6 ng/ mL (p < 0.007). There was a significant correlation between change in the depression score (the eight-question atypical symptom Hamilton Depression sub-scale) and 25-hydroxyvitamin D level (r2 = 0.26, p = 0.05). In 44 healthy students, age range 18–43, mean age 22.0, the addition of either 400 IU or 800 IU cholecalciferol daily for five days during winter months in Australia produced significantly greater increases in mood on the Positive and Negative Affect Schedule than a placebo (Lansdowne and Provost, 1998). Since individuals who live at latitudes closer to the equator receive more sunlight, which might increase vitamin D levels, several studies have attempted to ascertain if such persons who live closer to the equator have fewer depressive symptoms than those who live farther from the equator. These studies have thus far produced inconsistent results (Mersch et al., 1999). Several studies from North America and Europe found that seasonal affective disorder was more common at higher latitudes (Lingjarde, 1986; Potkin et al., 1986; Terman, 1988; Rosen et al., 1990; Mersch et al., 1999), whereas other investigations have failed to find such a relationship (Magnusson and Axelsson, 1993; Partonen et al., 1993; Mersch et al., 1999; Levitt and Boyle, 2002). Possible explanations may include the influence of cloud cover, hours of daylight, heat and humidity, and differences in sampling methodologies. It has been suggested that illuminance (light intensity) explains the seasonal variability in the incidence of depression better than total daylight hours (Axelsson et al., 2004). A review noted that when North American studies were combined, a correlation existed between higher latitudes and greater prevalence of seasonal affective disorder (r = 0.90, p = 0.003), but the significance was lost when combined with studies from the rest of the world (Mersch et al., 1999). Other smaller studies have also inferred a relationship between vitamin D and depression. In 75 patients with fibromyalgia, those with vitamin D

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deficiency (<10 ng/ml 25-hydroxyvitamin D) had higher indices of depression and anxiety (Armstrong et al., 2007). Seventeen people with either depression or bipolar illness were compared to a cohort of normal subjects who lived in the same region in Australia, collected in the same season as the patients with mental illnesses (Pasco et al., 2001; Berk et al., 2007). The mean 25-hydroxyvitamin D level in the depressed and bipolar subjects was 18.8 ng/mL, which was significantly lower than in the larger cohort of 861 subjects with a mean of 32.4 ng/ml (Berk et al., 2007). Bipolar illness also occurs more frequently in the winter months (Schaffer et al., 2003). However, there is no variation in the prevalence of bipolar illness by latitude and, thus far, no investigations have ascertained a specific relationship between bipolar illness and serum levels of vitamin D. There is also indirect evidence that vitamin D may also play a role in the development of schizophrenia. A deficiency of vitamin D before birth may be part of the disease pathogenesis (McGrath, 1999; Altschuler, 2001; Kinney et al., 2009). At latitudes farther from the equator in the US, children born in the months of least sunlight have the highest risk of becoming schizophrenic (Torrey et al., 1977; Kinney et al., 2009). Caribbean emigrants who move to urban areas in countries with fewer days of sunlight also have a greater chance of giving birth to children who will suffer from schizophrenia (Jarvis, 1998). However, a relationship between sunlight exposure and schizophrenia was not identified in two large cohorts of 30 000 children born in Scotland and Wales (Kendell and Adams, 2002), although this study did not consider the possible contribution of differences in the prevalence of breastfeeding to vitamin D intake. Breastfed children are less likely to have vitamin D deficiency than those who are not breastfed (Ziegler et al., 2006). Young male children who were given extra vitamin D as an oral supplement in Finland also had a lower risk of becoming schizophrenic than those who did not (McGrath et al., 2004). Rat models in which animals were deprived of vitamin D before birth share certain motor and anatomical features in common with schizophrenia (Meyer and Feldon, 2010). Prospective studies of vitamin D supplementation in schizophrenics have yet to be performed.

16.7 The diagnosis and treatment of vitamin D insufficiency Given the known benefits of vitamin D supplementation, the prospect of improved mental health, and the difficulty of obtaining sufficient quantities of vitamin D from diet or producing enough from sunlight, it seems prudent to assess elderly persons for vitamin D deficiency and recommend vitamin D supplementation. This may take the form of capsules, intramuscular injections, or the addition of vitamin D into foods.

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In an early study, 12 elderly nursing home residents (age range 68–92) were given 2000 IU daily of cholecalciferol for one month. Their mean serum vitamin D levels rose from 5.8 to 32 ng/mL (MacLennan and Hamilton, 1977). A daily supplement of 2000 IU cholecalciferol for six weeks in 15 hospital inpatients (mean age 82) raised their mean serum 25-hydroxyvitamin D level from 16 ng/mL to 32 ng/mL (Himmelstein et al., 1990). Thirty-four elderly veterans were given either an oral supplement of 2000 IU cholecalciferol or a placebo for six months (Cherniack et al., 2007). The mean serum level in the group receiving vitamin D rose from 28.4 ng/ mL at baseline to 42.7 ng/mL after six months, but did not significantly increase in the control group. However, 17 % of the treatment groups still had serum vitamin D levels below 32 ng/mL at the end of the trial. A daily dose of 800 IU cholecalciferol given to 104 black women aged 50–75 elevated the mean level of 25-hydroxyvitamin D from 18.8 ng/mL at baseline to 28.4 ng/ml (Aloia et al., 2005). Two years later, supplementation was increased to 2000 IU a day, and the mean serum 25-hydroxyvitamin D level rose further to 34.8 ng/mL. One study compared the impact of daily oral dosing with weekly or monthly intramuscular injections in 81 female hip fracture patients (mean age 81) (Ish-Shalom et al., 2008). The initial mean serum vitamin D concentration was rather low, 15.7 ng/mL. Subjects received either 1500 IU as a daily oral supplement, 10 500 IU intramuscularly once a week, or 45 000 IU intramuscularly once a month. Although the women who received the monthly dose had a higher initial increase in 25-hydroxyvitamin D levels, after two months there were no significant differences between all three groups. In another investigation, 45 elderly individuals who lived in a nursing home in Romania were given a daily piece of bread that was fortified with 5000 IU cholecalciferol (Mocanu et al., 2009). Mean serum vitamin D rose from a baseline of 11.4 ng/mL to 50.24 ng/mL after a year (Mocanu et al., 2009). In 92 % of subjects, the final mean serum vitamin D concentration was at least 29.6 ng/mL. Fifty older individuals (mean age 66.3) were given a single intramuscular injection of 600 000 IU cholecalciferol (Diamond et al., 2005). Serum vitamin D increased from a baseline of 13.12 ng/mL to 45.6 ng/ml at four months and was 29.2 ng/mL after a year. One approach to the diagnosis and treatment of possible vitamin D insufficiency would be to screen individuals by checking their serum vitamin D levels. Since the elderly are known to have a high prevalence of vitamin D deficiency, it is recommended at least in this population (Cherniack et al., 2008a). If serum levels are >10 ng/ml, but <32 ng/ml, initiation of supplementation with at least 2000 IU cholecalciferol should begin. Once three months have been completed, and compliance with the regimen has been verified, repeat assessment can take place. If 25-hydroxyvitamin D levels are still insufficient, further increases in supplementation can be made. For those with frank vitamin D deficiency (≤10 ng/ml 25-hydroxyvitamin D

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level), weekly supplementation with 50 000 IU or ergocalciferol should be undertaken for eight to 12 weeks and then vitamin D status again measured. Vitamin D supplementation with cholecalciferol is a safe, low-risk therapy in the absence of primary hyperparathyroidism (Cherniack et al., 2008a). Published cases of vitamin D toxicity with hypercalcemia involve doses ≥40 000 IU of cholecalciferol a day (Vieth, 1999). Indeed, the author stated that he could not find any verifiable published cases of vitamin D toxicity resulting from a daily intake of 10 000 IU of cholecalciferol. In the trial we conducted, treatment with 2000 IU cholecalciferol daily did not cause any elevation in serum or urine calcium (Cherniack et al., 2007). There were no cases of adverse events that could be attributed to vitamin D. In a longer previously mentioned study conducted over two years using the same dose, there were no incidences of hypercalcemia or hypercalciuria, and nephrolithiasis did not occur (Aloia et al., 2005). As with any medication, when vitamin D supplementation is considered, an effort should be made to ensure that cognitively and mentally impaired patients have the capability and willingness to take their medicine properly or have appropriate assistance to do so. Given the high prevalence of vitamin D insufficiency and deficiency in the elderly and the potential to improve the health of many individuals, several steps could be considered to increase the prevalence of vitamin D sufficiency and optimize vitamin D status. Many of the current recommendations for vitamin D intake by national health organizations remain low. The US Food and Drug Administration advises a daily dose of only 400 IU for those aged 51–70, and the US National Osteoporosis Foundation suggests 800–1000 IU for all over 50 (Cherniack et al., 2008a). The British Food Standards Agency recommends elderly persons and pregnant women consider adding 400 IU a day (FSA, 2010). Governmental and scientific advisory bodies should update recommended dosages to take into account new research on the effects of supplementation. In the absence of vitamin D insufficiency, we still suggest a daily dose of 2000 IU cholecalciferol for those over 65 years, particularly the frail elderly with multiple co-morbidities. For years, the food industry has supplemented several foods with vitamin D including milk, orange juice, cheese, breakfast cereals, butter yogurt, margarine, and baby formula (Holick, 2007). Ultraviolet light can increase the amount of vitamin D in mushrooms to 400 IU/3 oz (National Institute of Health). However, the amounts added, from 100–430 IU per serving, remain small. In Finland, a model for optimal vitamin D supplementation was developed (Hirvonen et al., 2007). It predicted that adding vitamin to only dairy foods would not be sufficient to replete the entire population. However, if all possible foods were fortified with at least 368 IU/100 kcal, the general population could achieve a dietary intake of 1600 IU a day.

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16.8 Future trends Previous research has suggested associations between cognitive function, depressive symptoms, and serum vitamin D levels. However, many important questions remain unanswered about the relationship between vitamin D and mental illness. First, it is not yet known if or how causation is part of this relationship. Do low vitamin D levels directly contribute to cognitive and mental pathology, or do cognitively or mentally ill patients get less sunlight or consume diets less rich in vitamin D than healthier persons? More research needs to be done to elucidate the potential mechanism through which vitamin D and cognitive illness might be related. Furthermore, what has been considered vitamin D ‘sufficiency’ until now has been based on levels of vitamin D needed to maintain bone health and suppress levels of the counter-regulatory hormone PTH, with which vitamin D maintains a complex relationship (Cherniack et al., 2008a). However, the amount of vitamin D necessary to maintain adequate mental health might be different. The few prospective trials of vitamin D to treat mental illness, used in the treatment of seasonal affective disorder, were negative, although they did not use doses high enough that they could be expected to correct vitamin D insufficiency and had small subject populations and short treatment durations. Well-designed randomized, controlled clinical trials using sufficient doses of vitamin D to alleviate manifestations of mental and cognitive illness still need to be performed.

16.9 Sources of further information and advice • Vitamin D council: www.vitamindcouncil.org • Michael Holick: www.VitaminDHealth.org • The Vitamin D Society (of Canada): www.vitamindsociety.org

16.10 References almeras l, eyles d, benech p, laffite d, villard c, patatian a, boucraut j, mackaysim a, mcgrath j and feron f (2007) Developmental vitamin D deficiency alters brain protein expression in the adult rat: implications for neuropsychiatric disorders. Proteomics, 7, 769–80. aloia j f, talwar s a, pollack s and yeh j (2005) A randomized controlled trial of vitamin D3 supplementation in African American women. Arch Intern Med, 165, 1618–23. altschuler e l (2001) Low maternal vitamin D and schizophrenia in offspring. Lancet, 358, 1464. annweiler c, allali g, allain p, bridenbaugh s, schott a m, kressig r w and beauchet o (2009) Vitamin D and cognitive performance in adults: a systematic review. Eur J Neurol, 16, 1083–9.

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annweiler c, schott a m, allali g, bridenbaugh s a, kressig r w, allain p, herrmann f r and beauchet o (2010) Association of vitamin D deficiency with cognitive impairment in older women. Cross-sectional study. Neurology, 74, 27–32. armstrong d j, meenagh g k, bickle i, lee a s, curran e s and finch m b (2007) Vitamin D deficiency is associated with anxiety and depression in fibromyalgia. Clin Rheumatol, 26, 551–4. axelsson j, ragnarsdottir s, pind j and sigbjornsson r (2004) Daylight availability: a poor predictor of depression in Iceland. Int J Circumpolar Health, 63, 267– 76. belmaker r h (2008) The future of depression psychopharmacology. CNS Spectr, 13, 682–7. berk m, sanders k m, pasco j a, jacka f n, williams l j, hayles a l and dodd s (2007) Vitamin D deficiency may play a role in depression. Med Hypotheses, 69, 1316–19. bertone-johnson e r (2009) Vitamin D and the occurrence of depression: causal association or circumstantial evidence? Nutr Rev, 67, 481–92. bjorkman m p, sorva a j and tilvis r s (2010) Does elevated parathyroid hormone concentration predict cognitive decline in older people? Aging Clin Exp Res, 22, 164–9. brewer l d, thibault v, chen k c, langub m c, landfield p w and porter n m (2001) Vitamin D hormone confers neuroprotection in parallel with downregulation of L-type calcium channel expression in hippocampal neurons. J Neurosci, 21, 98–108. brown j, bianco j i, mcgrath j j and eyles d w (2003) 1,25-dihydroxyvitamin D3 induces nerve growth factor, promotes neurite outgrowth and inhibits mitosis in embryonic rat hippocampal neurons. Neurosci Lett, 343, 139–43. buell j s and dawson-hughes b (2008) Vitamin D and neurocognitive dysfunction: preventing ‘D’ecline? Mol Aspects Med, 29, 415–22. buell j s, scott t m, dawson-hughes b, dallal g e, rosenberg i h, folstein m f and tucker k l (2009) Vitamin D is associated with cognitive function in elders receiving home health services. J Gerontol A Biol Sci Med Sci, 64, 888–95. burne t h, mcgrath j j, eyles d w and mackay-sim a (2005) Behavioural characterization of vitamin D receptor knockout mice. Behav Brain Res, 157, 299–308. burne t h, johnston a n, mcgrath j j and mackay-sim a (2006) Swimming behaviour and post-swimming activity in Vitamin D receptor knockout mice. Brain Res Bull, 69, 74–8. cherniack e p and troen b r (2008) Calciotropic hormones, in Duque G and Kiel D P (eds), Senile Osteoporosis: Advances in Pathophysiology and Therapeutic Approach. London: Springer-Verlag. cherniack e p, florez h, hollis b, roos b, levis s and troen b (2007) High dose of vitamin D3 reduces the prevalence of hypovitaminosis D in elderly veterans. The Gerontologist, 47, 13–14. cherniack e p, florez h, roos b a, troen b r and levis s (2008a) Hypovitaminosis D in the elderly: from bone to brain. J Nutr Health Aging, 12, 366–73. cherniack e p, levis s and troen b r (2008b) Hypovitaminosis D: a widespread epidemic. Geriatrics, 63, 24–30. cherniack e p, troen b r, florez h j, roos b a and levis s (2009) Some new food for thought: the role of vitamin D in the mental health of older adults. Curr Psychiatry Rep, 11, 12–19. cornet a, baudet c, neveu i, baron-van evercooren a, brachet p and naveilhan p (1998) 1,25-Dihydroxyvitamin D3 regulates the expression of VDR and NGF gene in Schwann cells in vitro. J Neurosci Res, 53, 742–6. diamond t h, ho k w, rohl p g and meerkin m (2005) Annual intramuscular injection of a megadose of cholecalciferol for treatment of vitamin D deficiency: efficacy and safety data. Med J Aust, 183, 10–12.

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dumville j c, miles j n, porthouse j, cockayne s, saxon l and king c (2006) Can vitamin D supplementation prevent winter-time blues? A randomised trial among older women. J Nutr Health Aging, 10, 151–3. evatt m l, delong m r, khazai n, rosen a, triche s and tangpricha v (2008) Prevalence of vitamin d insufficiency in patients with Parkinson disease and Alzheimer disease. Arch Neurol, 65, 1348–52. eyles d, brown j, mackay-sim a, mcgrath j and féron f (2003) Vitamin D3 and brain development. Neuroscience, 118, 641–53. eyles d w, smith s, kinobe r, hewison m and mcgrath j j (2005) Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat, 29, 21–30. eyles d w, feron f, cui x, kesby j p, harms l h, ko p, mcgrath j j and burne t h (2009) Developmental vitamin D deficiency causes abnormal brain development. Psychoneuroendocrinology, 34 (suppl), S247–57. fernandes de abreu d a, eyles d and féron f (2009) Vitamin D, a neuro-immunomodulator: implications for neurodegenerative and autoimmune diseases. Psychoneuroendocrinology, 34 (suppl), S265–77. féron f, burne t h, brown j, smith e, mcgrath j j, mackay-sim a and eyles d w (2005) Developmental Vitamin D3 deficiency alters the adult rat brain. Brain Res Bull, 65, 141–8. fsa (2010) Vitamin D. London: Food Standards Agency, see http://www.nhs.uk/ livewell/goodfood/pages/vitamins.aspx (accessed February 2011). galic s, oakhill j s and steinberg g r (2010) Adipose tissue as an endocrine organ. Mol Cell Endocrinol, 316, 129–39. garcion e, sindji l, leblondel g, brachet p and darcy f (1999) 1,25-dihydroxyvitamin D3 regulates the synthesis of gamma-glutamyl transpeptidase and glutathione levels in rat primary astrocytes. J Neurochem, 73, 859–66. garcion e, wion-barbot n, montero-menei c n, berger f and wion d (2002) New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab, 13, 100–105. gezen-ak d, dursun e, ertan t, hanagasi h, gurvit h, emre m, eker e, ozturk m, engin f and yilmazer s (2007) Association between vitamin D receptor gene polymorphism and Alzheimer’s disease. Tohoku J Exp Med, 212, 275–82. gloth f m, 3rd, alam w and hollis b (1999) Vitamin D vs broad spectrum phototherapy in the treatment of seasonal affective disorder. J Nutr Health Aging, 3, 5–7. harris s and dawson-hughes b (1993) Seasonal mood changes in 250 normal women. Psychiatry Res, 49, 77–87. himmelstein s, clemens t l, rubin a and lindsay r (1990) Vitamin D supplementation in elderly nursing home residents increases 25(OH)D but not 1,25(OH)2D. Am J Clin Nutr, 52, 701–6. hirvonen t, sinkko h, valsta l, hannila m l and pietinen p (2007) Development of a model for optimal food fortification: vitamin D among adults in Finland. Eur J Nutr, 46, 264–70. holick m f (2005) The vitamin D epidemic and its health consequences. J Nutr, 135, 2739S–48S. holick m f (2007) Vitamin D deficiency. N Engl J Med, 357, 266–81. hollis b w (2005) Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr, 135, 317–22. hoogendijk w j, lips p, dik m g, deeg d j, beekman a t and penninx b w (2008) Depression is associated with decreased 25-hydroxyvitamin D and increased parathyroid hormone levels in older adults. Arch Gen Psychiatry, 65, 508–12.

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ibi m, sawada h, nakanishi m, kume t, katsuki h, kaneko s, shimohama s and akaike a (2001) Protective effects of 1 alpha,25-(OH)(2)D(3) against the neurotoxicity of glutamate and reactive oxygen species in mesencephalic culture. Neuropharmacology, 40, 761–71. ish-shalom s, segal e, salganik t, raz b, bromberg i l and vieth r (2008) Comparison of daily, weekly, and monthly vitamin D3 in ethanol dosing protocols for two months in elderly hip fracture patients. J Clin Endocrinol Metab, 93, 3430–5. jarvis e (1998) Schizophrenia in British immigrants: recent findings, issues and implications. Transcultural Psychiatry, 35, 39–74. johnson j a, grande j p, windebank a j and kumar r (1996) 1,25-Dihydroxyvitamin D(3) receptors in developing dorsal root ganglia of fetal rats. Brain Res Dev Brain Res, 92, 120–24. kalueff a v, keisala t, minasyan a, kuuslahti m, miettinen s and tuohimaa p (2006) Behavioural anomalies in mice evoked by ‘Tokyo’ disruption of the Vitamin D receptor gene. Neurosci Res, 54, 254–60. kalueff a v, lou y r, laaksi i and tuohimaa p (2004) Increased anxiety in mice lacking vitamin D receptor gene. Neuroreport, 15, 1271–4. kalueff a v, lou y r, laaksi i and tuohimaa p (2005) Abnormal behavioral organization of grooming in mice lacking the vitamin D receptor gene. J Neurogenet, 19, 1–24. kalueff a v and tuohimaa p (2007) Neurosteroid hormone vitamin D and its utility in clinical nutrition. Curr Opin Clin Nutr Metab Care, 10, 12–19. keisala t, minasyan a, lou y r, zou j, kalueff a v, pyykko i and tuohimaa p (2009) Premature aging in vitamin D receptor mutant mice. J Steroid Biochem Mol Biol, 115, 91–7. kendell r e and adams w (2002) Exposure to sunlight, vitamin D and schizophrenia. Schizophr Res, 54, 193–8. kinney d k, teixeira p, hsu d, napoleon s c, crowley d j, miller a, hyman w and huang e (2009) Relation of schizophrenia prevalence to latitude, climate, fish consumption, infant mortality, and skin color: a role for prenatal vitamin D deficiency and infections? Schizophr Bull, 35, 582–95. kipen e, helme r d, wark j d and flicker l (1995) Bone density, vitamin D nutrition, and parathyroid hormone levels in women with dementia. J Am Geriatr Soc, 43, 1088–91. kuningas m, mooijaart s p, jolles j, slagboom p e, westendorp r g and van heemst d (2009) VDR gene variants associate with cognitive function and depressive symptoms in old age. Neurobiol Aging, 30, 466–73. lansdowne a t and provost s c (1998) Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacology (Berl), 135, 319–23. lee d m, tajar a, ulubaev a, pendleton n, o’neill t w, o’connor d b, bartfai g, boonen s, bouillon r, casanueva f f, finn j d, forti g, giwercman a, han t s, huhtaniemi i t, kula k, lean m e, punab m, silman a j, vanderschueren d and wu f c (2009) Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged and older European men. J Neurol Neurosurg Psychiatry, 80, 722–9. levitt a j and boyle m h (2002) The impact of latitude on the prevalence of seasonal depression. Can J Psychiatry, 47, 361–7. lingjarde o b t, hansen t and gotestam k g (1986) Seasonal affective disorder and midwinter insomnia in the far north: studies on two related chronobiological disorders in Norway. Clin Neuropharmacol, 9, 187–9. llewellyn d j, langa k m and lang i a (2009) Serum 25-hydroxyvitamin D concentration and cognitive impairment. J Geriatr Psychiatry Neurol, 22, 188– 95.

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maclennan w j and hamilton j c (1977) Vitamin D supplements and 25-hydroxy vitamin D concentrations in the elderly. Br Med J, 2, 859–61. magnusson a and axelsson j (1993) The prevalence of seasonal affective disorder is low among descendants of Icelandic emigrants in Canada. Arch Gen Psychiatry, 50, 947–51. mcgrath j (1999) Hypothesis: is low prenatal vitamin D a risk-modifying factor for schizophrenia? Schizophr Res, 40, 173–7. mcgrath j, saari k, hakko h, jokelainen j, jones p, jarvelin m r, chant d and isohanni m (2004) Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study. Schizophr Res, 67, 237–45. mcgrath j, scragg r, chant d, eyles d, burne t and obradovic d (2007) No association between serum 25-hydroxyvitamin D3 level and performance on psychometric tests in NHANES III. Neuroepidemiology, 29, 49–54. mersch p p, middendorp h m, bouhuys a l, beersma d g and van den hoofdakker r h (1999) Seasonal affective disorder and latitude: a review of the literature. J Affect Disord, 53, 35–48. meyer u and feldon j (2010) Epidemiology-driven neurodevelopmental animal models of schizophrenia. Prog Neurobiol, 90, 285–326. mocanu v, stitt p a, costan a r, voroniuc o, zbranca e, luca v and vieth r (2009) Long-term effects of giving nursing home residents bread fortified with 125 microg (5000 IU) vitamin D(3) per daily serving. Am J Clin Nutr, 89, 1132–7. moore m e, piazza a, mccartney y and lynch m a (2005) Evidence that vitamin D3 reverses age-related inflammatory changes in the rat hippocampus. Biochem Soc Trans, 33, 573–7. nanri a, mizoue t, matsushita y, poudel-tandukar k, sato m, ohta m and mishima n (2009) Association between serum 25-hydroxyvitamin D and depressive symptoms in Japanese: analysis by survey season. Eur J Clin Nutr, 63, 1444–7. national institute of health, office of dietary supplements. Dietary fact sheet: Vitamin D. Available at: http://ods.od.nih.gov/factsheets/vitamind/ (accessed February 2011). naveilhan p, neveu i, baudet c, ohyama k y, brachet p and wion d (1993) Expression of 25(OH) vitamin D3 24-hydroxylase gene in glial cells. Neuroreport, 5, 255–7. naveilhan p, neveu i, wion d and brachet p (1996) 1,25-Dihydroxyvitamin D3, an inducer of glial cell line-derived neurotrophic factor. Neuroreport, 7, 2171–5. neveu i, naveilhan p, baudet c, brachet p and metsis m (1994a) 1,25-dihydroxyvitamin D3 regulates NT-3, NT-4 but not BDNF mRNA in astrocytes. Neuroreport, 6, 124–6. neveu i, naveilhan p, menaa c, wion d, brachet p and garabedian m (1994b) Synthesis of 1,25-dihydroxyvitamin D3 by rat brain macrophages in vitro. J Neurosci Res, 38, 214–20. oudshoorn c, mattace-raso f u, van der velde n, colin e m and van der cammen t j (2008) Higher serum vitamin D3 levels are associated with better cognitive test performance in patients with Alzheimer’s disease. Dement Geriatr Cogn Disord, 25, 539–43. pan a, lu l, franco o h, yu z, li h and lin x (2009) Association between depressive symptoms and 25-hydroxyvitamin D in middle-aged and elderly Chinese. J Affect Disord, 118, 240–3. partonen t, partinen m and lonnqvist j (1993) Frequencies of seasonal major depressive symptoms at high latitudes. Eur Arch Psychiatry Clin Neurosci, 243, 189–92. pasco j a, henry m j, nicholson g c, sanders k m and kotowicz m a (2001) Vitamin D status of women in the Geelong Osteoporosis Study: association with diet and casual exposure to sunlight. Med J Aust, 175, 401–5.

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potkin s g, zetin m, stamenkovic v, kripke d and bunney w e, jr. (1986) Seasonal affective disorder: prevalence varies with latitude and climate. Clin Neuropharmacol, 9 Suppl 4, 181–3. przybelski r j and binkley n c (2007) Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function. Arch Biochem Biophys, 460, 202–5. rondanelli m, trotti r, opizzi a and solerte s b (2007) Relationship among nutritional status, pro/antioxidant balance and cognitive performance in a group of free-living healthy elderly. Minerva Med, 98, 639–45. rosen l n, targum s d, terman m, bryant m j, hoffman h, kasper s f, hamovit j r, docherty j p, welch b and rosenthal n e (1990) Prevalence of seasonal affective disorder at four latitudes. Psychiatry Res, 31, 131–44. roth r m, isquith, p k and gioia g a (2005) Executive function: concepts, assessment and intervention, in Koocher G P, Norcross J C and Hill S S (eds), Psychologist’s Desk Reference (2nd edn). New York: Oxford University Press, 38–41. saporito m s, brown e r, hartpence k c, wilcox h m, vaught j l and carswell s (1994) Chronic 1,25-dihydroxyvitamin D3-mediated induction of nerve growth factor mRNA and protein in L929 fibroblasts and in adult rat brain. Brain Res, 633, 189–96. schaffer a, levitt a j and boyle m (2003) Influence of season and latitude in a community sample of subjects with bipolar disorder. Can J Psychiatry, 48, 277– 80. shinpo k, kikuchi s, sasaki h, moriwaka f and tashiro k (2000) Effect of 1,25dihydroxyvitamin D(3) on cultured mesencephalic dopaminergic neurons to the combined toxicity caused by L-buthionine sulfoximine and 1-methyl-4phenylpyridine. J Neurosci Res, 62, 374–82. shipowick c d, moore c b, corbett c and bindler r (2009) Vitamin D and depressive symptoms in women during the winter: a pilot study. Appl Nurs Res, 22, 221–5. taniura h, ito m, sanada n, kuramoto n, ohno y, nakamichi n and yoneda y (2006) Chronic vitamin D3 treatment protects against neurotoxicity by glutamate in association with upregulation of vitamin D receptor mRNA expression in cultured rat cortical neurons. J Neurosci Res, 83, 1179–89. terman m (1988) On the question of mechanism in phototherapy for seasonal affective disorder: considerations of clinical efficacy and epidemiology. J Biol Rhythms, 3, 155–72. torrey e f, torrey b b and peterson m r (1977) Seasonality of schizophrenic births in the United States. Arch Gen Psychiatry, 34, 1065–70. usda (2009) National Nutrient Database for Standard Reference, Release 22, vitamin D (D2 + D3) (μg). (IU) Content of Selected Foods per Common Measure, Vitamin D sorted by nutrient content. Washington DC: US Department of Agriculture, available at: http:// www.ars.usda.gov/SP2UserFiles/Place/12354500/Data/SR22/nutrlist/sr22w328. pdf (accessed February 2011). veenstra t d, prufer k, koenigsberger c, brimijoin s w, grande j p and kumar r (1998) 1,25-Dihydroxyvitamin D3 receptors in the central nervous system of the rat embryo. Brain Res, 804, 193–205. vieth r (1999) Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr, 69, 842–56. wang j y, wu j n, cherng t l, hoffer b j, chen h h, borlongan c v and wang y (2001) Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats. Brain Res, 904, 67–75. wilkins c h, birge s j, sheline y i and morris j c (2009) Vitamin D deficiency is associated with worse cognitive performance and lower bone density in older African Americans. J Natl Med Assoc, 101, 349–54.

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wilkins c h, sheline y i, roe c m, birge s j and morris j c (2006) Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry, 14, 1032–1040. wion d, macgrogan d, neveu i, jehan f, houlgatte r and brachet p (1991) 1,25Dihydroxyvitamin D3 is a potent inducer of nerve growth factor synthesis. J Neurosci Res, 28, 110–14. ziegler e e, hollis b w, nelson s e and jeter j m (2006) Vitamin D deficiency in breastfed infants in Iowa. Pediatrics, 118, 603–10.

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17 Caloric intake, dietary lifestyles, macronutrient composition and dementia H. C. Fivecoat and G. M. Pasinetti, Mount Sinai School of Medicine, USA

Abstract: Alzheimer’s disease is a devastating neurodegenerative condition currently affecting over five million elderly individuals in the US. There is much evidence suggesting that certain dietary lifestyles can help to prevent and possibly treat Alzheimer’s disease. In this chapter, we discuss how certain cardiovascular and diabetic conditions can induce an increased susceptibility for Alzheimer’s disease and the mechanisms through which this occurs. We further discuss how the consumption of certain foods or food components can help to reduce one’s risk for Alzheimer’s disease and may possibly be developed as a therapeutic agent. Key words: Alzheimer’s disease, neurodegeneration, dietary lifestyle, nutritional medicine, preventative medicine.

17.1 Introduction Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a progressive decline in memory functions, which has become a growing public health concern. This condition of clinical dementia was first described by Alois Alzheimer in 1907 and, ever since, the incidence of AD has increased exponentially. There are presently five million Americans affected with AD, and the estimated annual health care cost is almost 100 billion dollars. Further, due to the expected increase in the number of individuals 65 years or older, it has been estimated that that the total incidence of AD will quadruple by the year 2050 (Brookmeyer et al., 1998). As there is presently no cure for this devastating condition, there is an urgent need to find a means of preventing, delaying the onset, or reversing the course of AD. Recent research has provided evidence that certain

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dietary lifestyle choices can help to prevent AD. This area of research has been quite exciting, in light of the fact that delaying the onset of AD by just five years could cut its incidence in half. In this chapter, we first discuss the major pathological features of AD clinical dementia, followed by an examination of research on certain dietary factors that have been found to influence AD. These dietary factors include calorie, fat, and glucose/sugar intake, in addition to the inclusion of foods like fish, certain fruits and vegetables, plant extracts, spices and red wine or polyphenol-rich foods in one’s diet.

17.1.1 Alzheimer’s disease neuropathology AD is characterized in the brain by accumulated extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles composed of abnormally hyperphosphorylated microtubular tau proteins. The manifestation of AD clinically is a progressive loss of cognitive abilities, including deficits in memory, planning etc. Neurotoxic Aβ is known to exist in multiple assembly states, which often result in varying pathophysiological effects. Additionally, although Aβ is classically understood to be deposited extracellularly, there is new evidence in mice and humans that Aβ peptides can also accumulate intraneuronally (LaFerla et al., 2007). Aβ species are generated from the ubiquitously expressed amyloid precursor protein (APP) through sequential proteolysis by β- and γ-secretases (Haas et al., 1992; Shoji et al., 1992; Busciglio et al., 1993). Although the 40-amino acid form of Aβ (Aβ1–40) is considered to be the major secreted species in AD, the 42-amino acid form of Aβ (Aβ1–42), which contains two additional residues at its carboxyl terminus, is thought to initiate AD pathogenesis (Golde et al., 2000). In addition, tau proteins in the brain (most particularly hyperphosphorylated tau), which aggregate into paired helical filaments and deposit as intracellular neurofibrillary tangles (Mi and Johnson, 2006; Sahara et al., 2008), are also considered to be a major pathology associated with AD. Researchers posit that abnormal hyperphosphorylation of tau leads to the sequestration of normal and hyperphosphorylated tau in microtubules, leading to alternations in the healthy functioning of tau in the brain (including changes in axon transport and microtubule stability and polymerization; Weingarten et al., 1975; Sorrentino and Bonavita, 2007). As Aβ species and tau neurofibrillary tangles are the major hallmarks of AD neuropathology, research on therapies or preventions for AD are often geared toward attenuating or treating these neuropathologies. In addition to Aβ and tau pathologies, mitochondrial functions also play a major role in AD clinical dementia (Bubber et al., 2005). Mitrochondria regulate energy metabolism in cells, and contribute largely to cell life or death (apoptosis). In the presence of increased Aβ content in the brain, mitochondria increase the generation of reactive oxygen species (ROS), which function as damaging agents and as signaling molecules. Highly

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reactive ROS, in fact, unleash a mechanism involving the liberation of cytochrome c, leading to neuronal apoptosis (Picklo and Montine, 2007; Vina et al., 2007). In human AD patients, positron emission tomography (PET) imaging assessments have suggested that the AD brain is characterized by impaired mitochondrial glucose metabolism, leading to neuronal hyperglycemic conditions (Haley et al., 2006). In light of this evidence, controlling mitochondrial glucose/energy metabolism in the brain has also been of high interest to AD researchers for the prevention and treatment of AD.

17.2 Obesity and the metabolic syndrome in Alzheimer’s disease (AD) High-fat diets and sedentary lifestyles have become major concerns throughout the world. They have led to a growing incidence of obesity, dyslipidemia, high blood pressure, and hyperglycemic conditions, known collectively to be components of metabolic syndrome (Torpy et al., 2006). These health conditions are well known to develop along with, or be precursors of, atherosclerosis, cardiovascular disease, and diabetes. Recent studies have found that most of these disorders can also be linked to an increased risk of AD. Of note, accumulating evidence suggests a mechanistic link between cholesterol metabolism in the brain and the formation of amyloid plaques in AD development (Martins et al., 2006; Reid et al., 2007). Epidemiological studies have demonstrated that individuals with obesity and diabetes have a four-fold increased risk for AD. Health risks associated with obesity, including evidence that obesity may causally promote the AD degenerative process, are of high concern for public health. By the beginning of the twenty-first century, the fraction of Americans considered to be obese reached ‘epidemic’ levels, according to a study published in the Journal of the American Medical Association (Mokdad et al., 1994). This study, carried out between 1991 and 1998, observed a steady increase in weight in all 50 states; across genders, age groups, races, and educational levels; and occurring regardless of smoking status. This study found that obesity had increased from 12.0 % in 1991 to 17.9 % in 1998. Likewise, national survey data has shown that in the periods 1976–1980 and 1988–1994, the age-adjusted prevalence of obesity increased by eight percentage points, from 14.5 % to 22.5 %, in the US adult population ages 20–74 years (Flegal at al., 2000). Several major studies have been conducted in humans to explore the relationship between obesity and the brain. Recently, Pannacculli and colleagues (2006) explored the association between body fat and regional alterations in brain structure using voxel-based morphometry (VBM) imaging (based on high-definition 3D magnetic resonance imaging (MRI)). Compared to lean subjects, obese individuals were found to have significantly lower gray matter density in the post-central gyrus, frontal operculum, putamen, and middle frontal gyrus, indicating differences in the brain

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regulation of taste, reward, and behavioral control. Additionally, Whitmer and colleagues (2005) evaluated the possible association between obesity (as measured by body mass index (BMI) and skinfold thickness) in middle age and risk of dementia in later life in a large-scale, multi-ethnic population-based cohort. Findings revealed that obese individuals (BMI > 30) in middle age had a 35 % higher risk for dementia compared to normal weight individuals (18.6 < BMI < 24.9), independent of other co-morbid conditions. Additionally, Balakrishnan and colleagues (2005) investigated the association between blood plasma Aβ levels (which promote AD development), BMI, and fat mass (FM) in healthy adults, and found significant correlations of BMI and FM with plasma Aβ1–42 levels, and also noted that the presence of certain proteins known to play a role in inflammation, cardiovascular disease and Type 2 diabetes strengthened these correlations. Researchers have also investigated the role of leptin, a protein hormone secreted in fat cells associated with obesity (which regulates appetite and metabolism), in AD pathogenesis. In pathological conditions of aging such as in AD, it has been demonstrated that the transport of leptin across the blood–brain barrier (BBB) is significantly impaired, in particular by the downregulation of megalin, a protein to which leptin must bind in order to enter the brain (Dietrich et al., 2007). Leptin has also been shown to reduce β-secretase activity in neuronal cells, possibly by altering the lipid composition of membrane rafts, and thereby affecting Aβ generation. In fact, chronic administration of leptin actually reduced Aβ load in the brains of AD transgenic mice, suggesting the potential of leptin as a treatment for AD (Fewlass et al., 2004) and providing further support for the hypothesized link between obesity and AD.

17.3 Calorie intake and caloric restriction Research has demonstrated that caloric intake (among other non-genetic factors) influences one’s risk for AD, and, accordingly, that curbing obesity/ calorie intake might play an important role in delaying the AD degenerative process. Clarifying the mechanisms through which caloric intake may ultimately influence AD neuropathology, and how caloric restriction (CR) may exert anti-β-amyloidogenic activities and may provide new avenues for designing preventive and/or therapeutic lifestyle strategies for AD and other neurodegenerative conditions. The hypothesized preventive effects of CR on the development of mild cognitive impairment (MCI) or AD are supported by epidemiological evidence indicating that individuals who habitually consume fewer calories have a reduced incidence of AD (Luchsinger et al., 2002; Gustafson et al., 2003). Additionally, studies have demonstrated that CR is one method (folic acid supplementation as the other) by which one can mitigate the risk factor presented by elevated plasma homocysteine levels (which increase with

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age) for AD. Specifically, as high homocysteine levels render neurons to be more vulnerable by impairing DNA repair mechanisms (and thereby promoting cell death), lowering homocysteine levels through CR could potentially help to maintain the brain’s neuroprotective abilities and help prevent against AD (Mattson, 2003). Halagappa and colleagues (2007) tested the hypothesis that two different dietary energy restriction regimens – 40 % CR and intermittent fasting (IF) – could protect against cognitive decline in the triple-transgenic mouse model of AD, and found that both regimens ameliorated age-related cognitive impairments, but they could not directly link the observed effects to Aβ and tau pathologies. Further, Wu and colleagues (2008) investigated the effects of CR for four months on different AD phenotypes in conditional double knockout (cDKO) mice, finding that CR diets improved cognitive impairments in treated mice, based on improved scores on assessments of novel object recognition and contextual fear conditioning memory. Further histological and biochemical analyses revealed that CR actually attenuated ventricle enlargement, caspace-3 activation, and astrogliosos, and reduced the induction of tau hyperphosphorylation, possibly through reduction of p25 accumulation and aberrant CDK5 activation. Importantly, DNA microarray analysis in this study also demonstrated that CR could increase the expression of neurogenesis-related genes and decrease the expression of inflammation-related genes in the hippocampus of the cDKO mice. In accordance with this line of work, we initiated a series of studies to investigate whether AD pathogenesis can be prevented by reducing calorie intake to levels appropriate for cardiac health. At the beginning of this endeavor, although evidence had supported a possible neuroprotective role of CR in neurodegeneration, there had been no information regarding whether CR could attenuate AD neuropathology until recently. We explored whether a clinically acceptable weight reduction/CR regimen, based on an approximately 30 %-reduced carbohydrate intake, could attenuate AD neuropathology, and possibly mitigate pre-existing amyloid neuritic pathology (by a reduction in plaque size) resulting in the recovery of amyloid-associated neuritic dystrophy as a function of time in Tg2576 AD-type mice (Hsiao et al., 1996), as assessed by 2-photon microscopy technology (Wang et al., 2005). In this study, 3-month old Tg2576 mice, which develop AD-type amyloid neuropathology at 8–10 months of age, were fed with a daily low-carbohydrate (low-carb) diet for nine months, resulting in 30 % lower caloric intake compared to age- and gender-matched control Tg2576 mice fed ad libitum (AL) with a standard laboratory rodent diet (dietary content of protein, fat, cholesterol, vitamins, and minerals were identical across both mice groups). We found that the low-carb/CR diet in mice resulted in body weight stabilization, three-fold lower ependymal fat pad weight, and improved glucose tolerance responses compared to the AL-fed mice at 9 months of age. This finding was consistent with clinical evidence indication that low-carb/CR diets considerably improve abnormal

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glucose control and obesity (Meckling et al., 2004; Stern et al., 2004; Yancy et al., 2004), which are risk factors for diabetes and AD (Vanhanen and Soininen 1998; Gustafson et al., 2003). Moreover, when examined for AD-type neuropathology by ELISA, we found that the nine-month CR treatment almost completely prevented cortical and hippocampal AD-type amyloid plaque (lower Aβ1–40 and Aβ1–42 concentrations) development relative to the AL-fed group. We next proceeded to explore APP processing and Aβ peptide generation using immunoprecipitation (IP)–mass spectrometry (IP–MS) in the CR- and AL-fed mice, and, consistent with our ELISA evidence, we confirmed decreased levels of Aβ1–40 and Aβ1–42, and also observed a relative proportional reduction in Aβ1–37, Aβ1–38, and Aβ1–39 peptide content in the neocortex in CR-fed compared to AL-fed mice. As no change was observed in the concentration of the ∼7 kDA carboxyl terminal fragment (CTF)-γ (cleavage product of APP and index of γ-secretase activity) in the neocortex of the CR group, γ-secretase activity likely had no involvement in the anti-amyloidogenic activity observed in CR-fed mice. We next explored in Aβ IP–MS studies the presence of any Aβ carboxytermini peptide fragments that would have been otherwise undetected in the 4G8 IP–MS studies. Consistent with our previous findings, decreased levels of Aβ1–40 and Aβ1–42, as well as Aβ1–37, Aβ1–38 and Aβ1–39 peptides were observed in the CR relative to AL groups. Additionally, however, we found a major elevation in the Aβ1–16 fragment concentration in the neocortex of the CR-fed group (and not in the AL-fed group). As α-secretase can cleave APP, eventually resulting in the generation of Aβ C-termini fragments ending at the AA residue leucine16 of Aβ, we next explored the role of CR in brain α-secretase activity. Current therapeutic approaches to AD are aimed at preventing the generation of amyloidogenic Aβ peptides and, for this reason, β- and γ-secretase activities required for the formation of Aβ peptides are central targets in the development of therapeutic agents in AD (Cummings, 2004). However, it has been difficult for scientists to find safe and selective β- and γ-secretase inhibitors, as these activities are vital in the processing of other cellular substrates (Cummings, 2004). Our ongoing studies continue to suggest that CR regimens based on low carbohydrate content may beneficially influence AD by promoting non-amyloidogenic processing of APP via the promotion of α-secretase activities. As α-secretase cleavage of APP is known to involve the release of a soluble and neuroprotective form of APP (sAPPα), it is possible that CR may not only promote a nonamyloidogenic pathway in the brain, but may also promote brain repair activities as a result of sAPPα neurotrophic function (Gandy, 2002). Cleavage of APP by α-secretase releases the amino-terminal extracellular domain, known as the sAPPα domain, in conjunction with an elevation in levels of membrane-bound α-secretase-cleaved APP CTF-α (Gandy, 2002). We therefore explored the regulation of sAPPα and CTF-α cleavage products of APP in the brain as indices of α-secretase activity in response to CR. We

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found that CR treatment in mice resulted in a greater than two-fold elevation in concentrations of neocortical sAPPα and membrane-associated CTF-α relative to AL-fed control mice. The increase in CTF-α was somewhat less (∼1.6-fold), likely because of further cleavage of CTF-α by γ-secretase. Compared with the CTF-α fragment, the abundance of CTF-β signaling was at the limit of detection in the neocortex of both CR and AL-fed Tg2576 mice, preventing reliable quantification. Collectively, however, our findings demonstrated that CR diets benefited AD mice by promoting α-secretase activity and thereby inhibiting the generation of high molecular weight oligomeric Aβ peptides.

17.3.1 Sirtuins (SIRT1) in CR-mediated AD prevention Sirtuins are class III histone deacetylases (HDAC) known as silent information regulators, which serve to catalyze deacetylation reactions in an NAD(+)-dependent manner. Sirtuins regulate important cell functions by deacetylating histone and non-histone targets. Activation of sirtuins extends one’s lifespan by promoting longevity and healthy aging in a variety of species, and help to protect crucial tissues in the body, including those in the heart and brain. In mammalian systems, sirtuin activators protect against axonal degeneration, poly-glutamine toxicity, and microglia-mediated amyloid beta toxicity, suggesting the potential therapeutic value of sirtuin activation in patients with AD (Gan, 2007). SIRT1 has been found to protect against microglia-dependent β-amyloid toxicity by inhibiting NF-κB signaling (Chen et al., 2005). In 2006, we reported for the first time that the promotion of SIRT1mediated deacetylase activity may be a mechanism through which CR influences AD-type amyloid neuropathology. CR by 30 % reduced carbohydrate intake was observed to prevent amyloid neuropathology in youngadult Tg2576, and this outcome may have been mediated in part through mechanisms involving activation of the mammalian SIRT1 (Qin et al., 2006b). Importantly, consistent with evidence in Tg2576 mice in ongoing studies in our laboratory, we confirmed this evidence in a new animal model by showing that a similar 30 % CR regimen in squirrel monkeys coincided with a significant reduction in Aβ1–40 and Aβ1–42 peptide content in the brain, which inversely correlated with elevation of SIRT1 protein concentrations, relative to AL-fed monkeys (Qin et al., 2006a). In view of the fact that several studies in squirrel monkeys have been successfully used to provide important human physiological and biological information at organism, tissue, cellular, and molecular levels, these studies in squirrel monkeys strongly support our hypothesis that clinically applicable CR regimens in humans might be effective in preventing amyloid neuropathology and possibly MCI and AD. Collectively, our studies on CR in AD mice and in squirrel monkeys revealed that certain experimental CR dietary regimens may promote,

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attenuate, or even partially reverse features of AD (Wang et al., 2005; Qin et al., 2006a, b). In our studies, we found that high caloric intake, in particular of saturated fat, promotes AD-type β-amyloidosis, and that reducing carbohydrate intake (CR) may actually prevent it, possibly through SIRT1mediated response mechanisms.

17.4 The role of insulin in AD Insulin and insulin signaling have been suggested to play a role in the pathophysiology of AD (Burns et al., 2007; Li and Holscher, 2007). In population-based studies, individuals with Type 2 diabetes mellitus are at an increased risk for cognitive impairment, dementia, and neurodegeneration. Mechanisms through which diabetes presents a risk factor include glycemia, insulin resistance, oxidative stress, advanced glycation endproducts, inflammatory cytokines, and microvascular and macrovascular disease (Whitmer, 2007). The principal defect in Type 2 diabetes is insulin resistance, leading to insulin deficiency. The islets of Langerhans (in the pancreas) in Type 2 diabetes is characterized by β-cell loss and islet amyloid derived from islet amyloid polypeptide (IAPP) (Cooper et al., 1987; Westermark et al., 1987; Johnson et al., 1988), a protein co-expressed and secreted with insulin by β-cells. As with Aβ peptides, IAPP spontaneously forms into amyloid aggregates in an aqueous environment (Glenner et al., 1988). Additionally, as with AD, the incidence of Type 2 diabetes strongly increases with age. Borderline diabetes is also associated with increased risks of dementia and AD, independent of whether one develops diabetes in later life, and may interact with severe systolic hypertension to multiply one’s risk for AD (Xu et al., 2007). These findings implicate a close biological relationship between Type 2 diabetes and AD. In addition to complications affecting the eyes, kidneys, heart, blood vessels, and nerves, diabetes mellitus is associated with damage to the central nervous system (CNS) and cognitive deficits (Gispen and Biessels, 2000; Knopman et al., 2001). Impairments in learning and memory have been documented in both Type 1 and Type 2 diabetes. CNS deficits range from moderate to severe, depending on the quality of glycemic control, and involve mainly verbal memory and complex information processing (Ryan, 1988; Strachan et al., 1997; Brands et al., 2005). Furthermore, it has been shown that insulin affects several brain functions including cognition and memory, and several studies have established links between insulin resistance, diabetes mellitus, and AD (Gasparini et al., 2002). Recent evidence indicates that insulin regulates the metabolism of Aβ and tau proteins (Mandelkow et al., 1992; Solano et al., 2000; Gasparini et al., 2001). It has also been suggested that desensitization of neuronal insulin receptors and certain signaling events in AD could lead to reduced acetylcholine levels and cerebral blood flow, resulting in chronic and increasing deficits in oxida-

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tive metabolism (Hoyer, 2002). Additionally, insulin is known to facilitate the hepatic clearance of plasma Aβ1–40 by intracellular translocation of lowdensity lipoprotein receptor-related protein 1 (LRP-1) to the plasma membrane in hepatocytes (Tamaki et al., 2007). Alzheimer’s disease (AD) is associated with major impairments in insulin and insulin-like growth factor (IGF) gene expression and signaling in the brain, which increase with severity of dementia and deficits in energy metabolism and acetylchoine homeostasis. This co-existence of insulin/IGF deficiency and resistance in the brain suggests that AD may represent a brain-specific form of diabetes (i.e., Type 3 diabetes). This hypothesis is supported by findings from de la Monte and colleagues (2006) in an experimental animal model in which intracerebral Streptozotocin (ic-STZ) was used to deplete brain, and not pancreatic, insulin. The ic-STZ treatment produced brain-specific insulin depletion and insulin resistance, and was associated with progressive neurodegeneration sharing many features in common with AD. They demonstrated that early treatment with peroxisome-proliferator activated receptor agonists can effectively prevent ic-STZ-induced neurodegeneration and its associated deficits in learning and memory, and that the observed effects were mediated by increased binding to insulin receptors, reduced levels of oxidative stress and tau phosphorylation, and increased choline acetyltransferase expression in the brain, suggesting potential therapeutic efficacy of insulin sensitizing agents in AD.

17.4.1 Diabetogenic diets and AD amyloid pathology There is in vitro evidence that insulin itself may significantly promote the generation of extracellular amyloidogenic Aβ peptides through mechanisms that involve accelerated APP/Aβ trafficking from the trans-Golgi network (a major cellular site for Aβ generation) to the plasma membrane (Craft and Watson, 2004). While this evidence tentatively suggests that abnormal carbohydrate metabolism might play an important role in AD through mechanisms that involve Aβ peptide generation, experimental studies also suggest that insulin resistance may promote AD amyloid neuropathology in Tg2576 mice, possibly by limiting Aβ degradation via competition with insulin for degradation by the insulin-degrading enzyme (IDE) (Farris et al., 2003), a zincmetallopeptidase that preferentially cleaves proteins with a propensity to form β-pleated sheet-rich amyloid fibrils, such as monomeric Aβ peptides (Farris et al., 2003). Recent evidence suggests a role for insulin even in normal memory function, thereby supporting the hypothesis that insulin by itself affects mechanisms related to neuronal activity and cognitive function. Of particular interest to our research group, chronic hyperinsulinemia and insulin resistance, or reduced insulin effectiveness, has been demonstrated to negatively influence memory (Luchsinger et al., 2004). For example, Hoyer (2002) proposed that low concentrations in circulating insulin in the CNS, along

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with reduced expression of insulin receptors and subsequent altered downstream signaling in AD, would ultimately lead to reduced levels of acetylcholine and a corresponding decrease in cerebral blood flow. Based on this evidence, and the fact that Type 2 diabetes appears to be associated with an increased relative risk for AD (Stolk et al., 1997; Hoyer 2002; Craft and Watson, 2004; Luchsinger et al., 2004), we recently explored in our laboratory the role of experimental Type 2 diabetes in a Tg2576 mouse model of AD amyloid neuropathology. We found that a diabetogenic diet, resulting in elevated circulating levels of insulin, promoted amyloidogenic Aβ1–40 and Aβ1–42 peptide generation and amyloid plaque burden in the brain of Tg2576 mice. This also corresponded with increased γ-secretase activities and decreased IDE activities. Moreover, the increased AD-type amyloid neuropathology also coincided with increased impairments in spatial memory function as assessed by the Morris water maze task (Ho et al., 2004). Further exploration of this interrelationship between insulin resistance and brain amyloidosis revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, as suggested by decreased IR β-subunit (IR–β Y1162/1163) autophosphorylation and reduced phosphatidylinositol 3 (Pl3)-kinase/pS473–AKT/protein kinase (PK)–B in these same brain samples (Ho et al., 2004). This study collectively suggests that diet-induced insulin resistance in AD mice may significantly promote AD-type amyloidosis in the brain through mechanisms involving the elevation of γ-secretase activity as a result of impaired IR signaling, and also that Type 2 diabetes may contribute to AD amyloid pathology by attenuating the degradation of Aβ peptide pathways associated with IDEs. Interestingly, a later study by Li and colleagues (2007) explored whether AD-type pathological changes in the brain occur in two rat experimental models which develop Type 1 and Type 2 diabetes. They found accumulations of β-amyloid and phosphor-tau in these mice, and that these pathologies were associated with neurite degeneration and neuronal loss. Changes in the rat model of Type 2 diabetes were more severe, and appeared to be associated with insulin resistance and possibly hypercholesterolemia. Additionally, Huang and colleages (2007) found that, compared to normal mice, a mouse model of hyperglycemia was more vulnerable to β-amyloid oxidative stress. These findings further support the role of insulin and insulin resistance in AD neuropathology, and provide evidence that preventing diabetic conditions may, in turn, help to prevent AD dementia.

17.5 Hypertension and AD Several studies have demonstrated an association between high blood pressure and AD (Skoog and Gustafson, 2003; Bellew et al., 2004; Goldstein et al., 2005). It has been suggested that hypertension can increase one’s risk for AD by potentially causing cerebrovascular disease, or changes in blood

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vessel walls (which could lead to hypoperfusion, ischemia, and hypoxia), among other conditions, which can potentially initiate the pathological degenerative AD process. Additionally, sub-clinical AD has also been suggested as a risk factor for high blood pressure; thus, similar biological mechanisms may be involved in the pathogenesis of these two conditions (Skoog and Gustafson, 2006). The relationship between cognitive function and anti-hypertensive drug therapy has been investigated in several studies of hypertensive elderly human patients. For example, Guo and colleagues (1999) found that a combination of certain calcium channel and β-adrenergic blockers used as antihypertensive agents protected elderly individuals from developing AD. Similarly, other studies have demonstrated that certain calcium channel blockers, such as dihydropyricine (López-Arrieta and Birks, 2002) and nitrendipine (Forette et al., 2002), decreased the incidence of AD in hypertensive individuals. Further, it has also been found that anti-hypertensive drugs that are K+-sparing diuretics in particular reduce the risk of AD in elderly individuals with hypertension (Kachaturian et al., 2006). Moreover, Najjar and colleagues (2005) demonstrated that anti-hypertensive agents that cross the BBB and affect the renin–angiotensin–aldosterone system (including perindopril or losartan), or brain calcium metabolism (like nitrendipine), provide additional protection against cognitive decline in addition to blood pressure control. All of these studies suggest a neuroprotective effect of certain anti-hypertensive agents. In light of these findings, animal studies in our laboratory have shown that the application of certain anti-hypertensive drugs can improve cognition in animal models of AD. We conducted a high-throughput drug screening of 55 commercially available anti-hypertensive drugs, and found seven candidate agents that significantly reduced AD-type Aβ accumulation in the brains of Tg2576 mice. Of these seven drugs, we found that valsartan, an angiotensin receptor blocker, attenuated the oligomerization of Aβ into high-molecular-weight (HMW) oligomeric peptides (known to be involved in cognitive deterioriation) in vitro, and reduced the content of soluble HMW oligomeric Aβ in the brain in preventive studies. Additionally, we also found that valsartan, delivered at a dose two-fold lower than the equivalent clinical dosage used in humans for hypertension, significantly attenuated the development of Aβ-mediated cognitive deterioration (Wang et al., 2007). A later study in this series of investigation found that four out of the 55 anti-hypertensive agents screened were capable of reducing Aβ1–42 oligomerization in a dose-dependent manner. Our in vitro studies revealed that furosemide, nitrendipine, and candesartan cilextil prevented Aβ1–40 and Aβ1–42 oligomerization, and that that furosemide in particular dissociated pre-aggregated Aβ1–42 oligomers. Further, we found that short-term treatment with furosemide in Tg2576 mice resulted in reduced Aβ content in the brain (Zhao et al., 2009). Most recently, we have investigated the potential beneficial effects of carvedilol, a non-selective α/β-adrenergic receptor

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blocker used to treat hypertension, on AD pathogenesis and treatment in two AD mouse models. We found that chronic oral treatment with carvedilol significantly attenuated brain contents of oligomeric Aβ and cognitive deterioration in two mouse models of AD (the Tg2576 model of β-amyloidosis and TgCRND8 model of tauopathy), which coincided with improvements in neuronal transmission and the maintenance of less stable ‘learning’ thin dendritic spines (associated with learning and memory functions) in the brains of these AD mice (Wang et al., 2010). A related study in our laboratory investigated the role of carvedilol in AD with a focus on an electrophysiological parameter of learning and memory, long-term potentiation (LTP), as assessed in the TgCRND8 mouse model (ArrietaCruz et al., 2010). In this ex vivo study, hippocampal slices from carvediloltreated TgCRND8 mice chronically treated with carvedilol showed improved basal neurotransmission and improved LTP, relative to slices from non-treated TgCRND8 mice, indicating that carvedilol improves neuroplasticity in this mouse model of AD. Collectively, these studies suggest a clear link between hypertensive conditions and AD, and importantly, that anti-hypertensive agents may benefit AD. In turn, these studies also indicate that taking dietary precautions to prevent hypertension may in turn reduce one’s risk for AD.

17.6 The link between dietary choices and AD A large area of research in the field of neurodegeneration has been focused on the role of specific foods and food components in the neurodegenerative process. Luchsinger and Mayeux (2004) posited that taking nutritional supplements alone (e.g., carotenoids versus carrots) might not be as effective as whole foods in providing nutrients, perhaps because the interaction of nutrients within whole foods or certain dietary patterns might contribute largely to any food’s benefit. As an example, one study (Gardner et al., 2005) demonstrated that plant-based low-fat diets might be superior to low-fat diets consisting of pre-packaged foods, even if the two diets have identical contents of fat, protein, carbohydrates, and cholesterol. The authors further noted that the beneficial effect of low-density lipoprotein (LDL) cholesterol in one’s diet should not be underestimated. One food of high interest in the AD prevention field has been fish. For example, researchers have investigated the benefits of certain omega-3 fatty acids found in fish and fish oils, specifically docasohexaenoic acid (DHA) and eicosapentaenoic acid, which have been shown to affect psychiatric and behavioral symptoms in AD, as demonstrated in animal studies and in human epidemiological studies (Morris et al., 2003; Young and Conquer, 2005). In this line of research, Lim and colleagues (2005) demonstrated that DHA-enriched diets significantly reduced AD-type amyloid neuropathology by approximately 70 %, including a decrease in Aβ1–42 levels, compared

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to low-DHA or control diets, in a mouse model of AD. Moreoever, Hashimoto and colleagues (2005) studied the effects of DHA on AD-type pathology following 12 weeks of DHA administration, and found that DHA treatment led to a decreased number of working memory errors in Aβinfused rats, in addition to an increase in cortico-hippocampal DHA levels and in the molar ratio of DHA/arachidonic acid, suggesting that DHA treatment attenuated impaired spatial cognition and learning abilities. They further demonstrated that DHA suppressed increases in levels of lipid peroxide and ROS in the cerebral cortex and hippocampus of these Aβinfused rats, which suggested that DHA may also increase anti-oxidative defenses. These findings collectively demonstrated DHA’s potential as a therapeutic agent in AD. Another area of interest to researchers has been the benefits of certain plant extracts and spices in AD. In traditional Asian medicine, various leaves, fruits, barks, roots, etc., have been used as agents to improve memory functions. In Ayurvedic medicine (a traditional system of Indian medicine), for example, Bacopa monnieri, Centella asiatica, Withania somnifera, Glycrrhiza glabra, Acorus calamus, and Emblica officinalis have been considered to enhance one’s memory. Based on this notion, various laboratories have tested some of these memory-enhancing compounds in mouse models of AD. Mulberry leaf, for example, has been shown to inhibit Aβ1–42 fibril formation and protect hippocampal neurons from Aβ1–42-induced cell death in a concentration-dependent manner (Niidome et al., 2007). Additionally, in a screening of 27 herbs for their ability to protect Aβ1–42-induced neuronal death, Curcuma aromatia and Zingiber officinale (ginger) extracts were found to most effectively protect neurons. Several other herbs were also found to be neuroprotective (such as Ginkgo bioloba [ginkgo], Polygonatum sp. [King Solomon’s seal], Cinnamum cassia [Chinese cinnamon], and Rheum coreanum [Korean rhubarb]), but did not exert as potent effects (Kim et al., 2007). Gingkgo bioloba extract in particular has been heavily investigated for its use as a preventive and therapeutic agent in AD. It has been shown to exhibit neuroprotective effects in several mouse models (Defeudis, 2002) and improve cognitive function in AD patients (Oken et al., 1998; Le Bars et al., 2003). Several studies have demonstrated the mechanisms by which ginkgo bioloba extract may benefit AD. For example, it has been shown to improve age-related memory deficits and Aβ-peptide burden, act as a nitric oxide scavenger (Bastianetto et al., 2000; Luo et al., 2002), and regulate APP metabolism toward the α-secretase pathway (Colciaghi et al., 2004). Ginkgo bioloba extract has also been shown to inhibit Aβ-induced free radical generation in a dose-dependent manner (Yao and Papadopaulos, 2001). Further, Yao and colleagues (2004) examined a specific ginkgo biloba extract EGb761 in relation to cholesterol and amyloidogenesis, and found that that EGb761 treatment reduced APP and Aβ generation coincidental with decreased levels of free circulating cholesterol in in vivo (in rats) and

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in vitro studies. Moreover, Lee and colleagues (2004) investigated ginkgolides A and B for their effect on Aβ-modulated acetylcholine release from hippocampal brain slices, and found that ginkgolide B may produce antiamnestic effects by mitigating Aβ peptides’ inhibitory effect on cholinergic transmission. These studies have provided evidence supporting further investigation of ginkgo bioloba extract in AD. Another plant extract, Curcumin, a polyphenolic yellow pigment in the turmeric spice used in Indian curries and in Indian herbal medicine, has been investigated for its potential use in AD therapy. Epidemiological studies demonstrated that the prevalence of AD in individuals 70–79 years of age is 4.4–fold less in India compared to the US (Ganguli et al., 2000). The curcumin compound (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6 heptadiene-2,5 dione) has been shown to be neuroprotective against Aβ toxicity in vitro (Shishodia et al., 2005), anti-amyloidogenic (Aksenov and Markesbery, 2001; Ringman et al., 2005), and capable of reducing brain amyloid load and plaque burden (Yang et al., 2005). Spectrophotometric studies have suggested that curcumin binds to the more readily redox-reactive metals Cu and Fe, but does not bind to Zn, and, in turn, acts as an antioxidant by chelating the redox active metal ions (Baum and Ng, 2004). Lim and colleagues (2001) found that dietary curcumin treatment in AD mice significantly lowered levels of oxidized proteins, interleukin-1 β (a proinflammatory cytokine elevated in these mice) insoluble and soluble Aβ in the brain, and reduced amyloid plaque burden by 43–50 %. Several other spices have been investigated for their role in AD. For example, aged garlic extract has been shown in vitro to suppress the generation of ROS, which are known to be involved in apoptosis as a result of Aβ-mediated neurotoxicity (Peng et al., 2002), suggesting that garlic compounds may enhance anti-oxidant defenses in the brain. Additional in vitro evidence demonstrated that garlic treatment inhibits caspase-3 in a dose-dependent manner, which indicates that garlic may inhibit apoptotic neuronal death in the brain (Jackson et al., 2002). Another spice of interest to researchers as been Crocus sativus, or saffron, due its unusually polar carotenoid components; certain saffron extracts have been shown to inhibit Aβ fibrillogenesis (Papandreou et al., 2006). Further research on these extracts may illuminate precise mechanisms of action on AD-neuropathology and their potential as a preventive or therapeutic agent in AD.

17.6.1 Fruit juices and wine Polyphenols, the most abundant dietary anti-oxidants, have been heavily investigated for their ability to provide neuroprotection against oxidative damage in the brain. One study that propagated research on polyphenols in AD, conducted by Dai and colleagues (2006), revealed that long-term fruit juice consumption can reduce one’s risk for AD. The investigators

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suggested that the neuroprotective effects of fruit juices can be enhanced by consuming a combination of juices that are rich in phenolic compounds, which include juices derived from purple grapes, grapefruit, cranberries, and apples. Several studies have examined the effects of certain fruit juices and extracts on AD. For example, apple juice was shown to prevent Aβ-induced oxidative damage in vitro (Ortiz and Shea, 2004), and blueberry treatment has been found to reverse the effects of aging on motor behavior and neuronal signaling in animal models (Joseph et al., 2003), possibly through mechanisms involving signal transduction, neuronal communication, and enhancement of hippocampal plasticity (Lau et al., 2005, 2007). Moreover, treatment with anti-oxidant-rich pomegranate juice has been shown to reduce Aβ1–42 content and amyloid deposition in the hippocampus by approximately 50 % in mice. A study conducted by Mullen and colleagues (2007) examined 13 different fruit juices and reported that purple grape juice contained the highest number of individual phenolic compounds, in addition to the highest concentration of total phenolics. The main components found in purple grape juice, accounting for 93 % of the total phenolic content, were flavan-3-ols, anthocyanins and hydroxycinnamates. White grape juice, in contrast, containing mainly hydroxycinnamates, had the lowest phenolic content of the juices examined. Resveratrol is a naturally occurring polyphenol, found in the skin of grapes and red wine as a result of exposure to fungi or bacteria, which has been investigated for its ability to neuroprotect. Resveratrol has been demonstrated to maintain cell viability, exert anti-oxidant activity, exert proteasome-dependent anti-amyloidogenic activity, and attenuate Aβ-induced cytotoxicity in PC12 cells in vitro (Jang et al., 2003; Savaskan et al., 2003; Marambaud et al., 2005). Importantly, resveratrol is also understood to activate the expression of sirtuins, often known as the ‘longevity gene,’ in yeast (Howitz et al., 2003) and in mammalian animal models of neurodegeneration (Araki et al., 2004; Parker et al., 2005), which, in turn, leads to enhanced protection from neuronal apoptosis. However, given recent evidence suggesting that resveratrol may not directly activate sirtuins (Pacholec et al., 2010), it is not quite clear if sirtuin activation plays a role in resveratrol’s observed benefits in AD-type neuropathology. Several studies have suggested that moderate red wine consumption reduces the incidence of AD clinical dementia (Orgogozo et al., 1997; Russo et al., 2003; Savaskan et al., 2003; Luchsinger and Mayeux, 2004; Panza et al., 2004), and may even benefit the course of AD (Scarmeas et al., 2006). Derived from red grapes, red wine is rich in anti-oxidants and holds neuroprotective properties. Studies in our laboratory, using an AD mouse model, examined whether moderate consumption of the red wine cabernet sauvignon reduces AD-type neuropathology and cognitive deterioration. We found that cabernet sauvignon treatment was capable of attenuating

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AD-type cognitive deterioration and Aβ neuropathology by mechanisms involving non-amyloidogenic processing of APP, ultimately inhibiting Aβ generation (Wang et al., 2006; Ho et al., 2009a).

17.6.2 Grape seed polyphenolic extract (GSPE) Another area of investigation of high interest in the AD field has been the potential beneficial role of grape seed polyphenolic extract (GSPE) in attenuating AD-type neuropathology and cognitive impairments. Studies in our laboratory have investigated a specific GSPE (MegaNatural), which comprises primarily catechin and epicatechin in monomeric, oligomeric, and polymeric forms; is readily absorbed through the intestinal mucosa due to modification of the constituent polyphenols in its preparation; and has been demonstrated to be safe in animal models (Bentivegna and Whitney, 2002; Ono et al., 2008; Wang et al., 2008; Ferruzzi et al., 2009) and in humans with pre-hypertensive conditions (Sivaprakasapillai et al., 2009). In an initial investigation in a mouse model of AD (Wang et al., 2008), mice were treated for five months with 200 mg/kg/day GSPE in drinking water (equivalent to 1 g/day in humans, according to Food and Drug Administration criteria for converting drug dosages across species), after which in vitro and in vitro assessments were conducted at six (for behavior) and 10 (for neuropathology) months. In vitro studies revealed that GSPE prevented Aβ peptides from aggregating into HMW oligomers, as assessed by immunodot blot assay. In in vivo studies, GSPE treatment led to a significant reduction in Aβ1–40 and Aβ1–42 peptide and HMW Aβ oligomer levels and amyloid plaque burden in the brain, relative to age- and gender-matched watertreated mice. Moreover, GSPE-treated mice also performed significantly better on the Morris Water Maze behavior test compared to age- and gender-matched water treated mice. A follow-up mechanistic study (Ono et al., 2008) investigated in vitro GSPE’s ability to alter the assembly of Aβ1–40 and Aβ1–42 oligomers and Aβ-induced cytotoxicity in Aβ-treated PC12 cells. These studies revealed that GSPE blocked Aβ protofibril formation, pre-protofibrillar oligomerization, and the structure transition from initial coil to α-helix/β-sheet. Additionally, GSPE exerted protective activities in assays of Aβ-induced cytoxicity (prior to peptide assembly, following assembly, and just prior to peptide addition in cells). These studies collectively suggest a neuroprotective and possibly therapeutic role of GSPE in AD-type Aβ neuropathology and cognitive deterioration. To follow this line of work, we also investigated in vitro the potential beneficial role of GSPE on AD-type tau neuropathology (Ho et al., 2009b). Using aggregations of a synthetic Ac-306VQIVYK311 tau peptide as an in vitro model system, we found that GSPE treatment significantly inhibited the aggregation of tau peptides into filaments, and was also capable of dissociating pre-formed tau aggregates. This finding suggests that GSPE treatment may attenuate desposits of tau aggregates in the AD brain. In light of our evidence that GSPE

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was capable of attenuating Aβ and tau pathology, we next explored GSPE bioavailability (Ferruzzi et al., 2009) to further assess its potential as an AD treatment. We found that acute oral administration of GSPE in Sprague Dawley rats led to detectable contents of catechin, epicatechin, and their metabolites in the brain. Following repeated GSPE exposure, we detected accumulations of catechin, epicatechin, gallic acid, and their metabolites in the blood and, similarly, catechin, epicatechin, and their metabolites in the brain. These studies, which demonstrate GSPE’s ability to attenuate AD-type Aβ pathology in vivo and in vitro and tau pathology in vitro, combined with its demonstrated safety and bioavailability, support the continued development of GSPE as a treatment for Aβ- and tau-mediated neurodegeneration and cognitive impairments.

17.7 Conclusions and future trends Collectively, epidemiological and experimental research has demonstrated that dietary choices can play a key role in the prevention of AD and dementia. For example, much of the research described here suggests that preventing and managing conditions such as diabetes, hypertension, obesity, and heart disease may, in turn, prevent the onset of pathological aging and dementia. Research from our laboratory and others has demonstrated that reducing calorie intake can help prevent AD and, similarly, given the demonstrated relationship between diabetogenic conditions and AD, that preventing diabetes (perhaps by limiting one’s glucose intake) may also decrease one’s risk for AD. Moreover, studies have demonstrated that consuming foods that are rich in polyphenols, such as blueberries or grapes, may also prevent AD and cognitive deterioration, perhaps through their anti-oxidant and anti-amyloidogenic activities. Based on the evidence described, it seems possible that in the near future, we may be able to utilize dietary intervention(s) to prevent or treat AD. However, when reviewing this body of scientific literature, one must understand that this area of research is still in its infancy, and further research must be conducted before making any dietary recommendations to the general public for preventing neurodegenerative conditions of aging. For example, conditions such as AD are chronic and have a long latency period, and conducting clinical trials for dietary interventions under such circumstances, over long enough periods of time and on large enough samples to draw accurate and repeatable conclusions, would be a highly complex endeavor. Moreover, any dietary recommendations made toward this aim must always be incorporated into a general healthy diet. Future research on dietary lifestyles and their role in the prevention or treatment of dementia will certainly elucidate which diets and foods are capable of exerting neuroprotective activities, in what quantities, and by what mechanism(s) of action.

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The current medical model for preventing and treating neurodegenerative conditions such as AD lacks a ‘whole organism’ approach. For example, the onset of AD is likely a result of genomic and proteomic factors, but also psychosocial and lifestyle factors, such as nutrient intake or levels of stress. Today, Medicare and other insurers and individuals will pay billions of dollars for various surgical and medical procedures to treat chronic conditions (such as heart disease or diabetes), and yet they pay very little for integrative and preventive medicine approaches (such as alterations in diet) that can prevent or reverse many chronic conditions. By further investigating the role that dietary choices may play in AD and other dementias and diseases of aging, we will work toward the utilization of an integrative approach to medicine, taking into account all aspects of an individual’s lifestyle when working toward the maintenance and curing of chronic diseases.

17.8 Sources of further information and advice For further information about this area of research, please see the website of the National Institute of Health’s National Center for Complementary and Alternative Medicine, which is highly active in this area of research and preventive healthcare (http://nccam.nih.gov/).

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savaskan e, olivieri g, meier f, seifritz e, wirz-justice a and müller-spahn f (2003) Red wine ingredient resveratrol protects from β-amyloid neurotoxicity. Gerontology, 49, 380–383. scarmeas n, stern y, mayeux r and luchsinger j a (2006) Mediterranean diet, Alzheimer disease, and vascular mediation. Archives of Neurology, 63, 1709–1717. scarmeas n, luchsinger j a, mayeux r and stern y (2007) Mediterranean diet and Alzheimer disease mortality. Neurology, 69, 1084–1093. shishodia s, sethi g and aggarwal b b (2005) Curcumin: getting back to the roots. Annals of the New York Academy of Sciences USA, 1056, 206–217. sivaprakasapillai b, edirisinghe i, randolph j, steinberg f and kappagoda t (2009) Effect of grape seed extract on blood pressure in subjects with the metabolic syndrome. Metabolism, 58(12), 1743–1746. skoog i and gustafson d (2003) Hypertension, hypertension-clustering factors and Alzheimer’s disease. Neurological Research, 25, 675–680. skoog i and gustafson d (2006) Update on hypertension and Alzheimer’s disease. Neurological Research, 28, 605–611. solano d c, sironi m, bonfini c, solerte s b, govoni s and racchi m (2000) Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway. Journal of the Federation of American Societies for Experimental Biology, 14, 1015–1022. stern l, iqbal n, seshadri p, chicano k l, daily d a, mcgrory j, williams m, gracely e j and samaha f f (2004) The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial. Annals of Internal Medicine, 140, 778–785. stolk r p, breteler m m, ott a, pols h a, lamberts s w, grobbee d e and hofman a (1997) Insulin and cognitive function in an elderly population. The Rotterdam Study. Diabetes Care, 20, 792–795. strachan m w j, deary i j, ewing f m e and frier b m (1997) Is type II diabetes associated with an increased risk of cognitive dysfunction? A critical review of published studies. Diabetes Care, 20, 438–445. tamaki c, ohtsuki s and terasaki t (2007) Insulin facilitates the hepatic clearance of plasma amyloid beta-peptide (1–40) by intracellular translocation of lowdensity lipoprotein receptor-related protein 1 (LRP-1) to the plasma membrane in hepatocytes. Molecular Pharmacology, 72, 850–855. vanhanen m and soininen h (1998) Glucose intolerance, cognitive impairment and Alzheimer’s disease. Current Opinion in Neurology, 11, 673–677. vina j, lloret a, valles s l, borras c, badia m c, pallardo f v, sastre j and alonso m d (2007) Effect of gender on mitochondrial toxicity of Alzheimer’s Aβ peptide. Antioxidants & Redox Signaling, 9, 1677–1690. wang j, ho l, qin w, rocher a b, seror i, humala n, maniar k, dolios g, wang r, hof p r and pasinetti g m (2005) Caloric restriction attenuates β-amyloid neuropathology in a mouse model of Alzheimer’s disease. Journal of the Federation of American Societies for Experimental Biology, 19, 659–661. wang j, zhao z, ho l, seror i, humala n, percival s and pasinetti g m (2006) Moderate consumption of Cabernet Sauvignon attenuates β-amyloid neuropathology in a mouse model of Alzheimer’s disease. Journal of the Federation of American Societies for Experimental Biology, 20, 2313–2320. wang j, ho l, chen l, zhao z, zhao w, qian x, humala n, seror i, bartholomew s, rosendorff c and pasinetti g m (2007) Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. Journal of Clinical Investigation, 117, 3393–3402. wang j, ho l, zhao w, ono k, rosensweig c, chen l, humala n, teplow d b and pasinetti g m (2008) Grape-derived polyphenolics prevent Abeta oligomerization

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18 Fatty acids and schizophrenia M. Peet and K. Williamson, Rotherham Early Intervention Service, UK

Abstract: This chapter discusses the role of omega-3 fatty acids in the treatment of schizophrenia. In the first instance, the chapter reviews the evidence for the roles of omega-3 and omega-6 fatty acids in cell membranes and the use of omega-3 fatty acids as a treatment for those who have had a schizophrenic episode. The chapter goes on to discuss the therapeutic benefits of providing nutritional assessments and interventions for those who have recently experienced a psychotic episode and concludes by considering the future role of omega-3 fatty acids in the prevention of psychosis in individuals. Key words: omega-3 fatty acids, schizophrenia, nutritional assessment, nutritional intervention.

18.1 Introduction Schizophrenia is one of the most serious mental health problems. It is characterised by a cluster of symptoms that are divided into ‘positive’ and ‘negative’ symptoms. Positive symptoms include such features as delusions and hallucinations. Delusions are false beliefs which are impervious to reasoned argument and which are not part of any recognised sub-culture. Hallucinations are sensory perceptions without any objective stimulus, the most common being auditory hallucinations, particularly hearing voices when nobody is actually speaking. Negative symptoms, on the other hand, are a deficiency of normal functioning including such features as apathy, lack of drive and lack of emotional responsiveness. Schizophrenia is usually preceded by a prodromal period in which non-specific changes occur, including social isolation, mood changes, the development of unusual ideas and interests and fleeting hallucinatory experiences. This is followed by the first episode of schizophrenia. Subsequently, the course is very variable, with some individuals making a full and permanent recovery whilst others develop a more chronic or relapsing disorder. The outlook is much improved by appropriate intervention and treatment early in the course of the

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disorder, and for that reason Early Intervention Teams for the identification and treatment of psychosis have been established throughout England and in many other parts of the world. Treatment is multidisciplinary, including the prescription of anti-psychotic medication, psychological therapies, social and occupational approaches, and involvement with families rather than just the affected individual. In this chapter, we shall be arguing that nutritional therapies should be another essential arm of care, particularly in early psychosis. There is no single cause of schizophrenia. There is a well-recognised genetic component that is thought to involve multiple genes of varying effect size. Psychological and social factors also play a role, as does the physical environment. The most obvious physical factor that can precipitate or worsen schizophrenia is the use of illicit drugs such as cannabis and amphetamine. There is evidence of an association between schizophrenia and other environmental factors that operate much earlier in the history of the individual such as the effects of viral infection and starvation on the foetus during pregnancy, and birth complications. This chapter will review the evidence that abnormalities of fatty acids, particularly in relation to the composition of the phospholipid bilayer of cell membranes, is associated with schizophrenia and may be of aetiological significance.

18.2 Tissue levels of polyunsaturated fatty acids in patients with schizophrenia All cell membranes, including those of neurons, are composed of a double layer of phospholipid which comprises a phosphorus-based head group and arms that contain either saturated or polyunsaturated fats. Polyunsaturated fatty acids (PUFA) are found in all the major fractions of phospholipids, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine and phosphatidylinosotol (PI), which form around 80 % of total phospholipids. The two PUFAs in highest concentration in neuronal cell membranes are the omega-3 fatty acid docosahexaenoic acid (DHA) and the omega-6 fatty acid arachidonic acid (AA). These two fatty acids together comprise around 20 % of the fatty acid content of the brain. AA is obtained from the diet either by metabolic synthesis from its precursor linoleic acid or directly from various food stuffs including eggs and meat. Linoleic acid is abundantly present in the normal western diet, particularly from vegetable oils such as soya, sunflower and corn oils. DHA and the related omega-3 fatty acid eicosapentaenoic acid (EPA) are obtained mostly direct from the diet, being found particularly in fish and other sea foods. The precursor omega-3 fatty acid in the metabolic chain is alpha-linolenic acid (ALA) which is present in some vegetable oils, but which is very poorly metabolised to DHA and EPA (Brenna, 2002; Burdge, 2004), particularly

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in the presence of excessive amounts of omega-6 PUFA (Hussein et al., 2005). There is now convincing evidence that cell membrane PUFA levels are abnormal in most groups of patients with a diagnosis of schizophrenia. The most consistent findings, and the most important from the perspective of brain function, relate to AA and DHA. Because of the difficulty in examining brain tissue directly, the majority of studies have focused on red blood cell (RBC) membranes. This has been regarded as relevant because there is a correlation, albeit weak, between levels of these fatty acids in RBC and those in neuronal membranes (Carver et al., 2001). However, it is plain that this approach can provide only a rough approximation of neuronal membrane structure, because RBC membranes are particularly sensitive to effects from such confounding factors as dietary intake of omega-3 fatty acids and oxidative stress, whereas the composition of brain phospholipid is more resistant to such external effects. Studies of RBC PUFA have been carried out in both medicated and non-medicated patients with schizophrenia. In medicated patients, some (Vaddadi et al., 1986; Glen et al., 1994; Yao et al., 1994; Peet et al., 1995; Khan et al., 2002) but not all (Vaddadi et al., 1996; Doris et al., 1998; Assies et al., 2001; Arvindakshan et al., 2003; Evans et al., 2003; Ranjekar et al., 2003) have found reductions in RBC membrane levels of AA. A more consistent finding is reduced levels of DHA (Glen et al., 1994; Yao et al., 1994; Peet et al., 1995; Vaddadi et al., 1996; Doris et al., 1998; Khan et al., 2002; Ranjekar et al., 2003), although other studies have reported no abnormality (Assies et al., 2001; Arvindakshan et al., 2003; Evans et al., 2003) or, in one early study, an increase (Vaddadi et al., 1996) of RBC DHA levels. Studies in medicated patients are always open to question because of the uncertain effects of different medications on the variable being measured. In addition, there are a number of other confounding variables. These include dietary intake of PUFA; RBC DHA and EPA are particularly sensitive to this (Dougherty et al., 1987; Edwards et al., 1998). Smoking is particularly prevalent amongst patients suffering from schizophrenia and is associated with reduced RBC levels of DHA (Hibbeln et al., 2003). A number of more recent studies have measured RBC PUFA in medicationfree schizophrenia patients early in their illness, taking account of confounding variables. Reddy et al. (2004) reported reduced RBC membrane levels of AA, DHA and docosapentaenoic acid (DPA), the immediate metabolic precursor of DHA, relative to age-matched controls. These findings were unrelated to smoking, but diet was not controlled for. Peet et al. (2004) investigated two cohorts of non-medicated patients from India and Malaysia. The Indian patients were relatively early in their illness, whereas the Malaysian subjects were long-term hospital patients. In both groups there was no significant difference from controls in RBC AA levels, whereas, in contrast to other studies, DHA levels were significantly increased. However, the largest difference by far was between the Indian population, who were predominantly vegetarian, and the Malaysian group that had high

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levels of fish in their diet. RBC DHA levels were four times higher in the Malaysian group than in the Indian population. The incidence of schizophrenia in India is similar to that in the rest of the world, and the long-term outcome is better than that in Western countries (Hopper and Wanderling, 2000), so it seems unlikely that low DHA levels are directly causal in schizophrenia. More recently, Kale et al. (2008, 2010) reported that RBC DHA levels are significantly reduced in a population from a different part of India, where a vegetarian diet is not the rule. Patients and controls were matched for confounding factors including diet, which was assessed using the standard method of a Food Frequency Questionnaire. Importantly, they found that the reduced RBC DHA level was associated with reduced levels of folic acid and vitamin B12, and increased levels of homocysteine. Similar reductions in folic acid and increases in homocysteine have been reported by others (Muntjewerff and Blom, 2005). Folic acid modulates PUFA metabolism. Pita and Delgado (2000) showed that RBC DHA levels in the rat are significantly increased by the administration of folic acid. Kale et al. (2010) proposed that there is an abnormal one-carbon metabolism in people with schizophrenia, leading to disturbance of the balance between folic acid, vitamin B12 and DHA. This supports the use of a nutritional approach to treatment, involving the use of folic acid, vitamin B12 and omega-3 fatty acids in combination. The fact that RBC DHA levels are modulated not only by dietary intake of omega-3 fatty acids, but also by dietary intake of folic acid (mainly from fruit and vegetables) might also help to explain the variability in DHA levels reported in previous studies of schizophrenic populations. Studies in RBC beg the question of whether the same changes are evident in the brain. There is an increasing body of evidence to support that conclusion. Several studies have investigated the fatty acid composition of brain tissue from patients with a diagnosis of schizophrenia. Such studies are particularly prone to the influence of confounding factors, particularly because of delays in obtaining postmortem tissues, the effects of medication and the difficulty of finding a well-matched control group. Horrobin et al. (1991) found no consistent changes in AA or DHA levels in lipid fractions from the frontal cortex of schizophrenic patients. Yao et al. (2000) reported reduced levels of linoleic acid and AA but not DHA, in the caudate nucleus. Landen et al. (2002) found no significant changes in AA or DHA in the cingulate cortex. All of these studies involved patients on anti-psychotic medication. More recently, McNamara et al. (2007) found reduced DHA levels in the orbitofrontal cortex of schizophrenic patients, relative to a matched control group. This reduction was found particularly in male patients and was more marked in the small number of drug-free patients relative to those on anti-psychotic medication. This is consistent with other studies suggesting that anti-psychotic drug treatment can normalise fatty acid deficits in RBC from schizophrenic patients (Khan et al., 2002; Arvindakshan et al., 2003; Evans et al., 2003). Hamazaki et al. (2010) recently

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reported no abnormality in phospholipid DHA levels in the hippocampus of medicated schizophrenic patients. However, they reported significant reductions in the long-chain n-6 PUFA DPA in some phospholipid fractions. They suggested that reduced DHA levels might be specific to certain brain regions, though they did not discuss the possible effect on their findings of anti-psychotic medication. The cause of reduced phospholipid DHA content in cell membranes from schizophrenic patients is not understood. There is also a reduction of cell membrane omega-3 PUFA levels in people who suffer from depression, and this appears to be due to a dietary insufficiency. For example, ecological studies have shown a strong correlation between the amount of fish and seafood in the national diet and the national prevalence of depression (Hibbeln, 1998; Peet, 2004). In contrast, no relationship has been found between the national dietary intake of fish and seafood, and either the prevalence or long-term outcome of schizophrenia (Peet, 2004). It is likely that the DHA deficiency in schizophrenia is primarily related to an abnormality of metabolism. Despite that, it may also be responsive to dietary influences depending on the nature of the abnormality. For example, there is a severe deficiency of DHA in patients with peroxisomal disorders, because an essential part of the metabolic pathway for DHA which takes place in the peroxisomes is missing. This inherited metabolic disorder leads to blindness, impaired brain development and early death, yet despite the metabolic origin it can be alleviated by the administration of high doses of DHA (Martinez, 2001). The early finding of reduced levels of omega-3 fatty acids in schizophrenic patients led to attempts to treat the condition with oral fish oil preparations.

18.3

Treatment studies with omega-3 fatty acids in schizophrenia

In an early open-label study of fish oil supplementation in patients with schizophrenia, Mellor et al. (1996) found significant improvement in both psychotic symptoms and tardive dyskinesia. The first double-blind placebocontrolled trials gave some support to this finding (Peet et al., 2001). In one of these studies, there was evidence that EPA was more effective than DHA. Because of this finding, subsequent studies have focused on EPA as the potentially active agent, so that the possible beneficial effects of DHA have not been investigated adequately. The controlled trials of omega-3 PUFA in schizophrenia can be divided into three general categories, depending on the type of patients included: those with long-term schizophrenia; patients early in their treatment; and patients at high risk of developing schizophrenia. In patients with chronic schizophrenia, results have been very mixed and, taken together, they do not suggest that EPA is of any consistent benefit. Two studies have reported

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a beneficial effect of EPA relative to placebo in the primary analysis (Peet et al., 2001; Emsley et al., 2002), one found evidence of clinical benefit from EPA only in a clozapine-treated subgroup of patients (Peet and Horrobin, 2002), one study reported no significant difference between EPA and placebo (Fenton et al., 2001), and one group found that EPA was significantly worse than placebo (Bentsen, 2006). All of the studies in long-term patients involved adding EPA onto antipsychotic medication that patients had been taking for many years. Studies of EPA treatment in schizophrenic patients earlier in their illness, when they have received little or no previous anti-psychotic treatment, have given somewhat more positive findings. In the first of these studies, non-medicated patients presenting for treatment were randomised to receive either EPA or placebo on a double-blind basis for the first three months (Peet et al., 2001). The primary outcome measure was their need during this time for anti-psychotic medication, which was prescribed at the discretion of the treating physician. In this small study, all 12 patients on placebo, but only eight of the 14 on EPA, required treatment with standard anti-psychotic drugs. The symptomatic outcome was similar between the two groups. Although non-medicated when they presented for treatment, the patients in this study had been unwell for a relatively long time (an average of around six years) and some had been given anti-psychotic medication earlier in their illness. A further study in patients earlier in their first episode of psychosis reported a reduced anti-psychotic drug dose in the group treated with EPA (Berger, 2004). These studies, taken together, indicate a possible ‘anti-psychotic-sparing’ effect when patients are treated with EPA. In recent years, it has been recognised that the first onset of psychotic symptoms in patients with schizophrenia is usually preceded by other, less severe symptoms that can last for a considerable period of time. These socalled ‘prodromal’ symptoms include social withdrawal, non-specific mood changes such as irritability and depression, and the development of new patterns of thinking including increased suspiciousness and poorly formed auditory hallucinations that take the form of indistinct mumblings and whispers. The risk of developing psychosis is further increased if the young person has one or more first degree relatives that suffer from schizophrenia. Some centres now provide specialist services for young people that are considered to be at high risk of developing schizophrenia (Yung et al., 2007). The evidence base for interventions that are effective in reducing the risk of transition from the prodromal state into full-blown psychosis is very limited. It is generally agreed that conventional anti-psychotic medication should be avoided at this stage, because of the risk of sideeffects and the relatively poor predictive power of prodromal symptoms. A treatment without side-effects would be of immense importance. Recently, a ground-breaking trial was published by Amminger et al. (2010) who showed that treatment with 1.2 g daily of omega-3 PUFA significantly

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reduced the risk of transition into psychosis relative to a placebo treatment of coconut oil, with a cumulative reduction in risk of 22.6 %. A significant reduction in positive, negative and combined symptoms and an improvement in their ability to function resulted from the omega-3 treatment relative to the placebo. This trial had 76 participants that completed the intervention and, if this can be replicated, then it is likely that omega-3 PUFA will become widely used as a preventive treatment for people who are regarded as being at high risk of developing schizophrenia.

18.4 The importance of diet for physical health in schizophrenia Studies focusing on the diet of mainly chronic schizophrenic patients have shown that they consume nutritionally inadequate diets, lower in nutritional value than the national average and far below that of optimum health. These diets are very low in omega-3 fatty acids (Henderson et al., 2006). Additionally, the diets of schizophrenic patients are often higher in saturated fat (Osborn et al., 2007), caffeine (Strassnig et al., 2006) and sugar (Stokes and Peet, 2004), and the nutritional deficit is further exacerbated through a lower dietary intake of the foods that are rich in vitamins, minerals and other antioxidant nutrients (McCreadie, 2003). The sub-optimal diets of schizophrenic patients are potentially detrimental to their physical health. Their diets are not only found to be lacking in beneficial nutrients; they are also known, as previously indicated, to be higher in saturated fat, which could be obesogenic due to a potential increase in energy density. One study of dietary intake data for 146 community dwelling schizophrenic patients found that the mean energy intake was 3057 (+/−1132) kcal per day (Strassnig et al., 2008), which is an excessive intake particularly in the context of only a limited daily energy expenditure. This study also found that the mean body mass index (BMI) was 32.7 (+/−7.9) kg/m2, which falls into the obese category. There is long-standing recognition of an association between schizophrenia and diabetes (Pendlebury and Holt, 2008; Chwastiak and Tek, 2009; Cohen and Correll, 2009). Speculation exists as to what extent the metabolic consequences of prescribed anti-psychotic medication and to what extent diet contributes to this association. Ryan and colleagues (2003) found that first episode, drug-naïve schizophrenic patients already have impaired fasting glucose tolerance at the outset of schizophrenia. This is particularly concerning as the onset of a first episode of psychosis often occurs in adolescence (Joa et al., 2009), before the body and brain has fully developed. There is mounting evidence that a variety of anti-psychotic medications are linked to an increased prevalence of diabetes in those with schizophrenia (Gianfrancesco et al., 2002; Ramaswamy et al., 2006; Okumura et al., 2010).

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A recent review of the literature reporting the links between anti-psychotic agents and metabolic side-effects by Simon and colleagues (2009) states the need for well-designed studies in this area. In addition to diabetes and obesity, potential consequences of the metabolic changes that occur following anti-psychotic medication consumption are an increased risk of cardiovascular problems (Correll et al., 2009). There have been several large-scale randomised, controlled trials, with sound methodological quality, exploring the cardioprotective effect of omega-3 fatty acids. Six of these studies have been systematically reviewed by Wang and colleagues (2006) who showed that for the majority of trials the measured outcomes, namely all-cause mortality, cardiac death and non-fatal myocardial infarction, favoured the omega-3 preparation relative to the control. One study conducted into the association between plasma phospholipid concentrations of omega-3 and omega-6 and cardiovascular predictors, such as total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and triacylglycerols (TAG) found a positive association between EPA concentrations and total cholesterol and the ratio of EPA:AA and total cholesterol (Dewailly et al., 2001). This suggests that omega-3 fatty acids may exert a cardioprotective effect.

18.4.1 Implications for clinical practice in schizophrenia The data relating to omega-3 fatty acids in schizophrenia, particularly early in its course, suggest that patients should be encouraged to consume more omega-3 fatty acids from the time of first presentation to mental health services. Whilst this can be achieved by using supplements, the preferred approach is to improve general diet with the aim of improving not only mental health but also physical wellbeing. Why the diets of those with schizophrenia should be much worse than that of healthy controls is multifactorial. It is interesting to note that those in both high- and low- intensity supported housing in the UK make poor dietary choices, and recent evidence indicates that those living in highintensity care consumed more of the unhealthy ‘fast food’ options (Gupta and Craig, 2009) than those with more choice over dietary intake. Furthermore, there is evidence that healthy foods, such as fruit and vegetables, are perceived by most to be expensive (Damman and Smith, 2009). A recent review of factors affecting food choices in women, by Lawrence and Barker (2009), indicated though that choices are affected by more than just perceived cost. There is a complex set of variables, which includes social circumstances and life choices, that will affect the nutrient intake. This is pertinent as the lifestyles of those with schizophrenia who are living in the community are known to be chaotic (Bob et al., 2009); this will undoubtedly have an adverse effect on the food purchasing and meal preparation habits of those individuals.

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There has been little systematic investigation of methods to improve the diet of schizophrenic patients. One randomised, controlled trial (RCT), conducted in Scotland by McCreadie and colleagues (2005) investigated the effects of improving the dietary patterns of fruit and vegetable consumption within schizophrenic patients. They effected this by providing either both fruit and vegetables free of charge, for a continuous six-month period, or by providing instruction on the importance of fruit and vegetable consumption for health. The effects were a short-term improvement in consumption of fruit and vegetables in both groups, with a greater and more sustained effect, albeit insignificant, over time noted for the instruction group compared to the free fruit and vegetable group. There was, however, no evidence of improvement in psychiatric symptoms, as rated by the Positive and Negative Syndrome Scale (PANSS), despite the desired increase in fruit and vegetables (McCreadie et al., 2005). This could be due to the long-term nature of the illness in these patients.

18.5 Recommended programme of assessment and intervention The Rotherham Early Intervention in Psychosis service, operated by Rotherham Doncaster and South Humber Mental Health NHS Foundation Trust, has developed and effected a fully operational, commissioned programme of tailored nutritional assessment and intervention for users of the service since 2007. This programme of care is open to all individuals on the team’s caseload, and it allows an evidence-based treatment plan to be formulated for each individual that engages with the process (see Fig. 18.1). A crucial part of the assessment process is first to engage the service user and their carers in the process and second to maintain that engagement. An individual’s care network, particularly family carers, has been proven to be an essential component in improving the outcomes of service delivery (Duchnowski and Kutash, 2009). Individuals who have endured an episode of psychosis are known to lack motivation and volition, irrespective of cognitive ability (Murray et al., 2008); the dietary assessment, therefore, must require little or no effort to complete on the part of the assessee and must be suitable irrespective of cognitive abilities. Furthermore, the assessment method must therefore assess current dietary intake because the recent occurrence of an acute psychotic episode is likely to alter their dietary intake. When formulating nutritional feedback, it is necessary to take account of the level of skills, motivation, food preferences and the service user’s budget, as these are strong determinants in how successful this plan will be. The recommended changes should be small to improve the rate of success (Grimstvedt et al., 2010) as even minor alterations to the diet would benefit nutrient status.

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Step 1

Make service user aware of the benefits of nutrients for both mental and physical health and well-being, then assess their actual dietary intake

Has the service user remained engaged?

Yes

No

Apply motivational techniques and provide information to encourage participation in the assessment process

Have these techniques been successful?

Yes

No

Step 2

Analyse dietary intake information to extract evidence of current mean daily nutrient intake

Step 3

Are there any omega-3 fatty acid, vitamin and mineral deficiencies that warrant supplementation? Yes

Repeat assessment when service user is willing to engage (repeat from step 1)

No

Benefits of short-term prescription explained to service user and if accepted a prescription is given

Step 4

Provide tailored written feedback on nutrient intake and suggest achievable dietary modifications where appropriate

Has the service user remained engaged?

Yes

No

Repeat offer at regular intervals

Provide more information

Fig. 18.1 The nutritional assessment and intervention process within a United Kingdom Early Intervention in Psychosis service.

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In addition to the long-term goal of improving dietary intake, there is also a short-term requirement to treat any nutritional deficiency that has been highlighted from the assessment. This can be achieved by using nutritional supplements including omega-3 fatty acids when indicated. Service users have previously indicated their preference to receive a natural therapeutic agent as part of their treatment plan (Cauffield and Forbes, 1999). There is also recent evidence that nutritional supplements are becoming more widely used by the general population, particularly omega-3 sources (fish oil preparations) (Lucas et al., 2009). The omega-3 supplements have been accepted readily by those who have been prescribed them. The interventions are repeated on a six-monthly rolling programme, to ensure maximum uptake of the information provided. The importance of booster sessions in maintaining dietary change has been highlighted in relation to dietary interventions aimed at weight reduction (Alvarez-Jimenez et al., 2010). This nutritional intervention has been developed into an accredited training course which gives a strict focus for the uptake and maintenance of evidence-based theoretical knowledge and practical skills, which are a vital component in maintaining sound clinical practice (Johansson et al., 2010).

18.5.1 National policy implications The importance for nutrition in the maintenance of mental wellbeing was highlighted in a report on The Links Between Diet and Behaviour that was published by the Associate Parliamentary Food and Health Forum (2008). This report noted the research linking diet and mental wellbeing and made a number of key recommendations, including the need for further research in this area, the importance of adequate consumption of oily fish in the daily diet, and more training in nutrition for mental health professionals. Most specifically, they concluded that: We recommend that the Department of Health encourages other NHS Trusts to adopt and approach similar to that pursued by the Doncaster and South Humber Healthcare NHS Trust which undertakes a nutritional assessment of patients suffering from depression and the patients with early symptoms of psychosis and provides dietary advice to them.

These recommendations for dietary intervention as a means of improving mental health have not yet found their way into National Policy Guidelines. However, there is an increasing focus on the need to take care of the physical and mental wellbeing of people with mental health problems, because of the high physical morbidity that these patients suffer. For example, a recent Department of Health Policy Document New Horizons: A Shared Vision for Mental Health (Department of Health, 2009), emphasises the need for physical health promotion in people with mental health problems, to include healthy diet and weight reduction as well as increased physical

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activity and smoking cessation. This report is expected to set the agenda for mental health care over the next decade.

18.6 Further research It is plain that understanding of the possible benefits to mental health of an improved diet and more specifically to increase consumption of omega-3 fatty acids is at a very early stage. In relation to schizophrenia, the most promising findings relate to the use of omega-3 fatty acids, and particularly EPA, very early in the natural history of the illness and most specifically in people exhibiting prodromal symptoms. In addition to more clinical trials of specific nutrients in the treatment of schizophrenia, more research is also necessary into the effects of the overall diet on the mental state of people with schizophrenia. Even with the existing evidence base, there is undoubtedly enough evidence to warrant dietary intervention in schizophrenic patients in order to improve their physical health, and this is now reflected in the Department of Health policy. Ideally, such intervention should take place early in the illness, with the intention of preventing later physical health complications. Implementing dietary change is notoriously difficult in any group of individuals, and particularly so in people suffering from schizophrenia who may lack motivation. One solution to the motivational barrier is for future interventions to be delivered comprising elements of the transtheoretical model of change: namely the Readiness to Change scale, which determines an individual’s confidence and willingness to change (Miller and Rollnick, 1991). Using Motivational Interviewing (MI), a technique that explores an individual’s intrinsic motivation, with the aim of initiating change would be beneficial. This would allow the clinician to deliver the intervention in a way that is appropriate and tailored to the individual’s actual readiness to act upon this information at that time. This technique has been reviewed recently for its efficacy in the area of dietary modification and it has proved successful, although a more consistent and refined methodology for application in nutritional care may improve the outcomes (Martins and McNeil, 2009). Another barrier to the success of the interventions for this hard to reach service user group is low income. There is a known correlation between families with low income and a lack of food preparation and purchasing skills (Broughton et al., 2006). This poses a difficulty when suggesting a lowcost meal option, made from wholefoods, as this option requires not only a degree of skill in both food shopping and preparation, but also the confidence to attempt it. One recent study that investigated the relationships between confidence to cook and sociodemographic characteristics found that those living in lower income households and those with less education lacked confidence to prepare vegetables (Winkler and Turrell, 2009).

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Furthermore, this study found that the variety and volume of vegetables purchased increased when at least one individual in the household was confident at food preparation. There is clearly a need for further research in these areas in people suffering from schizophrenia, in order to refine and optimise dietary interventions.

18.6.1 Food manufacture and nutritional improvement In addition to improving the quality of information and skills accessed by individuals with schizophrenia, there can also be dietary improvement at the population level. This is effected through the provision of healthier foods direct from the producers and manufacturers. Using fatty acids as an example, the use of some vegetable oils in processed foods has increased dramatically in the last few decades, with a resulting increase in omega-6 fatty acids entering the food chain (Hibbeln et al., 2006). They are now used in the manufacture of baked goods, both sweet and savoury, and, through their use in the feed of farmed animals and fish, their concentration is increased in the meat, eggs and dairy products that enter the human food chain. Recent data from the UK’s ‘National diet and nutrition’ survey suggests that the omega-6 : omega-3 ratio currently stands at 5 : 1 for adults (FSA, 2010), which will have a detrimental effect on the concentration of omega-3 fatty acids in human tissue (Hibbeln et al., 2006). One solution to this problem is to redress the balance. This can be done by improving the balance during food manufacture or by natural or artificial fortification of foods so that they contain more omega-3 relative to omega-6 PUFA. The best source of preformed EPA and DHA is fish oil. Certain species of fish naturally have a high proportion of oil relative to their body weight than other fish species. Examples of these fish include: herring, mackerel, salmon, tuna, pilchards and others. There are two main difficulties in relying on dietary intake of omega-3 fatty acids from these fish. First, these fish are known to have a stronger flavour than white fish, such as cod, whiting and haddock, the smell of which is not appreciated by the consumer. In one study comparing the perception of odours in Japanese and German subjects, 21.4 % of the German cohort likened the smell to decaying food or excrement (Ayabe-Kanamura et al., 1998). Second, there is a need to conserve fish stocks, which could potentially decline if there was an increase in consumption that exceeds their rate of reproduction. Farmed fish are a good alternative because, although they have been found to have different tissue levels of omega-3 fatty acids than those of their wild counterparts (Rodriguez et al., 2004), it has been suggested that the fatty acid profile of the fish flesh is easily controlled and modified by their dietary intake (Cejas et al., 2004). There is an emerging wealth of literature on the efficacy of using natural sources of ALA in commercial animal feeds; however, as discussed, these

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are often poorly converted into the long-chain-PUFA by the host animal (Hussein et al., 2005). ALA is vegetable-based and is therefore a preferred option over fish or sea food organisms when feeding animals. Experimentation with animal feeds to improve the availability of ALA in the tissues of red-meat producing animals, such as cattle and sheep, has not seen significant tissue increases (Bourre, 2005); however, trials into the effect on animals by ALA enhancement of the maternal diet could show more promising results (Hess et al., 2008). Some of the most promising research into the improvement of a foodstuff’s nutrient profile from ALA is through the modification of poultry diets, particularly for egg-laying chickens. There is evidence of a significant increase (33 %) of total omega-3 fatty acids and an increase in DHA in people consuming eggs from hens fed flaxseed-rich diets (Ferrier et al., 1995). Investigation into egg storage and quality have again found that the eggs from hens with flax-rich diets not only have increased EPA, DHA and an improved omega-6 : omega-3 ratio compared with controls, the n-3 fatty acid improvement remains stable during a moderate (four-week) storage period prior to consumption (Hayat et al., 2010). Marine sources are the best sources of the preformed DHA and EPA omega-3 fatty acids, but feeding marine fauna to animals is not a preferred option. A further line of investigation, other than ALA, is the use of farmed algal sources of DHA in animal feeds, as this is preformed thus negating the need for conversion. One RCT with promising results was done recently in Canada when pigs were fed for 25 days with a finisher diet containing either 0.06, 0.6 or 1.6 % microalga biomass, which itself contained ∼18 % DHA. The higher level – 1.6 % microalga diet actually led to a DHA content of finished bacon at ∼3.4 mg of DHA/g and 1.2 % total fat energy as omega-3 fatty acids (Meadus et al., 2010). In order to have an impact on schizophrenic patients whose diets are habitually poorer and who live chaotic lifestyles, particularly whilst acutely ill, or have limited confidence or skills around food preparation, food fortification, or changes in manufacturing processes, must consider the most regularly consumed and convenience foods. One food group that fits this definition as a convenient vehicle to increase dietary consumption of longchain PUFA is milk and milk products. The literature published on this reports on the findings from nine controlled trials, which resulted in an improvement in blood lipid profiles, particularly the total and LDL cholesterol and the TAG (Lopez-Huertas, 2010). These foods may be more acceptable to individuals than oily fish as a dietary source of EPA and DHA. One Canadian trial compared the omega-3 profile of enriched eggs and concluded that three chicken eggs would confer the same omega-3 intake as one portion of fish (Lewis et al., 2000). These options could all offer a suitable alternative to fish consumption in the future for individuals with schizophrenia.

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cohen d and correll c u (2009) ‘Second-generation antipsychotic-associated diabetes mellitus and diabetic ketoacidosis: mechanisms, predictors and screening need’. Journal of Clinical Psychiatry, 70(5), 765–766. correll c u, manu p, olshanskiy v, napolitano b, kane j m and malhorta a k (2009) ‘Cardiometabolic risk of second generation antipsychotic medications during first-time use in children and adolescents’. JAMA, 302(16), 1765–1773. damman k w and smith c (2009) ‘Factors affecting low income women’s food choices and the perceived impact of dietary intake and socioeconomic status on their health and weight’. Journal of Nutrition Education and Behaviour, 41(4), 242–253. dewailly e, blanchet c, gingras s, lemieux s, sauve l, bergeron j and holub b j (2001) ‘Relations between n-3 fatty acid status and cardiovascular disease risk factors among Quebecers’. Am J Clin Nutr, 74, 603–611. department of health (2009) New Horizons: Towards a New Vision for Mental Health – consultation. London: Crown Copyright. doris a b, wahle k, macdonald a, morris s, coffey i, muir w and blackwood d (1998) ‘Red cell membrane fatty acids, cytosolic phospholipase A2 and schizophrenia’. Schizophr Res, 31, 185–196. dougherty r m, galli c and ferro-luzzi a (1987) ‘Lipid and phospholipid fatty acid composition of plasma, red blood cells, and platelets and how they are affected by dietary lipids: a study of normal subjects from Italy, Finland, and the USA’. American Journal of Clinical Nutrition, 45, 443–455. duchnowski a j and kutash k (2009) ‘Integrating PBS, mental health services, and family driven care’, in Sailor W, Dunlap G, Sugai G and Horner R (eds), Handbook of Positive Behaviour Support. New York: Springer, 203–231. edwards r, peet m, shay j and horrobin d (1998) ‘Omega-3 polyunsaturated fatty acid levels in the diet and red blood cell membranes of depressed patients’. J Affect Disord, 48, 149–155. emsley r, myburgh c, ousthuizen p and van rensburg s j (2002) ‘Randomised, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia’. Am J Psychiatry, 159, 1596–1598. evans d r, parikh v v, khan m m, coussons c, buckley p f and mahadik s p (2003) ‘Red blood cell membrane essential fatty acid metabolism in early psychotic patients following antipsychotic drug treatment’. Postaglandins Leukotr Essent Fatty Acids, 69, 393–399. fenton w s, dickenson f m, boronow j, hibbeln j r and knable m (2001) ‘A placebocontrolled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia’. Am J Psychiatry, 258, 2071–2074. ferrier l k, caston l j, leeson s, squires j, weaver b j and holub b j (1995) ‘α-Linolenic acid- and docosahexaenoic acid-enriched eggs from hens fed flaxseed: influence on blood lipids and platelet phospholipids fatty acids in humans’. Am J Clin Nutr, 62, 81–86. food and health forum (2008) The Links between Diet and Behaviour: the Influence of Nutrition on Mental Health. Report of an Enquiry held by the Associate Parliamentary Food and Health Forum. London: Crown Copyright. Pp 4. food standards agency (2010) Information on PUFA Fatty Acid Ratios, National Diet and Nutrition Survey: Year 1 Results 2008–2009. London: The Stationery Office. gianfrancesco f d, grogg a l, mahmoud r a, wang r h and nasrallah h a (2002) ‘Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database’. J Clin Psychiatry, 63(10), 920–930. glen a i m, glen e m t, horrobin d f, vaddadi k s, spellman m, morse-fisher n, ellis k and skinner f s (1994) ‘A red blood cell membrane abnormality in a

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subgroup of schizophrenic patients; evidence for two diseases’. Schizophr Res, 12, 53–61. grimstvedt m e, woolf k, milliron b j and manore m m (2010) ‘Lower Healthy Eating Index-2005 dietary quality analysis scores in older women with rheumatoid arthritis v. healthy controls’. Public Health Nutrition, 13, 1170–1177. gupta a and craig t k (2009) ‘Diet, smoking and cardiovascular risk in schizophrenia in high and low care supported housing’. Epidemiologica e psichiatria sociale, 18(3), 200–207. hamazaki k, choi k h and kim h-y (2010) ‘Phospholipid profile in the post-mortem hippocampus of patients with schizophrenia and bipolar disorder: No changes in docosahexaenoic acid species’. J Psychiatr Res, 44, 668–693. hayat z, cherian g, pasha t n, khattak f m and jabbar m a (2010) ‘Oxidative stability and lipid components of eggs from flax-fed hens: effect of dietary antioxidants and storage’. Poultry Science, 89(6), 1285–1292. henderson d c, dorba c p, daley t b, boxill r, nguyen d d, culhane m a, louie p, cather c, eden evins a, freudenreich o, taber s m and goff d c (2006) ‘Dietary intake profile of patients with schizophrenia’. Annals of Clinical Psychiatry, 18(2), 99–105. hess b w, moss g e and rule d c, (2008) ‘A decade of developments in the area of fat supplementation research with beef cattle and sheep’. J Anim Sci, 86(14 Suppl), E188-204. hibbeln j r (1998) ‘Fish consumption and major depression’. Lancet, 351, 1213. hibbeln j r, makino k k, martin c e, dickerson f, boronow j and fenton w s (2003) ‘Smoking, gender and dietary influences on erythrocyte essential fatty acid composition among patients with schizophrenia or schizoaffective disorder’. Biol Psychiatry, 53, 431–441. hibbeln j r, nieminen l r g, blasbalg t l, riggs j a and lands w e m (2006) ‘Healthy intakes of n-3 and n-6 fatty acids: estimations considering worldwide diversity’. Am J Clin Nutr, 83(6), S1483–S1493. hopper k and wanderling j (2000) ‘Revisiting the developed versus developing country distinction in course and outcome in schizophrenia: results from ISOS, the WHO collaborative project’. Schizophr Bull, 26, 835–846. horrobin d f, manku m s, hillman h and glen a i m (1991) ‘Fatty acid levels in the brains of schizophrenics and normal controls’. Biol Psychiatry, 30, 795– 805. hussein n, ah-sing e, wilkinson p, leach c, griffin b a and millward d j (2005) ‘Long-chain conversion of [13C]linoleic acid and α-linolenic acid in response to marked changes in their dietary intake in men’. Journal of Lipid Research, 46, 269–280. joa i, johannessen j o, langeveld j, friis s, melle i, opjordsmoen s, simonsen e, vaglum p, mcglashan t and larsen t k (2009) ‘Baseline profiles of adolescent vs. adult-onset first-episode psychosis in an early detection program’. Acta Psychiatr Scand, 119(6), 494–500. johansson b, fogelberg-dahm m and wadensten b (2010) ‘Evidence-based practice: the importance of education and leadership’. Journal of Nursing Management, 18, 70–77. kale a, joshi s, naphode n, sapkale s, raju m s v k, pillai a, nasrallah h and mahadik s p (2008) ‘Opposite changes in predominantly docosahexaenoic acid (DHA) in cerebrospinal fluid and red blood cells from never-medicated firstepisode psychotic patients’. Schizophr Res, 98, 295–301. kale a, naphode n, sapkale s, kamaraju m, pillai a, joshi s and mahadik s (2010) ‘Reduced folic acid, vitamin B12 and docosahexaenoic acid and increased homocysteine and cortisol in never-medicated schizophrenia patients: implications for altered one-carbon metabolism’. Psychiatry Res, 175, 47–53.

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khan m m, evans d r, gunna v, scheffer r e, parikh v v and mahadik s p (2002) ‘Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first episode of psychosis and after years of treatment with antipsychotics’. Schizophr Res, 58, 1–10. landen m, davidsson p, gottfries c g, mansson j e and blennow k (2002) ‘Reduction of the synaptophysin level but normal levels of glycerophospholipids in the gyrus cinguli in schizophrenia’. Schizophr Res, 55(1–2), 83–88. lawrence w and barker m (2009) ‘A review of the factors affecting food choices of disadvantaged women’. The Proceedings of the Nutrition Society, 68(2), 189– 194. lewis n m, seburg s and flanagan n l (2000) ‘Enriched eggs as a source of n-3 polyunsaturated fatty acids for human’. Poultry Science, 79, 971–974. lopez-huertas e (2010) ‘Health effects of oleic acid and long chain omega-3 fatty acids (EPA and DHA) enriched milks. A review of intervention studies’. Pharmacol Res, 61(3), 200–207. lucas m, asselin g, merette c, poulin m-j and dodin s (2009) ‘Ethyl-eicosapentaenoic acid for the treatment of psychological distress and depressive symptoms in middle-aged women: a double-blind, placebo-controlled, randomised clinical trial’. American Journal of Clinical Nutrition, 89, 641–651. martinez m (2001) ‘Restoring the DHA levels in Zellweger patients’. J Mol Neurosci, 16, 309–316. martins r k and mcneil d w (2009) ‘Review of Motivational Interviewing in promoting health behaviours’. Clinical Psychology Review, 29(4), 283–293. mccreadie r g (2003) ‘Diet, smoking and cardiovascular risk in people with schizophrenia’. British Journal of Psychiatry, 183, 534–539. mccreadie r g, kelly c, connolly m, williams s, baxter g, lean m and paterson j r (2005) ‘Dietary improvement in people with schizophrenia: randomised controlled trial’. Br J Psychiatry, 187, 346–351. mcnamara r k, jandacek r, rider t, tso p, hahn c-g, richtand n m and stanford k e (2007) ‘Abnormalities in the fatty acid composition of the post-mortem orbitofrontal cortex of schizophrenic patients: Gender differences and partial normalization with antipsychotic medications’. Schizophr Res, 91, 37–50. meadus w j, duff p, uttaro b, aalhus j l, rolland d c, gibson l l and dugan m e r (2010) ‘Production of Docosahexaenoic Acid (DHA) Enriched Bacon’. J Agric Food Chem, 58, 465–472. mellor j, laugharne j d e and peet m (1996) ‘Omega-3 fatty acid supplementation in schizophrenic patients’. Human Psychopharmacol, 11, 243–251. miller w r and rollnick s (1991) Motivational Interviewing: Preparing People to Change Addictive Behaviour. New York: Guilford Press. muntjewerff j-w and blom h j (2005) ‘Aberrant folate status in schizophrenic patients: What is the evidence?’. Progr Neuro-Psychopharmacol Biol Psychiatry, 29, 1133–1139. murray g k, clark l, corlett p r, blackwell a d, cools r, jones p b, robbins t w and poustka l (2008) ‘Incentive motivation in first-episode psychosis: a behavioural study’. BMC Psychiatry, 8, 34. okumura y, ito h, kobayashi m, matsumoto y and hirakawa j (2010) ‘Prevalence of diabetes and antipsychotic prescription patterns in patients with schizophrenia: a nationwide retrospective cohort study’. Schizophrenia Research, 119(1–3), 145–152. osborn d p, nazareth i and king m b (2007) ‘Physical activity, dietary habits and Coronary Heart Disease risk factor knowledge amongst severe mental health illness: a cross-sectional comparative study in primary care’. Social Psychiatry and Psychiatric Epidemiology, 42(10), 787–793.

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peet m (2004) ‘International variations in the outcome of schizophrenia and the prevalence of depression in relation to national dietary practices: an ecological analysis’. Br J Psychiat, 184, 404–408. peet m and horrobin d f (2002) A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms’. J Psychiatr Res, 36, 7–18. peet m, laugharne j, rangarajan n, horrobin d and reynolds g (1995) ‘Depleted red cell membrane essential fatty acids in drug-treated schizophrenic patients’. J Psychiatr Res, 39, 227–232. peet m, brind j, ramchand c n, shah s and vankar g k (2001) ‘Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia’. Schizophr Res, 49, 243–251. peet m, shah s, selvam k and ramchand c n (2004) ‘Polyunsaturated fatty acid levels in red cell membranes of non-medicated schizophrenic patients’. World J Biol Psychiatry, 5, 92–99. pendlebury j and holt r i g (2008) ‘Supporting the lifestyle modification and treatment of type 2 diabetes for people with severe mental illness’. European Diabetes Nursing, 5(2), 58–63. pita m-l and delgado m-j (2000) ‘Folate administration increased n-3 polyunsaturated fatty acids in rat plasma and tissue lipids’. Thromb Haemost, 84, 420–423. ramaswamy k, masand p s and nasrallah h a (2006) ‘Do certain atypical antipsychotics increase the risk of diabetes? A critical review of 17 pharmacoepidemiologic studies’. Ann Clin Psychiatry, 18(3), 183–194. ranjekar p k, hinge a, hegde v, ghate m, kale a, sitasawad s, wagh u v, dedsikdar v b and mahadik s p (2003) ‘Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients’. Psychiatry Res, 121, 109–122. reddy r d, keshavan m s and yao j k (2004) ‘Reduced red blood blood cell membrane essential polyunsaturated fatty acids in first episode schizophrenia at neuroleptic-naïve baseline’. Schizophr Bull, 30, 901–911. rodriguez c, acosta c, badia p, cejas j r, santamaria f j and lorenzo a (2004) ‘Assessment of lipid and essential fatty acids requirement of black seabream (Spondlyiosoma cantharus) by comparison of lipid composition in muscle and liver of wild and captive adult fish’. Comp Biochem Pyshiol B Biochem Mol Biol, 139(4), 619–629. ryan m c, collins p and thakore j h (2003) ‘Impaired fasting glucose tolerance in first-episode, drug naïve patients with schizophrenia’. American Journal of Psychiatry, 160(2), 284–289. simon v, van winkel r and de hert m (2009) ‘Are weight gain and metabolic side effects of atypical antipsychotics dose dependent? A literature review’. Journal of Clinical Pyschiatry, 70(7), 1041–1050. stokes c and peet m (2004) ‘Dietary sugar and fatty acid consumption as predictors of severity of schizophrenia symptoms’. Nutritional Neuroscience, 7(4), 247–249. strassnig m, brar j s and ganguli r (2006) ‘Increased caffeine and nicotine consumption in community-dwelling patients with schizophrenia’. Schizophrenia Research, 86(1–3), 269–275. vaddadi k s, gilleard c j, mindham r h, butler r a (1986) ‘Controlled trial of prostaglandin E1 precursor in chronic neuroleptic resistant schizophrenia’. Psychopharmacology (Berl), 88, 362–367. vaddadi k s, gilleard c j, soosai e, polonowita a k, gibson r a and burrows g d (1996) ‘Schizophrenia, tardive dyskinesia and essential fatty acids’. Schizophrenia Res, 20, 287–294. wang g, harris w s, chung m, lichtenstein a h, balk e m, kupelnick b, jordan h s and lau j (2006) ‘n-3 Fatty acids from fish-oil supplements, but not α-linolenic

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acid, benefit cardiovascular disease outcomes in primary- and secondaryprevention studies: a systematic review’. Am J Clin Nutr, 84, 5–17. winkler e and turrell g (2009) ‘Confidence to cook vegetables and the buying habits of Australian households’. J Am Diet Assoc, 109(10), 1759–1768. yao j k, leonard s, reddy r d (2000) ‘Membrane phospholipid abnormalities in post-mortem brains from schizophrenic patients’. Schizophr Res, 42(1) 7–17. yao j k, van kammen d p and welker j a (1994) ‘Red blood cell membrane dynamics in schizophrenia II. Fatty acid composition’. Schizophr Res, 13, 217–226. yung a r, mcgorry p d, francey s m, nelson b, baker k, phillips l j, berger g and amminger g p (2007) ‘PACE: a specialised service for young people at risk of psychotic disorders’. Med J Australia, 187(Suppl. 7), S43–S46.

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19 Fatty acids, depression and suicide S. J. Long, Swansea University, UK

Abstract: The relationship between essential fatty acids (EFAs) and Major Depressive Disorder (MDD), post-natal depression (PND), Bipolar Disorder (BD), suicidality and some personality variables is considered. There is evidence that omega-3 and omega-6 fatty acids (FAs) may be involved in the aetiology of some psychological disturbances, including disorders of affect and certain maladaptive behaviours such as impulsivity, aggression and suicidality. The chapter examines the role of fatty acids in affective disorders and maladaptive behaviours by describing and evaluating relevant epidemiological, correlational/ clinical and intervention studies. Finally, implications for practice and directions for future research are suggested. Key words: essential fatty acids (EFAs), polyunsaturated fatty acids (PUFAs), Major Depressive Disorder (MDD), Bipolar Disorder (BD), post-natal depression (PND), suicide, impulsivity, aggression, neurotransmission, immune response.

19.1 Introduction There is mounting evidence that fatty acids may be involved in the regulation of mood and aspects of behaviour. Docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid (LC-PUFA), has been implicated in the development and functioning of the nervous system. It is the predominant fatty acid in the brain and retina (Singh, 2005). Both DHA and eicosapentaenoic acid (EPA) have been implicated in affective and psychological disorders, including Major Depressive Disorder (MDD), post-natal depression (PND), Bipolar Disorder (BD) and suicidality (Stoll et al., 1999a; Su et al. 2008; Appleton et al., 2010; Huan and Hamazaki, 2010). These LC-PUFA have also been implicated in aggression (Hamazaki et al., 1998; Benton, 2007), impulsivity and self-harm (Hallahan et al., 2007). Initially, the nomenclature and metabolism of essential fatty acids (EFAs) are briefly introduced after which relevant epidemiological, correlational and intervention studies that relate EFAs to disorders of affect are considered.

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19.2 Essential fatty acids (EFAs) 19.2.1 Nomenclature and metabolism Approximately half of the dry weight of the brain is made up of lipids, including phospholipids, cerebrosides, cholesterol, gangliosides, sulfatides and the essential fatty acids (EFAs) (Tacconi et al., 1997). Of these lipids a quarter is made up of DHA, an omega-3 fatty acid. There are two families of polyunsaturated fatty acids (PUFA), omega-3 (n-3) and omega-6 (n-6). They are described as essential fatty acids because they cannot be synthesized in the human body although they play an essential metabolic role: thus they must form part of the diet. PUFAs are hydrocarbon chains of varying length with a carboxyl (COOH) group at one end of the chain and a methyl (CH3) group at the other. The first carbon atom next to the carboxyl group is termed ‘α’, or alpha; whilst the final carbon is termed ‘ω’, or omega. Omega is often replaced with ‘n’ in this context. PUFAs are unsaturated fats as they contain more than one carbon–carbon double bond; in contrast, saturated fats have no carbon-carbon bonds. Figure 19.1 provides an overview of the metabolic pathway and structure of n-3 and n-6 fatty acids. The first number of the structural arrangement represents the length Omega-3 fatty acids

Omega-6 fatty acids

Alphalinolenic (ALA or LNA; 18:3n–3)

Alpha linoleic (LA; 18:2n–6)

Delta-6 desaturase Stearidonic acid (SDA; 18:4n–3)

Gamma-linoleic (GLA; 18:3n–6)

Elongation (addition of two carbon atoms) Eicosatetraenoic acid (ETA; 20:4n–3)

Dihomogamma linolenic (DGLA; 20:3n–6)

Delta-5 desaturase Eicosapentaenoic (EPA; 20:5n–3)

Arachidonic (AA; 20:4n–6)

Elongation (addition of two carbon atoms) Docosapentaenoic acid (DPA n–3; 22:5n–3)

Adrenic (22:4n–6)

Delta-4 desaturase Docosahexaenoic (DHA; 22:6n–3)

Dococsapentaenoic acid (DPA n–6; 22:5n–6)

Fig. 19.1 Metabolic pathway of elongation and desaturation processes involved in the metabolism of essential fatty acids to long-chain polyunsaturated fatty acids (LC-PUFAs). Omega-6 and omega-3 fatty acids compete for desaturation enzymes. Adapted from Horrobin (1997).

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of the carbon chain (for example with ALA 18:3n-3 there are 18 carbon bonds); the number preceding ‘n’ represents the number of double bonds (with ALA 18:3n-3 there are three double bonds); the final number indicates the number of carbons from the methyl segment to the first double bond (with ALA 18:3n-3 there are three carbons from the methyl end to the first double bond). The initial fatty acids in the metabolic chains are linoleic acid (LA; n-6) and alphalinolenic acid (ALA; n-3), that through a series of elongation and desaturation processes are converted to highly unsaturated LC-PUFAs. The liver plays a significant role in fatty acid metabolism: although LA and ALA can be converted to LC-PUFAs, in humans, this is not a particularly efficient process. In fact, it has been suggested that to obtain optimal DHA and EPA status, ideally the individual should ingest LC-PUFAs directly through fish consumption rather than relying on plant species containing ALA. In males, the conversion of ALA to EPA and then DHA is estimated to be around 8 % for EPA and <0.1 % for DHA; whereas in women, the comparable figures are 8 % and 9 %, respectively (Williams and Burdge, 2006). A diet rich in saturated fats will lower conversion rates to around 6 % for EPA and 3.8 % for DHA, (Gerster, 1998), although the conversion rate of DHA in males would be even lower than <0.1 % since women are better at the conversion of ALA and EPA to DHA (Williams and Burdge, 2006). Conversion rates also vary with age, being better during developmental stages (Bezard et al., 1994). A diet high in saturated fats is also likely to increase the n-6 : n-3 ratio (Gerster, 1998), which has been associated with several negative physical and psychological consequences that are discussed later. A diet high in n-6 is likely to reduce the conversion of ALA to EPA and DHA by 40–50 % (Gerster, 1998). The dietary intake of fatty acids influences the functioning of these metabolic pathways. For example, n-3 ALA inhibits the conversion of n-6 LA to n-6 LC-PUFAs, a process further inhibited by the presence of AA, EPA and DHA (Bezard et al., 1994). Thus the conversion of LA to longer chain n-6 FAs is modified by the levels of n-3 FAs that may reflect competition for the same enzymatic pathway. Specifically, n-6 and n-3 PUFAs compete to be positioned on part of the phospholipid fraction of the cell membrane. Omega-6 PUFAs will form part of the phospholipids when the levels of n-3 PUFAs are low (Mazza et al., 2007). Hormones may also influence n-3 FA conversion rates. Insulin and thyroxine are essential for the metabolism of n-3 and n-6 fatty acids, and low levels of insulin and thyroxine may inhibit conversion (Bezard et al., 1994). Glucagon, adrenaline, adrenocorticotropic hormone (ACTH) and glucocorticoids inhibit the metabolism of n-3 and n-6 FAs (Bezard et al., 1994). Thus, for example, it is possible that during times of stress the release of adrenaline, ACTH and glucocorticoids inhibits synthesis. Oestrogen also regulates enzymes involved in n-3 metabolism, perhaps the explanation for there being higher

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levels of DHA in women (Williams and Burdge, 2006). These greater levels of DHA in females may help to meet foetal demands for PUFAs during pregnancy (Hornstra, 2000). The need for LC-PUFAs is greater during development and their bioavailability is greater during early development (Bezard et al., 1994), suggesting that the control of PUFA metabolism changes with the developmental stage. Although there are no differences in the requirement of PUFAs between adults and the elderly, studies have suggested that fish consumption and the intake of DHA may prevent age-related cognitive decline (Issa et al., 2006; van Gelder et al., 2007), supporting suggestions of a DHA neuroprotective effect (Lukiw et al., 2005). Furthermore, low levels of DHA have been linked to neurodegenerative diseases such as dementia, Alzheimer’s disease and Parkinson’s disease (Barberger-Gateau et al., 2002; Morris et al., 2003). Despite the negative reputation of the n-6 FAs, research has suggested that arachidonic acid (AA) affects plasticity and fluidity, particularly within the hippocampus (Fukaya et al., 2007). AA may also protect against oxidative stress (Wang et al., 2006). In summary, the biological demand for PUFAs, and specifically DHA, is greater during the developmental stages when there is a high turnover of fatty acids. Also, increased PUFA levels during adulthood may have a preventative role in age-related cognitive decline.

19.2.2 Sources of EFAs and dietary needs Omega-3 FAs can be found in plant species such as flax, walnuts, leafy green vegetables, sunflower seeds and oily marine species including salmon, trout and herring. Vegetables largely provide the n-3 FA precursor ALA, whilst marine species provide LC-PUFAs such as EPA and DHA. Omega-3 FAs can also be obtained from supplements in the form of capsules and liquids, and increasingly there has been fortification of food products such as chicken, pork, milk, bread, eggs and spreads (Murphy et al., 2007). Omega-6 fatty acids are found mainly in animal and vegetable oil. It is suggested that for optimal functioning 3–6 % of total energy should be consumed as LA and 0.5–1 % as ALA (Bezard et al., 1994). However, these figures will vary as there are individual differences in the ability to metabolize EFAs. The ideal ratio for omega-3 : omega-6 fatty acids has been debated, and a figure of 1 : 4 has been proposed (Yehuda and Carrosa, 1993). The ratio of the two groups of EFA in the diet has, however, increased significantly from 2 : 4 at the beginning of the 1900s to around 1 : 10 at present (Tiemeier et al., 2003). It is suggested that recent changes to the Western diet have resulted in many people being deficient in n-3 PUFAs. Total fat consumption, and in particular the consumption of saturated fats, has

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increased whereas the intake of n-3 PUFAs has dropped considerably (Tiemeier et al., 2003). An increased intake of n-6 loaded vegetable oil had an unintended consequence: the incorporation of less n-3 FAs into cell membranes. Potentially, these changes have neurophysiological implications as the nature of the lipid component of cell membranes influences the functioning of the central nervous system (CNS) (Mazza et al., 2007).

19.2.3

The effect of EFAs on cell functioning, neurotransmission and behaviour In summary, omega-6 and omega-3 FAs compete for access to enzymatic sites. If dietary n-6 is high then the incorporation of n-3 FAs into the phospholipid fraction of the cell membrane will be reduced. High levels of n-3 in the diet may enhance membrane fluidity and flexibility by reducing levels of n-6 and cholesterol. Cholesterol is known to stiffen the cell membrane and reduce permeability (Fontani et al., 2005a). Mazza et al. (2007) suggested that the changes in the cell membrane that result from increasing the n-3 PUFA content of the diet may enhance neurotransmission by facilitating communication between cells. Alternatively, n-3 PUFAs may enhance neurotransmission by acting as secondary messengers in signal transduction: phospholipases release n-3s from cell membrane phospholipids, freeing n-3s for signalling processes. In rats, an association has been reported between n-3 dietary deficiencies and impaired sensory, motor and motivational behaviours (Reisbick and Neuringer, 1997; Wainright, 1997). In Caenorhabditis elegans, a soil living roundworm, it has been found that n-3 depletion resulted in low levels of serotonin (5-HT) and choline, suggesting that LC-PUFAs may play an essential role in neurotransmission in this creature (Lesa et al., 2003). In intervention studies, higher levels of brain 5-HT and DA have been reported in piglets fed on a diet containing adequate rather than low levels of n-3 PUFAs (Owens and Innis, 2000). In humans, serotonin (5-HT) has been implicated in the modulation of attention, motivation and affect (Steckler and Sahgal, 1994; Krakowski, 2003). Specifically 5-HT has been implicated in several human pathologies and personality traits, including depressive disorders, suicide, aggression, impulsivity and other anti-social behaviours such as violence (Brown and Linnoila, 1990; Krakowski, 2003; Hibbeln et al., 2006; Surtees et al., 2006). These aforementioned behaviours have all been associated with PUFA status (discussed below). A positive relationship has been found between levels of EFAs and metabolites of 5-HT and dopamine (DA) in the cerebrospinal fluid (CSF) of healthy individuals (Hibbeln et al., 1998). In particular, higher levels of DHA were associated with higher levels of 5-HT. In violent and/or depressed subjects, levels of DHA were negatively correlated with CSF 5-HIAA (metabolite of 5-HT), suggesting that

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lower DHA and reduced 5-HT status co-exist in violent or depressed individuals. A review of the literature that relates PUFA status and monoamine (MA) neurotransmission concluded that n-3 PUFAs may have beneficial effects on neuronal composition, neurochemical signalling and cognitive functioning (Heinrichs, 2010). Omega-3 FAs were found to regulate neurotransmission by two mechanisms – through the modulation of membrane fluidity and by enhancing the release of MA neurotransmitters (Heinrichs, 2010). Epidemiological and developmental evidence has supported a role for PUFA status in firstly the regulation of MA-mediated systems; and secondly cognitive and affective behaviours, including depressive disorders, suicide, aggression and impulsivity (Brown and Linnoila, 1990; Krakowski 2003; Hibbeln et al., 2006; Surtees et al., 2006).

19.2.4 The effect of EFAs on the immune response and behaviour There are also suggestions that the immune system may be involved in the aetiology of depression and that PUFAs may modulate these processes (Simopolous, 2002). EFAs are precursors for eicosanoids that are involved in inflammation, immune system responses and act as messengers in signal transduction. In the brain, eicosanoids may influence physiological processes such as synaptic plasticity, membrane excitability and neurotransmitter release (Phillis et al., 2006). It has been suggested that the n-6 eicosanoinds are pro-inflammatory and thus have negative health consequences: associations have been made with cardiovascular disease, rheumatoid arthritis, bowel disease and other inflammatory and immunomodulatory diseases that have been linked to depression (Simopoulos, 2002). Elevated levels of total n-6 FAs, and also an elevation of the n-6 : n-3 ratio, may cause over-production of n-6 eicosanoids (Simopoulos, 2002). In contrast, animal studies and clinical interventions have suggested that n-3 eicosanoids are anti-inflammatory, inhibiting the effects of n-6 eicosanoids (Simopoulos, 2002). Therefore, omega-3 FAs may be beneficial in the treatment of disorders associated with inflammation and the immune system, including depression. Not only is there an acute phase of depression that involves elevated levels of n-6 eicosanoids (Simopoulos, 2002), but somatosization when associated with depression resembles illness caused by pro-inflammatory cytokines – a class of eicosanoids (Su, 2009). Somatization disorder is present when there are complaints of numerous physical ailments that have no recognizable physical origin, but rather are caused by problems of a psychological nature. The high incidence of somatosization and poor physical health in depressed individuals cannot be accounted for solely by the serotonin hypothesis as serotonin-based therapies are not always successful, indicating that other

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biological mechanisms are involved in the aetiology of depression (Su, 2009).

19.2.5 Summary In summary, omega-3 FAs may be directly associated with depression through their anti-inflammatory properties, and by reducing the proinflammatory responses that are associated with n-6 FAs. Omega-3 FAs may also alleviate depression indirectly, through effects on the immune system when depression is secondary to a primary illness such as arthritis or another inflammatory or immune disorder (Maes et al., 1997). Furthermore, omega-3 FAs may alter the bio-physical structure of the cell membrane and also affect neurotransmitter systems. It is probable that these functions are interrelated. For example, the bio-physicality of the membrane may affect ion channels and enzymes involved in signal transduction; eicosanoids may influence the growth of synapses and nerve endings and ultimately cell signalling (Raz and Gabis, 2009). Hence, omega-3 FAs are potentially involved in the aetiology of depression through several separate and interrelated mechanisms.

19.3 EFAs and depression Clinical depression is characterized by dysfunctional mood that persists for at least two weeks, accompanied by at least five of the following symptoms: a lack of interest/pleasure in most pursuits, dysregulation of appetite, changes to weight, sleep patterns and activity level, fatigue, lack of concentration and thinking capacity, indecisiveness, feelings of worthlessness or guilt, suicidal thoughts or attempts. The relationship between EFAs and depression is thus considered using evidence from epidemiology, clinical and intervention studies.

19.3.1 Epidemiological studies Various approaches have been taken when relating PUFA intake to depression, including considering national levels of fish consumption, utilizing food frequency questionnaires or dietary recall. Table 19.1 lists epidemiological evidence. Of 17 studies, 13 investigated the relationship between PUFA intake and depressed mood. Ten reported a significant negative relationship where a higher PUFA intake was associated with a lower incidence of depression (Hibbeln, 1998; Tanskanen et al., 2001a,b; Silvers and Scott, 2002; Peet, 2004; Suzuki et al., 2004; Timonen et al., 2004; BarbergerGateau et al., 2005; Appleton et al., 2007a; Suominen-Taipale et al., 2010) although three did not (Hakkarainen et al., 2004; Jacka et al., 2004; Appleton et al., 2007b). However, of the ten that reported a significant association,

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FFQ – dichotomous

FFQ into tertiles of PUFA ingestion FFQ

12 countries – lifetime rates in different countries (n = not available) 8 countries – lifetime rates (n = not available)

Finland (n = 1767)

Finland (n = 3204)

New Zealand (n = 4644)

Finland (n = 29 133; males) Australia (n = 755; females)

3. Noaghiul and Hibbeln (2003)

5. Tanskanen et al. (2001b)

6. Tanskanen et al. (2001a) 7. Silvers and Scott (2002)

8. Hakkarainen et al. (2004) 9. Jacka et al. (2004)

4. Peet (2004)

22 countries (n = 14 532)

2. Hibbeln (2002)

Database of national food consumption, inc. imports minus exports and calculations of wastage Food frequency questionnaire (FFQ), split into consumers or non-consumers (dichotomous) FFQ – dichotomous

As above

As above

National production plus and annual imports less exports

8 countries (n = 35 000)

1. Hibbeln (1998)

Fatty acid assessment

Populations

Self-reported depression based on DSM

Self-reported mental health (SF-36; inc. both health and mental health scales) Depressed mood (SF-36)

NCD (BDI-21 cut-off)

Non-clinical depression (NCD) and suicidality (BDI cut-off)

National prevalence of clinical Major Depressive Disorder (MDD) using DSM Clinical post-natal depression (PND) (EPDS cut-off) National prevalence of Clinical Bipolar Disorder (BD) using DSM interviews MDD (DSM)

Outcome criteria

Epidemiological studies examining the role of PUFA status in affective disorders

Author

Table 19.1

No relationship

Negative relationship for women Negative relationship (association reduced after adjustment for potential confounders) No relationships

Negative relationship for depression and suicidality

Negative relationship (no control for confounds)

Negative relationship (DHA in mothers’ milk related to prevalence of PND) Negative relationship (no control for confounds)

Negative relationship (no control for confounds)

Results (direction of relationship)

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France (n = 9294)

Japan (n = 865; females) UK (n = 2982)

UK and France (n = 10 602) Denmark (n = 54 202)

FFQ

MDD (M-CIDI)

Self-reported post-natal depression (EPDS) Self-reported depressed mood (DASS-21) Self-reported depressed mood (ten item q) PND, prescription level

Self-reported depressed mood (HADS-D) Self-reported depression (DSM) and suicide ideation Self-reported depressed mood (CES-D)

Outcome criteria

No relationship between clinical diagnosis and fish consumption No relationship (higher risk of PND medical prescription in group with lowest fish consumption) Negative relationship in male population. Reduction in % of depressive episodes for total population after adjustment for lifestyle

No relationship after adjustments for confounders Negative relationship

No relationship

Negative relationship

Negative relationship in women but not men

Negative relationship

Results (direction of relationship)

Abbreviation: BDI – Beck Depression Inventory; CES-D – Centre for Epidemiological Studies (depression scale); DASS-21 – Depression, Anxiety and Depression Scales (21 items); DSM – Diagnostic and Statistical Manuel of Mental Disorders; EPDS – Edinburgh Post-natal Depression Scale; HADS-D Hospital Anxiety and Depression Scales (depression); M-CIDI – Munich Version of the Composite International Diagnostic Interview; SF-36 – MOS Short Form Health Survey.

17. SuominenTaipale et al. (2010)

Denmark (n = 1265)

FFQ split in to tertiles

Finland (n = 5689)

FFQ

FFQ split in to quartiles of PUFA ingestion FFQ – dichotomous

Japan (n = 771)

10. Suzuki et al. (2004) 11. Timonen et al. (2004)

12. BarbergerGateau et al. (2005) 13. Miyake et al. (2006) 14. Appleton et al. (2007b) 15. Appleton et al. (2007a) 16. Strom et al. (2009)

Fatty acid assessment

Populations

Continued

Author

Table 19.1

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three did not control for potentially confounding variables that represent risk factors for psychiatric disorders; for example, low socioeconomic status (SES), rural/urban ratios, marital relationship, alcoholism, smoking and a family history of psychiatric illness. After controlling for potentially confounding variables, a study found that the association between depressed mood and PUFA intake no longer remained significant (Appleton et al., 2007b), demonstrating the importance of taking into account these factors. However, there were seven studies that, after controlling for confounding variables, still found a significant negative relationship between n-3 FA and depressive symptoms: data consistent with there being an association. Although previous reviews of the epidemiology have concluded that a relationship existed between n-3 FA status and depressive symptoms (Liperoti et al., 2009), the majority of studies have used limited, population-based measures of n-3 FA intake that provided only crude indices of PUFA status. Typically, there has been no consideration of the precise type of fish consumed, an important factor as the LC-PUFA content varies from species to species. In addition, there is sometimes no account made of individual differences in metabolism, for example those related to age and gender (Bezard et al., 1994). In summary, although the epidemiological data support the suggestion that increasing n-3 FA intake decreases the incidence of depression, the data should be interpreted cautiously. The measures used are crude and causality cannot be demonstrated. These relationships do, however, warrant further consideration.

19.3.2 Correlational studies Another approach is to correlate biological measures of fatty acid status and depressive symptoms, an approach that allows the consideration of more accurate and detailed measures of fatty acid status. In some correlational studies, depressed individuals have been compared to controls who are not depressed; in other studies, the relationship between levels of PUFA and symptom severity has been examined. Studies of the relationship between fatty acid status and the severity of depression are listed in Table 19.2. Of 19 correlational studies, 14 investigated the relationship between the severity of depressive symptom and PUFA status. Ten studies reported a significant relationship between PUFA status and symptom severity (Fehily et al., 1981; Adams et al., 1996; Edwards et al., 1998; Mamalakis et al., 2002; Mamalakis et al., 2006a,b,c; Kilkens et al., 2006; Parker et al., 2006; Schiepers et al., 2009) whilst four did not (Maes et al., 1996; 1999; Mamalakis et al., 2004; Suominen-Taipale et al., 2010). The balance of evidence supports a relationship between depression, a lower n-3 status and a higher n-6 : n-3 ratio.

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Plasma choline phosphoacylglycerolsl (PCPG) Plasma cholesterol esters (PCE) and erythrocyte membrane (EM) Plasma phospholipids (PL) EM PL and PCE PL PL PL Adipose tissue (AT)

Endogenous depression (EG)

Clinical Major Depressive Disorder (MDD) (n = 38) MDD (n = 20)

MDD (n = 24)

MDD (n = 48) MDD (n = 100)

MDD and nonclinical depression (NCD) (n = 241) MDD (n = 1265)

NCD (n = 247)

1. Fehily et al. (1981)

2. Maes et al. (1996)

4. Edwards et al. (1998) 5. Maes et al. (1999) 6. Parker et al. (2006) 7. Schiepers et al. (2009)

8. SuominenTaipale et al. (2010) 9. Mamalakis et al. (2002)

3. Adams et al. (1996)

Fatty acid assessment

Populations

ZSDS

CIDI

CES-D, SCL-90

HDRS DMI-18

Negative relationship (DHA and DGLA)

No relationship

Negative relationship (DHA)

Negative relationship (total n-3; ALA and DHA) positive (LA) No correlation Negative relationship (DHA)

Positive relationship (AA : EPA; total n-6 : n-3)

Linear, HDRS BDI

No relationship

Positive relationship (DHA)

Results (relationship between symptom severity and n-3)

HDRS

BDI

Outcome criteria

Correlational studies examining the role of omega-3 in depressive symptom severity

Investigator

Table 19.2

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Suicide attempt (n = 200) Clinical self-harm patients (n = 80) MDD suicide patients (29)

NC post-natal depression (PND) NC PND (n = 112) NCD (n = 46)

NCD (n = 90; adolescents) NCD (n = 130)

NCD (n = 90; adolescents) NCD (n = 150)

HDRS; SIS BDI Number of attempts

Plasma lipids (L) (PL)

EPDS SCL

PL PL EM

BDI

ZSDS

PL

AT

BDI and CES-D

GDS-15

PCE and AT AT

BDI

AT

Negative relationship (DHA); positive relationship (n-6 : n-3 ratio)

No relationship (only total n-6 assessed) Negative relationship (total n-3); positive relationship (n-6 : n-3 ratio and AA : EPA ratio) No relationship (only EPA and DHA assessed) Negative relationship (n-3 and n-6)

Negative relationship (AA : DHA ratio; ALA) Negative relationship (EPA) positive (DGLA) Negative relationship (n-3 DPA and DHA) No relationship (only total n-6 assessed)

No relationship

Abbreviations: AA – arachidonic acid; ALA – alpha-linolenic acid; DHA – docosahexaenoic acid; DPA – docosapentaenoic acid; DGLA – Dihomogamma linolenic acid; EPA – eicosapentaenoic acid; LA – linoleic acid. BDI – Beck Depression Inventory; CES-D – Centre for Epidemiological Studies (depression scale); CIDI – Composite International Diagnostic Interview; DMI-18 – Depression in the Medically III (18 items); EPDS – Edinburgh Post-natal Depression Scale; GDS-15 – Geriatric Depression Scale-15 (15 items); HDRS – Hamilton Depression Rating Scale; SCL – Symptom Checklist 99 items); SIS – Suicide Intent Scale; ZSDS – Zung Self-Rating Depression Scale.

17. Huan et al. (2004) 18. Garland et al. (2007) 19. Sublette et al. (2009)

10. Mamalakis et al. (2004) 11. Mamalakis et al. (2006a) 12. Mamalakis et al. (2006b) 13. Mamalakis et al. (2006c) 14. Llorente et al. (2003) 15. Otto et al. (2003) 16. Kilkens et al. (2004)

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Lifetime nutritional influences on behaviour and psychiatric illness

Despite generally significant findings, there are inconsistencies in the type of PUFAs reported to be associated with depression, although different methods of FA assessment might have contributed to these inconsistencies. There is also variability in the diagnostic criteria employed and whether the sample consisted of those with clinical depression, sub-clinical depression or those without symptoms. The body of evidence suggested that omega-3 FAs are significantly associated with depression when the symptoms are severe or when the disorder is clinically diagnosed, although n-3 FA’s may not be significantly associated with mild depression or a slightly depressed mood. In summary, a low omega-3 FA status may be associated with a severe clinical mood disturbance. It is relevant that a systematic review similarly reported that individuals with a more severe illness (patients with MDD and BD) benefited significantly more from n-3 FA supplementation than patients with mild to moderate depression (Martins, 2009). Table 19.3 reports studies that have examined the relationship between n-3 FA status and depression in control and clinical groups. The clinical disorders that have been included are Major Depressive Disorder (MDD), post-natal depression (PND), Bipolar Disorder (BD), suicidality and selfharm. Studies of patients with depressed mood, sub-clinical and clinical scores of depression but without a clinical diagnosis are also listed. Of the 15 correlational studies that investigated the relationship between PUFA status and MDD, 12 reported a significant relationship. There were reduced levels of several n-3 PUFAs and also an elevated n-6 : n-3 ratio in clinical rather than a control group (Maes et al., 1996; Edwards et al., 1998; Peet et al., 1998; Tiemeier et al., 2003; Frasure-Smith et al., 2004; Kobayakawa et al., 2005; Parker et al., 2006; Schins et al., 2007; McNamara et al., 2007). In some investigations, n-6 FAs were significantly higher. Only three studies did not report a significant relationship (Maes et al., 1999; Assies et al., 2004; Astorg et al., 2009). Of the four studies that involved non-clinical or sub-clinical groups, two significant differences were found, reduced DHA (Mamalakis et al., 2002) and ALA levels in the sub-clinical groups (Maes et al., 1996). Thus, the evidence suggests a relationship between fatty acid status and clinical affective disorders. A highly cited study by Tiemeier et al. (2003) is an example of a well-controlled correlational study. Fatty acid status was assessed in the red blood cells of 725 community dwelling elderly. It was found that those with clinical depression had elevated n-6 : n-3 ratios. Also, when compared to control subjects, the percentages of n-3 FAs were significantly lower in those with depression. Potential confounders such as inflammatory disorders, atherosclerosis and demographics were ruled out, suggesting that low n-3 FA levels were associated with depression. A limitation of this study, as with all other correlation studies, is that causality cannot be ascertained. It is feasible that adhedonia, a symptom of depression, adversely affected dietary habits. Adhedonia involves a loss of

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Endogenous Depression (ED) vs controls (C) (n = 16) ED vs C

1. Ellis and Sanders (1977)

Clinical post-natal depression (PND) vs C (n = 48) MDD vs C (n = 44) MDD vs C (n = 54)

8. De Vriese et al. (2003)

9. Assies et al. (2004) 10. Frasure-Smith et al. (2004) 11. Parker et al. (2006) 12. Schins et al. (2007) 13. McNamara et al. (2007) 14. Astorg et al. (2009) C (n = 100) C (n = 50) C (n = 42) C

MDD vs C (n = 264)

7. Tiemeier et al. (2003)

MDD vs MDD vs MDD vs MDD vs

MDD vs C (n = 24) MDD vs C (n = 48)

5. Edwards et al. (1998) 6. Maes et al. (1999)

4. Peet et al. (1998)

Clinical Major Depressive Disorder (MDD) vs nonclinical (NC) and subclinical (SC) (n = 38) MDD vs C (n = 30)

3. Maes et al. (1996)

2. Fehily et al. (1981)

Populations (clinical versus)

PL PL Brain PL

EM and plasma lipids (PL) PL

PL and CE

Erythrocyte membrane (EM) EM PL and plasma cholesterol esters (PCE) PL

Plasma choline phosphoacylglycerols (PCPG) PCPG and erythrocyte ethanolamine phosphoacylglycerols (EEPG) Plasma phospholipids (PL) and plasma cholesterol esters (CE)

Fatty acid assessment

No significant differences Reduced total n-3 and DHA; elevated n-6 fatty acids; elevated n-6 : n-3 ratios Decreased n-3 DHA and DPA Elevated AA : EPA ratio Lower DHA No significant differences

Reduced total n-3, particularly EPA; and elevated n-6 : n-3 ratios Reduced total n-3, DHA; elevated n6 : n-3 ratio

Decreased total n-3 and DHA (but not EPA) and n-6 Lower total n-3 Reduced n-6 and n-3; in particular EPA

No significant differences between clinical vs Control, however reduced ALA in sub-clinical group

Higher EPA and DHA; lower LA

Higher EPA and DHA

Results (Clinical group)

Correlational studies examining fatty acid levels in individuals with affective disorders versus controls

Investigator

Table 19.3

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Brain

Suicide death vs Nonsuicide death Non-clinical suicide attempt vs Controls (n = 200) Suicide death vs Nonsuicide death BD vs C (n = 40) BD vs C BD vs C (n = 37) BD vs C (n = 14) BD vs C (n = 69)

16. McNamara et al. (2007)

NC vs C (GDS-15) (n = 150) NC PND vs C (EPDS) (n = 112) NC PND vs C (BDI and EPDS) (n = 80)

27. Mamalakis et al. (2006a) 28. Otto et al. (2003)

Lower DHA in depressed group No significant differences

PL L

CE

No differences between Clinical and control group; however reduced levels of total n-3, DHA and DPA in SC subjects No significant differences

Reduced DHA and AA Reduced ALA and EPA Reduced DHA and AA No relationship Reduced levels of n-6 DPA, no effects to levels of n-3 Reduced DHA in sub-clinical group No significant differences

EM

Adipose tissue (AT) AT

EM EM Brain Brain Brain

Brain

Reduced total n-3; DHA and EPA; elevated n-6 : n-3 ratio No significant differences

Lower n-6 and n-3 in depressed subjects, higher levels of n-6 AA. Correlation between age of death and levels of metabolites in MDD group. Significant correlation between age and n-6 : n-3 ratio in subjects as compared to controls. No significant differences

Results (Clinical group)

Abbreviations: ALA – alpha-linolenic acid; DHA – docosahexaenoic acid; DPA – docosapentaenoic acid; EPA – eicosapentaenoic acid; LA – linoleic acid; AA – arachidonic acid. BDI – Beck Depression Inventory; EPDS – Edinburgh Post-natal Depression Scale; GDS-15 – Geriatric Depression Scale (15 items); HAD-S-D – Hospital Anxiety and Depression Scales (depression scale); ZSDS – Zung Self-Rating Depression Scale.

29. Browne et al. (2006)

26. Kobayakawa et al. (2005)

NC vs SC (ZSDS) (n = 247) NC vs C (BDI) (n = 90; adolescents) Clin vs SC vs C (HADS-D) (n = 81)

Chiu et al. (2003) Ranjekar et al. (2003) McNamara et al. (2008) Igarashi et al. (2010) Hamazaki et al. (2010)

24. Mamalakis et al. (2002) 25. Mamalakis et al. (2004)

19. 20. 21. 22. 23.

18. McNamara et al. (2009)

EM

Brain (post-mortem)

MDD vs C`

15. Conklin et al. (2010)

17. Huan et al. (2004)

Fatty acid assessment

Populations (clinical versus)

Continued

Investigator

Table 19.3

Fatty acids, depression and suicide

499

pleasure in most activities, including eating. It is therefore possible that individuals with adhedonia experience a loss of appetite accompanied by changes in nutritional status. However, this explanation of the significant relationship between PUFA status and depression is improbable as levels of saturated fats, monounsaturated fats and n-6 and n-3 PUFAs were also measured: with the exception of n-3 FAs, the levels of other fats were not significantly different. It is unlikely that a change in diet would have selectively altered levels of n-3 FAs whilst the levels of other fats remained unchanged. A more plausible explanation is that n-3 FA metabolism is affected in individuals with depression, altering the levels of n-3 FAs and the n-6 : n-3 ratio. A polymorphism has been identified for an enzyme involved in fatty acid metabolism (FACL4) that is more prevalent in depressed individuals (Covault et al., 2004), suggesting that individual differences in fatty acid metabolism are associated with a higher prevalence of depression. Although it is possible that some individuals may be genetically predisposed to disorders of mood or behaviour, with differences in fatty acid metabolism as part of the underlying mechanism, a limitation of this argument is that not all individuals with a clinical disorder have disturbed fatty acid levels which possibly reflects heterogeneity in the causes of depression. However, the fact that not all studies have reported disturbed fatty acid levels could also reflect the use of different methodologies; for example, there have been assays of adipose tissue, erythrocyte membranes and brain tissue, and some methods may not pick up on the subtle differences in fatty acid metabolism that are evident when considering gene-induced changes in fatty acid metabolism. These measures may be differentially related to biological processes that affect mood; thus, it is possible that some methods of fatty acid assessment may be better suited to investigating the relationship between n-3 and mood. At present, it is not possible to discern which methods of assessment yield relationships and which do not. The possibility, however, remains that the gene/n-3 FA/depression link may explain why some people with depression respond to n-3 FA supplementation whilst others do not. We await the specific examination of this suggestion. It is also possible that a deficiency of n-3 FA in one bodily tissue may not indicate a deficiency in another area. For example, a short-term low blood level of n-3 FAs may not in the short-term indicate low levels in the brain. The remaining five studies reported no association between PUFA status and clinical depression (Maes et al., 1996; De Vriese et al., 2003; Assies et al., 2004; Parker et al., 2006; Astorg et al., 2009). Like epidemiological studies, correlational studies are also limited by their cross-sectional nature. Despite using more accurate methods of measurement, causality cannot be ascertained. Although the associations are stronger than with epidemiological studies, the relationships are potentially

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Lifetime nutritional influences on behaviour and psychiatric illness

bidirectional and the association between depression and PUFA levels may reflect other aspects of nutrition. For example, erythrocyte levels of folate have been linked with mania in humans (Hasanah et al., 1997), and low levels of folate in the rat lead to a reduction of DHA; hence, it is possible that the reduced levels of DHA found in some depressed individuals are secondary to changes in folate status. Thus altered folate levels, rather than fatty acids, might cause depression (see Chapter 14). In humans a positive association has been found between folate and DHA status, irrespective of age, smoking and alcohol consumption (Umhau et al., 2006). Folate supplementation has been found to enhance plasma levels of DHA and EPA (Das, 2008). This evidence suggests a link between folate levels and DHA status and may explain why separate studies have associated both DHA and folate with phenomena such as depression, dementia and cognitive decline (Das, 2008). More research is required to determine the relative contribution of each of these nutrients to psychological disorders. The effects of DHA supplementation on folate levels, and the effects of folate supplementation on DHA levels, should be further examined.

19.3.3 Intervention studies Intervention studies using randomized, double-blind placebo controlled procedures (RCTs) have the great advantage that they are able to establish causality. Table 19.4 presents a series of intervention studies. It is apparent that most studies have been conducted with individuals diagnosed with clinical depression; however, some have examined those with BD or even without a clinical diagnosis of an affective disorder. Table 19.4 includes 26 intervention studies, nine of which have investigated the effects of n-3 FAs in the treatment of MDD. Two of these studies found a reduction in depressive symptoms after EPA plus DHA supplementation (Su et al., 2003; Nemets et al., 2006); four reported a reduction in symptoms after EPA ethyl-ester (E-EPA) or EPA alone (Nemets et al., 2002; Peet and Horrobin, 2002; Da Silva et al., 2008) or in combination with pharmacological medication (Jazayeri et al., 2008). In contrast, three studies reported no effects of supplementation with DHA alone or EPA plus DHA (Marangell et al., 2003; Silvers et al., 2005; Grenyer et al., 2007). A study administering EPA plus DHA to a population with a non-clinical diagnosis of moderate–severe depression also reported a significant reduction in depression scores in the experimental rather than control group (Lucas et al., 2009). It is notable that in studies that found no significant differences between the experimental and placebo group after EPA and DHA supplementation, small doses of EPA were used (Grenyer et al., 2007; 0.6 g EPA). In contrast, in most studies that have reported a significant effect in adult populations at least 1 g EPA had been administered (Nemets et al., 2002; Peet and Horrobin, 2002). Reviews have concluded that beneficial effects are

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© Woodhead Publishing Limited, 2011

9. Da Silva et al. (2008)

7. Grenyer et al. (2007) 8. Freeman et al. (2008)

5. Silvers et al. (2005) 6. Nemets et al. (2006)

Post-natal depression (PND) vs C (n = 59) MDD vs C (n = 29) 0.64 EPA, 0.48 DHA

0.6 EPA + 2.2 DHA 1.1 EPA, 0.8 DHA

MDD vs C (n = 83)

MDD vs C (n = 28; 6–12 years old)

MDD vs C (n = 77)

4.4 EPA + 2.2 DHA 0.6 EPA + 2.4 DHA 0.38 EPA + 0.2 DHA

1, 2 or 4 E-EPA 2 DHA

2 E-EPA

Type and dose (grams)

MDD vs C (n = 28)

MDD vs C (n = 36)

Clinical Major Depressive Disorder (MDD) vs control (C) (n = 20) MDD vs C (n = 70)

1. Nemets et al. (2002)

2. Peet and Horrobin (2002) 3. Marangell et al. (2003) 4. Su et al. (2003)

Population

Investigator

12.6

8

16

16

12

8

6

12

4

Duration (weeks)

MADRS, BDI, CGI

EPDS, HDRS, CGI

HDRS, BDI

CDRS, CDI, CGI

HDRS-SF, BDI

HDRS, MADRS, BDI MADRS, HDRS, GAF HDRS

HDRS

Outcome measure

Significant decrease (MADRS only)

Significant decrease in depression on all outcome measures; significant effect of time No effect of treatment; significant effect of time Significant decrease (EPDS only)

None

Significant reduction in depression

Significant effect of 1 g E-EPA only; significant effect of time None

Significant decrease in depression

Effect of treatment (treatment group compared to controls)

Table 19.4 Randomized, double-blind placebo-controlled trials investigating the effects of omega-3 supplementation on clinical depression and non-clinical depressed mood

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1 E-EPA 0.42 EPA, 1.64 DHA 2.2 EPA, 1.2 DHA 6.2 EPA 3.4 DHA

5 EPA + 3 DHA; or 1.3 EPA + 0.7 DHA 1 or 2 EPA

2 E-EPA 6 E-EPA 0.2 DHA

MDD vs C (n = 60)

PND vs C (n = 26)

Clinical Bipolar Disorder (BD) vs C (n = 21)

BD (n = 21)

BD vs C (n = 75)

BD vs C (14)

BD vs C (n = 116)

NC PND (n = 99)

10. Jazayeri et al. (2008) 11. Rees et al. (2008) 12. Su et al. (2008)

13. Stoll et al. (1999)

14. Hirashima et al. (2004)

15. Frangou et al. (2006)

16. Frangou et al. (2007) 17. Keck et al. (2006) 18. Llorente et al. (2003)

PND vs C (n = 36)

Type and dose (grams)

Population

Continued

Investigator

Table 19.4

7.1

17.3

12

12

4

16

8

6

8

Duration (weeks)

IDS-C, YMRS, CGI-BP BDI

HDRS

HDRS, YMRS CGI

HDRS, YMRS

EPDS, HDRS, MADRS HDRS, EPDS, BDI-II HDRS, YMRS, CGI, GAF

HDRS

Outcome measure

None

Significant decrease in depression with both doses; no significant differences in mania scores (YMRS); significant effect of 1 g and 2 g on mania symptoms (CGI) Significant decrease in depression (no assessment of bipolar symptoms) None

Significant decrease in depression; no significant differences between groups for mania, however significant improvements over time; significant improvement of bipolar symptoms (CGI and GAF) None

Significant decrease on all measures

Significant decrease when used in combination with fluoxetine None

Effect of treatment (treatment group compared to controls)

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13 12

0.63 EPA + 0.09 DHA 0.63 EPA 0.85 DHA 1.6 EPA + 0.8 DHA

BDI, HDRS

28 12

4

1.74 EPA + 0.25 DHA 0.22 AA, 0.22 DHA 1.22 EPA + 9.08 DHA

CES-D, MADRS, GDS-15

POMS – depression

DASS, BDI, GHQ

DASS

PGWB, HDRS-21, CGI, HSCL-D-20

Outcome measure

MINII, BDI-II5, POMS, LEIDSR EPDS, PPBQ

26

1.093 EPA + 0.847 DHA

5

8

Duration (weeks)

1.05 EPA, 0.15 DHA

Type and dose (grams)

Significant decrease in depression on both measures

Non-significant

None

None

None

Significant decrease in depression

None

Significant decrease in depression

Effect of treatment (treatment group compared to controls)

Abbreviations: BDI – Beck Depression Inventory; BDI-II – Beck Depression Inventory (short form); CDI – Children’s Depression Inventory; CDRS – Children’s Depression Rating Scale; CES-D – Centre for Epidemiological Studies (depression scale); CGI – Clinical Global Impression; CGI–BP – Clinical Global Impression – Bipolar Disorder; DASS – Depression Anxiety and Stress Scales; DHA – docosahexaenoic acid; EPA – eicosapentaenoic acid; E-EPA – ethyl ester EPA; EPDS Edinburgh Post-natal Depression Scale; GAF – Global Assessment of Functioning; GDS-15 – Geriatric Depression Scale (15 items); GHQ – General Health Questionnaire; HDRS – Hamilton Depression Rating Scale; HDRS-SF – Hamilton Depression Rating Scale (short form); HDRS-21 – Hamilton Depression Rating Scale (21 items); HSCL-D-20 – Hopkins Symptom Checklist (20 items); IDS-C – Inventory of Depressive Symptomology; LEIDSR – Leiden Index of Depression Sensitivity (revised version); MADRS – Montgomery–Asberg Depression Rating Scale; MINI – Mini International Neuropsychiatric Interview; PGWB – Psychological General Well-being Index; POMS – Profile of Mood States Questionnaire; PPBQ – Postpartum Blues Questionnaire; YMRS – Young Mania Rating Scale.

24. Antypa et al. (2009) 25. Doornbos et al. (2009) 26. Hallahan et al. (2007)

23. Van de Rest et al. (2008)

21. Rogers et al. (2008) 22. Fontani et al. (2005)

Non-clinical healthy population (n = 33) Non-clinical healthly older adult population (n = 302) Healthy population (n = 56) Healthy pregnant women (n = 119) Clinical self-harm patients (n = 49)

Moderate-severe depression (non-clinical) Non-clinical depressed mood (NDM) (n = 218) NDM (n = 218)

19. Lucas et al. (2009)

20. Rogers et al. (2008)

Population

Investigator

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Lifetime nutritional influences on behaviour and psychiatric illness

possible with high doses of EPA, or when EPA and DHA are combined (Lin and Su, 2007); however, neither DHA alone (Marangell et al., 2003) nor a low dosage of EPA had a major beneficial effect. In contrast, it has been reported that 1 g E-EPA, but not 2 g or 4 g, can reduce depressive symptoms (Peet and Horrobin, 2002), suggesting an optimal dose of EPA. In support of this view, Hirashima et al. (2004) and Keck et al. (2006) also found that large doses of E-EPA (5 g and 6 g, respectively) were ineffective, although this was in a population of BD patients. However, it has been found that high doses may be effective in some cases of depression (4.4 g EPA + 2.2 g DHA, Su et al., 2008; 6.2 g EPA + 3.4 g DHA, Stoll et al., 1999b). These inconsistent results may reflect methodological differences, although more importantly they may reflect individual differences in PUFA metabolism, perhaps related to polymorphisms and gender. Adequate dosage levels need to be established, taking into account individual differences in metabolic processing and the preexisting diet. Five studies have examined the effects of PUFA supplementation on depressed mood in healthy populations. One study found significant results in individuals without a clinical diagnosis but with mild to moderate depression (Rogers et al., 2008). The four remaining studies in healthy populations reported no effects of supplementation on depressed mood (Fontani et al., 2005b; Rogers et al., 2008; Van de Rest et al., 2008; Antypa et al., 2009).

19.3.4 Summary In summary, most correlational studies are small scale and selective in that they focus on clinical populations; as such, the findings cannot be generalized. Furthermore, with small-scale studies the potential is increased for the role of confounding variables. Although the evidence concerning the role of n-3 FAs in depression is inconclusive, there are some positive findings that suggest the importance of continued research. Where PUFA status has been associated with disorders of affect, the relationship has been found to be more pronounced when symptoms were severe. Intervention studies that employed clinical populations with high severity of depression have found a more positive response to supplementation (Appleton et al., 2010). In contrast, experiments with non-clinical populations are less likely to report significant findings (Table 19.4). This pattern of selective response has similarly been observed with traditional pharmacological medication (Kirsch et al., 2008). In terms of the nature of the fatty acids, there are suggestions with the treatment of MDD that DHA alone is less effective than EPA or a combination of EPA and DHA (Martins, 2009).

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Small sample sizes are also a concern as, to date, all studies of depressed populations have used less than 100 subjects per group. Typically there has also been at the most a very limited reporting of the pre-existing dietary status and a failure to consider individual differences in fatty acid metabolism. Without such information, it is difficult to establish why some individuals benefit from supplementation and to establish the appropriate dose.

19.4 EFAs and post-natal depression (PND) Post-natal depression is characterized by the same symptoms as MDD, but there is increased anxiety and episodes of crying. Clinical PND may affect 10–13 % of women and less frequently men; in fact, 3–5 % of men suffer from moderate to severe depression after childbirth (Oates, 2003). It may last for a few months up to a year.

19.4.1 Epidemiological studies A negative non-linear relationship between national fish consumption and post-partum depression in 22 countries has been reported (Hibbeln, 2002). The relationship remained significant after adjusting for potential confounding variables such as low socioeconomic status and the high prevalence of unmarried mothers. An explanation for this finding is that during pregnancy there is often an elevated n-6 : n-3 ratio and a reduction in the n-3 PUFA status of the mother due to the increased demands of the foetus. The PUFA status of the mother slowly begins to normalize after birth, a process that is quicker if the mother does not breastfeed (Hornstra, 2000). It is possible that the reduction of n-3 FA status during pregnancy, as a result of foetal demands, may create an imbalance in serotonin neurotransmission and hence depression (Peet et al., 1998). Alternatively n-3 FAs may regulate mood during post-partum depression by changing the ‘AA cascade’ and in this way reduce the levels of n-6 fatty acids (Rapoport and Bosetti, 2002). In contrast, two studies did not report a significant association between fish consumption and post-partum depression (Miyake et al., 2006; Strom et al., 2009). An explanation for these non-significant findings is that as the Japanese consume high amounts of fish, post-partum depression is unlikely to reflect low PUFA status. The second study involved Danish women, and although the relationship between fish consumption and PND did not reach significance, there was a reduced likelihood of receiving medication for PND in frequent fish consumers. Again, inconsistent findings may reflect different methods of assessing fish intake; for example, some studies use national import and export figures to estimate fish consumption (e.g.

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Lifetime nutritional influences on behaviour and psychiatric illness

Hibbeln, 2002), whereas others have used food frequency questionnaires (Miyake et al., 2006; Strom et al., 2009).

19.4.2 Correlational studies Table 19.3 reports only one study that investigated that relationship between fatty acid status and clinically diagnosed PND that included a control group (De Vriese et al., 2003). In a population of depressed mothers, there was an elevated n-6 : n-3 ratio and lower levels of total n-3 FAs and DHA, supporting a link between lower PUFA status and post-partum depression. An additional study that assessed PUFA status and non-clinical PND found lower DHA levels in mothers who were depressed, although they did not have a clinical diagnosis (Otto et al., 2003). A final study found no relationship (Browne et al., 2006). In summary, the balance of these findings support the suggestion that abnormal PUFA levels are more prevalent in those with severe and chronic PND. Two studies have related PUFA status to post-partum symptom severity and found no significant association (Llorente et al., 2003; Otto et al., 2003). These findings conflict with the suggestion that n-3 FAs are more influential as symptom severity increase. However, these contrasting findings may reflect the use of non-clinical populations.

19.4.3 Intervention studies Table 19.4 lists two studies that support the use of n-3 FAs in the treatment of clinical PND (Freeman et al., 2008; Su et al., 2008); however, there are two studies that do not (Llorente et al., 2003; Rees et al., 2008). An explanation for this inconsistency is that the studies reporting nonsignificant results used low doses of EPA (0.42 g; Rees et al., 2008) or did not administer EPA at all (Llorente et al., 2003). EPA has been suggested to be the active constituent when treating depressive disorders (Lin and Su, 2007). A meta-analysis considered women with a diagnosis of post-partum depression who had received prescription medication, herbal medication or dietary supplements (Ng et al., 2010). It was concluded that the heterogeneity of studies prevented a pooled analysis of treatment effects. In contrast, another review supported the therapeutic use of n-3 PUFAs during pregnancy, suggesting a reduction in depressive symptoms of up to 50 % (Su et al., 2008).

19.4.4 Summary Fatty acid status, particularly DHA, may be reduced during pregnancy, a reflection of the increased demands of the foetus (Hornstra, 2000). A study involving a non-clinical PND found lower DHA levels in mothers who were

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depressed (Otto et al., 2003), suggesting a link between PND and lowered fatty acid status. The evidence concerning post-partum depression is, however, preliminary and inconclusive. While we await more well-designed RCTs, the relative safety of n-3 FAs tentatively suggests the use of EPA, or a combination of EPA plus DHA, in the treatment of PND in those who do not wish to use pharmaceuticals or do not respond well to such treatment.

19.5 EFAs and bipolar disorder (BD) Bipolar disorder is characterized by the presence of one or more episodes of abnormally increased energy, cognitive activity and affect: such episodes are clinically termed mania or, at a less severe level, hypomania. This pattern occurs with or without one or more depressive episodes with individuals experiencing swings between mania and depression, often separated by episodes of normal affect. In the more severe cases, a manic episode can cause psychoticism, leading to delusions and hallucinations. Diagnoses are sometimes made along the bipolar spectrum, an approach used to assess the severity of symptoms.

19.5.1 Epidemiological studies Table 19.1 lists one epidemiological study that found a negative non-linear association between BD and national fish consumption in 12 countries (Noaghiul and Hibbeln, 2003). However, this study did not control for potential confounding variables such as SES.

19.5.2 Correlational studies Of a total of five BD studies in Table 19.3, one reported no significant differences in PUFA levels between BD and control subjects, although this study employed a small sample size (Igarashi et al., 2010; eight BD patients and six controls). Another study reported reduced ALA and EPA in BD patients compared to controls (Ranjekar et al., 2003) and two studies reported reduced DHA and AA (Chiu et al., 2003; McNamara et al., 2008). Finally, one postmortem study that included a control group found lower levels of the n-6 FA docosapentaenoic acid (DPA) in the hippocampus of subjects with BD, although it failed to find an association between n-3 FAs and BD (Hamazaki et al., 2010). This finding may reflect brainspecific regions that are n-3 deficient in BD but were not investigated in this study or alternatively the ratio between n3 : n6 may be important. Reduced AA and DHA concentrations have been found in the postmortem brain of BD subjects (Chiu et al., 2003; McNamara et al., 2008), and it has

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Lifetime nutritional influences on behaviour and psychiatric illness

therefore been postulated that DHA and AA are the predominant fatty acids involved in mania (Igarashi et al., 2010). However, subsequent research has not supported the role of DHA and AA in BD (Igarashi et al., 2010).

19.5.3 Intervention studies Two BD studies in Table 19.4 reported a decrease in depressive and bipolar symptoms following supplementation with EPA plus DHA, or E-EPA alone, although these studies did not significantly reduce mania (Stoll et al., 1999b; Frangou et al., 2006). Elsewhere, EPA has been reported to be a successful treatment for depressive but not manic symptoms (Frangou et al., 2006; Montgomery and Richardson, 2008). However, three studies did not report a significant effect of EPA plus DHA, or E-EPA, on depressive or manic symptomology (Hirashima et al., 2004; Keck et al., 2006; Frangou et al., 2007). There is no obvious explanation for this inconsistency, although it is notable that the intervention periods varied, and different doses and types of PUFA were administered. Although there was a significant reduction of bipolar symptoms in two out of five studies, other studies were non-significant, possibly reflecting individual differences in PUFA metabolism (Covault et al., 2004; Williams and Burdge, 2006).

19.5.4 Summary The majority of studies on BD have employed an open design and a small sample size, making it difficult to draw conclusions. In comparison to the literature on depression, there are fewer studies, making summation and evaluation difficult. A Cochrane Review identified only one RCT with data sufficient to be used for pooled analysis, demonstrating the need for further RCTs (Montgomery and Richardson, 2008). In summary, the literature that has examined the link between n-3 PUFAs and BD has produced inconsistent findings. Despite some evidence suggesting n-3 FAs may be effective in the treatment of bipolar symptoms, there are no clear guidelines concerning which type of fatty acid may be beneficial. There have been suggestions that DHA and AA are effective in the treatment of manic symptoms (Chiu et al., 2003); however, this finding has not been replicated (Irigashi et al., 2010). Although there are some reports that EPA is effective in the treatment of depression, it is necessary to determine the role of fatty acids in manic as opposed to depressive symptoms. It would be informative if future research used double-blind RCTs in populations with a clinical diagnosis of mania without depression to establish whether there is a general or selective response to fatty acid supplementation.

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Inconsistent findings may reflect individual differences in fatty acid metabolism, including those relating to genetics and gender; varying length of intervention; varying doses of n-3 FAs; different types of FAs; inadequate population size; the use of different bodily tissues to assess fatty acid status.

19.6

EFAs and suicide

It has also been suggested that n-3 FAs may be beneficial in the treatment of suicidality and self-harm, a phenomenon that may result from a reduction in depression or alternatively an independent response. The term suicidality encompasses suicide ideation, suicide attempts and successful suicide.

19.6.1 Epidemiological evidence Table 19.1 presents two epidemiological studies that found a negative association between fish consumption and suicide ideation after controlling for possible confounding variables including SES (Tanskanen et al., 2001a; Timonen et al., 2004). One study found the association to be significant in females, but not males (Timonen et al., 2004).

19.6.2 Correlational studies Table 19.3 shows that at postmortem, suicide patients with MDD had significantly lower levels of DHA in the prefrontal cortex (PFC), although associations with other fatty acids did not reach significance (McNamara et al., 2007). Although EPA appears to be the most therapeutic fatty acid in the treatment of depression, this study suggested that ultimately the levels of DHA may be significantly affected in the brain. Another study that employed a control group reported significantly less DHA plus EPA, and an elevated n-6 : n-3 ratio, in the blood of those who had attempted suicide (Huan et al., 2004). In addition, two studies from Table 19.2 reported a negative relationship between self-harm and plasma n-3 and n-6 status (Huan et al., 2004; Garland et al., 2007), and also an elevated n-6 : n-3 ratio in MDD suicide patients. There are also non-significant findings. For example a postmortem examination of adolescent suicide victims and age-matched controls found no significant differences in the fatty acid content of the PFC (McNamara et al., 2009). Inconsistent findings may reflect the use of different biological tissues to assess levels of fatty acids and the heterogeneity of the samples studied, for example adults as opposed to adolescents. It has been suggested that low fatty acid levels in suicidal individuals may result from the differential expression of genes involved in lipid

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metabolism (Lalovic et al., 2010). However, studies supporting this assertion have often employed a sample diagnosed with MDD with a suicidal tendency (Lalovic et al., 2010). Thus it is difficult to determine whether genetic differences in lipid metabolism and fatty acid levels are related to MDD, suicide, or both. Studies of individuals with a suicidal tendency, but without a diagnosis of MDD, are necessary to establish the influence of fatty acid status and gene expression.

19.6.3 Intervention studies Table 19.4 lists the first intervention study to report a significant beneficial effects of EPA plus DHA in self-harm patients (Hallahan et al., 2007). This double-blind RCT found that a higher number of participants in the n-3 FA group reported an amelioration of suicide ideation. Supplementation also reduced the level of stress, and had a beneficial effect on wellbeing independent of changes in depression scores, suggesting that n-3 FA supplementation benefited suicide ideation irrespective its anti-depressant effects. It seems that several processes are potentially affected by n-3 FA supplementation including those involved in suicide ideation, depression, stress and wellbeing.

19.6.4 Summary Additional well-designed RCT are needed, although studies of the effects of n-3 FAs on suicidality and self-harm are inhibited by obvious ethical concerns. However, the possibility that n-3 FAs might be used to treat selfharm and suicidality warrants further consideration. Ideally, samples experiencing suicidality without depression should be examined to establish the precise effects of n-3 FAs.

19.7

Personality factors associated with suicide

A series of factors contribute to suicidality including genetics, social and familial networks, a history of psychopathology, traumatic, stressful and abusive experiences, previous suicide attempts and personality variables (Brezo et al., 2006). A qualitative and systematic review of personality variables that are risk factors for suicide suggested that neuroticism, anxiety, guilt, aggression, impulsivity, hopelessness and irritability among others are predisposing factors (Brezo et al., 2006). Besides specific personality traits, personality clusters have been associated with suicidality, such as introversion–negativity–avoidance–dependence–borderline–neurotic and impulsivity–hostility–anti–sociality (Engstrom et al., 1997; Rudd et al., 2000). There is evidence of a link between altered PUFA status and personality

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variables that contribute towards suicidality including impulsivity, aggression and hostility.

19.7.1 Aggression, hostility and anger Epidemiological evidence has suggested a negative relationship between hostility and DHA/total fish consumption (Iribarren et al., 2004); one correlational study reported lower levels of total n-3 FA and DHA and an elevated n-6 : n-3 ratio in aggressive compared to non-aggressive cocaine addicts (Buydens-Branchey et al., 2003). However, other correlational studies have not reported differences in n-3 FA between aggressive and non-aggressive subjects, although plasma phospholipid levels of n-6 PUFA were significantly higher in violent subjects rather than controls (Virkkunen et al., 1987). Taken together, this evidence suggests the possibility that alterations to the n-6 : n-3 ratio may be significantly associated with aggressive and hostile behaviour. Intervention studies have found that supplementation with DHA, EPA or a combination of both can reduce behaviours such as aggression, anger, tension, irritability and anti-social behaviour (Gesch et al., 2002; Hamazaki et al., 2002; Zanarini and Frankenburg, 2003; Fontani et al., 2005b; BuydensBranchey and Branchey, 2006; Benton, 2007; Zaalberg et al., 2010). These behaviours are manifestations of personality variables such as Neuroticism (N) and Psychoticism (P). Meta-analysis of double-blind RCTs has revealed that a dietary deficiency of micronutrients and PUFAs may predispose to anti-social, violent and aggressive behaviour, that may be reduced by supplementation with PUFAs and/or micronutrients (Benton, 2007). It is notable that some intervention studies of anti-social behaviour (Gesch et al. 2002; Zaalberg et al., 2010) used a combination of PUFAs and vitamins and minerals, causing uncertainty concerning the active constituent. It was, however, possible that both constituents had an effect, or alternatively that there was a synergistic interaction. Nutrients do not act in the body in isolation. The response to a particular nutrient may be blocked further down the metabolic pathway by a mechanism that requires the presence of another nutrient. Further research is required on the nature of an interaction between n-3 FAs and other nutrients and the potential effects on mood and behaviour. The above findings are not supported by other studies that have reported non-significant effects of PUFAs on aggression, hostility or anger (Hallahan et al., 2007; Hamazaki et al., 1998, 2002). A potential explanation for the discrepancy is that supplementation may prevent individuals with a predisposition to behave aggressively from doing so in stressful situations. In support of this view, it has been found that DHA can reduce aggressive behaviour in the presence of a stressor (Hamazaki et al., 1996), a possibility warranting further investigation. Another possible

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explanation is the supplementation reduces some facets of aggression but not others.

19.7.2 Impulsivity Aggression has been associated with impulsivity such that aggressive and hostile behaviour may result in a diagnosis of an Impulsive Control Disorder (ICD). ICDs have been defined as ‘the failure to resist an impulse drive or temptation to perform an act that is harmful to the individual or others’. Suicide and self-harm are forms of intra-aggression, defined as the act of behaving aggressively towards oneself. Intra-aggression may be linked with impulsivity. In support of this view, correlational studies have associated impulsivity with self-harming, suicidal and anti-social behaviour (Cremniter et al., 1999). Experimental trials have found that supplementation with n-3 FAs can reduce impulsivity (Itomura et al., 2005; Conklin et al., 2007). In contrast, Hallahan et al. (2007) found that omega-3 FA supplementation had no significant effect on irritability, aggression or impulsivity.

19.7.3 Summary The evidence is preliminary that PUFAs may have a role in modulating suicidality and the personality variables associated with suicidality, such as aggression, impulsivity and hostility. The inconsistency is likely to reflect the use of different outcome measures, the dosage and type of PUFAs, the sampling methods used and the intervention period. In summary, suicidality has been associated with certain personality variables (particularly N and P) and behavioural manifestations of these variables such as impulsivity, anger and aggression. There are reasons to hypothesize that omega-3 FAs may regulate these behaviours. In particular, omega-3 FAs may regulate suicidality, self-harm and other anti-social behaviours indirectly by inhibiting behavioural manifestation of certain personality traits.

19.8 Future trends The topic of depression requires further studies using larger sample sizes and RCTs. In epidemiological studies, potential confounding variables such as age, gender and SES should be statistically controlled. Dietary information or biochemical measures should also be obtained to establish baseline fatty acid status. A better understanding of PUFA metabolism will help to identify the time required to incorporate PUFAs into the cell membrane which will in turn help clarify on optimal intervention period. There is a gap in the literature concerning the biochemical mechanisms by which PUFAs affect mood and cognition. In addition, the role of genetics and the effect of PUFAs on

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neurotransmission, inflammatory mechanisms and the consequences for mood need to be established. Until these mechanisms are understood, the dose and type of PUFA administered will be based on no more than an educated guess. A greater understanding of the implications of PUFA status and metabolism will allow the identification of populations that will benefit from supplementation. Symptom type and severity must also be taken into account when deciding which populations to study and which treatments to administer. It appears that PUFAs are better suited to treating clinical mood disorders, as opposed to mood within the normal range. Different types of PUFAs may differently influence the various affective disorders (e.g. MDD and BD). The possibility should be considered that changes to fatty acid status will alleviate only some symptoms of depression, or that different fatty acids may differentially impact on the variety of symptoms.

19.9 Implications for practice Despite inconsistencies, there is a literature suggesting an association between omega-3 status and affective disorders. A positive is that omega-3 FAs do not cause side-effects unless administered in very large doses. Thus, potentially PUFAs may provide an alternative treatment for individuals who do not respond to, or cannot tolerate, contemporary medication. Furthermore, the benign influence of PUFAs means they can safely be used as an adjunctive treatment where individuals respond suboptimally to current medication. For example, an RCT found that EPA and fluoxetine had an equally therapeutic effect in those with MDD, although the group that received a combined treatment of EPA and fluoxetine showed a significantly higher response rate than with either treatment alone (Jazayeri et al., 2008). This evidence is preliminary and is currently insufficient to establish any guidelines for the use of n-3 FAs in affective disorders. However, given the relative safety and putative beneficial effects of n-3 FAs for general health, there are grounds for considering its use in particular cases while awaiting the results of further well-powered RCTs. There are currently no established dietary guidelines for n-3 FAs. However, the UK Food Standards Agency (FSA) recommended around 1–2 portions of fish per week, which would provide around 450 mg EPA plus DHA. In 2004, The European Food Standards Agency recommended between 200 and 500 mg EPA plus DHA per day, similar to the Scientific Advisory Committee on Nutrition/Committee on Toxicity in 2004 who suggested the recommended intake should increase from 200 mg to 450 mg EPA plus DHA daily. The food industry can potentially help by providing food items offering additional sources of fatty acids. Animals could be fed a diet containing high levels of omega-3 FAs and low levels of n-6 fatty acids. This practice is

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becoming more common since this is an easy method of altering the content of DHA and EPA (Givens and Gibbs, 2008). However, if animals are fed a diet high in n-6 FAs, there is will be reduced availability of n-3 (Givens and Gibbs, 2008). Fortifying food products after production is an alternative option; however, it should be ensured that the n-6 content of the foods does not increase. In summary, recent increases in the consumption of n-6 FAs have led to the suggestion that levels of dietary n-3 FA must be increased. Although health recommendations advise people to consume more oily fish, there is not a sustainable supply of n-3 LC-PUFAs (Brunner, 2006) as the global stock of fish has declined by 90 % (Myers and Worm, 2003). The levels of n-3 FA in farmed fish are typically considerably lower than in those from the wild. The nature of the diet offered in fish farms is critical. If fish are not fed foods high in n-3 FA, there will, in turn be lower levels for human consumption. Sea algae are a major origin of n-3 FA as they synthesize LC-PUFAs including EPA and DHA (Pohl, 1982). Given the large decline in the fish stock, the supply of algal oils offers an alternative source for supplementation and the fortification of food products for both human and animal consumption.

19.10 Sources of further information and advice The International Society for the Study of Fatty Acids and Lipids (ISSFAL) is the foremost society dealing solely with the health effects of dietary fats. The Society is open to individuals with an interest in the healthrelated effects of dietary fats, oils, and lipids including n-3 and n-6 FAs, conjugal linoleic acid (CLA), saturated and monounsaturated fatty acids as well as other lipids. To access the site you can go to http://www.issfal.org/. An education website from Purdue University contains useful information about omega-3 FAs including details about their importance to health, development and wellbeing (http://www.omega3learning.uconn.edu/). The Global Organisation for EPA and DHA (GOED) was set up in 2006 and aims to develop, sustain and expand markets for EPA and DHA whilst promoting health benefits, education and public safety. The GOED website has some useful links to current issues surrounding PUFA research (http:// www.goedomega3.com/news.html). For some general information on nutrition, you can go to the Food Standard Agency (FSA) at http://www.eatwell. gov.uk/. For useful information on depression including the causes, symptoms, diagnosis and treatment you can go to the National Health Service (NHS) website, which also contains links to relevant resources (http://www.nhs.uk/ Conditions/Depression/Pages/Introduction.aspx).

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frangou s, lewis m and mccrone p (2006) Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomized double-blind placebo-controlled study. British Journal of Psychiatry, 188, 46–50. frangou s, lewis m, wouard j and simmons a (2007) Preliminary in vivo evidence of increased N-acetyl-aspartate following eicosapentanoic acid treatment in patients with bipolar disorder. Journal of Psychopharmacology, 21, 435–439. frasure-smith n, lesperance f and julien p (2004) Major depression is associated with lower omega-3 fatty acid levels in patients with recent acute coronary syndromes. Biological Psychiatry, 55, 891–896. freeman m p, davis m, sinha p, wisner k l, hibbeln j r and gelenberg a j (2008) Omega-3 fatty acids and supportive psychotherapy for perinatal depression: a randomized placebo-controlled study. Journal of Affective Disorders, 110, 142–148. fukaya t, gondaira t, kashiyae y, kotani s, ishikura y, fujikawa s, kiso y and sakakibara m (2007) Arachidonic acid preserves hippocampal neuron membrane fluidity in senescent rats. Neurobiological Aging, 28, 1179–1186. garland m r, hallahan b, mcnamara m, carney p a, grimes h, hibbeln j r, harkin a and conroy r m (2007) Lipids and essential fatty acids in patients presenting with self-harm. British Journal of Psychiatry, 190, 112–117. gerster h (1998) Can adults adequately convert alpha-linolenic acid (18:3n-3) to eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3)? International Journal of Vitamin and Nutrition Research, 68, 159–173. In Mazza, M., Pomponi, M., Janiri, L., Bria., P. and Mazza, S. (2007) Omega-3 fatty acids and antioxidants in neurological and psychiatric diseases: an overview. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 31, 12–26. gesch b c, hammond s m, hampson s e, eves a and crowder m j (2002) Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners: randomised, placebo-controlled trial. British Journal of Psychiatry, 181, 22–28. givens d i and gibbs r a (2008) Current intakes of EPA and DHA in European populations and the potential of animal-derived foods to increase them. Proceedings of Nutrition Society, 67, 273–280. grenyer b f s, crowe t, meyer b, owen a j, grigonis-deane e m, caputi p and howe p r c (2007) Fish oil supplementation in the treatment of major depression: A randomised double-blind placebo-controlled trial. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 31, 1393–1396. hakkarainen r, partonen t, haukka j, virtamo j, albanes d and lonnqvist j (2004) Is dietary intake of omega-3 fatty acids associated with depression? The American Journal of Psychiatry, 161, 567–569. hallahan b, hibbeln j r, davis j m and garland m r (2007) Omega-3 fatty acid supplementation in patients with recurrent self-harm: single-centre double-blind randomised controlled trial. British Journal of Psychiatry, 190, 118–122. hamazaki t, sawazaki s, itomura m, asaoka e, nagao y, nishimura n, yazawa k, kuwamori t and kobayashi m (1996) The effect of docosahexaenoic acid on aggression in young adults – a placebo-controlled double-blind study. Journal of Clinical Investigation, 97, 1129–1133. hamazaki t, sawazaki s, nagao y, kuwamori t, yazawa k, mizushima y and kobayashi m (1998) Docosahexaenoic acid does not affect aggression of normal volunteers under nonstressful conditions. A randomized, placebo-controlled, double-blind study. Lipids, 33, 663–667. hamazaki t, thienprasert a, kheovichai k, samuhaseneetoo s, nagasawa r and watanabe s (2002) The effect of docosahexaenoic acid on aggression in elderly Thai subjects – a placebo-controlled double-blind study. Nutritional Neuroscience, 6, 37–41.

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20 Fatty acid intake and cognitive decline M. Plourde, Université de Sherbrooke, Canada

Abstract: Aging is the most important risk factor of cognitive decline and dementia. Genetics clearly increase the risk of cognitive decline whereas nutrition is an environmental factor potentially affecting the risk. This chapter reviews the available data with regard to dietary fatty acid intake and risk of cognitive decline. The focus is specifically on the relation between omega-3 fatty acid metabolism and cognition in humans, with emphasis on aging, genetics and Alzheimer’s disease. Key words: aging, omega-3 fatty acids, apolipoprotein E ε4, cognitive decline, Alzheimer’s disease.

20.1 Introduction Aging is accompanied by a higher prevalence of various forms of cognitive decline and dementia, including Alzheimer’s disease (AD) (Blennow et al., 2006). AD has emerged as a major challenge to quality of life for the elderly and their caregivers. Once it is clinically diagnosed, there is little prospect of improving its prognosis (Blennow et al., 2006). Moreover, there are no effective drugs for the treatment of cognitive decline and AD. Progression of the disease to more severe stages is not well understood. Hence, closer attention needs to be paid to prevention strategies to reduce the risk of cognitive decline in the elderly. Lifestyle and other non-genetic factors are probable modifiable risk factors compared to the non-modifiable risk factors such as aging and genetics. Diet is one of the environmental factors that can modify the risk of cognitive decline. It is possible that dietary intake of saturated fats increases the risk of cognitive decline, while, in contrast, consumption of monounsaturated fatty acids such as olive oil as well as the consumption of fish is likely associated with a lower risk of cognitive decline (Cunnane et al., 2009). This chapter aims to (i) overview the epidemiological evidence of a potential link between dietary fats and cognitive decline; (ii) investigate the

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impact of aging and genetic factors on omega-3 fatty acid metabolism and risk of cognitive decline; (iii) outline the implications for the food industry, nutritionists and policy-makers; and (iv) propose future trends in nutrition for better cognition.

20.2 Epidemiological link between dietary fats and cognitive decline Prospective studies, as opposed to cross-sectional studies, have the best experimental design to support an association between dietary fat intake and risk of AD. However, strictly, the only evidence of causality comes from intervention studies in which individuals similar at the outset are randomly allocated to a treatment such as dietary intake of omega-3 fatty acids and the outcomes of the groups are compared after sufficient follow-up time. The main issues with intervention studies to investigate cognitive decline are (i) follow-up of the intervention would be in the range of years; (ii) the incidence of cognitive decline in Canada is about 10 % between 65 and 84 years old so that hundreds of participants per intervention group would be needed; (iii) metabolic problems and strokes are more likely to occur in the elderly during the follow-up, thereby contributing indirectly to the incidence of some vascular forms of cognitive decline such as vascular dementia; (iv) compliance over years would be difficult to achieve and there would probably be a high dropout rate; and (v) such intervention studies would be very costly and time-consuming. Therefore, the best available data on the link between dietary intake and risk of cognitive decline are to be found from prospective epidemiological studies, but the effectiveness by the latter depends crucially on their experimental design. Good practice should include follow-up of more than seven years because this reduces any bias due to sub-clinical dementia (Engelhart et al., 2002). Indeed, in individuals susceptible to decline in specific cognitive domains, a three-year follow-up period was not sufficient to detect a statistical difference based upon dietary intakes (Wahlin et al., 2005). Another good practice is to select the administered food frequency questionnaires (FFQ) carefully in order to accurately evaluate intakes, most specifically of fish and omega-3 fatty acids. Because questions regarding fish intake often amount to: ‘How many times per week do you eat fish?’, dietary intakes of omega-3 fatty acids are not well estimated. Indeed, omega-3 fatty acid concentration differs in lean vs fatty fish and in fried vs non fried fish, suggesting that the administered FFQ needs to ask additional and specific questions on fish and seafood intakes. Finally, comparison between prospective studies is often not possible because there is no consensus about the definition of cognitive decline (Cunnane et al., 2009). A diagnosis of cognitive decline based on a single

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Fatty acid intake and cognitive decline Saturates Stearic acid

Monounsaturates Oleic acid

O

527

OH

OH O

Polyunsaturates Eicosapentaenoic acid (EPA)

Docosahexaenoic acid (DHA)

OH O OH O

Fig. 20.1 Chemical structures of saturates, monounsaturates and polyunsaturates fatty acids.

cognitive test shouldn’t be considered valid whereas the gold standard should include a battery of cognitive tests evaluating the different cognitive domains. Signs of dementia should be evaluated by a neuropsychologist and diagnosis should be confirmed by a geriatrician.

20.2.1 Prospective studies on saturated and trans fatty acid intakes Figure 20.1 shows the chemical structure of saturated fatty acids while trans fatty acids (not represented in Fig. 20.1) have the same straight chemical structures as saturated fatty acids. Saturated and trans fatty acids have been associated with higher risk of cardiovascular disease. The impact of saturated and trans fats on cognition has, however, been less investigated, and to our knowledge, there are only four studies reporting a potential association between saturated and/or trans fat consumption and risk of cognitive decline as reported in Table 20.1 (Kalmijn et al., 1997b; Engelhart et al., 2002; Morris et al., 2003a; Eskelinen et al., 2008). Of these four studies, three reported increased risk of cognitive decline with higher intake in saturated or trans fats. Morris et al. reported that the risk in cognitive decline was 2.2 times higher for people eating 25.1 g/day vs 13.0 g/day of saturated fats after adjusting the multivariate model for age, sex, race, education and apolipoprotein E ε4 (ApoE4) status (Morris et al., 2003a). Hence, there may be a link between saturated and trans fatty acid intake and higher risk of cognitive decline but, because the number of studies is limited, we can not draw a definite conclusion.

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Table 20.1 Prospective observational studies relating saturated, trans and monounsaturated fatty acid intake to risk of dementia or cognitive decline Study

N

Age (years)

A. Saturated and trans fatty acids 5386 Kalmijn et al. (1997b) Engelhart et al. (2002) Morris et al. (2003) Eskelinen et al. (2008)

5395

≥55

815

≥65

1449

60–80

B. Monounsaturated fatty acids Engelhart et al. (2002) 5395 Solfrizzi et al. (2006)

≥55

704

≥55 65–84

Results (multivariate models) Increase risk with saturated fatty acid intake No association with saturated and trans fatty acids Risk increased by 2.2 times for people eating 25.1 g/day vs. 13.0 g/day of saturated fats. Saturated fatty acids associated with poorer cognitive function and increase risk of mild cognitive impairment No association with monounsaturated fatty acids Monounsaturated fatty acid was associated with preservation of cognitive function.

20.2.2 Prospective studies on monounsaturated fatty acids intakes The Mediterranean diet is composed of a high intake of olive oil which has a high concentration of non-hydrogenated monounsaturated fatty acids (Fig. 20.1). The cardio-protective effect of the Mediterranean diet is likely due to the high intake of extra virgin olive oil and to consumption of ample fruits and vegetables. Only three prospective studies have investigated the link between the intake of monounsaturated fats and risk of cognitive decline (Table 20.1B). The prospective study of Solfrizzi et al. (2006) reported an association between monounsaturated fat intake and preservation of cognitive functions over time, but the others found no association. Because of the scarcity of studies, it is too early to draw conclusions about monounsaturated fatty acid intake and risk of cognitive decline.

20.2.3

Prospective studies on polyunsaturated fatty acids: omega-3 fatty acids intakes Fish and seafood are rich sources of long-chain omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA; 20 : 5 omega-3) and docosahexaenoic acid (DHA; 22 : 6 omega-3) (Fig. 20.1). In North America, fish consumption is low compared to Asiatic countries such as Japan (Lucas et al., 2010). Among the dietary nutrients most closely associated with optimal function of the brain, DHA is particularly important.

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Table 20.2 Prospective observational studies relating fish or dietary DHA consumption to risk of dementia or cognitive decline Study

N

A. Protective association 1 Kalmijn et al. (1997b) 5386

Age (years) ≥55

Results (multivariate models)

2 Barberger-Gateau et al. (2002) 3 Morris et al. (2003b) 4 Morris et al. (2005)

1416

≥68

815 3718

65–94 ≥65

5 Huang et al. (2005)

2233

≥65

6 Barberger-Gateau et al. (2007) 7 Van Gelder et al. (2007) 8 Eskelinen et al. (2008) 9 Beydoun et al. (2008)

8085

≥65

210

70–89

Fish consumption of at least 18.5 g/day Fish intake at least once per week Fish consumption Fish intake at least once per week Nonfried fish intake but only in non-carriers of ApoE4 Fish intake but only in non-carriers of ApoE4 Fish and EPA + DHA intake

1449

60–80

Higher intake of PUFA and fish

7814

50–65

Higher omega-3 PUFA and balanced omega-6/omega-3 ratio

B. Non-protective or non-significant association 1 Kalmijn et al. (1997a) 342 69–89 Fish inversely but not significantly associated 2 Engelhart et al. 5395 No association with any class of ≥55 fatty acids (2002) 3 Schaefer et al. (2006) 488 76 No significant association 1025 n/a No association with fish or EPA 4 van de Rest et al. + DHA intake (2009)

Prospective studies on the intake of fish or omega-3 fatty acids have been conducted in France, the Netherlands, Scandinavia, Italy and the US (Table 20.2). Of the 13 such published prospective studies, nine reported lower risk of cognitive decline, dementia or AD in the elderly with the highest intake of fish or long-chain omega-3 fatty acids (Kalmijn et al., 1997b; BarbergerGateau et al., 2002, 2007; Morris et al., 2003b, 2005; Huang et al., 2005; Beydoun et al., 2007; van Gelder et al., 2007; Eskelinen et al., 2008.), while four studies reported either a non-significant association or no association (Kalmijn et al., 1997a; Engelhart et al., 2002; Schaefer et al., 2006; van de Rest et al., 2009) (Table 20.2). Hence, there is emerging evidence supporting the link between higher fish intake and lower risk of cognitive decline. However, the link between higher EPA + DHA intake and lower risk of cognitive decline is less consistent, suggesting the possibility that there is a nutrient in fish other than EPA and DHA that lowers risk of cognitive decline. Fish consumption is viewed as a component of a healthy diet, one that also includes the higher fruit and vegetable consumption which

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provides vitamin C, carotenoids and polyphenols exerting potentially important anti-oxidant effects which could contribute to slowing down brain aging. Fish also contains fish protein, iodine and selenium which might also have synergistic effects which would enhance the protective action of DHA against brain aging. For instance, selenium is an anti-oxidant that may help protect DHA against lipid peroxidation. EPA and DHA intake from food frequency questionnaires may not be well estimated since it changes according to fish species, origin of the fish and the time of year the fish was caught. To date, data from prospective studies are the best available to support a link between higher dietary intake of fish and lower risk of cognitive decline, dementia or AD. However, while they are much better than crosssectional studies due to the temporal relationship, prospective studies still do not establish causality. Epidemiology only offers correlations and as diet is predictive of so many social, cultural, psychological and economic factors, it is difficult to be certain that diet is key. Data from prospective studies are adjusted because independent correlations have shown that age, sex, socioeconomic status, dietary habits, depression and vascular risk are potential confounders to be considered in the relationship between fish consumption and risk of dementia (Barberger-Gateau et al., 2005). Another possibility to explain the inconsistencies in the link between EPA + DHA intake and lower risk of cognitive decline is the potential alteration in the metabolism of EPA and DHA during aging or the differences associated with the ApoEgene.

20.3 Omega-3 fatty acids metabolism and risk of cognitive decline 20.3.1 The impact of aging Emerging evidence suggests that omega-3 fatty acid metabolism changes during aging. Indeed, a recent study by de Groot et al. (2009) reported that DHA in plasma phospholipids (PL) is age-dependent such that after correction for fish intake, age explained 2.3 % of DHA concentration variance and 3.9 % of the variance in EPA concentration (de Groot et al., 2009). A multivariate analysis, Sands et al. (2005) reported that four factors significantly and independently influencing EPA + DHA in red blood cells: fish servings, age, body mass index and diabetes. The study population included 163 individuals between the ages of 20 and 80 years. They showed that every additional 10 years of age increased EPA + DHA in red blood cell by 0.5 % expressed as a percentage of total fatty acids (Sands et al., 2005). In contrast, a study with 200 women over 75 years of age reported that EPA and DHA in erythrocytes, plasma total lipids, triglycerides (TG), cholesteryl esters (CE) and PL was not significantly different in 50 young female volunteers aged between 20 and 48 years (Babin et al., 1999). However, the statistical

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methods used by Sands et al. (2005) differed from those in Babin et al. (1999), and this may in part explain the discrepancy in the results. With regard to the plasma response to an omega-3 fatty acid supplement, omega-3 of plasma total lipids was higher in the elderly compared to the young (Vandal et al., 2008). At baseline, EPA was on average about 50 % higher in elderly compared to young adults (Rees et al., 2006;Vandal et al., 2008, Plourde et al., 2009a). Moreover, EPA in plasma PL and total lipids of elderly consuming an EPA-enriched supplement was 50–100 % higher compared to that of the young (Rees et al., 2006; Vandal et al., 2008). In response to a supplementation of 320 mg/day of EPA and 680 mg/day of DHA for three weeks, DHA rose 42 % more in plasma total lipids of the elderly compared to the young. We also have unpublished results using a much more sensitive and precise method, 13C-DHA tracing, which evaluated the incorporation and degradation of DHA and showed that incorporation and β-oxidization of 13C-DHA was significantly higher in the elderly four hours after tracer intake. Hence, there is increasing evidence that the metabolism of EPA and DHA is altered with aging, but whether or not these changes impact cognition is not clear. EPA and DHA are precursors of molecules used in gene regulation and anti-inflammatory mechanisms (Calder, 2003). They are also important building blocks for neuronal cell membranes that have key roles in neurotransmission (Bazan, 2007). Hence, alterations in the metabolism of EPA and DHA during aging can potentially counteract the changes induced by inflammation and neurotransmission, although these are speculative suggestions. There is a clear need for studies of aging to use a multidisciplinary approach to link cognitive testing, inflammatory markers, neurotransmission and gene regulation with omega-3 metabolism.

20.3.2 The impact of genetics Genetics also plays an important role in the incorporation and degradation of omega-3 fatty acids in the blood. Having the ApoE4 allele is the most important genetic risk factor associated with Alzheimer’s disease, but not all carriers develop AD, suggesting that factors in the environment are possibly interacting with ApoE in the risk of AD. ApoE genotype is highly responsive to dietary fat manipulation (Minihane et al., 2007). For instance, in 11 studies a gene–diet interaction was observed that supported the view that those carrying ApoE4 were most responsive to dietary fat manipulation, including modification in saturated, monounsaturated or polyunsaturated fats (reviewed by Masson and McNeill (2005, and Minihane et al., 2007). For example, in a recent study, total cholesterol increased by 10 % in ApoE4 carriers whereas there was a non-significant 4 % reduction in ApoE3 carriers after a supplementation with 3.7 g/day of DHA (Olano-Martin et al., 2010). However, little is known about whether the ApoE4 allele affects specifically omega-3 fatty acid metabolism. In two prospective

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epidemiological studies on fish intake and risk of cognitive decline, unlike those without the ApoE4 allele, those carrying the ApoE4 allele were not protected against cognitive decline by fish intake (Huang et al., 2005; Barberger-Gateau et al., 2007). Since fish contains high concentration of omega-3 fatty acids, it was proposed that there may be alterations in the omega-3 fatty acid metabolism in the ApoE4 carriers (Huang et al., 2005; Cunnane et al., 2009). The proposed alteration in the link between cognition and omega-3 fatty acid metabolism is also supported by the study of Whalley et al. (2008), who showed that cognitive scores were correlated with erythrocyte omega-3 concentration in only those without an ApoE4 allele. In a pilot study with 20 non-carriers of ApoE4 and eight carriers of at least one allele of ApoE4, EPA and DHA in plasma TG was 67 % and 60 % higher in carriers of ApoE4 (Plourde et al., 2009b). After receiving a supplement of 1.9 g/day of EPA and 1.1 g/day of DHA for six weeks, there were significant gene–diet interactions in the incorporation of both EPA in free fatty acids (FFA) and DHA in TG of plasma such that in carriers of ApoE4, increases in the two fatty acids were lower compared to the non-carriers. Since ApoE is a component of lipoproteins, the altered incorporation of omega-3 fatty acids is possibly linked with altered transport of both EPA and DHA. This is supported by a recent study with the objective of investigating the impact of ApoE4 genotype on the response of the plasma lipoprotein profile to EPA versus DHA (Olano-Martin et al., 2010). In this study, 38 healthy normolipideamic subjects received either 3.7 g/day of DHA or 3.3 g/d of EPA in random order, or a placebo oil in a double-blind placebo-controlled crossover trial (Olano-Martin et al., 2010). They reported a gene–diet interaction with DHA intake such that total cholesterol in ApoE4 carriers was increased following the supplementation, possibly due to an increase in low-density lipoprotein cholesterol (LDL-C) (Olano-Martin et al., 2010). In the plasma very low-density lipoprotein (VLDL2) fraction of ApoE4 carriers, intake of DHA resulted in a significant 32 % reduction in LDL uptake relative to control oil intake, thus supporting the idea that ApoE is involved in the alteration of transport and uptake of lipoproteins (Olano-Martin et al., 2010). However, this study did not investigate whether the incorporation of DHA in the different type of lipoproteins differed by ApoE4 genotype or whether differences in LDL uptake account for differences between those with and without the ApoE4 allele. The genome-wide association scan (GWAs) is another genetic approach linking variance of biochemical factors such as plasma fatty acid concentration with single-nucleotide polymorphisms. The technique has gained considerable momentum over the last few years in the identification of new genes responsible for various diseases such as diabetes (Rampersaud et al., 2007), obesity (Lindgren et al., 2009; Thorleifsson et al., 2009), and cognitive decline (Bertram and Tanzi, 2009). One recent study has also looked at the impact of single-nucleotide polymorphisms on the incorporation of long-

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chain polyunsaturated fats in plasma (Tanaka et al., 2009). They reported that polymorphisms of genes encoding enzymes in the metabolism of PUFAS contribute to plasma concentration of fatty acids (Tanaka et al., 2009). Their strongest association was with three fatty acid desaturases (FADS1, FADS2 and FADS3) for arachidonic acid and EPA but not DHA. Outside the FADS gene cluster, the strongest association was with the elongase of very long fatty acid 2 (ELOV2) for EPA and DHA. However, the association with ELOV2 for EPA was not replicated in another cohort where the association with this gene was with DHA (Tanaka et al., 2009). Replication is imperative and the gold standard in GWAs studies because there is a high probability of false positive results due to multi-statistical testing. Therefore, since the ELOV2 gene association has not been replicated, other studies are needed to confirm whether this gene could interfere with the incorporation of EPA and DHA into erythrocytes and plasma lipids. The impact of genetic factors in the incorporation of EPA and DHA in plasma may explain in part the discrepancy in the literature on blood levels of EPA and DHA in cognitive decline. This new field of research that focuses on gene–diet interactions should be expanded in order to increase our awareness of who may respond to such treatment and who may not. With this knowledge, better nutritional recommendations could be made for a targeted population.

20.4 Implications for the food industry, nutritionists and policy-makers 20.4.1 How much of each fatty acid does the brain need? Most of the fatty acids ingested are in the form of TG. They are efficiently absorbed in the small intestine via facilitated diffusion. TGs are coupled to fatty acid binding proteins, which increase membrane permeability and promote cellular uptake of fatty acids and monoglycerides (Mu and Hoy, 2004). While saturated and monounsaturated fatty acids can be synthesized within the brain, long-chain omega-3 and omega-6 fatty acids must be supplied by the diet and then transported from peripheral circulation to the brain and other organs (Fig. 20.2) (Cooper, 2003; Igarashi et al., 2007). There is general agreement that diets in developed countries contain excess linoleic acid (18 : 2 omega-6) and even though the conversion rate of linoleic acid into arachidonic acid is low (the main long-chain omega-6 in brain membranes), it is apparently enough to prevent omega-6 deficiency and adverse health implications. Dietary intakes of omega-3 are, however, low in developed countries to the extent that those not eating fish are potentially deficient. The conversion rate from α-linolenic acid (ALA) to EPA is around 5 %, while that from ALA to DHA is less than 0.5 % (Plourde and Cunnane, 2007). Therefore, the majority of the available EPA

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Passive diffusion

Protein-mediated transport

DHA

Fatty acid transporters DHA-VLDL DHA-LDL

Peripheral lipoprotein lipase

Fig. 20.2 DHA transport in either lipoproteins or in its free form from the liver to the brain. There are two different pathways of transport and brain uptake represented by the different colors (white and grey) of the arrows and circles. DHA = docosahexaenoic acid, VLDL = very low-density lipoprotein.

and DHA in plasma comes from the diet, as evidenced in a trial by Vidgren et al. (1997) who found that fish consumption was associated with higher plasma or erythrocyte EPA and DHA levels. Because omega-6 and omega-3 compete for a number of enzyme systems, it is tempting to use a ratio of omega-6 /omega-3 as a biomarker on which to base nutritional recommendations. However, there are few human experiments that support this view; rather the EPA and DHA intake and the levels in the blood appear to be of greater importance than the ratio of omega-6 (Harris, 2006). Because there is only one method to study brain uptake of EPA and DHA – positron emitting tomography – the use of animal models is imperative. Studies in rats using labelled DHA show that the liver plays a major role in DHA esterification, its uploading into lipoproteins and its subsequent delivery to the brain, heart and other organs (Polozova and Salem, 2007). DHA is selectively incorporated into the VLDL-TG pool in animals and a significant proportion of the labelled DHA-derived activity is in LDL (Fig. 20.2). This is probably because DHA is a poor substrate for peripheral lipoprotein lipase and therefore when VLDL is converted to LDL, DHA remains associated with the LDL (Polozova and Salem, 2007). Then, DHA is hydrolyzed and taken up by the fatty acid transporters to the brain where

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it is esterified to PL or metabolized (grey path, Fig. 20.2). Alternatively, unesterified PUFAs enter the brain via protein-mediated transport or passive diffusion (white path, Fig. 20.2) (Chen et al., 2008). If DHA is available, it is incorporated into brain PL much faster than other fatty acids, such as linoleic and ALA, that circulate simultaneously with DHA (Robinson et al., 1992; Chen et al., 2008). If DHA is not available, as when rats are fed a diet deficient in omega-3 fatty acid, the fatty acid profile of the brain is altered. Indeed, brain DHA was reduced by 30–50 % compared to the control diet containing ALA (Ximenes daSilva et al., 2002) and DHA was replaced by the omega-6 docosapentaenoic acid (DPA; 22 : 5 omega-6). These changes in fatty acid composition resulted in a 30 % decrease in brain glucose uptake and in a 20–40 % decrease in cytochrome oxidase activity, a metabolic marker of neuronal functional activity (Ximenes daSilva et al., 2002). Deficiencies in omega-3 have been reported in three human studies reviewed by Plourde and Cunnane (2007), but naturally the brain fatty acid profile is not available. Two of these cases involved girls of 6 and 7 years old (Holman et al., 1982; Bjerve et al., 1988) and the other study involved three adults (Bjerve et al., 1989), all of them being fed solely by gastric tube with very low concentration of ALA and no EPA + DHA. After five months of parenteral nutrition, the six years old girl experienced episodes of numbness, paresthesia, weakness, inability to walk, pain in the legs and blurring of vision (Holman et al., 1982). The 7 year old girl was fed solely by gastric tube from the age of 3 years. She weighed 9.5 kg at the age of 3, and 10.3 kg at the start of the study, the weight being constant the last 15 months. After giving her linseed and cod liver oil for seven months, she gained 4 kg and 5 cm in length, suggesting that omega-3 fatty acids are required for normal growth of the children (Bjerve et al., 1988). In the three adults, observed clinical symptoms were hemorrhagic dermatitis, hemorrhagic folliculitis, skin atrophy and scaly dermatitis, all of which began to normalize within 10 days after starting a supplementation with ALA followed by purified fish oil (Bjerve et al., 1989). Hence, these examples show that the omega-3 fatty acids are essential for normal growth and for general health. Therefore, we may speculate that in countries with a low consumption of omega-3 fatty acids, the alteration in brain fatty acid composition over the lifespan may have the potential to cause disorders of the brain in later life. Although EPA enter the brain at a similar rate compared to DHA in the rat, its accumulation into brain membrane is very limited. This is potentially because EPA is much more rapidly β-oxidized upon its uptake by the brain (Chen et al., 2009). However, total brain uptake of EPA evaluated by an in situ brain perfusion technique in mice is similar to brain DHA uptake (Ouellet et al., 2009). These results address the question of the role of EPA versus DHA in the brain. It remains unclear as to whether each are essential for brain function, and whether they are both an essential part of our diet.

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In humans, studies suggest that DHA is rapidly and preferentially incorporated into the TG fraction of most lipoproteins after intake and that, within a few hours, TG concentration tends to decrease. Usually, after dietary supplementation with either fish or fish oil, blood EPA and DHA concentrations increase in a dose-dependent manner (Blonk et al., 1990; Vidgren et al., 1997; Arterburn et al., 2006), reaching a plateau after 15 days of supplementation (Sadou et al., 1995;Vandal et al., 2008). Moreover, a plateau was reached in plasma PL with 2–3 g/day of DHA for one month, (Blonk et al., 1990; Arterburn et al., 2006), but not for EPA, suggesting that the metabolism of EPA is not similar to that of DHA. EPA may be preferentially incorporated into the cholesteryl ester of all lipoproteins, reaching a saturation point by day 15 (Sadou et al., 1995). Many health organizations such as the American Heart Association have recommended an intake of 500 mg/day of EPA + DHA since at this dose, there is lower risk of cardiac infarction. However, no clear recommendation regarding the dose of EPA + DHA was set for the brain. The team led by Dr Rapoport support the proposition that DHA turnover is an estimate of what the brain needs (Rapoport, 2006). However, they have suggested that the DHA turnover is about 4 mg/day, suggesting that the amount the brain needs is well below the recommendation of 500 mg/d of both omega-3s for the cardio-protective effect. The gap between the recommendations and the turnover of DHA in brain membranes can potentially be compensated by the other roles DHA has in the body, such as being a precursor of signalling pathways and gene regulation and being implicated in neurotransmission. However, whether the turnover rate estimated by Rapoport et al. takes into account all these biochemical reaction is not clear. Therefore, there is clearly a crucial need for more fundamental research on the role of EPA and DHA and how much we need for optimal brain function.

20.4.2 Stability and taste of polyunsaturated fats in food products Incorporating marine long-chain omega-3 fatty acids in food products is a real challenge because of its fishy taste and poor oxidation stability. This is why many food products are enriched with flax oil containing ALA (18 : 3 omega-3) instead of fish oil. However, we believe that fish oil remains the best and probably the only source of preformed EPA and DHA because the conversion rate from ALA to EPA and DHA is low (Plourde and Cunnane, 2007). Because this conversion is much more efficient in rats (Igarashi et al., 2007), many food companies have extrapolated this evidence to make inaccurate conclusions with regards to omega-3 metabolism in humans. One way to address the problems associated with the addition of DHA and EPA in food products is to encapsulate fish oil. This technology is pro-

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posed as a suitable way to lower fishy taste and increase the oxidation stability of the oil (Kolanowski et al., 2004) leading to enhanced shelf life of the enriched food products. However, there are rising concerns about the sustainability of a potential massive increase in omega-3 fatty acid consumption in a context of decreasing fish stocks. There are also various concerns regarding the safety of fish sources of EPA and DHA. Some fish contain relatively high concentrations of mercury and other pollutants, although the fish containing the highest concentration in omega-3 are smaller and tend to be less contaminated (Doughman et al., 2007). Moreover, fish from different sources contains different ratios and concentrations of EPA and DHA. For instance, whitefish such as cod contain oil only in the liver and much less overall compared to fatty fish such as mackerel which has oil in its tissues and in the belly cavity around the gut. Mackerel fillet may contain around 1.8 g omega-3 fatty acids per 100 g fish. An alternative to fish is the use of ocean algae from which an oil rich in DHA but low in EPA is extracted (Doughman et al., 2007). Hence, there is increased interest in providing new sources of omega-3, and DHA-rich microalgae oils have recently been proposed as a safe and apparently sustainable solution to the problem of an adequate supply (Doughman et al., 2007). Another alternative to fish oil is the development of genetically modified seed-crops that are able to synthesize long-chain omega-3 fatty acids (Venegas-Caleron et al., 2010). However, whether this alternative will be well accepted by consumers has still to be established.

20.4.3 Personalized nutrition or general recommendations? Nutrigenetics is a relatively new area of nutritional science and there is still controversy about whether it should be used to establish dietary requirements. Although the body of evidence in nutrigenetics is growing, its potential currently suffers from a lack of reproducibility in the findings. Since genes such as ApoE4 affect fatty acid metabolism, there maybe a need for personalized nutritional guidelines. However, few people know their genetic background, and the reliability of their genetic information remains questionable. Thus, there is a need for a comprehensive understanding of the penetrance of the genotypes in population sub-groups, their mechanisms of action, and whether multiple genetic variants interact (Rimbach and Minihane, 2009). Although genetic profiling is becoming increasingly cost-effective, the idea of personalised nutrition based on genetics is currently not ready for widespread use as a public health strategy. Hence, currently it is best to follow dietary recommendations from your country or the recommendations made by the International Society for the Study of Fatty Acids and Lipids (see ‘Sources of further information and advice’).

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20.5 Future trends for better cognition While one’s genes and age are two non-modifiable factors in the risk of cognitive decline, there are other ways to help preserve cognitive functioning as one ages. Diet is definitely one of them, and there is a need for more research on the association between EPA and DHA intake and cognition, and on requirements as they vary over the life-cycle. Although the current dose needed is not well established, the intake is low in North America (Lucas et al., 2010), and thus there is a need for more food products enriched in EPA and DHA. Indeed, discrepancies with regard to the metabolism and health effects of each particular omega-3 fatty acid in humans vs animal models have confused the industries formulating new food products. The blurring of the distinction between the plant-derived and marine-derived omega-3 in industry but also by scientists has confused customers. In 2002 in Canada, nutrient content claims were no longer permitted for PUFAS; nor may claims be made about individual fatty acids such as DHA. Only claims such as ‘source of omega-3 fatty acid’ or ‘contains or provides omega-3 fatty acid’ were allowed. If the claim for omega-3 fatty acid is made, then the label of that food product must comply with all the requirements of the Canadian regulation, and must include a Nutrition Facts table. There is an additional regulation regarding the quantitative statements for individual fatty acids requiring that it appears as a separate statement such as ‘0.1 g of DHA’. If a dietary reference intake were to be established, there would be the additional concern of whether suppliers could meet the increased demand for marine-derived omega-3 fatty acids in a sustainable manner (Harris et al., 2009). Since many don’t like fish and because it is not part of their usual dietary intake, food products enriched in EPA and DHA may help to increase EPA + DHA intake. However, it will be difficult to achieve the recommendation of 500 mg/day with food supplementation without altering the taste of the food product.

20.6 Sources of further information and advice Book chapters • Plourde M. Does altered omega-3 fatty acid metabolism contribute to cognitive aging? In Cognitive Aging: Causes, Processes and Effects, Gariépy, Q. Méward, R. (eds), Nova Science Publishers, Hauppauge, NY, USA, 2009. • Bégin ME, Plourde M, Pifferi F, and Cunnane SC. Are fish and docosahexaenoic acid linked to lower cognitive decline and Alzheimer’s disease? In Recent Advances on Nutrition and the prevention of

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Alzheimer’s Disease, Ramassamy C and Bastianetto S (eds), Research Signpost/Transworld Research Network, Philadelphia, PA, 2009. Websites • International Society for the Study of Fatty Acids and Lipids (ISSFAL): http://www.issfal.org.uk/ • Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA) journal: http://www.sciencedirect.com/science/journal/09523278 • Omega-3 learning for health and medicine: http://www.omega3learning. purdue.edu/

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acid deficiency: effect on lymphocyte function, plasma and red cell lipids, and prostanoid formation. Am J Clin Nutr, 49 (2), 290–300. blennow k, de leon m j, and zetterberg h (2006) Alzheimer’s disease. Lancet, 368 (9533), 387–403. calder p c (2003) N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. Lipids, 38 (4), 343–352. chen c t, ma d w, kim j h and others (2008) The low density lipoprotein receptor is not necessary for maintaining mouse brain polyunsaturated fatty acid concentrations. J Lipid Res, 49 (1), 147–152. chen c t, liu z, ouellet m, calon f and others (2009) Rapid beta-oxidation of eicosapentaenoic acid in mouse brain: an in situ study. Prostaglandins Leukot Essent Fatty Acids, 80, 157–163. cooper j l (2003) Dietary lipids in the aetiology of Alzheimer’s disease: implications for therapy. Drugs Aging, 20, 399–418. cunnane s c, plourde m, pifferi f and others (2009) Fish, docosahexaenoic acid and Alzheimer’s disease. Prog Lipid Res, 48 (5), 239–256. de groot r h, van boxtel m p, schiepers o j and others (2009) Age dependence of plasma phospholipid fatty acid levels: potential role of linoleic acid in the ageassociated increase in docosahexaenoic acid and eicosapentaenoic acid concentrations. Br J Nutr, 102 (7), 1058–1064. doughman s d, krupanidhi s and sanjeevi c b (2007) Omega-3 fatty acids for nutrition and medicine: Considering microalgae oil as a vegetarian source of EPA and DHA. Curr Diabetes Rev, 3, 198–203. engelhart m j, geerlings m i, ruitenberg a and others (2002) Diet and risk of dementia: Does fat matter? The Rotterdam Study. Neurology, 59 (12), 1915–1921. eskelinen m h, ngandu t, helkala e l and others (2008) Fat intake at midlife and cognitive impairment later in life: a population-based CAIDE study. Int J Geriatr Psychiatry, 23 (7), 741–747. harris w s (2006) The omega-6/omega-3 ratio and cardiovascular disease risk: uses and abuses. Curr Atheroscler Rep, 8 (6), 453–459. harris w s, mozaffarian d, lefevre m and others (2009) Towards establishing dietary reference intakes for eicosapentaenoic and docosahexaenoic acids. J Nutr, 139, 804S–819S. holman r t, johnson s b and hatch t f (1982) A case of human linolenic acid deficiency involving neurological abnormalities. Am J Clin Nutr, 35 (3), 617–623. huang t l, zandi p p, tucker k l and others (2005) Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4. Neurology, 65 (9), 1409–1414. igarashi m, ma k, chang l and others (2007) Dietary n-3 PUFA deprivation for 15 weeks upregulates elongase and desaturase expression in rat liver but not brain. J Lipid Res, 48 (11), 2463–2470. kalmijn s, feskens e j m, launer l j and others (1997a) Polyunsaturated fatty acids, antioxidants, and cognitive function in very old men. Am J Epidemiol, 145 (1), 33–41. kalmijn s, launer l j, ott a and others (1997b) Dietary fat intake and the risk of incident dementia in the Rotterdam study. Ann Neurol, 42 (5), 776–782. kolanowski w, laufenberg g and kunz b (2004) Fish oil stabilisation by microencapsulation with modified cellulose. Int J Food Sci Nutr, 55 (4), 333–343. lindgren c m, heid i m, randall j c and others (2009) Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution. PLoS Genet, 5 (6), e1000508.

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lucas m, asselin g, plourde m and others (2010) n-3 Fatty acid intake from marine food products among Quebecers: comparison to worldwide recommendations. Public Health Nutr, 13 (1), 63–70. masson l f and mcneill g (2005) The effect of genetic variation on the lipid response to dietary change: recent findings. Curr Opin Lipidol, 16 (1), 61–67. minihane a m, jofre-monseny l, olano-martin e and others (2007) ApoE genotype, cardiovascular risk and responsiveness to dietary fat manipulation. Proc Nutr Soc, 66 (2), 183–197. morris m c, evans d a, bienias j l and others (2003a) Dietary fats and the risk of incident Alzheimer disease. Arch Neurol, 60 (2), 194–200. morris m c, evans d a, bienias j l and others (2003b) Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol, 60 (7), 940– 946. morris m c, evans d a, tangney c c and others (2005) Fish consumption and cognitive decline with age in a large community study. Arch Neurol, 62 (12), 1849–1853. mu h and hoy c e (2004). The digestion of dietary triacylglycerols. Prog Lipid Res, 43, 105–133. olano-martin e, anil e, caslake m j and others (2010) Contribution of apolipoprotein E genotype and docosahexaenoic acid to the LDL-cholesterol response to fish oil. Atherosclerosis, 209 (1), 104–110. ouellet m, emond v, chen c t and others (2009) Diffusion of docosahexaenoic and eicosapentaenoic acids through the blood-brain barrier: An in situ cerebral perfusion study. Neurochem Int, 55, 476–482. plourde m (2009) Does altered omega-3 fatty acid metabolism contribute to cognitive aging? In Gariépy Q and Ménard R (eds), Cognitive Aging: Causes, Processes and Effects. Hauppauge, NY: Nova Science Publishers, 305–322. plourde m and cunnane s c (2007) Extremely limited synthesis of long chain polyunsaturates in adults: Implications for their dietary essentiality and use as suppements. Appl Physiol Nutr Metab, 32 (4), 619–634. plourde m, tremblay-mercier j, fortier m and others (2009a) Eicosapentaenoic acid decreases postprandial beta-hydroxybutyrate and free fatty acid responses in healthy young and elderly. Nutrition, 25 (3), 289–294. plourde m, vohl m c, vandal m and others (2009b) Plasma n-3 fatty acid response to an n-3 fatty acid supplement is modulated by apoE epsilon4 but not by the common PPAR-alpha L162V polymorphism in men. Br J Nutr, 102 (8), 1121–1124. polozova a and salem n, jr (2007) Role of liver and plasma lipoproteins in selective transport of n-3 fatty acids to tissues: a comparative study of 14C-DHA and 3H-oleic acid tracers. J Mol Neurosci, 33, 56–66. rampersaud e, damcott c m, fu m and others (2007) Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations. Diabetes, 56 (12), 3053–3062. rapoport s i (2006) What are the normal rates of human brain metabolism of arachidonic and docosahexaenoic acids, and what may happen when their metabolic ballance is altered by dietary n-3 PUFA deprivation? ISSFAL (conference abstract). Cairns, Australia, July 23–28. rees d, miles e a, banerjee t and others (2006) Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men. Am J Clin Nutr, 83 (2), 331–342. rimbach g and minihane a m (2009) Nutrigenetics and personalised nutrition: how far have we progressed and are we likely to get there? Proc Nutr Soc, 68, 162–172.

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robinson p j, noronha j, degeorge j j and others (1992) A quantitative method for measuring regional in vivo fatty-acid incorporation into and turnover within brain phospholipids: review and critical analysis. Brain Res Brain Res Rev, 17 (3), 187–214. sadou h, leger c l, descomps b and others (1995) Differential incorporation of fish-oil eicosapentaenoate and docosahexaenoate into lipids of lipoprotein fractions as related to their glyceryl esterification: a short-term (postprandial) and long-term study in healthy humans. Am J Clin Nutr, 62 (6), 1193–1200. sands s a, reid k j, windsor s l and others (2005) The impact of age, body mass index, and fish intake on the EPA and DHA content of human erythrocytes 1. Lipids, 40 (4), 343–347. schaefer e j, bongard v, beiser a s and others (2006) Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol, 63 (11), 1545–1550. solfrizzi v, colacicco a m, d’introno a and others (2006) Dietary intake of unsaturated fatty acids and age-related cognitive decline: a 8.5-year follow-up of the Italian Longitudinal Study on Aging. Neurobiol Aging, 27, 1694–1704. tanaka t, shen j, abecasis g r and others (2009) Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study. PLoS Genet, 5 (1), e1000338. thorleifsson g, walters g b, gudbjartsson d f and others (2009) Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet, 41 (1), 18–24. van de rest o, spiro a, iii, krall-kaye e and others (2009) Intakes of (n-3) fatty acid and fatty fish are not associated with cognitive performance and 6-year cognitive change in men participating in the Veterans Affairs Normative Aging Study. J Nutr 139 (12), 2329–2336. van gelder b m, tijhuis m, kalmijn s and others (2007) Fish consumption, n-3 fatty acids, and subsequent 5-y cognitive decline in elderly men: the Zutphen Elderly Study. Am J Clin Nutr, 85 (4), 1142–1147. vandal m, freemantle e, tremblay-mercier j and others (2008) Plasma omega-3 fatty acid response to a fish oil supplement in the healthy elderly. Lipids, 43 (11), 1085–1089. venegas-caleron m, sayanova o and napier j a (2010) An alternative to fish oils: Metabolic engineering of oil-seed crops to produce omega-3 long chain polyunsaturated fatty acids. Prog Lipid Res, 49 (2), 108–119. vidgren h m, agren j j, schwab u and others (1997) Incorporation of n-3 fatty acids into plasma lipid fractions, and erythrocyte membranes and platelets during dietary supplementation with fish, fish oil, and docosahexaenoic acid-rich oil among healthy young men. Lipids, 32, 697–705. wahlin a, bunce d and wahlin t b (2005) Longitudinal evidence of the impact of normal thyroid stimulating hormone variations on cognitive functioning in very old age. Psychoneuroendocrinology, 30 (7), 625–637. whalley l j, deary i j, starr j m and others (2008) n-3 Fatty acid erythrocyte membrane content, APOE epsilon4, and cognitive variation: an observational follow-up study in late adulthood. Am J Clin Nutr, 87 (2), 449–454. ximenes dasilva a, lavialle f, gendrot g and others (2002) Glucose transport and utilization are altered in the brain of rats deficient in n-3 polyunsaturated fatty acids. J Neurochem, 81 (6), 1328–1337.

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Index

1-α-hydroxylase, 421 α-linolenic acid, 36, 37–8, 306–7, 465, 476–7 classification and structure, 33–4 α-secretase, 444 acetyl-L-carnitine (ALC), 333 acuity card procedure, 52 adenosine, 252–3 adhedonia, 496–7, 499 adult-onset hypothyroidism, 120 Ages and Stages Questionnaire, 42–3 Alcohol Amnesic Syndrome, 368 Alzheimer’s disease, 525 association with hypertension, 448–55 fruit juices and wine, 452–4 grape seed polyphenolic extract, 454–5 calorie intake and caloric restriction, 442–6 diabetogenic diets and AD amyloid pathology, 447–8 dietary lifestyles, macronutrient composition and caloric intake, 439–56 future trends, 455–6 neuropathology, 441 obesity and metabolic syndrome, 441–2 role of insulin, 446–8

Alzheimer’s Disease Assessment Scalecognitive sub-scale (ADAS-cog), 285 American ginseng see Panax quinquefolium American Thyroid Association, 121 amino acids, 331–4 carnitine, 332–4 L-tyrosine and tryptophan, 332 melatonin, 334 phenylalanine, 331–2 S-adenosyl-methionine, 332 amyloid precursor protein (APP), 402–3, 440 anaemia, 329 anthocyanins, 399 anti-social behaviour carbohydrate consumption and mood, 160–76 chocolate – macronutrients or palatability, 173–5 future trends, 175 hypoglycaemia, 162–4 metabolism and mood, 161–2 refined carbohydrate, 170–3 serotonin synthesis, 164–70 micronutrient status and refined carbohydrate consumption, 171–3

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544

Index

antioxidants, 377–82 dementia, 392–412 anxiety, 260–3 caffeine consumption and levels of depressed mood, anxiety and stress, 262 ApoE4, 531–2, 537 arachidonic acid, 465 accretion in human brain development, 37–8 levels in human milk, 36 neuronal membrane, 38–9 neurotransmission, 39–40 Aricept, 275 ascorbic acid, 101 Asian Ginseng see Panax ginseng atomoxetine, 340 attention deficit hyperactivity disorder, 87–8, 119, 303–4 alternative treatments, 325–6 botanicals, 337–40 Hypericum perforatum (St. John’s wort), 339–40 Panax quinquefolium (American ginseng) and Ginkgo biloba, 339 Passiflora incarnata, 340 Pinus pinaster bark extract (Pycnogenol), 337–8 food intolerance, 344–5 future trends, 347–8 implications for food industry, nutritionists and policy-makers, 346–7 multi-ingredient formulations, 340–4 nutrients, 327–37 amino acids, 331–4 iron, 329–30 magnesium, 331 polyunsaturated fatty acids, 334–7 pyridoxine (vitamin B6), 327 zinc, 327–9 nutrition and diet in learning and behaviour of children with symptoms, 323–48 nutrition and the brain, 326–7 treatment, 324–5 autism, 372–4 Ayurvedic medicine, 451

β-amyloid, 440 B vitamins, 200 and homocysteine levels, 202–222 biochemical status, 202–222 dietary intake, 222 intervention studies, 224–234 randomised controlled trials, 225 Bacopa monnieri, 283–4 Bayley Scales of Infant Development, 42, 82, 98 beri-beri amnesia, 367–8 Berocca Stress Index, 235 bioflavonoids, 378 bipolar disorder essential fatty acids, 507–9 correlational studies, 507–8 epidemiological studies, 507 intervention studies, 508 role of vitamin D, 429 black tea, 402 blood glucose, 136–7 blood glucose control, 164 Boehm Test of Basic Concepts – Preschool version, 304 Brahmi, 283 brain development, 6–7 sequence of events in brain structural development, 7 brain growth spurt, 6 Brazelton Neonatal Behavioural Assessment Scale, 81–2 caffeic acid, 398 caffeine alerting and psychomotor effects, 255–60 contrasting effects, 258 anxiety, 260–3 caffeine consumption and levels of depressed mood, anxiety and stress, 262 effect on mood and cognition, 251–67 implications for food industry, nutritionists and policy-makers, 265–7 intake and its physiological effects, 252–3 reinforcement, 253–5

© Woodhead Publishing Limited, 2011

Index tea and coffee consumption and risk of cognitive decline, 263–5 caloric intake, 439–56 caloric restriction, 442–6 CaNa2EDTA, 101 carbohydrate craving depression, 169–70 carbohydrates chocolate – macronutrients or palatability, 173–5 psychological or physiological reaction, 174–5 cognitive performance, 135–44 blood glucose, 136–7 glucose regulation, 142–4 glycaemic index, 138–40 glycaemic load, 140–2 inconsistencies in the glucosecognition relationship, 138 observed effects of glucose, 135–6 consumption, anti-social behaviour and mood, 160–76 fat manipulations, 134–5 future trends, 175 hypoglycaemia, 162–4 blood glucose control and mood, 164 metabolism and mood, 161–2 mood under demanding condition, 161–2 short-term effects of intake, 161 protein manipulations, 133–4 refined, consumption of, 170–3 micronutrient status and anti-social behaviour, 171–3 serotonin synthesis, 164–70 consumption and depression, 167–70 carnitine, 332–4 carotenoids, 378 carvedilol, 449–50 catechins, 399, 402–5 anti-inflammatory property, 404 antioxidant properties, 402–3 Aβ-mediated pathology, 404–5 catechins and apoptosis, 403–4 CDR08, 284 central conduction time, 99

545

Centre for Epidemiologic Studies Depression Scale (CESD), 223 Child Behaviour Checklist, 304 child development, 96–7 conceptual model of iron deficiency and child behaviour, 96 Children’s Behaviour Questionnaire, 304 chocolate macronutrients or palatability, 173–5 psychological or physiological reaction, 174–5 choline, 312 Clinical Dementia Rating, 425 cognition, 183–4 effect of caffeine, 251–67 and mood and vitamin status, cognitively intact adults, 194–241 epidemiological studies evidence, 201–224 future trends, 240 information sources and advice, 240–1 intervention studies evidence, 224–236 vitamin deficiency in developed countries, 196–8 vitamins mechanisms of action, brain function, 198–201 role of vitamin D, 420–32 cognitive decline epidemiological link with dietary fats, 526–30 monounsaturated fatty acids intakes, 528 observational studies relating fish or dietary DHA consumption to dementia or cognitive decline, 529 observational studies relating saturated, trans and monounsaturated fatty acid intake, 528 polyunsaturated fatty acids intakes, 528–30 saturated and trans fatty acid intakes, 527–8 saturates, monounsaturates and polyunsaturates fatty acids, 527

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546

Index

influence of fatty acid intake, 525–38 future trends for better cognition, 538 implications for food industry, nutritionists and policy-makers, 533–7 omega-3 fatty acids metabolism and risk of cognitive decline, 530–3 tea and coffee consumption, 263–5 cognitive development influence of long-chain polyunsaturated fatty acids, 32–66 adequate supply for neonates and infants, 41–60 developmental and functional development, 36–41 future trends, 64–6 implications for food industry, nutritionists and policy-makers, 63–4 intake recommendations and supply situation, 61–3 levels in human milk, 36 placental transfer and fetal lipid transport, 35–6 potential consequences of deficiency/imbalances, 60–1 structure, metabolism and general physiological functions, 33–5 iodine deficiency, 109–24 effect on cognition, 113–20 future trends, 122–3 implications for food industry, nutritionists and policy-makers, 121–2 iodine and thyroid hormones, 109–13 spectrum of the disorder throughout the life cycle, 113 iron deficiency, 94–104 definitions of anaemia and iron deficiency, 95 effects on development, 96–100 future trends, 102–4 implications for food industry, nutritionists and policy-makers, 100–2

observational studies results, 53–5 maternal and infant PUFA status, 53–4 maternal PUFA intake during pregnancy, 54–5 randomised controlled interventional trials infant supplementation via infant formula or breastfeeding, 57–8 randomised controlled trials prenatal LC-PUFA supplementation, 55–6 zinc deficiency, 79–89 future trends, 88–9 implications for food industry, nutritionists and policy-makers, 88 measurement of zinc status, 80–8 RCT on zinc supplementation on infant/toddler cognitive and motor development, 83–5 cognitive outcomes, 9–11 18 months, 9 adolescence, 10–11 seven to eight years, 9–10 cognitive performance macronutrients, 131–51 carbohydrates, 135–44 effect of meals, 132–5 future trends, 150–1 implications for food industry, nutritionists and policy-makers, 149–50 stress, 145–9 mood measures, 182–3 cognitive reserve, 382, 383 comfort eating, 173–4 Commission Directive 2006/141/EC, 64 Communicative Development Inventory, 52 Conners Rating Scales, 87, 329, 333 Continuing Survey of Food Intakes of Individuals, 88 cortisol, 145–6 glucoregulation, 146 cretinism, 112, 115–16 Crocus sativus, 452 Curcuma longa, 405

© Woodhead Publishing Limited, 2011

Index curcumin, 405–7, 452 anti-inflammatory effect, 406 antioxidant effect, 405 Aβ pathology, 406–7 cyanocobalamin, 374 Cylert, 324 cystathionine β-synthase, 360 Datura stramonium, 272 dehydration see also voluntary dehydration levels, 185 mood and cognition, 183–4 older individuals, 187–8 delusions, 464 dementia antioxidants, diet, polyphenols, 392–412 antioxidants and diet approach for cognitive functioning, 393–8 association between antioxidants, fruits and vegetables intake and dementia, 395–6 flavonoids intake and cognitive functioning, 393–4 results from clinical trials, 396–7 beneficial effects of polyphenols with neuroprotective potential, 400–1 brain targets and sources of polyphenols, 398 caloric intake, dietary lifestyles and macronutrient composition, 439–56 future trends, 411–12 homocysteine, 365–7 important polyphenols with neuroprotective potential, 402–10 catechins, 402–5 curcumin, 405–7 effects of polyphenols from berries on cognitive performance, 409–10 resveratrol, 407–9 polyphenols classification, 398–402 role of vitamin D, 426 dependence, 266

547

depression carbohydrate consumption, 167–70 carbohydrate craving depression, 169–70 pre-menstrual syndrome, 167–8 seasonal affective disorder, 168–9 essential fatty acids, 490–505 correlational studies, 493–500 epidemiological studies, 490–3 intervention studies, 500–5 homocysteine, 361–2 relation to fatty acids, 484–524 role of vitamin D, 426–9 Detroit Tests of Learning Aptitudes, 86–7 deuterium dilution techniques, 182 Dexedrine, 324 dextroamphetamine see Dexedrine diabetogenic diets, 447–8 diet, 377–8 importance for physical health in schizophrenia, 470–2 role in dementia, 392–412 role in learning and behaviour of children with symptoms of ADHD, 323–48 dietary lifestyle, 439–56 diffusion imaging, 22 digit symbol substituted task (DSST), 223 Digital Symbol Substitution Test, 425 dihydropyricine, 449 diiodotyrosine, 110 docosahexaenoic acid (DHA), 306–7, 311, 451, 465, 477, 484, 531, 533–5, 536, 538 accretion in human brain development, 37–8 classification and structure, 33–4 levels in human milk, 36 neuronal membrane, 38–9 neurotransmission, 39–40 placental transfer, 35–6 transport in either lipoproteins or in its free form, 534 visual acuity maturation, 40 docosapentaenoic acid (DPA), 466 Donepezil, 275 dopamine, 311

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548

Index

Early Nutrition Programming Project, 61 EGb761, 277, 280, 451 eicosapentaenoic acid, 306–7, 465, 484, 531, 535, 536, 538 classification and structure, 33–4 LC-PUFAs as precursors, 41 electroretinography, 52 EMPowerplus, 342 ‘empty calorie’ hypothesis, 171 endorphins, 174 epidemiological studies, 201–224 B Vitamins and homocysteine levels, 202–222 biochemical level and psychological function, 203–12 biochemical status, 202–222 dietary intake, 222 vitamin dietary intake and psychological function, 213–16 Vitamins A, C, D and E, 222–4 biochemical level and cognitive function and mood, 217–20 biochemical status, 222–3 dietary intake, 223–4 essential fatty acids, 485–90 bipolar disorder, 507–9 correlational studies, 507–8 epidemiological studies, 507 intervention studies, 508 cell functioning, neurotransmission and behaviour, 488–9 correlational studies examining fatty acid levels in individuals with affective disorders, 497–8 examining role of omega-3 in depressive symptom severity, 494–5 depression, 490–505 correlational studies, 493–500 epidemiological studies, 490–3 intervention studies, 500–5 epidemiological studies examining role of PUFA status in affective disorders, 491–2 immune response and behaviour, 489–90

nomenclature and metabolism, 485–7 metabolic pathway and structure of n-3 and n-6 fatty acids, 485 postnatal depression, 505–7 correlational studies, 506 epidemiological studies, 505–6 intervention studies, 506 sources and dietary needs, 487–8 suicide, 509–10 correlational studies, 509–10 epidemiological evidence, 509 intervention studies, 510 essential reactive hypoglycaemia, 162–3 European Food Safety Authority (EFSA), 189 event-related potential, 99 externalising behaviour dietary influences, 303–13 food additives, 309–10 iron and zinc micronutrient deficiencies, 303–6 omega-3 fatty acids, 306–9 possible brain mechanisms underlying malnutrition– externalising behaviour relationship, 310–13 future trends, 315 impact of malnutrition, 301–15 implications for food industry, nutritionists, and policy-makers, 313–15 FADS1, 34 FADS2, 34 Fangan Test, 52 fat, 134–5 fat soluble vitamins, 198–200 Vitamin A, 198–9 Vitamin D, 199 Vitamin E, 199–200 fatty acids epidemiological link between dietary fats and cognitive decline, 526–30 monounsaturated fatty acids intakes, 528

© Woodhead Publishing Limited, 2011

Index observational studies relating fish or dietary DHA consumption to dementia or cognitive decline, 529 observational studies relating saturated, trans and monounsaturated fatty acid intake, 528 polyunsaturated fatty acids intakes, 528–30 saturated and trans fatty acid intakes, 527–8 saturates, monounsaturates and polyunsaturates fatty acids, 527 implications for food industry, nutritionists and policy-makers, 533–7 amount of each fatty acid needed by the brain, 533–6 DHA transport in either lipoproteins or in its free form, 534 personalised nutrition or general recommendations, 537 polyunsaturated fats stability and taste in food products, 536–7 intake and cognitive decline, 525–38 future trends for better cognition, 538 omega-3 fatty acids metabolism and risk of cognitive decline, 530–3 impact of ageing, 530–1 impact of genetics, 531–3 relation to depression and suicide, 484–524 bipolar disorder, 507–9 depression, 490–505 essential fatty acids, 485–90 future trends, 512–13 implications for practice, 513–14 personality factors associated with suicide, 510–12 postnatal depression, 505–7 role of omega-3 in depressive symptom severity, 494–5 suicide, 509–10

549

schizophrenia, 464–77 further research, 475–7 importance of diet for physical health, 470–2 recommended programme of assessment and intervention, 472–5 tissue levels of polyunsaturated fatty acids, 465–8 treatment studies with omega-3 fatty acids, 468–70 Feeding Infants and Toddler Survey, 88 Feingold diet, 309 ferulic acid, 398 ‘few-food’ diet see oligoantigenic diet fish oil, 64 flavanones, 399 flavonoids, 289–91, 398–9 foetal brain development, 113–14 folate, 500 food additives, 309–10 Food Frequency Questionnaire, 467 food intolerance, 344–5 forced-choice preferential-looking method, 52 functional magnetic resonance imaging, 23 furosemide, 449 G115, 280 galantamine, 272–3, 275 Galanthus nivalis, 272 garlic extract, 452 gene expression, 40–1 genome-wide association scan (GWAs), 532–3 Gerimax Ginseng extract, 282 GHQ-12, 235 GHQ-28, 235 Ginkgo biloba, 277, 279–80, 339, 451–2 Ginkgo Evaluation of Memory (GEM), 279 ginseng, 280–3 Ginsenipure, 280 ginsenosides, 280 glial cell line derived neurotrophic factor, 199

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550

Index

glucoregulation, 142–4 cortisol and cognitive performance, 146 diagnostic criterion for type 2 diabetes, 142 glucose, 327 glucose tolerance test, 163 glycaemic index, 138–40 glycaemic load, 140–2 goitre, 111 grape seed polyphenolic extract (GSPE), 454–5 green tea, 402 Griffiths Mental Development Scales, 42, 86 guaraná see Paullinia cupana haemosiderosis, 330 hallucinations, 464 Hamilton Anxiety Rating Scale, 235 Helsinki Ageing Study, 425 herbal extracts Bacopa monnieri, 283–4 evolution of psychoactives in plants, 273–4 flavonoids, 289–91 future trends, 291 Ginkgo biloba, 277, 279–80 ginseng, 280–3 guaraná, 287–9 herbs with known neurocognitive effects, 279 history of use of herbal products for neurocognition, 272–3 Melissa officinalis, 286–7 monotherapy vs polypharmacology, 274–7 classic drug development from plant extracts, 275 influences on Alzheimer’s disease progression, 276 neurocognitive effects, 272–91 salvia, 284–5 homocysteine, 359, 360–5 and B vitamins, 202–222 dementia, 365–7 depression, 361–2 folic acid and mood, 363–4 genetic variation, 364–5

micronutrient supplementation, 363 remethylation, 361 hormesis, 273 Hospital Anxiety and Depression Scale (HADS-D), 221 human milk, 36 hydration, 184–6 mental performance, 180–190 cognition, mood and hydration status, 182–8 future trends, 190 implications for food industry, nutritionists and policy-makers, 188–9 information sources and advice, 190 thirst and water intake regulation, 181–2 hydration status, 182–8 dehydration levels, 185 hyperactivity, 170 Hypericum perforatum, 339–40 hypertension, 448–55 hypertonicity, 182 hypoglycemia, 162–4 blood glucose control and mood, 164 hypothyroidism, 118 impaired fasting glucose, 142–4 impaired glucose tolerance, 142–4 Impulsive Control Disorder (ICD), 512 infant nutrition effect on cognition and brain, 3–26 cognitive outcomes at different stages, 9–11 further research, 24–6 imaging studies, 11–15 issues, 15–20 nutrition, cognition and the brain, 5–7, 20–4 preterm cohort studies, 7–9 Infant Planning Test, 52 insulin, 446–8 insulin-degrading enzyme (IDE), 447 insulin-like growth factor (IGF), 447 International Society for the Study of Fatty Acids and Lipids (ISSFAL), 337

© Woodhead Publishing Limited, 2011

Index intervention studies, 224–236 B vitamins, 224–234 randomised controlled trials, 225 multivitamins, 235–6 randomised controlled trials, 230 Vitamins A, C, D and E, 234–5 randomised controlled trials, 228 intracerebral Streptozotocin (ic-STZ), 447 iodine deficiency, 112 cognitive development, 109–24 effect on cognition, 113–20 adults, 120 foetal brain development, 113–14 IQ score, 116 moderate and mild iodine deficiency in children, 118–20 moderate and mild iodine deficiency in pregnancy, 116–17 severe iodine deficiency and cretinism, 115–16 future trends, 122–3 implications for food industry, nutritionists and policy-makers, 121–2 iodine and thyroid hormones, 109–13 assessment of iodine status, 112–13 iodine deficiency disorders, 112 regulation, 111 role, 111–12 thyroid hormones synthesis, 109–10 spectrum of disorder throughout the life cycle, 113 iodine status, 112–13 iron, 329–30 cognitive development, 98–100 effect on developing brain, 97–8 iron deficiency cognitive development, 94–104 effects on development, 96–100 child development, 96–7 cognitive development, 98–100 conceptual model, 96 iron in the developing brain, 97–8 future trends, 102–4 public health developments, 104 scientific developments, 102–4

551

implications for food industry, nutritionists and policy-makers, 100–2 food industry, 100–1 nutritionists and policy-makers, 101–2 iron deficiency anaemia, 95 iron micronutrient deficiency, 303–6 islet amyloid polypeptide (IAPP), 446 isoflavones, 399 Knobloch, Passamanick and Sherrard’s Developmental Screening Inventory, 42 knockout psychopharmacology, 291 L-tyrosine, 332 Lemon balm see Melissa officinalis leptin, 442 lignans, 399 linoleic acid, 465 classification and structure, 33–4 longevity gene, 453 Longitudinal Aging Study Amsterdam (LASA), 427 lycopene, 378 macronutrients, 302 carbohydrates, 135–44 blood glucose, 136–7 glucose effects, 135–6 glucose regulation, 142–4 glycaemic index, 138–40 glycaemic load, 140–2 inconsistencies in the glucosecognition relationship, 138 cognitive performance, 131–51 effect of meals, 132–5 meal size and time of day, 132 mixed macronutrient meals, 133–5 future trends, 150–1 implications for food industry, nutritionists and policy-makers, 149–50 influence on dementia, 439–56 stress, 145–9 glucoregulation, cortisol and cognitive performance, 146 glucose and cortisol, 145–6

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552

Index

macronutrients and cognitive performance under stress, 146–9 magnesium, 331 magnetic resonance spectroscopy, 22–3 malnutrition impact on externalising behaviour, 301–15 WHO definition, 302 meal size, 132 Mean Length of Utterance, 52 medhyarasayana, 283 Mediterranean diet, 397–8, 528 ‘Mediterranean diet,’ 195 melatonin, 334 Melissa officinalis, 273, 286–7 mental health child, 184–6 role of vitamin D, 420–32 mental performance hydration, 180–90 cognition, mood and hydration status, 182–8 future trends, 190 implications food industry, nutritionists, and policy-makers, 188–9 information sources and advice, 190 thirst and water intake regulation, 181–2 metabolic syndrome, 441–2 methionine synthase, 360 methylenetetrahydrofolate reductase (MTHFR), 361, 364–5 methylphenidate see Ritalin micronutrients, 171–3, 302, 377–82 Mini-Mental State Examination, 221, 383–4, 393, 424 mitochondria, 440 mixed macronutrient meals, 133–5 carbohydrate and fat manipulations, 134–5 carbohydrate and protein manipulations, 133–4 mono-iodotyrosine, 110 monosodium glutamate, 310 monotherapy, 274–7

mood, 183–4 carbohydrate consumption and antisocial behaviour, 160–76 chocolate – macronutrients or palatability, 173–5 future trends, 175 hypoglycemia, 162–4 metabolism and mood, 161–2 refined carbohydrates, 170–3 serotonin synthesis, 164–70 and cognition and vitamin status, cognitively intact adults, 194–241 epidemiological studies evidence, 201–224 future trends, 240 information sources and advice, 240–1 intervention studies evidence, 224–236 vitamin deficiency in developed countries, 196–8 vitamins mechanisms of action, brain function, 198–201 effect of caffeine, 251–67 folic acid, 363–4 mood measures, 182–3 Morris Water Maze behaviour test, 454 Motivational Interviewing (MI), 475 multivitamins, 235–6 randomised controlled trials, 230 Na2EDTA, 101 naloxone, 174 National Diet and Nutrition Survey (NDNS), 196–8 National Health and Nutrition Examination Survey (NHANES), 189, 197 Neonatal Behavioural Assessment Scale, 117 neurohormesis, 273–4 neuroimaging, 11–15 infant formula and caudate nucleus, 12–13 breast milk, IQ and brain structure, 13–14 comparison of sub-cortical structures in two diet groups, 13

© Woodhead Publishing Limited, 2011

Index MRI clinical methods of interpretation, 11–12 rationale, 11 NeuroKare, 123 neuronal membrane, 38–9 neurotoxicity, 306 neurotransmission, 39–40 neurotrophin-3, 199 neurotrophins, 422 New Horizons: A Shared Vision for Mental Health, 474 niacin, 371–2 nicotinic acid see niacin nitrendipine, 449 nutrigenetics, 537 nutrition role in learning and behaviour of children with symptoms of ADHD, 323–48 ADHD overview, 323–6 botanical, 337–40 food intolerance, 344–5 multi-ingredient formulation, 340–4 nutrients, 327–37 nutrition and the brain, 326–7 obesity, 441–2 oleanolic acid group, 280 oligoantigenic diet, 345 omega-6 fatty acid see arachidonic acid omega-3 fatty acids, 306–9, 487 see also docosahexaenoic acid correlational studies examining role in depressive symptom severity, 494–5 metabolism and risk of cognitive decline, 530–3 impact of ageing, 530–1 impact of genetics, 531–3 prospective studies on intakes, 528–30 schizophrenia treatment studies, 468–70 trials investigating the supplementation effects on clinical and non-clinical depression, 501–3 omega-6 fatty acids, 487

553

optical imaging, 23 oral glucose tolerance test, 142–4 oxidative stress, 393 resveratrol as blocker, 407 oxidative stress hypothesis of ageing, 377–82 Panax ginseng, 282, 286, 291 Panax quinquefolius, 291, 339 Panaxadiol group, 280 Panaxatriol group, 280 paraxanthine, 252 Parkinson’s disease, 426 Passiflora incarnata, 340 Paullinia cupana, 287–9 Peabody Picture Vocabulary Test, 52 pemoline see Cylert Perceived Stress Scale (PSS), 235 Perinatal Lipid Nutrition Project, 61 Pfeiffer Short Portable Mental State Questionnaire, 425 phenylalanine, 331–2 phytic acid, 101 Pinus pinaster, 337–8 polypharmacology, 274–7 polyphenols, 378, 452–3 beneficial effects of polyphenols with neuroprotective potential, 400–1 catechins, 402–5 classification, 398–402 curcumin, 405–7 dementia, 392–412 effects of polyphenols from berries on cognitive performance, 409–10 neuroprotective potential, 402–10 resveratrol, 407–9 catechins anti-inflammatory property, 404 antioxidant properties, 402–3 Aβ-mediated pathology, 404–5 catechins and apoptosis, 403–4 curcumin anti-inflammatory effect, 406 antioxidant effect, 405 Aβ pathology, 406–7

© Woodhead Publishing Limited, 2011

554

Index

resveratrol anti-amyloidogenic compound, 407–8 attenuated the neuroinflammatory responses, 408 blocker of oxidative stress, 407 sirtuins activator, 408–9 polyunsaturated fatty acids, 306, 334–7 tissue levels in patients with schizophrenia, 465–8 polyunsaturated fatty acids, long chain see also specific fatty acids adequate supply for neonates and infants, 41–60 cognitive outcome measures, 42, 52 observational studies results, 53–5 RCT on cognitive functions of preterm and term infants, 45–8 RCT on effect of maternal LC-PUFA supplementation during pregnancy, 43–4 RCT on visual functions of term and preterm infants, 49–51 visual outcome measures, 52 brain and retina development and function, 36–41 accretion of LC-PUFAs in the human brain, 37–8 effect on neuronal mechanisms, 38–41 major effects in the brain, 39 classification and structure, 34 effect on cognitive and visual development, 32–66 future trends, 64–6 list of abbreviations, 77–8 implications for food industry, nutritionists and policy-makers, 63–4 intake recommendation and supply situation, 61–3 DRI for linoleic acid and α-linolenic acid, 63 infants, 62–3 pregnant and lactating women, 61–2 levels in human milk, 36 placental transfer and foetal lipid transport, 35–6

potential consequences of deficiency or imbalances, 60–1 randomised controlled interventional trials, 55–60 infant supplementation via infant formula or breastfeeding, 56–60 prenatal supplementation, 55–6 structure, metabolism and general physiological functions, 33–5 classification and structure, 34 Porsolt forced-swim test, 307 Positive and Negative Syndrome Scale (PANSS), 472 postnatal depression (PND) essential fatty acids, 505–7 correlational studies, 506 epidemiological studies, 505–6 intervention studies, 506 pre-menstrual syndrome, 167–8 pregnancy, 116–17 preterm cohort studies, 7–9 setting of the study, 7–8 study design, 8–9 trial diet constituents, 8 pro-inflammatory cytokines, 489 proanthocyanidins, 399 Profile Of Mood States, 234 proteins, 133–4 Prozac, 311–12 psychiatric disorders relation to vitamin status, 359–84 antioxidants, micronutrients and oxidative stress hypothesis of ageing, 377–82 dementia and homocysteine, 365–7 future trends, 383–4 homocysteine, 360–5 niacin, 371–2 vitamin B1, 367–71 vitamin B6, 372–4 vitamin B12, 374–7 Psychological General Well-being Schedule, 235 Pycnogenol, 337–8 pyridoxine, 327 quercetin, 399

© Woodhead Publishing Limited, 2011

Index reactive hypoglycaemia, 162 reactive oxygen species (ROS), 403, 440 recommended dietary allowances (RDAs), 196 Reminyl, 275 resveratrol, 399, 407–9, 453 anti-amyloidogenic compound, 407–8 attenuated the neuroinflammatory responses, 408 blocker of oxidative stress, 407 sirtuins activator, 408–9 Revised Behaviour Problem Checklist, 304 Rey Auditory Verbal Learning Test, 234, 284 Ritalin, 324 rosmarinic acid, 287 Rotherham Early Intervention in Psychosis service, 472 S-adenosyl-methionine (SAM-e), 332 saffron see Crocus sativus sage see Salvia officinalis salicylates, 309 salvia, 284–5 Salvia lavandulaefolia, 284, 285 Salvia officinalis, 273, 284–5 saponins, 283 sAPPα, 444 schizophrenia fatty acids, 464–77 further research, 475–7 food manufacture and nutritional improvement, 476–7 importance of diet for physical health, 470–2 implications for clinical practice, 471–2 niacin, 371–2 recommended programme of assessment and intervention, 472–5 national policy implications, 474–5 nutritional assessment and intervention process, 473 role of vitamin D, 429 tissue levels of polyunsaturated fatty acids, 465–8

555

treatment studies with omega-3 fatty acids, 468–70 seasonal affective disorder, 168–9 selenoproteins, 378 serotonin, 311 synthesis, 164–70 serum ferritin, 329 Short Blessed Test, 424 silent information regulators, 445 Sirt1, 399 sirtuins, 445–6, 453 resveratrol as activator, 408–9 Society for the Study of Fatty Acids and Lipids, 61 somatisation, 489–90 Special Supplemental Nutrition Program for Women, Infants, and Children, 88 St. John’s wort see Hypericum perforatum Stanford Binet IQ, 52 statistical parametric processing map, 21 illustration, 22 Sternberg memory scanning task, 147 stilbenes, 399 stress macronutrients and cognitive performance, 145–9 glucoregulation, cortisol and cognitive performance, 146 glucose and cortisol, 145–6 Stroop test, 425 sugar rush, 160, 161 suicide associated personality factors, 510–12 aggression, hostility and anger, 511–12 impulsivity, 512 essential fatty acids, 509–10 correlational studies, 509–10 epidemiological evidence, 509 intervention studies, 510 relation to fatty acids, 484–524 Teller Acuity Cards, 52 The Links Between Diet and Behaviour, 474 theanine, 264

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556

Index

thiamine, 367–71 beri-beri amnesia, 367–8 restricted intake, 369–70 sub-clinical deficiencies, 370–1 Wernicke-Korsakoff syndrome, 368–9 thirst, 181–2 thyroid hormones, 113–14 regulation, 111 role, 111–12 synthesis, 109–10 thyroid follicle and pathway of iodide incorporation, 110 thyroid-stimulating hormone, 111 thyroid volume, 112 Tower and Trail Making tests, 425 tryptophan, 165, 332 turmeric see Curcuma longa UNICEF, 104 Universal Salt Iodisation, 121 urinary iodine concentration, 112 urine osmolality, 182 Valerian, 287 valsartan, 449 verbal fluency test, 425 visual acuity, 40 visual development, 58–60 influence of long-chain polyunsaturated fatty acids, 32–66 adequate supply for neonates and infants, 41–60 developmental and functional development, 36–41 future trends, 64–6 implications for food industry, nutritionists and policy-makers, 63–4 intake recommendations and supply situation, 61–3 levels in human milk, 36 placental transfer and fetal lipid transport, 35–6 potential consequences of deficiency/imbalances, 60–1 structure, metabolism and general physiological functions, 33–5

randomised controlled interventional trials infant supplementation via infant formula or breastfeeding, 58–60 randomised controlled trials prenatal LC-PUFA supplementation, 56 visual evoked potential, 52 vitamin A, 198–9 vitamin B1 see thiamine vitamin B3 see niacin vitamin B6, 372–4 vitamin B12, 374–7 dementia, 374–5 interaction with folate, 376–7 vitamin C, 201, 395–6 vitamin D, 199 action on the brain, 421–4 cognition, 424–6 basic cognitive functions, 424–5 executive cognitive functions, 425–6 cognitive function and mental health, 420–32 dementia and Parkinson’s disease, 426 depression, biopolar illness, and schizophrenia, 426–9 diagnosis and treatment of vitamin D insufficiency, 429–31 epidemic of vitamin D insufficiency, 420–1 future trends, 432 vitamin D receptors (VDR), 421–2 vitamin deficiency, 196–8 vitamin E, 199–200, 378, 395–6, 397 vitamin P, 378 vitamin status antioxidants, micronutrients and oxidative stress hypothesis of ageing, 377–82 cross-sectional studies, 379 intervention studies, 380–1 post-mortem studies of those with dementia, 378–9 prospective studies, 379–80 status of oxidative stress hypothesis, 381–2 and cognition and mood, cognitively intact adults, 194–241

© Woodhead Publishing Limited, 2011

Index epidemiological studies evidence, 201–224 future trends, 240 information sources and advice, 240–1 intervention studies evidence, 224–236 vitamin deficiency in developed societies, 196–8 vitamins mechanisms of action, brain function, 198–201 relation to psychiatric disorders, 359–84 dementia and homocysteine, 365–7 future trends, 383–4 homocysteine, 360–5 niacin, 371–2 vitamin B1, 367–71 vitamin B6, 372–4 vitamin B12, 374–7 vitamins, 194 evolution, 194–6 voluntary dehydration, 182 adults, 186–7 children, 186 voxel-based morphometry, 21, 441 water requirements, 189 water soluble vitamins, 200–1 B Vitamins, 200 Vitamin C, 201

557

Wechsler Intelligence Scale for Children (WISC), 120, 304 Wechsler Memory Scale, 284 Wechsler Preschool and Primary Scale of Intelligence, 52 Wernicke-Korsakoff syndrome, 368–9 Wisconsin Card Sorting test, 425 withdrawal reversal hypothesis, 259–60, 266 xanthophylls, 378 zinc, 79, 327–9 zinc deficiency, 303–6 cognitive development, 79–89 future trends, 88–9 implications for food industry, nutritionists and policy-makers, 88 measurement of zinc status, 80–8 cognitive development, 81–6 health effect, 80–1 mental health, 87–8 supplementation trials among school-age children, 86–7 zinc status, 80

© Woodhead Publishing Limited, 2011