Vitamins and Minerals in Neurological Disorders
- 1st Edition - June 6, 2023
- Editors: Colin R Martin, Vinood Patel, Victor R Preedy
- Language: English
- Hardback ISBN:9 7 8 - 0 - 3 2 3 - 8 9 8 3 5 - 5
- eBook ISBN:9 7 8 - 0 - 3 2 3 - 9 1 5 7 2 - 4
Vitamins and Minerals in Neurological Disorders offers readers a comprehensive reference addressing their relationship to brain health in a wide variety of neurological diseas… Read more

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Request a sales quoteVitamins and Minerals in Neurological Disorders offers readers a comprehensive reference addressing their relationship to brain health in a wide variety of neurological diseases. Examining various compounds, this broad coverage allows readers to learn about the role nutrient deficiency plays in the pathology of many conditions, as well as their potential in treatment. The book covers diseases including Alzheimer’s, Parkinson’s, ALS, and MS, along with severe neurological conditions like brain injury, stroke, headache and migraine. This volume provides a platform for research on vitamins, minerals and future investigations of these compounds.
- Summarizes vitamin and mineral research for a variety of neurological conditions
- Contains chapter abstracts, key facts, a dictionary and a summary
- Covers nutraceutical and botanical use in Alzheimer’s, Parkinson’s, ALS, MS, and more
- Includes conditions like migraine, headache, stroke and brain injury
Researchers in neuroscience and the biomedical sciences, neurologists, dietitians
- Cover image
- Title page
- Table of Contents
- Copyright
- Dedication
- Contributors
- Preface
- Chapter 1: Vitamins and minerals in the context of reference values and requirements
- Abstract
- Dietary reference values
- Caveats of the dietary reference values
- The dilemma for the dietetic and medical professions
- References
- Part I: Alzheimer's disease and dementias
- Chapter 2: α-Tocopherol for Alzheimer's disease
- Abstract
- Introduction
- α-Tocopherol
- α-Tocopherol in AD
- Preclinical studies
- Clinical studies of α-Tph supplementation
- Other components of interest
- Mini-dictionary of terms
- Key facts of Alzheimer's disease
- Summary points
- References
- Chapter 3: Cognitive impairment and micronutrients: Vitamin B12, folate, and homocysteine and implications for dementia
- Abstract
- Introduction
- Dementia and cognitive impairment: Clinical aspects
- Evidences from observational studies
- Evidences from interventional studies
- B vitamins metabolism
- Molecular mechanisms of interaction with central nervous system
- Application to other neurological conditions
- Other components of interest
- Mini-dictionary of terms
- Key facts of B vitamins
- Key facts of dementia
- Summary points
- References
- Chapter 4: Magnesium and Alzheimer's disease
- Abstract
- Introduction
- Metabolism of Mg: Generalities on physiology and neurodegeneration pathophysiology
- Alzheimer's disease: Generalities
- Neuroglial processes underlying the potential relationship between AD neurodegeneration and abnormalities of Mg metabolism
- Should Mg be used in the treatment of AD?
- Applications to other neurological conditions
- Other components of interest
- Mini-dictionary of terms
- Key facts of Alzheimer's disease (AD)
- Key facts of the role of magnesium (Mg) in AD
- Summary points
- References
- Chapter 5: Copper, oxidative stress, Alzheimer's disease, and dementia
- Abstract
- Introduction
- Alzheimer's disease
- Cu intake and regulation in physiology
- Cu imbalance in Alzheimer's disease
- Implementation of a Cu diet to decrease the CuAD risk
- Application to other neurological conditions
- Other component of interest: Oxidative stress and Alzheimer's disease
- Applications to other areas: Cu in type 2 diabetes
- Mini-dictionary of terms
- Summary points
- References
- Chapter 6: Chromium and Alzheimer's disease
- Abstract
- Introduction
- Alzheimer's disease
- Characteristic features of AD in terms of brain insulin resistance
- Other triggers associated with AD and brain insulin resistance
- Chromium
- Nutrition and neuroprotection
- Neuroscientific aspects
- Nutritional aspects
- Applications to other neurological conditions
- Other components of interest
- Mini-dictionary of terms
- Key facts of Alzheimer's disease
- Key facts of chromium
- Summary points
- References
- Part II: Amyotrophic lateral sclerosis
- Chapter 7: Riboflavin and lower motor neuron diseases
- Abstract
- Introduction
- Riboflavin transporters deficiencies (RTD)
- Riboflavin and amyotrophic lateral sclerosis (ALS)
- Conclusion
- Summary points
- References
- Part III: Brain injury
- Chapter 8: Vitamin C (l-ascorbic acid) in brain injury
- Abstract
- Introduction
- Vitamin C
- Traumatic brain injury
- Therapeutic effects of vitamin C
- Risks and adverse effects
- Conclusions
- Applications to other neurological conditions
- Other components of interest
- Mini-dictionary of terms
- Key facts
- Summary points
- References
- Chapter 9: Antioxidants in brain injury with or without antibiotics
- Abstract
- Acknowledgments
- Introduction
- Epidemiology
- Mechanism of TBI propagation
- Classification of TBI for targeted therapy
- Antioxidants used in TBI
- Antibiotics in combination with antioxidants
- Concluding remarks
- Applications to other neurological conditions
- Key facts
- Summary points
- References
- Chapter 10: Vitamin D level and the outcome after traumatic brain injury
- Abstract
- Introduction
- Vitamin D
- Traumatic brain injury and neuroendocrine disturbance
- Vitamin D deficiency and androgen synthesis in TBI
- Role of vitamin D in neuroprotection
- Paucity of vitamin D in association with severity of TBI
- Applications to other areas of neurological conditions
- Other component of interest
- Conclusion
- Mini-dictionary terms
- Key facts
- Summary points
- References
- Chapter 11: Zinc and traumatic brain injury
- Abstract
- Introduction
- Zinc in physiology
- Implications of altered zinc homeostasis in TBI
- Dietary zinc in TBI
- Zinc deficiency in TBI
- Zinc supplementation in TBI
- The potential for therapeutic approaches that target zinc
- Conclusion
- Applications to other neurological conditions
- Other components of interest
- Mini dictionary of terms
- Key facts of TBI
- Key facts of zinc in the brain
- Summary points
- References
- Part IV: Cerebral palsy
- Chapter 12: Cerebral palsy: Evaluating vitamin D levels
- Abstract
- Introduction
- Vitamin D physiology
- Role of vitamin D
- Cerebral palsy and vitamin D
- Conclusion
- Applications to other neurological conditions
- Other components of interest
- Key facts of cerebral palsy (CP): Evaluating vitamin D levels
- Dictionary of terms
- Summary points
- References
- Part V: Dietary neurotoxins
- Chapter 13: Linking copper and neurotoxic activities to the CNS
- Abstract
- Introduction
- How do we get copper?
- Nutritional aspects and disease
- Homeostasis of copper in the brain
- Copper and cellular neurodegeneration
- Copper supplementation
- Conclusion
- Mini-dictionary of terms
- Key facts
- Summary points
- References
- Part VI: Epilepsy
- Chapter 14: Vitamin E and neuroprotection in epilepsy
- Abstract
- Introduction
- The pathogenic triad
- Vitamin E: General characteristics
- VE and its effects on the pathogenic triad of epilepsy
- Conclusion
- Mini dictionary
- Key facts of vitamin E
- Summary points
- References
- Chapter 15: Selenium use in epilepsy
- Abstract
- Introduction
- Selenium as an antioxidant
- Glutathione peroxidase
- Thioredoxin reductase
- Selenium deficiency
- Selenium toxicity
- Selenium and neurological disorders
- Selenium and epilepsy
- Human studies
- Animal studies
- Conclusions
- Applications to other neurological conditions
- Other components of interest
- Mini-dictionary of terms
- Key facts of selenium
- Summary
- References
- Chapter 16: Correlation of reduced vitamin C and minerals with epilepsy
- Abstract
- Introduction
- Neuronal distortion in epilepsy
- Classification of epileptic seizures
- Reduced vitamin C in epilepsy
- Reduced minerals in epilepsy
- Conclusion
- Applications to other neurological conditions
- Other components of interest
- Mini-dictionary of terms
- Key facts of reduced vitamin C and minerals in epilepsy
- Summary points
- References
- Chapter 17: Thiamine, transporters, and epilepsy
- Abstract
- Introduction
- Chemical structure and biological forms of thiamine
- Absorption and transport of thiamine
- Thiamine transporters
- Functions of thiamine in metabolic processes
- Role of thiamine other than as a cofactor
- Applications to other neurological conditions
- Other components of interest
- Mini-dictionary of terms
- Key facts of thiamine metabolism
- Summary points
- References
- Part VII: Headaches and migraines
- Chapter 18: Riboflavin usage in pediatric migraine
- Abstract
- Introduction
- Underlying research on riboflavin
- Clinical studies of riboflavin
- Applications to other neurological conditions
- Other components of interest
- Summary
- Mini-dictionary of terms
- Summary points
- References
- Chapter 19: Vitamin B12, folate, and migraine
- Abstract
- Introduction
- The pathogenesis of migraine
- Serum homocysteine, folate, and vitamin B12 in migraine
- Folate and vitamin B12 supplementation for migraine prophylaxis
- Homocysteine-induced vascular risk—Clinical implications
- Folate-B12 deficiency and homocysteine in the pathogenesis of migraine
- Applications to other primary headache disorders
- Other components of interest
- Mini-dictionary of terms
- Key facts of migraine
- Summary points
- References
- Chapter 20: Vitamin D and migraine
- Abstract
- Introduction
- Applications to other neurological conditions
- Other components of interest
- Summary points
- References
- Part VIII: Multiple sclerosis
- Chapter 21: Iron, zinc, and multiple sclerosis patients
- Abstract
- Introduction
- Brain iron metabolism
- Iron deposition in the brain of MS patients
- Iron and oligodendrocytes
- Possible sources of iron deposit
- Genetics of iron metabolism
- The molecular mechanisms of zinc-induced neurotoxicity and the possible role of zinc in MS
- Role of zinc in oligodendrocyte death
- Applications to other neurological conditions
- Other components of interest
- Key facts
- Mini-dictionary of terms
- Summary points
- References
- Chapter 22: Considerations on vitamin D supplementation in multiple sclerosis
- Abstract
- Introduction
- Vitamin D metabolism and cellular effects
- Vitamin D status and supplement use associate with MS activity
- Heterogeneity in causality and confounding
- Heterogeneity in participant selection
- Heterogeneity in dosing
- Benefits of vitamin D supplements beyond MS
- Conclusion
- Applications on other neurological conditions
- Other components of interest
- Mini dictionary of terms
- Summary points
- References
- Part IX: Neuroinflammation
- Chapter 23: Neuroinflammation: Role of magnesium
- Abstract
- Neuroinflammation
- Magnesium and neurological disorders
- Mg deficiency and neuroinflammation
- Conclusions
- Applications to other neurological conditions
- Key facts
- Mini-dictionary of terms
- Other components of interest
- Summary points
- References
- Chapter 24: Vitamin B12 as a neuroprotectant in neuroinflammation
- Abstract
- Introduction
- B12 regulates energy metabolism and immune response
- B12 is antioxidant and modulates the oxidative stress response
- B12 boosts the synthesis of H2S within the CNS
- B12 prevents NMDAR-mediated glutamate excitotoxicity
- B12 rescues neurons from homocysteine-mediated cell death
- B12 modulates the expression of inflammatory genes through cell epigenetic landscape changings
- B12 regulates pivotal neuroinflammation signaling pathway-associated genes
- Final remarks and conclusion
- Applications to other neurological conditions
- Other components of interest
- Mini-dictionary of terms
- Applications to other areas
- Summary points
- References
- Chapter 25: Vitamin D3 (VD3) effects on neuroinflammation and neurodegenerative disorders: Focus on Alzheimer's and Parkinson's diseases
- Abstract
- Introduction
- Vitamin D3 and physiological features
- Vitamin D: Neuroinflammation and OS
- VD3 and neurodegenerative diseases
- Applications of VD3 to other neurological/pathological conditions
- Other components of interest for neurological conditions
- Concluding remarks
- Mini-dictionary of terms
- Key facts of vitamin D3 (VD3) effects on neuroinflammation and neurodegenerative disorders: Focus on Alzheimer's and Parkinson's diseases
- Summary points
- References
- Further reading
- Chapter 26: Vitamin C and neuroinflammation
- Abstract
- Introduction
- Neuroinflammation overview
- Vitamin C overview
- Application to other neurological conditions
- Other areas of interest
- Mini-dictionary terms
- Key facts
- Summary points
- References
- Chapter 27: Vitamin A and all-trans retinoic acid (ATRA) on neuroinflammatory changes in the brain
- Abstract
- Introduction
- Vitamin A
- Vitamin A metabolism
- Brain, vitamin A, and its metabolites
- ATRA and alcoholic neurotoxicity
- Conclusion
- Applications to other neurological conditions
- Other components of interest
- Key facts of ATRA
- Mini-dictionary of terms
- Summary points
- References
- Chapter 28: Fluoride excess and neuroinflammation
- Abstract
- Introduction
- Sources of fluoride exposure
- Fluoride exposure-associated major health burden
- Impact of fluoride in neurotoxicity and neurobehavioral
- Effect of sodium fluoride on free radical enzymes and oxidative stress
- Mini-dictionary of terms
- Key facts of neuroinflammation
- Summary points
- References
- Part X: Parkinson's disease
- Chapter 29: Vitamin D and Parkinson's disease
- Abstract
- Vitamin D metabolism
- Introduction to Parkinson's disease
- Parkinson's disease and vitamin D
- Gut dysfunction in Parkinson's disease and vitamin D
- Applications to other neurological conditions
- Other components of interest
- Mini-dictionary of terms
- Key facts of Parkinson's disease
- Key facts of hypovitaminosis D
- Summary points
- References
- Chapter 30: Tocotrienols and Parkinson's disease: In vitro and in vivo modeling
- Abstract
- Introduction
- Chemical structure and bioavailability of vitamin E
- Antioxidant activity of vitamin E
- Nonantioxidant activities of vitamin E
- Clinical studies on effects of α-Toc treatment for PD
- Neuroprotective effects of T3s in PD models in vitro and in vivo via nonantioxidant activities
- Applications to other neurological conditions
- Other components of interest
- Mini-dictionary of terms
- Key facts of Parkinson's disease
- Key facts of vitamin E
- Summary points
- References
- Chapter 31: B vitamins: Pyridoxal phosphate and parkinsonism
- Abstract
- Introduction
- Pyridoxal phosphate and the brain in health and disease
- Conclusion
- Applications to other areas of neurological conditions
- Other components of interest
- Mini-dictionary of terms
- Key facts of B vitamins: Pyridoxal phosphate and parkinsonism
- Summary points
- References
- Chapter 32: Antioxidant vitamins in Parkinson's disease: Vitamins A, C, E
- Abstract
- Introduction
- The “oxidative stress” hypothesis
- Vitamin A
- Vitamin C
- Vitamin E
- Interventional studies
- Conclusions
- Applications to other neurological conditions
- Other components of interest
- Key facts of antioxidant vitamins
- Mini-dictionary of terms
- Summary points
- References
- Chapter 33: Role of calcium in Parkinson's disease
- Abstract
- Introduction
- Parkinson's disease: Influence of diet in neurodegenerative mechanisms
- Nutritional sources of calcium
- Determinants of calcium levels
- Calcium and Parkinson's disease
- Conclusions
- Applications to other neurological conditions
- Other components of interest: Role of magnesium in Parkinson's disease
- Mini-dictionary of terms
- Key facts
- Summary points
- References
- Chapter 34: Micronutrient levels in Parkinson's disease
- Abstract
- Neurodegeneration
- Types of neurodegeneration
- Role of micronutrients in pathogenesis of neurological disorders
- Evaluate the correlation of electrolytes with biochemical parameters in biological samples of Parkinson's disease patients at different stages
- Discussion
- Summary
- Summary points
- References
- Chapter 35: Genes and dietary metals in Parkinson's disease
- Abstract
- Introduction
- Dietary metals and minerals in PD
- Chromosomal genes and PD
- Mitochondrial genes and PD
- Genes and dietary metals in PD
- Other components of interest
- Key facts
- Summary points
- References
- Part XI: Peripheral neuropathy
- Chapter 36: Vitamin D and diabetic peripheral neuropathy
- Abstract
- Introduction
- Applications to other neurological conditions
- Others components of interest
- Key facts of Vitamin D
- Mini-dictionary of terms
- Summary points
- References
- Chapter 37: B vitamins on the nervous system: A focus on peripheral neuropathy
- Abstract
- Introduction
- Peripheral neuropathy due to vitamin B deficiency
- B vitamins in the management of peripheral neuropathies
- Conclusions
- Applications to other neurological conditions
- Other components of interest
- Key facts of peripheral neuropathy induced by B vitamins deficiency
- Mini-dictionary of terms
- Summary points
- References
- Further reading
- Part XII: Prenatal effects and neurodevelopment
- Chapter 38: Dietary B-vitamin deficiencies and maternal oversupplementation on neurodevelopment: An updated narrative
- Abstract
- Introduction
- Dietary deficiencies in B-vitamins
- Dietary oversupplementation of folates
- Conclusion
- Applications to other neurological conditions
- Other components of interest
- Key facts
- Mini-dictionary of terms
- Summary points
- References
- Further reading
- Chapter 39: Essential trace elements in neurodevelopment: An updated narrative
- Abstract
- Introduction
- Iron
- Zinc
- Iodine
- Manganese
- Copper
- Selenium
- Applications to other neurological conditions
- Other components of interest
- Key facts
- Mini-dictionary of terms
- Applications to other areas
- Summary points
- References
- Further reading
- Chapter 40: Role of folic acid in neuronal development, neurotransmission and hypothalamic regulation of energy intake
- Abstract
- Introduction
- Effect of deficiency and excess of folate on neuronal development
- Role of folate in neurotransmission
- Hypothalamic development and food intake regulation
- Programming effects of maternal methyl donor vitamins on hypothalamic regulation of food intake and metabolism
- Conclusion
- Applications to other neurological conditions
- Other components of interest
- Mini-dictionary of terms
- Key facts of folate
- Summary points
- References
- Part XIII: Stroke
- Chapter 41: Vitamin B12, hyperhomocysteinemia, and stroke
- Abstract
- Introduction
- Forms of B12
- Homocysteine metabolism
- B12 deficiency: “Biochemical” and “metabolic” deficiency
- Risk of stroke with hyperhomocysteinemia
- Prevention of stroke with B vitamins
- Applications to other neurological conditions
- Other components of interest
- Mini-dictionary of terms
- Summary points
- References
- Chapter 42: Dietary sodium and stroke: A new narrative
- Abstract
- Introduction
- Epidemiologic studies
- Potential mechanisms
- Regional difference in the sodium-stroke association
- The shape of the association between sodium intake and stroke risk
- Measuring sodium intake
- Applications to other neurological conditions
- Other components of interest
- Current recommendations for sodium intake
- Conclusions
- Mini-dictionary of terms
- Key facts of stroke
- Key facts of stroke
- Summary points
- References
- Chapter 43: Calcium intake and the risk of stroke
- Abstract
- Introduction
- Calcium and stroke
- Calcium and atherosclerosis
- Calcium and hypertension
- Calcium intake and the risk of type 2 diabetes
- Calcium intake and the risk of obesity
- Conclusion
- Summary points
- Definition of terms and abbreviations
- References
- Chapter 44: Recommended resources for the study and investigation of vitamins and minerals in neurological disorders
- Abstract
- Acknowledgments (in alphabetical order)
- Introduction
- Resources
- Other resources
- Summary points
- References
- Index
- No. of pages: 812
- Language: English
- Edition: 1
- Published: June 6, 2023
- Imprint: Academic Press
- Hardback ISBN: 9780323898355
- eBook ISBN: 9780323915724
CR
Colin R Martin
Colin R. Martin RN, BSc, MSc, PhD, MBA, YCAP, FHEA, C.Psychol, AFBPsS, C.Sci is Professor of Clinical Psychobiology and Applied Psychoneuroimmunology and Clinical Director of the Institute of Health and Wellbeing at the University of Suffolk, UK. He is a Chartered Health Psychologist and a Chartered Scientist. He also trained in analytical biochemistry, this aspect reflecting the psychobiological focus of much of his research within mental health. He has published or has in press well over 300 research papers and book chapters. He is a keen book author and editor having written and/or edited more than 50 books. These outputs include the prophetic insight into the treatment of neurological disease, Handbook of Behavior, Food and Nutrition (2011), Nanomedicine and the Nervous System (2012), Oxidative Stress and Dietary Antioxidants in Neurological Disease (2020), Zika Virus Impact, Diagnosis, Control and Models (2021), Factors Affecting Neurodevelopment: Genetics, Neurology, Behavior and Diet (2021), Diagnosis and Treatment of Spinal Cord Injury (2022), The Neurobiology, Physiology, and Psychology of Pain (2022) and The Handbook of Lifespan Cognitive Behavioral Therapy: Childhood, Adolescence, Pregnancy, Adulthood, and Aging (2023). Professor Martin is particularly interested in all aspects of the relationship between underlying physiological substrates and behavior, particularly in how these relationships manifest in both acute and chronic psychiatric disorder. He has published original research germane to significant mental health disorders including the areas of schizophrenia, anxiety, depression, self-esteem, alcohol and drug dependency, high secure forensic mental health and personality disorder. He has a keen interest in the impact of postviral illness and is actively involved in clinical research post-Covid pandemic and in particular, the impact of Long Covid on psychological, neurological, physiological and social functioning. He is involved in collaborative International research with many European and Non-European countries.
Affiliations and expertise
Professor of Clinical Psychobiology and Applied Psychoneuroimmunology and Clinical Director: Institute for Health and Wellbeing, University of Suffolk, Ipswich, UKVP
Vinood Patel
Vinood B. Patel, BSc, PhD, FRSC, is currently Professor in Clinical Biochemistry at the University of Westminster. In 2014 Dr Patel was elected as a Fellow to The Royal Society of Chemistry. Dr Patel graduated from the University of Portsmouth with a degree in Pharmacology and completed his PhD in protein metabolism from King’s College London in 1997. His postdoctoral work was carried out at Wake Forest University Baptist Medical School, NC, USA studying structural-functional alterations to mitochondrial ribosomes, where he developed novel techniques to characterize their biophysical properties. Research is being undertaken to study the role of nutrients, antioxidants, phytochemicals, iron, alcohol and fatty acids in the pathophysiology of liver disease. Other areas of interest are identifying new biomarkers that can be used for the diagnosis and prognosis of disease and understanding mitochondrial oxidative stress in neurological disorders and iron dysregulation in diabetes. Dr Patel is a nationally and internationally recognized researcher and has several edited biomedical books related to the use or investigation of active agents or components. These books include The Handbook of Nutrition, Diet, and Epigenetics, Branched Chain Amino Acids in Clinical Nutrition, Cancer: Oxidative Stress and Dietary Antioxidants, Toxicology: Oxidative Stress and Dietary Antioxidants, Molecular Nutrition: Vitamins, The Neuroscience of Pain, Cognitive Behavioural Therapy. He is Editor of the ten-volume series Biomarkers in Disease: Methods, Discoveries and Applications.
Affiliations and expertise
Reader, Clinical Biochemistry, University of Westminster, London, UKVP
Victor R Preedy
Victor R. Preedy BSc, PhD, DSc, FRSB, FRSPH, FRSC, FRCPath graduated with an Honours Degree in Biology and Physiology with Pharmacology. After gaining his University of London PhD, he received his Membership of the Royal College of Pathologists. He was later awarded his second doctorate (DSc), for his contribution to protein metabolism in health and disease. He is Professor of Clinical Biochemistry (Hon) at King’s College Hospital and Emeritus Professor of Nutritional Biochemistry at King’s College London. He has Honorary Professorships at the University of Hull, and the University of Suffolk. Professor Preedy was the Founding Director and then long-term Director of the Genomics Centre at King’s College London from 2006 to 2020. Professor Preedy has been awarded fellowships of the Royal Society of Biology, the Royal College of Pathologists, the Royal Society for the Promotion of Health, the Royal Institute of Public Health, the Royal Society for Public Health, the Royal Society of Chemistry and the Royal Society of Medicine. He carried out research when attached to the National Heart Hospital (part of Imperial College London), The School of Pharmacy (now part of University College London) and the MRC Centre at Northwick Park Hospital. He has collaborated with international research groups in Finland, Japan, Australia, USA, and Germany. To his credit, Professor Preedy has published over 750 articles, which includes peer-reviewed manuscripts based on original research, abstracts and symposium presentations, reviews and edited books.
Affiliations and expertise
Professor, Department of Clinical Biochemistry, King’s College Hospital, London, UK; Emeritus Professor, Faculty of Life Sciences and Medicine, King’s College London, UK Visiting Professor, University of Hull, UKRead Vitamins and Minerals in Neurological Disorders on ScienceDirect