Free ebooks ==> www.Ebook777.com www.Ebook777.com   i Free ebooks ==> www.Ebook777.com K E TO G E N I C D I E T A N D M E TA B O L I C T H E R A P I E S www.Ebook777.com ii   iii K E TO G E N I C D I E T A N D M E TA B O L I C T H E R A P I E S Expanded Roles in Health and Disease EDITED BY S U S A N A M A S I N O,   P H D Vernon Roosa Professor of Applied Science Professor of Psychology and Neuroscience Trinity College Hartford, CT SECTION EDITORS D E T L E V B O I S O N,   P H D D O M I N I C P D ’ AG O S T I N O,   P H D E R I C H KO S S O F F,   M D J O N G M R H O,   M D iv Free ebooks ==> www.Ebook777.com Oxford University Press is a department of the University of Oxford It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide Oxford is a registered trade mark of Oxford University Press in the UK and certain other countries Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America © Oxford University Press 2017 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license, or under terms agreed with the appropriate reproduction rights organization Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Library of Congress Cataloging-in-Publication Data Names: Masino, Susan, editor Title: Ketogenic diet and metabolic therapies : expanded roles in health and disease / edited by Susan A Masino Description: Oxford ; New York : Oxford University Press, [2017] | Includes bibliographical references and index Identifiers: LCCN 2016019577 | ISBN 9780190497996 (alk paper) Subjects: | MESH: Ketogenic Diet | Metabolism—physiology Classification: LCC RM237.73 | NLM WB 427 | DDC 613.2/83—dc23 LC record available at https://lccn.loc.gov/2016019577 This material is not intended to be, and should not be considered, a substitute for medical or other professional advice Treatment for the conditions described in this material is highly dependent on the individual circumstances And, while this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues is constantly evolving and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation The publisher and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material Without limiting the foregoing, the publisher and the authors make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the material The authors and the publisher not accept, and expressly disclaim, any responsibility for any liability, loss or risk that may be claimed or incurred as a consequence of the use and/or application of any of the contents of this material 1 3 5 7 9 8 6 4 2 Printed by Sheridan Books, Inc., United States of America www.Ebook777.com   v CONTENTS Preface  ix Contributors  xi SECTION I:   in the Clinic Ketogenic Diet for Epilepsy 16 26 A G Christina Bergqvist, md Glut1 Deficiency and the Ketogenic Diets  35 Joerg Klepper, MD, PhD Ketogenic Diet in Established Epilepsy Indications  40 Ann M Bergin, MB, ScM, MRCP(UK) Ketogenic Diet for Other Epilepsies  50 David T Hsieh, MD and Elizabeth A Thiele, MD, PhD The Ketogenic Diet and Related Therapies in “Novel” Situations: Idiopathic Generalized Epilepsy Syndromes  56 Sudha Kilaru Kessler, MD, MSCE Ketogenic Diet in Status Epilepticus  Rima Nabbout, MD, PhD 11 Overview: Expanded Uses of Ketogenic Therapies  77 12 Metabolism-​Based Treatments to Counter Cancer: Scientific Rationale  79 Thomas N Seyfried, PhD and Laura M Shelton, PhD Emily L Johnson, md and Mackenzie C Cervenka, md How Do You Implement the Diet?  Jong M Rho, MD, Section Editor Jong M Rho, md Elizabeth Neal, RD, MSc, PhD Dietary Therapy in Adults: History, Demand, and Results  Cherie L Herren, MD and Rana R Said, md Ketogenic Diet: Emerging Clinical Applications and Future Potential Eric H Kossoff, md “Alternative” Ketogenic Diets  66 SECTION II:   Eric H Kossoff, MD, Section Editor Overview: Ketogenic Diets and Pediatric Epilepsy: An Update  10 Preventing Side Effects and Diet Discontinuation  60 13 Ketogenic Diet as Adjunctive Therapy for Malignant Brain Cancer  88 Eric C Woolf, PhD and Adrienne C Scheck, PhD 14 Metabolic Therapy for Autism Spectrum Disorder and Comorbidities  101 Ning Cheng, PhD, Susan A Masino, PhD, and Jong M Rho, md 15 Glucose and Ketone Metabolism in the Aging Brain: Implications for Therapeutic Strategies to Delay the Progression of Alzheimer’s Disease  113 Stephen C Cunnane, PhD, Alexandre Courchesne-​Loyer, msc, Valerie St-​Pierre, bsc, Camille Vandenberghe, BSC, Etienne Croteau, PhD, and Christian-​Alexandre Castellano, PhD vi vi Contents 16 Ketogenic Diet and Ketones for the Treatment of Traumatic Brain and Spinal Cord Injury  133 Femke Streijger, PhD, Ward T Plunet, PhD, and Wolfram Tetzlaff, MD, Dr Med, PhD 17 Anti-​Inflammatory Effects of a Ketogenic Diet: Implications for New Indications  147 Nina Dupuis, PhD and Stéphane Auvin, MD, PhD 18 Dietary Therapy for Neurological Disorders: Focus on Amyotrophic Lateral Sclerosis, Parkinson’s Disease, Mood Disorders, and Migraine  156 Carl E Stafstrom, MD, PhD SECTION III:   the Laboratory 165 186 196 209 Theresa A Lusardi, PhD and Detlev Boison, PhD Jacob P Harney, PhD, Kathryn Gudsnuk, ms, Ami Patel, md, Anantha R Vellipuram, md, Sathyajit Bandaru, ms, and David Butler, PHD 281 289 Manoj Banjara, PhD and Damir Janigro, PhD Dominic P D’Agostino, PhD, Section Editor 31 Overview of Ketone-​Based Metabolism: General Health and Metabolic Alternatives  216 310 Angela M Poff, PhD, Shannon L Kesl, PhD, and Dominic P D’Agostino, PhD 33 Identifying the Molecular Mechanism of the Medium Chain Triglyceride (Ketogenic) Diet  227 307 Dominic P D’Agostino, PhD 32 Ketone Supplementation for Health and Disease  Kui Xu, MD, PhD, Joseph C LaManna, PhD, and Michelle A Puchowicz, PhD 25 Endocrine and Reproductive Effects of Ketogenic Diets  Juan Ramún Martớnez-Franỗois, PhD, Nika N Danial, PhD, and Gary Yellen, PhD Ketone-​Based Metabolism: General Health and Metabolic Alternatives David N Ruskin, PhD 24 Ketogenic Diet, Aging, and Neurodegeneration  271 SECTION IV:   Masahito Kawamura JR., MD, PhD 23 Ketogenic Diet, Adenosine, Epigenetics, and Antiepileptogenesis  28 Metabolic Seizure Resistance via BAD and KATP Channels  167 Timothy A Simeone, PhD 22 Metabolic Therapy and Pain  254 William Curtis, Martin Kemper, PhD, Alexandra Miller, PhD, Robert Pawlosky, PHD, M Todd King, and Richard L Veech, MD, PhD, DPhil 30 Effects of the Ketogenic Diet on the Blood-​Brain Barrier  Detlev Boison, PhD 21 Ketogenic Diet in a Hippocampal Slice: Models and Mechanisms  27 Mitigation of Damage from Reactive Oxygen Species and Ionizing Radiation by Ketone Body Esters  Nagisa Sada, PhD and Tsuyoshi Inoue, PhD Detlev Boison, PhD, Section Editor 20 Ketogenic Diet and PPARgamma  241 Richard L Veech, MD, PhD, DPhil and M Todd King 29 Lactate Dehydrogenase: A Novel Metabolic Target  Ketogenic Diet in 19 Overview of Ketogenic Diet in the Laboratory: Progress on Models and Mechanisms  26 Alzheimer’s Disease: Causes and Treatment  328 Matthew C Walker, FRCP, PhD and Robin S.B Williams, PhD 34 Triheptanoin in Epilepsy and Beyond  Karin Borges, PhD 336   vii Contents vii 35 Amino Acids in the Treatment of Neurological Disorders  376 346 Adam L Hartman, md 36 2-​Deoxyglucose: Metabolic Control of Seizures through Inhibition of Glycolysis  Parker Hyde, CSCS, CISSN, Vincent J Miller, MS, and Jeff S Volek, PhD, RD 353 Carl E Stafstrom, MD, PhD and Thomas P Sutula, MD, PhD 37 Ketogenic Diets as Highly Effective Treatments for Diabetes Mellitus and Obesity  Eric C Westman, MD, MHS, Emily Maguire, MSc, and William S Yancy Jr., MD, MHS 38 Keto-​Adaptation in Health and Fitness  362 39 Advancing the Awareness and Application of Ketogenic Therapies Globally: The Charlie Foundation and Matthew’s Friends  386 Beth Zupec-​Kania, RD, CD, Jim Abrahams, Emma Williams, MBE, and Susan A Masino, PhD Index  397 viii   ix Free ebooks ==> www.Ebook777.com P R E FA C E Metabolism is a fundamental cellular process, and metabolic dysfunction is associated with disease The ketogenic diet is a metabolic therapy first published in 1921 as an effective treatment for seizures in both children and adults, and it has been prescribed to a subset of patients with epilepsy ever since Today there are many drugs available to control epileptic seizures, yet this metabolic therapy can stop seizures even when all medications fail: for some patients a ketogenic diet is superior to all known drug treatments The ketogenic diet was developed nearly 100 years ago because it had been observed—​for centuries—​that fasting would stop seizures Adhering to a medically prescribed and carefully formulated high-​fat ketogenic diet can maintain the ketone-​based metabolism used during fasting Metabolic therapy targets the most fundamental aspect of cell function: cell energy Targeting cell function or dysfunction metabolically is conceptually distinct from treating a disease specifically and pharmacologically While a pharmacological approach has dominated drug development, and can be effective for some symptoms and conditions, it is also more likely to produce off-​target side effects and less likely to produce lasting changes In contrast, supporting cell energy and promoting metabolic homeostasis can improve overall health and may offer long-​term benefits in preventing or modifying disease Recent basic and translational research has provided new insight into mechanisms as well as evidence that metabolic therapy with a ketogenic diet can treat diverse conditions beyond epilepsy New research has also provided evidence that alternatives which can substitute for or complement the diet—​ and potentially augment its efficacy—​may be close at hand Evidence is also mounting that ketogenic diets can reverse chronic health conditions and provide general health benefits beyond treating any particular disease Understanding key mechanisms underlying the success of metabolic therapy is of the highest biomedical significance: it is anticipated these mechanisms will apply to provide breakthroughs for multiple common, chronic, and poorly treated disorders Similarly, a comprehensive understanding of the range and type of acute and chronic conditions that metabolic therapies can prevent, delay, or reverse is of urgent clinical importance Here we provide a fresh view on the promise of using the biochemistry of metabolism to treat disease and promote health by compiling the latest research and perspectives of leading experts on ketogenic diets and metabolic therapies This volume is an up-​to-​date and comprehensive resource organized into four key subsections spearheaded by leaders in each area: the latest clinical research for treatment of epilepsy (Eric Kossoff, MD), emerging clinical applications (Jong Rho, MD), laboratory research into key mechanisms (Detlev Boison, PhD), and diverse metabolic therapies to treat disease and improve health (Dominic D’Agostino, PhD) The last chapter is devoted to two key organizations:  the Charlie Foundation, established in 1994 in the United States, and Matthew’s Friends, established in 2004 in the United Kingdom In the last two decades growth of research in the ketogenic diet field has been exponential, and the Charlie Foundation played an enormously important role in raising awareness and spearheading its resurgence in the clinic and the laboratory Ongoing efforts of the Charlie Foundation have been furthered and multiplied by Matthew’s Friends, and together these foundations are devoted to research, education, outreach, and applications of ketogenic therapies throughout the world www.Ebook777.com 394 394 section IV: Ketone-Based Metabolism guidelines A  new publication, Does What I  Eat Affect My Epilepsy? outlines steps that can be taken to eliminate sugar and refined foods and to consume a mostly whole foods diet This has been distributed widely (in English and Spanish) for all people with epilepsy regardless of their interest in ketogenic diet therapy For conditions that may benefit from ketogenic therapies, the Foundation designed a Pre-​ ketogenic Diet This document is distributed (free) to health professionals to provide to their patients or clients who are potential candidates for ketogenic diet therapy Similar to the classic ketogenic diet, it eliminates gluten and sugar; however, it is not intended to induce ketosis Instead, it can be described as a whole foods Mediterranean-​style diet that prepares the user for the transition to ketogenic therapy and also aids in determining which diet in the spectrum is best suited for their needs and preferences In addition, healthcare professionals can use the Pre-​ketogenic Diet as a screening tool to identify which individuals are able to adhere to the lifestyle changes required for ketogenic diets T H E C H A R L I E F O U N D AT I O N A N D M AT T H E W ’ S F R I E N D S —​ L O O K I N G TO   T H E   F U T U R E In 2013 the Charlie Foundation renamed itself the Charlie Foundation for Ketogenic Therapies to better define its mission for the future: advocacy, awareness, and education An expansion of education efforts includes adult-​focused media and training Development of new resources in both English and Spanish remains a goal A list of current publications is shown in Box 39.1 Throughout the 22  years of its existence, the Charlie Foundation has continued to receive daily e-​mails and letters from families and health professionals requesting assistance Jim Abrahams has responded to the majority of these requests, triaging some of them to support staff Although Charlie has been seizure-​and drug-​free and off of the diet since 1999, Charlie’s family continues to represent ketogenic therapies in their Los Angeles community and on a national level through partnerships with other nonprofits and with supportive commercial organizations Over 160 medical centers have been trained in the spectrum of ketogenic therapies in the United States and beyond, including Canada, Portugal, Austria, Jamaica, Slovenia, Kuwait, Saudi Arabia, and the Republic of Georgia Beginning in 2008, the Charlie Foundation has also sponsored and organized global symposia bringing together leading scientists and medical BOX 39.1 CHARLIE FOUNDATION EDUCATION RESOURCES Parent’s Guide to the Ketogenic Diet Modified Ketogenic Diet Therapy:  1:1 and 2:1 Prescriptions Does What I Eat Affect My Epilepsy? Preketogenic Diet; Low-​Carb, Gluten-​Free, High-​Fat KetoDietCalculator Guide for the Nutritionist and the User Professional’s Guide to the Ketogenic Diet Frequently Asked Ketogenic Diets Questions about Comparison of Ketogenic Diet Therapies Ketogenic Diet Primer for Health Professionals professionals with the intent of advancing research and clinical use of ketogenic therapies Plans for future symposia are in-​the-​making through the year 2022 As new clinical and scientific research continues to emerge, the Foundation will respond with further resources to promote safe and effective use of ketogenic therapies and make it less daunting for the user to manage Matthew’s Friends grew rapidly from Emma’s kitchen table, and in 2011 opened its own clinic The charity has continued to grow rapidly, and recently expanded into New Zealand and Canada In 2016 it embarked on a new program called KetoCollege, to offer training for teams around the globe, adding to and complementing the efforts of the Charlie Foundation to train ketogenic diet teams at their home institutions around the world Now seizure-​free young adults—​no longer on a special diet—​Charlie Abrahams and Matthew Williams are two clear examples that even catastrophic epilepsy can be cured by a ketogenic diet A  question frequently asked about Charlie, Matthew, and others who have become seizure-​ free on a ketogenic therapy is “How is it possible that they can come off of the diet and remain seizure-​free?” At the present time, there is no clear answer to this question Emerging genetic research may soon clarify whether early application of ketogenic therapy may either ameliorate the disease or even cure it The field of nutritional genomics   395 Chapter 39: Awareness and Application of Ketogenic Therapies Globally 395 the ketogenic diet in refractory childhood epilooks at the effect of nutritional changes on genes lepsy Acta Neuro Scand doi: 10.1111/​ane.12592 and suggests that maladaptive epigenetic changes can be altered by diet Targeted diet therapies are Lustig, R.H., Mulligan, K., Noworolski, S.M., Tai, V.W., Wen, M.J., Erkin-​Cakmak, A., Gugliucci, A., and already being prescribed along with genetic testing Schwarz, J.M (2016) Isocaloric fructose restricfor certain metabolic disorders tion and metabolic improvement in children with Implementation of a restrictive diet is easiest obesity and metabolic syndrome Obesity (Silver in infants and children (given their reliance on the Spring) 24, 453–​460 parents) and becomes more challenging as children Mohanraj, R., and Brodie, M.J (2006) Diagnosing gain independence Early initiation of ketogenic refractory epilepsy:  response to sequential treattherapies is better tolerated in young children—​ ment schedules Eur J Neurol 13, 277–​282 which may result in improved compliance and Neal, E.G., Chaffe, H., Schwartz, R.H., Lawson, M.S., outcomes Nevertheless the diet does work in Edwards, N., Fitzsimmons, G., Whitney, A., and adults, and has ever-​increasing applications Cross, J.H (2008) The ketogenic diet for the treat- 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 Coppola, G., D’Aniello, A., Messana, T., Di Pasquale, F., della Corte, R., Pascotto, A., and Verrotti, A (2011) Low glycemic index diet in children and young adults with refractory epilepsy: first Italian experience Seizure 20, 526–​528 Karimzadeh, P., Sedighi, M., Beheshti, M., Azargashb, E., Ghofrani, M., and Abdollahe-​Gorgi, F (2014) Low glycemic index treatment in pediatric refractory epilepsy: the first Middle East report Seizure 23, 570–​572 Kinsman, S.L., Vining, E.P., Quaskey, S.A., Mellits, D., and Freeman, J.M (1992) Efficacy of the ketogenic diet for intractable seizure disorders: review of 58 cases Epilepsia 33, 1132–​1136 Kossoff, E.H., Krauss, G.L., McGrogan, J.R., and Freeman, J.M (2003) Efficacy of the Atkins diet as therapy for intractable epilepsy Neurology 61, 1789–​1791 Kossoff, E.H., Zupec-​ Kania, B.A., Åmark, P.E., Ballaban-​Gil, K.R., Bergqvist, A.G.C., Blackford, R., Buchhalter, J.R., Caraballo, R.H., Cross, J.H., Dahlin, M.G., et  al (2009) Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group Epilepsia 50, 304–​317 Lambrechts, D.A.J.E., de Kinderen, R.J.A., Vles, J.S.H., de Louw, A.J.A., Aldenkamp, A.P., and Majoie, H.J.M (2016) A randomized controlled trial of ment of childhood epilepsy:  a randomised controlled trial Lancet Neurol 7, 500–​506 Perucca, E., Gram, L., Avanzini, G., Dulac, O (1998) Antiepileptic drugs as a cause of worsening seizures Epilepsia 39, 5–​17 Pfeiffer, H.H., and Thiele, E.A (2005) Low-​glycemic-​ index treatment:  a liberalized ketogenic diet for treatment of intractable epilepsy Neurology 65, 1810–​1812 Seyfried, T.N., and Mukherjee, P (2005) Targeting energy metabolism in brain cancer:  review and hypothesis Nutr Metab 2, 30 Sharma, S., Sankhyan, N., Gulati, S., and Agarwala, A (2013) Use of the modified Atkins diet for treatment of refractory childhood epilepsy: a randomized controlled trial Epilepsia 54, 481–​486 Shorvon, S.D., and Reynolds, E.H (1979) Reduction in polypharmacy for epilepsy Br Med J 2:1023–​5 Thibert, R.L., Pfeifer, H.H., Larson, A.M., Raby, A.R., Reynolds, A.A., Morgan, A.K., and Thiele, E.A (2012) Low glycemic index treatment for seizures in Angelman syndrome Epilepsia 53, 1498–​1502 Veech, R.L (2004) The therapeutic implications of ketone bodies:  the effects of ketone bodies in pathological conditions:  ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism Prostaglandins Leukot Essent Fatty Acids 70, 309–​319 Volek, J.S., Fernandez, M.L., Feinman, R.D., and Phinney, S.D (2008) Dietary carbohydrate restriction induces a unique metabolic state positively affecting atherogenic dyslipidemia, fatty acid partitioning, and metabolic syndrome Prog Lipid Res 47, 307–​318 396   397 INDEX Page references followed by an italics f indicate figures, t indicate tables, and b indicate boxes Abbott, N. J., 289, 292–​294 Abdallah, D. M., 174–​175 Abrahams, Charlie, 386 Abrahams, Jim, AC-​1202, 319–​320 acetoacetate see also ketone bodies acetone from, 113 administration, 124 Alzheimer’s, 122f brain energy source, 113 brain uptake, 296f hippocampal slices, 187–​190, 189t inflammation, 150–​151 ketogenic diet, 90, 136 Krebs cycle, 243f mitochondrial metabolism, 315f NADP system, 263f neuroprotection, 135 prolyl-​hydroxylase inhibition, 220 redox potential, 262t synthesis and metabolism, 177, 187, 228, 244, 247–​248, 248f, 296f VGLUTs, 281 acetone from acetoacetate, 113 ketogenesis, 119f acidosis, 67 actin, 293 Adabi Mohazab, R., 174 adenosine on inflammation, 151f, 152–​153 pain, 201 retaliatory metabolite, 210 adenosine homeostasis seizures, 209–​210 temporal lobe epilepsy, 211–​213, 212f adenosine kinase, epilepsy overexpression, 209–​210 adherence, 19 Adk gene, epilepsy, 210–​211 adult polyglucosan body disease, triheptanoin, 341–​342 adverse effects see side effects aerobic fermentation, 80 aerobic glycolysis, 80 aging cell senescence, 257 neuroprotection, ketosis, 221–​222, 221f reactive oxygen species, 256–​257 telomere shortening, 256–​257 aging and neurodegeneration, 216–​222 cataplerosis–​anaplerosis balance, 218 glucose and ketone metabolism, 113–​127 (see also Alzheimer’s disease) glucose metabolism, oxidative stress, 217–​218, 218f HIF1α stabilization, 219–​221 ketone bodies, 216–​217 ketosis, 217 ketosis neuroprotection, clinical relevance, 218–​219, 219f Ahn, Y., 107 D-​alanine, seizure onset protection, 348 Allen, B. G., 92, 367 Allen, Frederick Madison, 364, 365 Alpers disease, status epilepticus, 61 “alternative” ketogenic diets, 5–​13 see also specific types choice, 11–​12 effectiveness, vs classical ketogenic diet, 10–​12, 10t initiation and follow-​up, 12–​13 low glycemic index treatment, 6f, 9–​10, 9b medium chain triglyceride, 5–​7, 6b, 6f modified Atkins diet, 6f, 7–​9, 8b, 8t Alzheimer, Alois, 242 Alzheimer’s disease, 113–​127, 241–​249 anaplerosis, 124–​125 arteriovenous difference, brain, 114–​115, 115t brain energy status, neuroprotection, and mitochondrial function, 125–​126 early brain development and evolution, 126 environmental factors, 241–​241–​242 genetics, 241 glucose, cerebral use, 243–​244 398 398 Index Alzheimer’s disease, (cont.) glucose, presymptomatic hypometabolism, 116–​118, 116t, 117f glucose, uptake and metabolism, 113–​114 hyperketonemia with cognitive deficit, 123–​124, 125t hypometabolism, 216–​217 incidence, 241 ketone bodies, available forms, 247–​249, 248f, 249f ketone kinetics and transport, 118–​120, 120f, 120t ketone regional uptake, early disease, 121–​122, 121f, 122f ketones, brain fuel, 113, 118, 119f ketone supplementation, 318–​320, 319f medium chain triglycerides, dose-​response ketogenesis, 6f, 122–​123, 123f medium chain triglycerides, safety, 126 nutritional and metabolic factors, 241–​242 pathophysiology, 242–​244, 243f perspectives, 126–​127, 127t PET-​FDG protocol, 114 predisposing factors, 241–​242 prevention, 113 risk factors, 113 treatment, 244–​247, 245f–​246f amyloid, 244 ketone body metabolism, 244–​247, 245f–​246f triheptanoin, 341 amino acids, for neurological disorders, 346–​349 seizures and epilepsy D-​amino acids, 347–​349, 349b L-​amino acids, 346–​347, 347b traumatic brain injury, 349 AMPA receptor agonists, medium chain fatty acids, 331–​332, 331t amyloid precursor protein (APP), 242, 243 amyotrophic lateral sclerosis (ALS), 157–​158 triheptanoin, 341 anaplerosis, 124–​125, 218 propionyl-​CoA carboxylation pathway, 336–​337, 338f TCA cycling, 336, 337f, 338f Angelman syndrome, 52–​53 low glycemic index treatment, 9–​10, 9b anorexigenic food intake, 229, 229f antiepileptogenesis see epileptogenesis actions anti-​excitotoxic effects, 137 antioxidants see also specific types mechanisms of action, 257–​258, 258f neuroprotective mechanisms, 137–​138 apolipoprotein E (ApoE), 241 apolipoprotein E-​4 (ApoE-​4), 241, 242 L-​arginine seizure onset protection, 347 traumatic brain injury, 349 ascorbate, 258, 261, 262t ascorbic acid, 258f, 259 astrocyte-​neuron lactate shuttle, 282–​285, 283f–​285f antiepileptic effects, 283–​286, 284f, 285f electrical regulation, 284, 285f astrocytes BAD-​altered, metabolic changes, 272 blood-​brain barrier, 290f, 292–​293 athlete, keto-​adapted, 382, 383f autism spectrum disorder, 101–​107 animal models, 105–​107 definition, 101 effects, 105 epidemiology, 101 etiology, 101 future research, 107 ketogenic diet, 103–​105 mitochondrial and metabolic dysfunction, 102–​103, 104t–​105t pathophysiology, 101–​102 Babayan, Vigen K., 311 BAD, 271 on KATP channels, 271, 275 BAD channels, metabolic seizure resistance, 271–​274, 277f glucose and ketone body metabolism, 271–​272, 282 KATP channels, 275–​277, 276f metabolic function alteration, 272, 273f, 277f neurons and astrocyte metabolic changes, 272 vs other BCL-​2 family proteins, 273 Bansal, S., 29 Banting, William, 363 Barborka, C. J., 16–​17, 23 basement membranes, blood-​brain barrier, 290f, 292 Bastible, C., 16–​17 BCL-​2-​associated agonist of cell death (BAD), 271 see also BAD channels, metabolic seizure resistance behavioral effects, 231 Bellisario, V., 236 Bergqvist, A. G. C., 69 beta-​oxidation metabolic pathway, 248, 249f β-​hydroxybutyrate (BHB), 307 see also ketone bodies aging brain and Alzheimer’s disease, 113, 115t, 121–​122, 121f aging brain and Alzheimer’s disease, kinetics, 120, 120t antioxidant function, 138 brain energy source, 115t, 121–​122, 121f brain uptake, 296f cancer, 81–​82, 83 on cellular processes, 381 hippocampal slices, 187–​190, 189t inflammation, 150–​151, 151f KATP channels, 157 ketogenesis, 119f ketogenic diet, 90, 281 liver synthesis, 156 medium chain triglycerides, 123f metabolism and sum reactions, 243, 243f, 246f–​248f, 247–​248 mineral salts supplementation, with medium chain triglycerides, 311–​312 neuroprotection, 124, 124f, 125t, 134   399 Index nutritional ketosis, 377, 379 Parkinson disease, 158 on reactive oxygen species, 83 rodent model, 233f, 235–​236 synthesis and metabolism, 187, 228, 296f D-​β-​hydroxybutyrate administration, 124 ionizing radiation protection, 263, 264f ketogenesis, 119f ketogenic diets, 136 mitochondrial metabolism, 315f neuroprotection, 135 on redox states, cellular, 261–​263, 262f, 263f on transcription, 261t, 264 Blackburn, Elizabeth, 256–​257 Blomqvist, G., 121, 121f, 122 blood-​brain barrier, 289–​299 caveoline-​based vesicle trafficking, 291f, 293 cellular associations, 289–​292 astrocytes, 290f, 291–​292 basement membranes, 290f, 292 endothelial cells, 289–​292, 290f, 291f pericytes, 290f, 292 endothelial cells, 289, 290f functions nutrient transport to brain, 291f, 294–​295, 296f transit regulation, 290f, 291f, 294 glucose transporters, 294–​295, 296f, 297f ketogenic diet, 295–​299 cerebral ketone uptake regulation, 295–​297, 297f ketone bodies on, 298–​299 neuroinflammation, 297–​298 neuroprotection, 298 molecules leukocyte adhesion molecules, 293 tight junctions, 290f, 292–​293 plasmalemma vesicle-​associated protein number, 293 structure and functions, 289, 290f transporters, 290f, 291f, 293, 296f body composition, keto-​adaptation, 378–​379 Bough, K. J., 192 brain ketones, 113 metabolic rate, glucose, 115 PPARγ, 170–​172, 172f brain, aging, glucose and ketone metabolism, 113–​127 see also Alzheimer’s disease brain cancer, 392 brain cancer, malignant, 88–​94 glioblastoma multiforme, 88 ketogenic diet, humans, 93–​94 ketogenic diet, with standard therapies, 90–​91 metabolic remodeling, 88 preclinical evidence, 91 standard therapies, 91–​93, 92f tumor metabolism and Warburg effect, 88–​90, 89f brain development, ketones, 126 brain energy acetoacetate, 113 Alzheimer’s disease, 126 β-​hydroxybutyrate, 115t, 121–​122, 121f bioenergetics, 77 ketones, 113, 118, 119f, 380–​381 mitochondria, 125–​126 requirements, 113 brain energy metabolism PET-​FDG protocol, 114 triheptanoin, 339–​340 brain evolution, ketones, 126 brain injury, traumatic see traumatic brain injury brain ketones, 113, 118, 119f Bucher, T., 258 Buckley, J. A., 105 1,3-​butanediol supplementation, 311 Cahill, G. F., 81, 258, 307, 317, 376 calorie restriction classic ketogenic diet, 29 on inflammation, 151–​152, 151f pain, 197–​198 on tumor growth, 81–​82 Canavan disease, triheptanoin, 341 cancer, 79–​83 see also brain cancer aspartate, 80–​81 calorie restriction, 81–​82 cell metabolism, 80–​81 genetics and somatic mutation theory, 79 as genetic vs mitochondrial metabolic disease, 79–​80 glucose, 80–​81 Glucose/​Ketone Index calculator, 82–​83 glutamine, 81 hypoxia-​inducible factor 1, 89–​90 ketogenic diet, 82–​83 ketone supplementation, 320–​321 mitochondrial dysfunction, 80 nuclear factor-​kappa B, 90 PI3K/​AKT signaling pathway, 89 radiation therapy, 92 reactive oxygen species, 90 Caraballo, R. H., 44–​47 carbohydrate depletion, 376 stored, 376 carbohydrate, dietary decreasing, 376 glycemic effect, 366f, 367 carbohydrate loading, 380 carbohydrate restriction, dietary diabetes mellitus, controlled studies, 367, 368t diabetes mellitus, randomized controlled trials, 367, 369t obesity, randomized controlled trials, 363, 363t carboxy-​terminal binding protein (CtBP), 356 399 400 400 Index cardiac arrest and resuscitation ketosis neuroprotection, 218–​219, 219f survival after, 217–​218, 218f cardiac hypertrophy, triheptanoin, 342 cardiac side effects, 69–​70 cardiomyopathy, 69–​70 Castellano, C. A., 121, 121f, 122f cataplerosis, 124–​125, 218 caveoline-​based vesicle trafficking, 291f, 293 cell senescence, 257 cerebral metabolic rate, glucose, 115 Champ, C. E., 94 Chang, P., 7, 328–​332, 329f, 330t, 331t Charlie Foundation, 3, 27, 386–​392, 391f, 392f achievements, 388–​389, 389f education resources, 393–​394, 394b future, 394–​395 genesis, 386–​387 history, 386 ketogenic diet therapy spectrum, 389–​392, 390t research support, 393–​394 childhood absence epilepsy (CAE), 56–​57 Chuang, Y. C., 173–​174 claudins, 292 clinical trials, 77 cognition, 22 cognitive impairment, mild ketogenic treatments, 127, 127t medium chain triglycerides, 123f, 124, 125t cognitive impairment, severe see Alzheimer’s disease constipation, 67–​68 convulsive status epilepticus, 61 Coppola, G., 317 cortical spreading depression, 160 Couch, S. C., 70 counseling, prediet, 27 Crabtree effect, 80 Cross, Helen, 388 D’Agostino, D. P., 91, 310–​313, 317 Darlington, C. D., 79 Davidson, T. E., 231 Deanna Protocol, 158 decanoic acid, 331 see also medium chain fatty acids AMPA receptors and seizure control, 331 blood-​brain barrier penetration, 328 mitochondrial proliferation, 332 seizure control, 330, 332 2-​deoxyglucose, 353–​359 anticonvulsant actions, 353–​355 antiepileptic actions, 355–​356 chemical structure, 354f glucose metabolism and glycolytic pathway, 353, 354f depression, 159 diabetes mellitus, Alzheimer’s disease and vascular dementia, 242 diabetes mellitus type 2, 362–​371 carbohydrate, glycemic effect, 366f, 367 carbohydrate restriction, randomized controlled trials, 367, 369t dietary recommendations, evolution, 365 dietary recommendations, post-​insulin era, 364 keto-​adaptation, 378 ketogenic diet metabolic ward study, 367 nonrandomized studies, 370, 370t origins and use, 363–​364 pilot study, 367–​370 remission case report, 370, 371f ketone supplementation, 321 low carbohydrate diets, controlled studies, 367, 368t nutrition therapy, low glycemic dietary patterns, 365–​367 pathophysiology, 362 prevalence, 362 progression and morbidity, 362 dietary therapy, adults, 16–​24 see also specific types demand, 17–​19 children transitioning to adult epilepsy providers, 17–​18 refractory epilepsy, 18 super-​refractory status epilepticus, 18–​19 effects, adverse gastrointestinal, 22–​23 lipids, 23 menstrual cycle, 23 other, 23 effects, beneficial, 22t cognition and mood, 22 weight loss, 22 history, 16–​17 results efficacy, 19–​22, 20f, 21t feasibility, tolerability, and adherence, 19 discontinuation, ketogenic diet, 70–​71 prevalence, 66, 67t DNA methylation levels, epilepsy, 211–​213, 212f Does What I Eat Affect Epilepsy?, 394 Doose syndrome, 35, 46–​47 Dravet syndrome, 45–​46 Drenick, E. J., 114, 118, 121f Dressler, A., 43, 45–​46 drug resistant epilepsy, 40 duration, treatment, 31 dyslipidemia, 229, 230t education, prediet, 27 effectiveness, timing, 29–​30 efficacy, 19–​22, 20f, 21t electrolyte imbalances, 69 Ellenbroek, J. H., 229, 229f El-​Rashidy, O. F., 30 endocrine effects, 227–​230, 228t, 229f, 230f, 230t endothelial cells, blood-​brain barrier, 289–​292, 290f, 291f energy, brain see brain energy   401 Index energy regulation dysregulation, 77 long-​term, 228–​229 short-​term, 228 epigenetics, epilepsy, 210–​211 epilepsy see also specific topics adenosine kinase overexpression, 209–​210 Adk gene, 210–​211 2-​deoxyglucose for, 355–​356 DNA methylation levels, 211–​213, 212f energy metabolism and triheptanoin, 337–​339, 338f epigenetics, 210–​211 fasting, 209 kainic acid status epilepticus (KASE) model, 210, 211 ketogenic diet mechanisms, 281–​282 ketone supplementation, 317 PPARγ, 173–​174 epilepsy indications, established, 40–​47 Doose syndrome, 35, 46–​47 Dravet syndrome, 45–​46 infantile spasms, 42–​44 Lennox Gastaut syndrome, 44–​45 refractory nonsurgical epilepsy, 40–​42 epileptic encephalopathies, 44 see also specific types epileptogenesis actions, 209–​213 adenosine homeostasis and seizures, 209–​210 definition, 355 DNA methylation levels, 211–​213, 212f epigenetics, 210–​211 ketogenic diet, 137, 165, 198 (see also ketogenic diet; seizure control) ketogenic diet and adenosine homeostasis, 211–​213, 212f erythropoietin, neuroprotection, 220 Eun, S. H., 43–​44 evaluation, pre-​treatment, 66–​67, 67t, 71t Evangeliou, A., 105 excitotoxic effects, 137 family-​centered, team-​based approach, 26 fasting classic ketogenic diet, 28–​29 epilepsy, 209 hyperketonemia, 307 neuroprotection, 134 pain, 196–​197 spinal cord injury, 134 fats dietary, as fuel, 380–​381 (see also brain energy) stored, 376 fatty acid metabolism, beta-​oxidation metabolic pathway, 248, 249f Feinman, R. D., 378 fever, on inflammation, 147–​148 fever-​induced refractory epileptic encephalopathy in school-​age children (FIRES), 147 status epilepticus, 60, 61 fibroblast growth factor 21, 147–​148 First Do No Harm, 3, 41, 386, 391f 401 fitness, keto-​adaptation, 380–​381 food refusal, 70 Freeman, J. M., 3, 40, 387 Freemantle, E., 123, 124f free radicals see also reactive nitrogen species (RNS); reactive oxygen species (ROS) Alzheimer’s disease, 243–​244 redox state, 261, 262t removal, in vivo, 263–​264 fructose-​1,6-​diphosphate (FDP), 357 Gahring, L. C., 170–​171 gene theory of cancer, 79 Geyelin, H. R., 16 Gibson, C. L., 298 Giménez-​Cassina, A., 272–​274 glioblastoma multiforme, 88 see also brain cancer, malignant glioma, malignant, 88 see also brain cancer, malignant glucagon, 229–​230 glucose, 336 blood levels, ketogenic diet, 228, 228t chemical structure, 354f decreases, 281–​282 pain, 200–​201 glucose, brain blood-​brain barrier, 294–​295, 296f, 297f cerebral metabolic rate, 115 requirements, 113 glucose, brain, Alzheimer’s hypometabolism, presymptomatic, 116–​118, 116t, 117f uptake vs metabolism, 118 glucose-​insulin axis, 376 Glucose/​Ketone Index Calculator (GKIC), 82–​83 glucose metabolism BAD on, 271–​272 2-​deoxyglucose, 353, 354f oxidative stress, 217–​218, 218f glucose suppression, 313–​314 glucose transporters (GLUTs), 294–​295, 296f, 297f GLUT (glucose transporter type 1), 293, 297f GLUT (glucose transporter type 1) deficiency, 18, 35–​37, 308 clinical presentation and phenotype, 35–​36, 36f diagnosis, 35 ketogenic diet efficacy, 20 ketogenic diet therapies, 36–​37 ketone supplementation, 317–​318 metabolic concept, 35, 36f open questions, 37 triheptanoin, 341 glutamate, 349 D-​glutamate, seizure onset protection, 348 glutathione mechanisms of action, 259, 261, 262t on reactive oxygen species, 264 glycemic dietary patterns, diabetes mellitus, 365–​367 glycemic index (GI), 9, 365 glycemic load, 366 402 402 Index glycine, seizure onset protection, 346 glycolysis, 336, 354f glycolytic flux, neuroprotection, 157 glycolytic pathway, 2-​deoxyglucose, 353, 354f Go Lower Low Carbohydrate Diet, 367–​370 Gottstein, U., 114 GPR40, 199, 200 GPR41, 201 GPR120, 201 Greenwood, C. E., 231 growth, 70 Gudsnuk, K., 233f, 235–​236, 235f, 235t Guelpa, G., 16 Hadera, M. G., 340 Harmon, Denon, 256 Hayflick, L., 256, 257 HDAC inhibitor, 321 ionizing radiation protection, 264 hepatitis, 69 Herbert, M. R., 105 HIF1α activation, redox state, 216 ketones, 219 neuroprotection ketosis, 221–​222, 221f stabilization, 219–​221 oxygen homeostasis, hypoxia, 220 regulation, 221 hippocampal slice, 186–​193 for ketogenic diet and epilepsy studies, 187 ketogenic diet–​fed animal slices, 188f, 189t, 191 ketone body direct application, 187–​190, 188f, 189t temporal lobe epilepsy model, 186–​187 whole-​cell patch clamp for glucose and ATP control, 188f, 189t, 190–​191, 191f Hippocrates, 16, 28 Hong, A. M., 43 Hong, S., 175 hormonal mechanisms, 227 Hoyer, S., 114–​115, 122 Huntington’s disease, triheptanoin, 342 Huttenlocher, P. R., 5, 328 hydrogen peroxide, 264 synthesis, monoamine oxidase, 254–​255, 255f 3-​hydroxybutyrate ketone monoester (KME), 318–​320, 319f 3-​hydroxybutyrate methyl ester (HBME), 318 hyperglycemia, 313–​314 hyperinsulinemia, 313–​314 hyperketonemia benefits, 307 with cognitive deficit, clinical studies, 123–​124, 125t hyperlipidemia, 69 hypoglycemia, 68 hypometabolism, Alzheimer’s disease, 216–​217 hypoxia-​inducible factor (HIF-​1), 89–​90 implementation, 26–​31 classic ketogenic diet caloric restriction, 29 fasting, 28–​29 liquid/​formula vs food, 29 education and counseling, prediet, 27 effectiveness, timing of determination, 29–​30 family-​centered, team-​based approach, 26 initiation, in-​patient vs out-​patient, 27–​28 ketogenic diet team, composition, 26–​27 ratios, importance, 30–​31 response predictor, 31 seizure freedom, 30 treatment duration, 31 infantile spasms, 42–​44 infections, 68 inflammasome, 138–​139 NOD-​like receptor P3, 298 inflammation, 147–​153 animal models, neurological disease, 148–​150 multiple sclerosis, 148–​150 pain, 148 Parkinson’s disease, 150 studies, 148, 149t clinical evidence, 153 fever, 147–​148 fibroblast growth factor 21, 147–​148 FIRES, 147 future indications, 153 ketone supplementation, 314–​316 mechanisms, 150–​153, 151f adenosine modulation, 151f, 152–​153 caloric restriction, 151–​152, 151f ketone bodies, 150–​151 mitochondrial membrane potential, 153 polyunsaturated fatty acids, 151f, 152 reactive oxygen species, 151f, 153 uncoupling proteins, 153 neuroinflammation, 297–​298 neuroprotection, 138–​140 pain, 147, 148, 196 (see also pain) initiation, in-​patient vs out-​patient, 27–​28 Inoue, T., 283–​286, 284f, 285f insulin blood levels, ketogenic diet, 228, 228t glucose-​insulin axis, 376 hyperinsulinemia, 313–​314 insulin resistance brain, Alzheimer’s disease, 243 keto-​adaptation, 377–​378 ketone supplementation, 321 nonalcohoic fatty liver disease, 378 weight loss, keto-​adaptation, 379 insulin sensitivity brain ketone use, 118 ketone supplementation, 313–​314 International Consensus Statement for Ketogenic Diet (ICSKD), 26 intrauterine growth restriction (IUGR), 234   403 Index ionizing radiation HDAC inhibitor protection, 264 ketone ester effects, post-​exposure, 266–​267, 267f ketosis protection, 263 in vitro studies, 264–​266, 265f, 266f L-​isoleucine, seizure onset protection, 346 JAMs, 292–​293 Jaworski, D. M., 80–​81 Jeong, E. A., 176, 177 Joensson, E. A., 370 Joslin, Elliott P., 364, 365, 367 Juge, N., 188–​190 junctional adhesion molecules (JAMs), 292–​293 juvenile myoclonic epilepsy (JME), 18, 57–​58 kainic acid status epilepticus (KASE) model, 210, 211 Kang, H., 69 Kashiwaya, Y., 314, 316, 318, 321, 322 KATP channels, BAD on, 271 KATP channels, metabolic seizure resistance, 274–​277, 277f BAD disruption on, 275 metabolism and excitability link, 274–​275 seizure protection, BAD-​elicited, 275–​277, 276f Kelly, Millicent, 387 Kessler, S. K., 30–​31 keto-​adaptation, 312, 376–​383 athlete, 382, 383f effects, 376–​377 fundamentals, 376–​377 health implications, 377–​380 insulin resistance, metabolic syndrome, diabetes type 2, 377–​378 lipoprotein profile, 379–​380 weight loss and body composition responses, 378–​379 history, 376 nutritional ketosis, 377, 377f sport and fitness, 380–​381 starvation ketosis, 377 Keto Cookbook II, 393 KetoDietCalculator, 388 ketogenesis, 118, 119f ketogenic diet see also specific types and topics history and early research, 3–​4, 26 ketosis, 217 mechanisms of action, 90–​91 (see also specific types) pediatrics indications, 4 spectrum, 389–​392, 390t types, 3–​4 use, 26 ketogenic diet, advancing awareness, 386–​395 brain cancer, 392 Charlie Foundation, 3, 27, 386–​392, 391f, 392f (see also Charlie Foundation) Matthew’s Friends, 386, 388–​389, 392f (see also Matthew’s Friends) metabolic syndrome, 392 403 other applications, 392–​393 research support, 393–​394 ketone-​based metabolism, 282 ketone bodies and ketones,271 see also acetoacetate; β-​ hydroxybutyrate (BHB); specific types alternative energy substrates, 216–​217 Alzheimer’s disease, 244–​247, 245f–​246f available forms, 247–​249, 248f, 249f on blood-​brain barrier, 298–​299 blood levels, ketogenic diet, 228, 228t brain, 113, 118, 119f development and evolution, 126 fuel, 113, 118, 119f, 380–​381 uptake, 295–​297, 297f uptake, regional, early Alzheimer’s, 121–​122, 121f, 122f breakdown, 28 exogenous, 307 vs glucose, 217 as “good medicine,” 81 increased, 281 on inflammation, 138–​140, 150–​151 kinetics and transport, 118–​120, 120f, 120t metabolism, BAD on, 271–​272 neuroinflammation, 297–​298 neuroprotection, 126, 156–​157, 298 on pain, 200 on radiation effects, post-​exposure, 266–​267, 267f on tumors, 91 ketone ester supplementation, 312 ketone salts supplementation, 311–​312 ketone supplementation, 310–​322 applications, 317–​322 Alzheimer’s disease, 318–​320, 319f cancer, 320–​321 epilepsy/​seizure disorders, 317 GLUT1 deficiency syndrome, 317–​318 insulin resistance/​type diabetes mellitus, 321 weight loss, 321–​322 development and testing, 310–​312 1,3-​butanediol, 311 formulations, 310 ketone esters, 312 ketone salts, 311–​312 medium chain triglycerides, 310–​311 βHB mineral salts and medium chain triglycerides, 311–​312 therapeutic ketosis from, 310 therapeutic mechanisms, 313–​316 glucose suppression and insulin sensitivity enhancement, 313–​314 on inflammation, 314–​316 metabolic efficiency, enhanced, 314, 315f mitochondrial health and function, 316 oxidative stress, inhibition, 316 ketosis, nutritional (therapeutic), 217, 307, 310, 379 see also ketone supplementation benefits, 377, 377f β-​hydroxybutyrate, 377, 379 404 404 Index ketosis, starvation, 377 kidney stones, 68 Kilaru, S., 47 Kim, D. Y., 190 Kimura, R., 188 kindling, 355 Klein, P., 19 Klement, R. J., 94 Klingenberg, M., 258 Kossoff, E. H., 7, 8b, 20, 30–​31, 57, 389 Krebs, H. A, 258–​261 Kreb’s cycle, 244 Kverneland, M., 58 laboratory, 165–​166 lactate dehydrogenase (LDH), 281–​286 astrocyte-​neuron lactate shuttle, 282–​283, 283f epilepsy mechanisms, 281–​282 metabolic target, 283–​286, 284f, 285f future directions, 286 lactate fermentation, 80 Lambrechts, D. A., 20 Lardy, Henry, 314 Laux, L., 45 Lemmon, M. E., 44 Lennox Gastaut syndrome, 44–​45 D-​leucine, 347–​348 L-​leucine, 346–​347 leukocyte adhesion molecules, blood-​brain barrier, 293 lipids, 23 lipogenesis, 379 lipoprotein profile, keto-​adaptation, 379–​380 liquid/​formula vs food, classic ketogenic diet, 29 Liu, Christiana, 5 Lomax, M. E., 265–​266 long chain fatty acid oxidation disorders, triheptanoin, 341 long-​chain triglycerides, 5 low glycemic index treatment (LGIT), 6f, 9–​10, 9b development, 389 initiation and follow-​up, 12–​13 Luna-​Medina, R., 175 Lying-​Tunell, U., 114, 115, 115t, 121f, 122 Magee, B. A., 320 Magrath, G., 9 Mantis, J. G., 106 Marie, A., 16 Marin-​Valencia, I., 339 Martinez, C. C., 17 Matthew’s Friends, 27, 392f, 393f achievements, 388–​389 future, 394–​395 genesis, 387–​388 ketogenic diet therapy spectrum, 389–​392, 390t research support, 393–​394 Maurois, P., 174 McDonald, T. S., 339 medium chain fatty acids, 329f AMPA receptor agonists, 331–​332, 331t seizure control, 328–​330, 329f, 329t medium chain triglyceride (MCT) ketogenic diet, 5–​7, 6b, 6f history, 328 initiation and follow-​up, 12–​13 mechanisms, 328–​333 AMPA receptor agonism, 331–​332, 331t implications, 332–​333 seizure control, 328–​330, 329f, 329t seizure control, ketones, 332 molecular mechanism, 328–​333 medium chain triglycerides (MCTs), 5 coconut oil and palm kernel oil, 123 ketogenesis, dose-​response, 6f, 122–​123, 123f products, 123–​124, 125t safety, 126 supplementation, 310–​311 supplementation, with βHB mineral salts, 311–​312 MELAS, status epilepticus, 61 menstrual cycle, 23 metabolic acidosis, 67 metabolic diseases autism spectrum disorders, 102–​103, 104t–​105t cancer, 79–​80 metabolic potential energy, 376 metabolic remodeling, 88 metabolic syndrome keto-​adaptation, 378 ketogenic therapy, 392 plasma markers, ketogenic diet, 229, 230t metabolism see also specific types ketogenic diet mechanisms, 227 ketone supplementation, 314, 315f metabolism, mitochondrial acetoacetate, 315f D-​β-​hydroxybutyrate, 315f D-​methionine, seizure onset protection, 348 middle cerebral artery occlusion, triheptanoin, 341 migraine, 159–​160 mild cognitive impairment ketogenic treatments, 127, 127t medium chain triglycerides, 123f, 124, 125t mitochondrial dysfunction autism spectrum disorders, 102–​103 brain energy status and neuroprotection, 125–​126 cancer, 79–​80 cytopathies, 27 function, 102 ketone supplementation, 316 membrane potential, inflammation, 153 nervous system, 102 mitochondrial metabolism acetoacetate, 315f D-​β-​hydroxybutyrate, 315f   405 Index modified Atkins diet (MAD), 6f, 7–​9, 8b, 8t development, 389 effectiveness, vs classical ketogenic diet, 10–​11, 10t efficacy, 19–​22, 20f, 21t initiation and follow-​up, 12–​13 mood, 22 mood disorders, 159 Moorman, M. A., 256, 257 Moreno, S., 170 multiple sclerosis, 148–​150 myoclonic astatic epilepsy (MAE), 35, 46–​47 Nabbout, R., 45, 60, 61, 63 NADPH, 264 NADP-​linked enzymes, liver activity, 259, 259t NADP system, 261–​263, 262f, 263f D-​β-​hydroxybutyrate on, 264 Neal, E. G., 3, 4, 10, 10t Nebeling, L. C., 83, 93 Nei, M., 20 neurodegeneration and aging, 216–​222 see also aging and neurodegeneration neuroinflammation, 297–​298 neurological disorders, 156–​160 see also specific types amino acid treatment, 346–​349 (see also amino acids, for neurological disorders) amyotrophic lateral sclerosis, 157–​158 glycolytic flux, 157 ketone bodies, 156–​157 migraine, 159–​160 mood disorders, 159 neuroprotection, 156–​157 Parkinson disease, 158–​159 neuron restrictive silencing factor (NRSF), 356 neurons, BAD-​altered, metabolic changes, 272 neuropathic pain, 196 see also pain neuroprotection, 156–​157, 298, 376 acetoacetate, 136 aging, 218–​219, 219f aging, ketosis, 221–​222, 221f antioxidants, 137–​138 β-​hydroxybutyrate, 124, 124f, 125t, 134 D-​β-​hydroxybutyrate, 134 cardiac arrest and resuscitation, 218–​219, 219f erythropoietin, 220 fasting, 134 glycolytic flux, 157 HIF1α, 219–​222, 221f inflammation, 138–​140 ketone bodies, 156–​157, 298 ketones, 126 neurological disorders, 156–​157 Parkinson’s disease, 158–​159 polyunsaturated fatty acids, 156–​157 PPARγ, post-​SE and during SRS, 171, 172f spinal cord injury, drug candidates, 133–​134 stroke, 218–​219, 219f vascular endothelial growth factor, 220–​221 405 neuroprotection, mechanisms, 216, 221–​222, 221f anaplerotic, 136 anti-​excitotoxic, 137 antioxidant, 137–​138 inflammation, 138–​140 non-​anaplerotic, 137 neurovascular unit, 289, 290f Newport, M. T., 318, 320 NF E2-​related factor 2(Nrf2) transcription factor, 138, 172, 221, 266 Nielsen, J. V., 370 Nizamuddin, J., 69 NLRP3 inflammasome, 138–​139, 148, 149t, 150, 151f, 153, 197, 298, 315–​316 NOD-​like receptor P3 (NLRP3) inflammasome, 138–​ 139, 148, 149t, 150, 151f, 153, 197, 298, 315–​316 nonalcohoic fatty liver disease, insulin resistance, 378 nonconvulsive status epilepticus, 61–​62 nonsurgical epilepsy, refractory, 40–​42 Nordli, D. R., 43 NORSE, status epilepticus, 60, 61 Nrf2, 138, 172, 221, 266 nuclear factor-​kappa B, 90 Numis, A. L., 43–​44 nutritional ketosis see ketosis, nutritional Nylen, K., 106 obesity, 362–​371 carbohydrate restrictions, randomized controlled trials, 363, 363t diabetes mellitus type 2, 362 (see also diabetes mellitus type 2) ketogenic diet origins and use, 363 pilot study, 367–​370 prevalence, 362 occludin, 292–​293 Ogawa, M., 115, 121f, 122 Oguni, H., 46 Olovnik, A. M., 256 oncogenic paradox, 80 orexigenic food intake, 229, 229f osteopenia, 70 overweight, prevalence, 362 Owen, O. E., 114, 118, 121f, 376 oxidative phosphorylation, 80 oxidative stress on glucose metabolism, 217–​218, 218f ketone supplementation, 316 oxygen free radicals see also reactive oxygen species (ROS) redox state, 261, 262t pain, 196–​201 adenosine transmission, 201 calorie restriction, 197–​198 economic cost, 196 fasting, 196–​197 glucose, 200–​201 406 406 Index pain, (cont.) GPR40, 199, 200 GPR41, 201 GPR120, 201 inflammation, 147, 148, 196 inflammatory, 196 ketogenic diet, 198–​199, 198f, 199f ketone bodies, 200 neuropathic, 196 polyunsaturated fatty acids, 200 quality of life, 196 severe, treatment, 196 pancreatitis, 69 Paoli, A., 228–​229, 228t, 229f, 236–​237 Parent’s Guide to the Ketogenic Diet, 393 Parkinson’s disease on inflammation, animal models, 150 neuroprotection, 158–​159 Pasteur effect, 80 Patel, S. P., 136 pentose phosphate shunt (PPP), 354f, 357 pentylenetetrazole (PTZ), 317, 346 pericytes, blood-​brain barrier, 290f, 292 peroxisome proliferator-​activated receptors (PPARs) historical overview, 167 isoforms and domains, 168, 169f polyunsaturated fatty acids, 200 structure and functional diversity, 167–​168 peroxisome proliferator-​activated receptor γ (PPARγ), 7, 137, 151, 151f, 152, 157, 167–​179 activation, 168 agonists, 174 neuroprotection post-​SE and during SRS, 175 pretreatment, acute seizure models, 174 on seizure thresholds and kindling models, 174–​175 on SRS and spatial learning, 175 brain, 170–​172, 172f epilepsy, 173–​174 functional consequences, 177–​178 gene regulation and activity, 169–​170, 169f ketogenic diet activation, evidence, 175–​176 activation, potential mechanisms, 176–​177 regulation, 173–​177 mechanisms of action, 178–​179, 179f neuroprotection, homeostatic, 171, 172f splice variants and activity, 168–​169, 169f structure and domains, 168, 169f Pfeifer, Heidi, 389 Phinney, S. D., 379, 382 PI3K/​AKT signaling pathway, 89 Pires, M. E., 43 plasmalemma vesicle-​associated protein number, 293 polycystic ovary syndrome, 117 polyunsaturated fatty acids (PUFAs) on inflammation, 151f, 152 neuroprotection, 156–​157 pain, 200 peroxisome proliferator-​activated receptors, 200 pregnancy establishment and maintenance, 233–​234 before and during gestation, 233f, 234–​236, 235f, 235t, 236f Pre-​ketogenic diet, 394 presenilin 1/​2 genes, 241 Prins, M. L., 298–​299 D-​proline, seizure onset protection, 348 prolyl-​hydroxylase (PHD), 220, 221, 221f propionyl-​CoA carboxylation pathway, anaplerosis, 336–​337, 338f puberty, ketogenic diet long-​term effects, 231–​234, 232f, 232t, 233f pyruvate decarboxylase deficiency, triheptanoin, 341 pyruvate dehydrogenase deficiency, 50 inhibition, Alzheimer’s disease, 242, 243 QT interval prolongation, 69 radiation, ionizing HDAC inhibitor protection, 264 ketone ester effects, post-​exposure, 266–​267, 267f ketosis protection, 263, 264f in vitro studies, 264–​266, 265f, 266f radiation therapy, cancer, 92 Raju, K. N., 30 Rasmussen syndrome, status epilepticus, 61 ratios, importance, 30–​31 reactive nitrogen species (RNS), 92, 254–​268 damage caused by, 255–​256, 255f, 256f origins, reactions, and target molecules, 254–​255, 255f, 256t reactive oxygen species (ROS), 254–​268 in aging, 256–​257 Alzheimer’s disease, 243–​244 D-​β-​hydroxybutyrate on cellular redox states, 261–​263, 262f, 263f on transcription, 261t, 264 cancer, 90 cellular redox states vs standard redox potentials, 258–​261, 259f, 259t, 261t, 262t damage, 255–​256, 255f, 256f enzymes destroying, 264 on inflammation, 151f, 153 mechanisms of action, 257–​258, 258f origins, reactions, and target molecules, 254–​255, 255f, 256t redox state of oxygen free radicals and other reactants, 261, 262t removal, in vivo, 263–​264 removal, NADPH generation, 264 redox potentials, standard, vs cellular redox states, 258–​261, 259f, 259t, 261t, 262t redox states, cellular D-​β-​hydroxybutyrate on, 261–​263, 262f, 263f oxygen free radicals and other reactants, 261, 262t vs standard redox potentials, 258–​261, 259f, 259t, 261t, 262t   407 Index refractory epilepsy, 18 refractory nonsurgical epilepsy, 40–​42 renal calculi, 68 reproduction, 227–​237 behavioral, 231 endocrine, 227–​230, 228t, 229f, 230f, 230t high-​fat/​ketogenic diets, 227 long-​term effects, 233–​234 pregnancy establishment and maintenance, 233–​234 before and during gestation, 233f, 234–​236, 235f, 235t, 236f puberty, 231–​233, 232f, 232t, 233f reproduction, 233–​234 response predictor, 31 resting energy expenditure (REE), 29 Rett syndrome, 50–​51, 106 triheptanoin, 342 Richardson, R., 364 Rouach, N., 282–​283 Ruskin, D. N., 106 Sada, N., 283–​286, 284f, 285f S-​adenosylhomocysteine (SAH) hydrolase, 212, 212f S-​adenosylmethionine (SAM) dependent transmethylation pathway, 211–​212, 212f Samoilova, M., 188 Sansum, W. D., 364 Sarruf, D. A., 170 Scheck, A. C., 83, 91–​92, 92f Schmid, W., 267 Schoeler, N. E., 41 Schrödinger, Erwin, 257 SCN1A gene mutations, 45 screening, pre-​treatment, 66–​67, 67t, 71t medical, 66 social, 66–​67 seizure see also epilepsy fasting, 209 freedom from, 30 ketone supplementation, 317 seizure control see also epileptogenesis actions ketones, 332 medium chain fatty acids, 328–​330, 329f, 329t senescence, cell, 257 D-​serine, seizure onset protection, 348 L-​serine seizure onset protection, 347 traumatic brain injury, 349 severe myoclonic epilepsy of infancy (SMEI), 45–​46 Seyfried, T. N., 80 Sharma, S., 3, 10, 10t Shimazu, T., 81 side effects, 66–​71 acidosis, 67 cardiac, 69–​70 constipation, 67–​68 electrolyte imbalances, 69 food refusal, 70 407 growth, 70 hepatitis, 69 hyperlipidemia, 69 hypoglycemia, 68 infections, 68 kidney stones, 68 osteopenia, 70 pancreatitis, 69 vitamin deficiencies, 68–​69 vomiting, 67 Simard-​Tremblay, S., 47 Slc2a1, 293 social screening, 66–​67 somatic mutation theory, 79 Spilioti, M., 105 spinal cord injury, 133–​141 epidemiology, 133 inflammation, 138–​140 intermittent fasting, 134 ketogenic diet, mechanisms anaplerotic, 136 anti-​excitotoxic, 137 antioxidant, 137–​138 non-​anaplerotic, 137 ketogenic diet, outcome, 134–​135 ketogenic diet, translation to clinical setting, 140–​141 management, acute, 133 neuroprotective drug candidates, 133–​134 rehabilitation, 133 spontaneous recurrent seizures, PPARγ agonists on, 175 sport, keto-​adaptation, 380–​381 Stafstrom, C. E., 192 status epilepticus (SE), 60–​63 cause, 60 challenges, 61t, 62–​63 convulsive, 61 duration, 60 efficacy, ketogenic diet, 60, 61t implementation, 62, 62f incidence, 60 nonconvulsive, 61–​62 super-​refractory, 60 treatment, first-​line, 60 types, 60 stroke neuroprotection, 218–​219, 219f triheptanoin, 341 Sturge-​Weber syndrome, 53 succinic semialdehyde dehydrogenase (SSADH) deficiency, 105–​106 sugar, dietary, children, 393 superoxide dismutase (MnSOD), 138, 264 oxidative stress, 172f PPARγ deficiency on, 172 reactive oxygen species, 254–​255, 255f, 256t, 264 super-​refractory status epilepticus (SRSE), 18–​19, 60 Sussman, D., 234–​235 408 Free ebooks ==> www.Ebook777.com 408 Index Tanner, G. R., 190 Taub, K. S., 30 TCA cycle, 336, 337f, 338f team-​based approach family-​centered, 26 team composition, 26–​27 telomere shortening, 256–​257 temporal lobe epilepsy hippocampus model, 186–​187 ketogenic diet and adenosine homeostasis, 211–​213, 212f Thakur, K. T., 19 therapeutic ketosis, 310 see also ketone supplementation Thio, L. L., 188 thioredoxin, 259, 259f, 261 tight junctions, blood-​brain barrier, 290f, 292–​293 tocopherol, 258, 258f transcription, D-​β-​hydroxybutyrate on, 261t, 264 transmethylation pathway, 211, 212f transporters see also specific types blood-​brain barrier, 290f, 291f, 293, 296f traumatic brain injury, 133–​141, 298 amino acid treatment, 349 on inflammation, 138–​140 ketogenic diet, translation to clinical setting, 140–​141 ketogenic diet effects, 135–​136 ketogenic diet mechanisms anaplerotic, 136 anti-​excitotoxic, 137 antioxidant, 137–​138 non-​anaplerotic, 137 triglycerides, 5 triheptanoin, 317–​318, 336–​342 anaplerosis, 336–​337, 337f, 338f anticonvulsant effects, 338f, 340 brain energy metabolism, 339–​340 cardiac hypertrophy, 341 epilepsy, energy metabolism, 337–​339, 338f GLUT1 deficiency, 341 long chain fatty acid oxidation disorders, 341 muscle disorders, 342 neurological conditions, 341–​342 pyruvate decarboxylase deficiency, 341 tuberous sclerosis complex, 51–​52 tumor metabolism, 88–​90, 89f uncoupling proteins, on inflammation, 153 unlimited protein diet see modified Atkins diet (MAD) vascular endothelial growth factor (VEGF), neuroprotection, 220–​221 Veech, R. L., 81, 258–​260, 259t, 307, 314, 318 Verdin, ERic, 316 vesicular glutamate transporters (VGLUTs), 190, 193, 286 acetoacetate on, 281 functions, 281 ketogenic diet, 282 Viggiano, A., 317 Villeneuve, N., 61 Vining, E., 70 vitamin deficiencies, 68–​69 Volek, J. S., 378, 379–​380, 382, 383f vomiting, 67 Warburg, Otto, 88 Warburg effect, 80, 82, 88–​90, 89f Warburg’s theory, 79–​80 weight loss, 22 keto-​adaptation, 378–​379 ketone supplementation, 321–​322 Westman, E. C., 367–​370, 370t Wilder, R. M., 16, 26, 165 Williams, Matthew, 386, 387–​388, 393f Williams, S., 70 Williams-​Karnesky, R. L., 210, 211–​212 Willis, S., 340 Winocur, G., 231 Wirrell, E. C., 28 Worden, L. T., 71 Yudkin, John, 363 zona occludin proteins, 293 Zuccoli, G., 93 Zupec-​Kania, Beth, 388, 393 www.Ebook777.com ... other form and you must impose this same condition on any acquirer Library of Congress Cataloging -in- Publication Data Names: Masino, Susan, editor Title: Ketogenic diet and metabolic therapies : expanded. .. I:   in the Clinic Ketogenic Diet for Epilepsy 16 26 A G Christina Bergqvist, md Glut1 Deficiency and the Ketogenic Diets  35 Joerg Klepper, MD, PhD Ketogenic Diet in Established Epilepsy Indications ... promise of using the biochemistry of metabolism to treat disease and promote health by compiling the latest research and perspectives of leading experts on ketogenic diets and metabolic therapies