bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ketogenic Diet for Other Epilepsies
Authors: Hsieh David T. , Thiele Elizabeth A. 
Published: March 2022

Abstract
The ketogenic diet is the treatment of choice for epilepsy in certain disorders of brain metabolism, particularly glucose transporter type 1 deficiency and pyruvate dehydrogenase deficiency. The International Ketogenic Diet Study Group has listed several other conditions for which the ketogenic diet has been reported as being consistently more beneficial than average and for which the diet could be offered earlier. Whether efficacy in these conditions is due in part to the broad-spectrum efficacy of the ketogenic diet or due to mechanisms specific to these conditions is still under investigation. This chapter covers the use of dietary therapies for the treatment of epilepsy in certain genetic disorders, including Angelman syndrome and tuberous sclerosis complex, as listed by the International Ketogenic Diet Study Group, and in addition the chapter considers the use of epilepsy dietary therapies in patients with Rett syndrome and Sturge-Weber syndrome.
The Ketogenic Diets in Genetic Generalized Epilepsy Syndromes
Authors: Kessler Sudha Kilaru 
Published: March 2022

Abstract
This chapter reviews the evidence for the effectiveness of the ketogenic diet and related therapies in idiopathic (genetic) generalized epilepsy. The discussion focuses chiefly on the two most common syndromes—childhood absence epilepsy and juvenile myoclonic epilepsy. Perhaps because the proportion of patients with genetic generalized epilepsy that have pharmacoresistant seizures is lower than for other epilepsy types, they constitute a small percentage of patients treated with the ketogenic diet and related therapies. However, for patients with genetic generalized epilepsy who are pharmacoresistant, limited evidence shows that the ketogenic diet can be an effective therapy.
Overview
Authors: Rho Jong M. 
Published: March 2022

AbstractAfter a century of clinical use, the ketogenic diet is firmly established as a highly effective treatment for medically intractable epilepsy in both children and adults. Intriguingly, there is growing experimental evidence that the ketogenic diet and its metabolites also render neuroprotective and potentially disease-modifying effects. Hence, dietary and metabolic therapies have been attempted in a variety of neurologic disorders other than epilepsy, including malignant brain cancer, neurodegenerative conditions such as Parkinson’s disease and Alzheimer’s disease, other cognitive disorders, autism spectrum disorder, neurotrauma, pain, and multiple sclerosis. More recently, a parallel approach has been taken to treat mental health disorders such as depression, anxiety, bipolar disorder, and even schizophrenia. This section, “Ketogenic Diet—Emerging Clinical Applications and Future Potential,” explores the current preclinical and clinical evidence for metabolism-based treatments designed to counter the myriad disease processes seen in many neurologic (and potentially psychiatric) conditions. Specific attention has been given to the effects of the ketogenic diet in malignant brain cancer, autism spectrum disorder, Alzheimer’s disease, traumatic brain and spinal cord injury, pain, and schizophrenia. Furthermore, the anti-inflammatory effects of the ketogenic diet and dietary effects on the gut microbiome are summarized.
Metabolism-Based Treatments for Managing Cancer
Authors: Seyfried Thomas N. , Mukherjee Purna , Chinopoulos Christos 
Published: March 2022

AbstractMounting evidence indicates that cancer is primarily a mitochondrial metabolic disease rather than a genetic disease. Abnormalities in cancer cell mitochondria impair oxidative phosphorylation, thus causing a gradual shift in cellular energy production from respiration to fermentation. Glucose and glutamine are the two major fermentable fuels for cancer cells. Glucose drives tumor growth through glycolysis in the cytoplasm, while glutamine drives tumor growth through glutaminolysis in the mitochondria. Restriction of fermentable fuels is therefore an effective therapeutic strategy for cancer management. Ketogenic metabolic therapy (KMT) lowers blood glucose while elevating blood ketone bodies, a “super fuel” for normal cells, but a nonfermentable fuel for cancer cells. The efficacy of KMT for cancer management can be enhanced when used together with glutamine-targeting drugs and procedures that further inhibit fermentation. Hence, KMT represents an alternative, nontoxic strategy for managing and preventing a broad range of cancers and could also be important in reducing healthcare costs in the emerging era of global budgeting.
Ketogenic Diet as Adjunctive Therapy for Malignant Brain Cancer
Authors: Scheck Adrienne C. , Syed Nelofer 
Published: March 2022

Abstract
Malignant brain tumors are devastating despite aggressive treatments, including surgical resection, chemotherapy, and radiation therapy. The average life expectancy of patients with newly diagnosed glioblastoma is approximately 18 months, and increased survival requires the design of new therapeutic modalities, especially those that enhance currently available treatments. One novel therapeutic arena is the metabolic dysregulation that results in an increased need for glucose in tumor cells. This phenomenon suggests that a reduction in tumor growth could be achieved by decreasing glucose availability, which can be accomplished through pharmacologic means or through the use of a high-fat, low-carbohydrate ketogenic diet (KD). Preclinical work has shown that the KD does indeed reduce tumor growth in vivo, and it reduces angiogenesis, inflammation, peritumoral edema, migration, and invasion. Furthermore, the KD can enhance the activity of radiation and chemotherapy in a mouse model of glioma, thus increasing survival. Additional studies in vitro have indicated that increasing ketones in the absence of glucose reduction can also inhibit cell growth and potentiate the effects of radiation. The pluripotent effects exhibited by ketogenic therapy may be due, in part, to epigenetic changes. The main ketone, β-hydroxybutyrate, is a class 1 histone deacetylase inhibitor, and we have shown that the expression of a number of microRNAs is altered in tumors of mice fed a KD compared to standard diet. Thus, the emerging data provide strong support for the use of a KD in the treatment of malignant gliomas.
Ketogenic Diet and Ketones for Improving Neurologic Outcomes after Acute Neurotrauma
Authors: Seira Oscar , Kolehmainen Kathleen L. , Plunet Ward T. , Yarar-Fisher Ceren , Tetzlaff Wolfram 
Published: March 2022

Abstract
Traumatic injuries to the brain and spinal cord have a global estimated incidence of several million people every year. Despite strong research efforts to find possible neuroprotective or neurorestorative therapies, treatment for people with neurotrauma is limited. For spinal cord injury (SCI), the standard of care is surgical stabilization followed by rehabilitation programs. Hence, there is an urgent need for treatments aiming to protect the nervous system from the secondary damage that occurs after the primary injury event. Preclinical data in rodents show that ketogenic diets (KDs) or ketone supplementation initiated after injury improves the outcomes from SCI or traumatic brain injury. This chapter describes the potential mechanisms by which KDs or ketone bodies provide protection after neurotrauma and reviews their current translation from the preclinical to the early clinical settings, where pilot trials in humans have shown promise.
Overview: Ketogenic Diet in the Laboratory
Authors: Boison Detlev 
Published: March 2022

Abstract
Clinical and public interests in the ketogenic diet and metabolic treatments continue to spur research into mechanisms underlying their anticonvulsant, neuroprotective, and antiepileptogenic efficacy. Opportunities beyond seizure control are being explored and discovered in basic, translational, and clinical research paradigms. The range of specific mechanisms includes transcription factors, enzymes, energy molecules, ion channels, and more. Clinical opportunities discussed in this section include neurodegenerative disease, seizure disorders, and psychiatric disorders, as well as pan-disease benefits, such as reduced inflammation and even increased longevity. Many of these benefits are likely due to a combination of acute and long-lasting effects of metabolic therapy.
Ketogenic Diet and PPARγ‎
Authors: Simeone Timothy A. 
Published: March 2022

AbstractThe ketogenic diet (KD) is an effective therapy for many patients with refractory epilepsy. It engages a wide array of antioxidant and anti-inflammatory processes and improves mitochondrial functions that are thought to underlie its neuroprotective, antiseizure, and disease-modifying effects. Potential roles of ketone bodies in these mechanisms are discussed elsewhere in this volume. Here, we focus on the role of KD fatty acids as potential ligands for the nutritionally regulated nuclear transcription factor peroxisome proliferator-activated receptor γ (PPARγ). PPARγ regulates many of the pathways identified in the mechanism of the KD and, in recent years, has become a potential therapeutic target for neurodegenerative diseases. This chapter reviews current knowledge concerning PPARγ in the brain, the evidence that PPARγ has neuroprotective and antiseizure properties, and the evidence suggesting that PPARγ may be involved in the antiseizure mechanisms of the KD.
Ketogenic Diet and Epigenetic Mechanisms of Epileptogenesis
Authors: Murugan Madhuvika , Tescarollo Fabio C. , Boison Detlev 
Published: March 2022

AbstractApproximately 60% of all epilepsy cases occur as a consequence of acute insults to the brain, such as traumatic brain injury, cerebrovascular insult, or infections. After an insult, the brain enters a period during which progressive neurobiologic alterations convert a non-epileptic brain into a brain capable of generating spontaneous and recurrent seizures, which are defined as epilepsy. The series of events is known as epileptogenesis. Epigenetic (DNA methylation) changes may affect several genes thought to represent risk factors for epilepsy; epigenetic changes are potentially reversible and may constitute a novel target for therapeutic intervention. DNA hypermethylation related to adenosine deficiency results in a vicious cycle associated with the onset of epileptogenesis and leading to chronic pharmacoresistant epilepsy. DNA hypermethylation is restored by the ketogenic diet (KD) via adenosine augmentation, a shift in the S-adenosylhomocysteine and S-adenosylmethionine homeostasis, and aiding DNA methylation by DNA methyltransferases. The KD-induced increase in ketone bodies inhibits histone deacetylases and prevents histone deacetylation. A clearer understanding of how KD therapy affects adenosine metabolism and its epigenetic sequelae may guide the development of therapies designed to directly restore adenosine homeostasis.
Effects of the Ketogenic Diet on the Blood–Brain Barrier
Authors: Janigro Damir 
Published: March 2022

AbstractThe ketogenic diet (KD) is considered a valuable nonpharmacologic approach for treating multiple neurologic disorders, for attenuating the neurologic sequelae of brain injury, and for reducing seizure burden. The mechanisms by which the KD works are largely unknown. Glucose is virtually the sole energy source for the brain. However, during times of starvation, the liver produces ketone bodies (KBs), which can supply up to 70% of the brain’s energy needs. Acetoacetate and β-hydroxybutyrate (βHB) are the most abundant KBs, whereas acetone, present in small quantities, is not commonly utilized as an energy source. Ketones are also advantageous in neuroinflammatory conditions because they decrease the production of free radicals. Studies suggest a significant increase in cerebral ketone uptake after brain injury. KBs are always present in the blood, and their levels increase after high-fat dietary intake, prolonged exercise, or extended fasting. Thus, one can predict an effect on the brain capillary endothelium from high levels of ketones in the blood. Prolonged exposure of blood–brain barrier (BBB) endothelial cells to KBs induces expression of monocarboxylate transporters and enhances the cerebral uptake rate of KBs. In addition, cell migration and expression of gap junction proteins are upregulated by KBs. Altogether, reports suggest that the beneficial effects of the KD may depend on increased brain uptake of KBs to match metabolic demand as well as repair of the disrupted BBB. As the effects of KBs on the BBB and transport mechanisms across the BBB are better understood, it will be possible to develop alternative strategies to optimize therapeutic benefits for brain disorders where the BBB is compromised.
Nicotinamide Adenine Dinucleotide as a Central Mediator of Ketogenic Therapy
Authors: Elamin Marwa , Ruskin David N. , Masino Susan A. , Sacchetti Paola 
Published: March 2022

AbstractThe ability of a ketogenic diet to treat seizures and to render a neuronal network more resistant to strong electrical activity has been observed for a century in clinics and for decades in research laboratories. Along with ongoing efforts to understand how this therapy works to stop seizures, metabolic health is increasingly appreciated as a critical buffer to resisting and recovering from acute and chronic disease. Accordingly, links between metabolism and health, and the broader emerging impact of the ketogenic diet in improving diverse metabolic, immunologic, and neurologic conditions, have served to intensify the search for its key and/or common mechanisms. Here, diverse evidence for increased levels of NAD+, and thus an altered NAD+/NADH ratio, during ketogenic therapy is reviewed. Increased NAD+ is a potential unifying mechanism, and the chapter highlights some of the evidence linking an altered NAD+/NADH ratio with reduced seizures and with a range of short and long-term changes associated with the beneficial effects of a ketogenic diet. An increase in the NAD+/NADH ratio is consistent with multiple lines of evidence and hypotheses, and therefore increased NAD+ may be a common mechanism underlying beneficial effects of ketogenic diet therapy.
Overview
Authors: D’Agostino Dominic P. 
Published: March 2022

Abstract
The ketone bodies β-hydroxybutyrate and acetoacetate are produced from fatty acids in the liver and serve as alternative energy sources for the brain, heart, skeletal muscle, and other peripheral tissues during prolonged fasting, calorie restriction, strenuous exercise, or adherence to a low-carbohydrate diet. Emerging evidence has revealed nutritional ketosis as a powerful metabolic therapy for general health and a growing number of medical conditions in addition to epilepsy. Data indicate that many of the benefits of the ketogenic diet are mechanistically attributable to elevated ketone bodies, leading researchers to investigate the use of ketone body-boosting supplements to circumvent the need for restrictive diets. This section includes chapters that discuss the expanding medical and performance applications of nutritional ketosis and the emerging science of ketones and related metabolites.
Ketone Supplementation for Health and Disease
Authors: Poff Angela M. , Kesl Shannon L. , Koutnik Andrew P. , Moss Sara E. , Rogers Christopher Q. , D’Agostino Dominic P. 
Published: March 2022

AbstractThe physiologic state of ketosis is characterized by decreased blood glucose, suppression of insulin, and an increase in the blood ketones β-hydroxybutyrate (βHB) and acetoacetate (AcAc), which serve as alternative sources of ATP in the brain. Ketones are elevated by fasting, caloric restriction, exercise, or the ketogenic diet (KD), and until recently these were the only known methods of inducing and sustaining ketosis in a nonpathologic setting. Many studies have revealed therapeutic effects of the KD, and data suggest that the benefits are mediated largely by ketone body metabolism and signaling. However, the KD often causes reduced patient compliance, which can make the KD a suboptimal long-term treatment. This has led researchers to develop exogenous ketone supplements—compounds that release or are metabolized into βHB and/or AcAc. The supplements rapidly elevate blood ketones in a dose-dependent manner, making them a practical method for inducing therapeutic ketosis. Ketone supplementation could potentially be used as stand-alone therapy in certain conditions, or possibly as a way to further augment the efficacy of the KD in the conditions in which it is being used or investigated, and it could increase compliance by allowing patients to maintain a less restrictive diet. Ketone supplements may also serve as an effective preventative medicine due to their potential to protect and enhance mitochondrial function. Preliminary evidence suggests there are several conditions for which ketone supplementation may be beneficial, including epilepsy, Alzheimer’s disease, glucose transporter type 1 deficiency syndrome, cancer, atrophy-related diseases, and metabolic syndrome.
Neuroprotective and Behavioral Benefits of Exogenous Ketone Supplementation-Evoked Ketosis
Authors: Kovacs Zsolt , D’Agostino Dominic P. , Ari Csilla 
Published: March 2022

AbstractEmerging evidence from numerous studies suggests that administration of exogenous ketone supplements, such as ketone salts and ketone esters, may have a therapeutic influence on several central nervous system disorders through neuroprotective and behavioral effects. Therefore, ketone supplementation is a potential therapeutic tool for epilepsy, neurodegenerative, and psychiatric disorders. Ketosis evoked by exogenous ketone supplements can exert its beneficial effects, for example, through modulation of mitochondrial function, hydroxycarboxylic acid receptor 2, histone deacetylases, and the NOD-like receptor pyrin domain 3 inflammasome. In this chapter, the ketone-induced metabolic and downstream signaling effects associated with mitigating treatment-resistant neurodegenerative and behavioral disorders are summarized and the rationale for the development and testing of specific ketone-based adjunctive treatments is outlined.
Identifying the Molecular Mechanism of the MCT (Ketogenic) Diet
Authors: Walker Matthew C. , Williams Robin S. B. 
Published: March 2022

AbstractThe medium-chain triglyceride (MCT) ketogenic diet is a highly effective and commonly used approach for treating drug-resistant epilepsy. Due to the restrictive nature of the diet and compliance issues, it is mainly used in children. The diet is associated with elevated levels of ketone bodies and two MCT-derived fatty acids, decanoic and octanoic acid. The therapeutic role for decanoic acid and a range of novel related chemicals has been shown in seizure control in multiple acute in vitro and in vivo models. Furthermore, a principal mechanism of decanoic acid has been shown to be through direct inhibition of AMPA receptors, a key excitatory neurotransmitter receptor widely recognized as a therapeutic target for seizure control. These data suggest that a therapeutic mechanism of action of the MCT ketogenic diet may be through a direct fatty acid-dependent mechanism, independent of ketosis. This discovery will enable the development of an improved and, potentially, better-tolerated diet and the generation of a corresponding pharmaceutical approach. Thus, the MCT ketogenic diet should be more correctly termed the MCT diet, because the ketosis may not be necessary for seizure control.
Low-Carbohydrate, Ketogenic Diets for the Treatment of Type 2 Diabetes and Obesity
Authors: Westman Eric C. , Tondt Justin , Yancy William S. 
Published: March 2022

Abstract
Obesity and type 2 diabetes mellitus (T2DM) have reached epidemic proportions in the modern world. Because the excessive fat mass of obesity leads to insulin resistance, and insulin resistance contributes to T2DM, obesity is an underlying contributing cause of T2DM. So, treating obesity and T2DM simultaneously would be of particular interest in the treatment of T2DM. Low-carbohydrate diets, also known as carbohydrate-restricted diets, have been used since the late 1800s to treat obesity and type 2 diabetes, but only recently have they been included in clinical research to assess their mechanisms and long-term safety. Clinical studies have shown that carbohydrate restriction leads to appetite reduction, weight loss, and improvements in glycemic and insulin control. Over a 2-year period, carbohydrate restriction can lead to remission and cure of T2DM. The recent clinical research supporting the use of a carbohydrate-restricted diet in individuals with obesity and T2DM is reviewed.
Intermittent Exogenous Ketosis for Athletic Performance, Recovery, and Adaptation
Authors: Stubbs Brianna J. , Hespel Peter 
Published: March 2022

Abstract
Sports nutrition science seeks to determine optimal dietary protocols for athletes pushing the limits of human physiology in power, endurance, and skill. Traditionally, dietary interventions aimed to stimulate performance have focused on strategic intake of carbohydrates, protein, and fat. However, recent development of oral ketone supplements has increased the popularity of intermitted exogenous ketosis (IEK) as a potential nutritional strategy to stimulate training adaptation and performance in athletes. Several physiologic mechanisms are implicated in acute modulation of exercise performance by IEK. These include use of ketone bodies as an alternative substrate for oxidative ATP production in contracting muscles and ketone-mediated inhibition of glycolytic flux. The latter could lead to glycogen sparing, which may increase endurance; on the other hand, glycolytic inhibition in conjunction with ketoacidosis could be ergolytic in short maximal exercise bouts. Furthermore, preliminary evidence suggests that acute and chronic post-exercise ketosis may stimulate recovery from training. Acute IEK could stimulate muscle protein synthesis and glycogen repletion, and chronic ketone ester intake blunted overreaching symptoms during short-term endurance training overload. This protection could be attributed to improved autonomic neural balance, appetite and stress hormone regulation, and possibly attenuation of exercise-induced inflammation and oxidative stress. Such effects could conceivably either down- or upregulate training adaptation. However, research to date describing both acute and chronic exogenous ketosis in exercise and training is limited and inconclusive. Further studies are required to elucidate the specific contexts and mechanisms whereby IEK could maximally benefit athletes.