Introduction
The ketogenic diet (KD), characterized by high-fat, low-carbohydrate, and adequate-protein intake, has garnered significant attention as a potential therapeutic intervention for various neurological disorders (NDs). This dietary approach induces a metabolic state known as "nutritional ketosis," where the body primarily utilizes fat-derived ketone bodies (KBs) as an energy source instead of glucose. The KD was formally introduced in 1921 to mimic the biochemical changes associated with fasting and gained recognition as a potent treatment for pediatric epilepsy in the mid-1990s.
Historical Perspective
The use of fasting to treat epilepsy dates back to ancient times. In 1921, Woodyatt discovered that both starvation and a high-fat diet led to ketosis. Russell Wilder implemented KD at the Mayo Clinic as a treatment for epilepsy in the same year. Interest in KD for neurological disorders was renewed at the end of the last century. Vining et al. studied the efficacy of KD in reducing seizures in children unresponsive to anticonvulsant drugs. Freeman et al. confirmed the neuroprotective effects of KD in patients with drug-resistant epilepsy. Neal et al. conducted a randomized controlled trial that confirmed the important role of KD in controlling epileptic seizures. Recent research suggests that KD may have a favorable effect on the course of other neurological diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD).
Types of Ketogenic Diets
Nowadays, there are many types of ketogenic diets, varying in the proportions of macronutrients, which allows the diet to be tailored to the specific needs of the patient.
Classic Ketogenic Diet
The classic ketogenic diet is characterized by a high dietary fat content, moderate protein intake, and low carbohydrate intake, with a macronutrient ratio of 4:1. The ketogenic diet limits carbohydrate intake to 10% of total daily caloric intake. However, in the initial phase of diet, carbohydrates should be limited to about 20 g per day. Such a low carbohydrate supply ensures that the body adapts and redirects the metabolism to use fatty acids as the main source of energy.
High-Protein Ketogenic Diet (Modified Atkins Diet)
The high-protein ketogenic diet is also known as the Modified Atkins Diet (MAD). The induction phase lasts indefinitely, and during this phase, the carbohydrate intake is no more than 20 g per day. MAD assumes that the ratio of fats to carbohydrates and protein together is 1-2:1.
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Medium-Chain Triglycerides Diet
MTCD is a type of KD where medium-chain triglycerides (MTC) are predominant. MTCD provides faster absorption of the triglycerides into the bloodstream. The substitution of long-chain fatty acids for short-chain fatty acids, which are metabolized faster, results in obtaining more ketone bodies per kilocalorie. Higher efficiency of this process results in a lower requirement for fats, hence making it possible to consume larger amounts of carbohydrates and proteins. Carbohydrate intake on this diet varies between 20-50 g per day or may be less than 10% on a 2000 kcal per day.
Low Glycaemic Index Treatment
Low Glycaemic Index Treatment (LGIT) is an alternative to the ketogenic diet. It is a high-fat diet in which replacement of high glycaemic index (GI) foods with low-GI foods is fundamental. The GI indicates how much food raises blood glucose levels compared to the same amount of reference carbohydrates. Although this diet does not lead to continuous ketosis, it has a positive effect on carbohydrate metabolism. This consists of cyclical periods of a classic ketogenic diet and a high carbohydrate diet (with 45-65% carbohydrates). This type of ketogenic diet allows a person to consume more carbohydrates around intense physical activity to maintain performance while not affecting the state of ketosis.
Mechanisms of Action
Although the brain makes up only about 2% of body weight, it is the most energy-intensive organ in the body. It is known that not only glucose can be a source of energy for the brain, but also ketones which can meet up to 60% of the brain’s total energy needs. The aim of a fat-rich diet is to induce a state of ketosis in the body, characterized by increased lipolysis as well as ketogenesis. As shown in Figure 2 the fatty acids are intensively oxidized in the liver, resulting in the formation of significant amounts of ketone bodies (KBs), such as acetoacetate (ACA), D(-)3-hydroxybutyrate (D-βHB, β-HB) and acetone.
Ketogenesis
Fatty acids undergo the process of β-oxidation in the liver, resulting in the formation of ketone bodies. These are then transported to the blood vessels and then to the neurons where, after conversion to acetyl-CoA, they enter the TCA cycle. The alternative energy source compensates for the smaller contribution of glucose to the ATP yield. Leino et al. demonstrated that the level of monocarboxyl transporter (MCT), which is responsible for KBs transport across the blood-brain barrier (BBB), is increased in animals fed KD diet compared to controls fed a predominantly carbohydrate diet. Increased transport of ketone bodies was also confirmed by Bentourkia et al. using positron emission tomography (PET) and 11C-labeled ACA. Subsequently, the produced KBs are converted to acetyl-CoA in extrahepatic tissues and participate in the citric acid cycle as an energy source. As shown in animal experiments, the obtaining of energy from ketone bodies has many benefits that relate to the nervous system functions. Interestingly, β-HB inhibits lipolysis, thus controlling haemostasis and ketogenesis, through activation of hydroxycarboxylic acid receptor 2 (HCA2, PUMA-G, GPR109A). The latest research shows that KD can change the ratio of NAD+/NADH, increasing the availability of NAD+ in the brain, which has a significant impact on cellular pathways involved in inflammatory response, DNA damage repair, and circadian rhythm regulation.
Brain Metabolism and Ketone Bodies
When the supply of carbohydrates from the diet is insufficient, the brain acquires energy through ketogenesis. Multiple studies indicate that the shift of brain metabolism from glucose oxidation to ketone bodies utilization requires adaptation. Once the organism has adapted to using KBs as the main source of energy, they can cover up to 60-70% of the energy required for proper function of the brain. The Zilberter et al. analysis concluded that KBs act by sparing glucose rather than inhibiting glycolysis. Glucose is transported in the brain by three isoforms of glucose transporters (GLUT): (1) 55 kDa GLUT 1, expressed by endothelial cells, (2) 45 kDa GLUT 1, expressed by astrocytes, (3) GLUT 3, produced by neurons. Leino et al. revealed that GLUT1 levels are elevated in endothelial cells and neuropil of rats put into ketosis, compared to a group fed a high carbohydrate diet. Enhanced glucose transport to the brain may also be associated with the action of insulin-like growth factor (IGF1). At the same time, astrocyte metabolism has been shown to be augmented by KD. Astrocytes activate glycolysis and glycogenolysis, which provide energy to maintain essential functions of these cells, such as the removal of excess glutamate and K+ ions from the synaptic cleft.
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Glutamate and GABA
Glutamate is an excitatory amino acid, and therefore its concentration in the synaptic gap must be kept at a low level. It is transported via vesicular glutamate transporters (VGLUTs). Their action is dependent on Cl− ions, which act as allosteric modulators. Juge et al. demonstrated that ketone bodies cause reversible inhibition of glutamate transport in hippocampal neurons by binding to the Cl− ion site. Long-term consumption of a fat-based diet with a concomitant reduction in carbohydrates increases the flow through the TCA cycle via amplified production of acetyl-CoA, and enhanced activity of the acetyl-CoA reaction with oxaloacetate. The pathway for obtaining glutamate is also intensified due to the reduced availability of oxaloacetate compared to the physiological state, as a result of the increased utilisation of this compound in the reaction with acetyl-CoA in the citric acid cycle. Studies on ketonic mice have shown that leucine concentrations were higher in both blood and forebrain of these animals, while glutamate and glutamine concentrations were not different compared to controls fed a predominantly carbohydrate diet. This may result in the increased transport of glutamate by astrocytes to neurons, which requires the delivery of an ammonia molecule, mostly generated from leucine. These studies indicate an enlargement of the available glutamate pool that can favor synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), as confirmed by studies on synaptosomes using high concentrations of ACA. Moreover, studies using 13C-labeled glucose and acetate revealed that the carbon found in GABA in the ketosis state was derived from acetate. An increased GABA/glutamine ratio was also observed.
Insulin Signaling
Insulin is a hormone produced by pancreatic β cells that increases glucose uptake by the cells, thereby reducing blood glucose levels. The lack of tissue sensitivity to insulin, that is, insulin resistance, as well as defective secretion of this hormone is associated with type 2 diabetes mellitus (T2DM). Nevertheless, its action is not limited to peripheral tissues. Insulin crosses the blood-brain barrier and binds to insulin receptors (IRs) in the brain, resulting in the activation of signalling pathways. However, certain structures in the brain, like the hypothalamus, are more susceptible to its action due to the absence of the BBB, which allows insulin to pass more freely. The PI3K/Akt cascade is one of the main signalling pathways activated by insulin. There is limited information on the impact of KD on insulin signalling in the brain. Some research shows that insulin can regulate the secretion of neurotrophic factors and neurotransmitters and also interact with the gastrointestinal microbiome. Taking into consideration that impaired insulin signalling in the brain is heavily associated with Alzheimer’s disease, affecting levels of this hormone may improve a patient’s condition. Studies in the last few years confirm that KD enhances insulin responsiveness and reduces fluctuations in glucose levels. This effect is manifested by higher scores on cognitive tests, namely the Montreal Cognitive Assessment, suggesting that KD may have a significant influence on alleviating insulin resistance in the brain. Case studies of subjects suffering from Alzheimer’s disease (heterozygous ApoEɛ4 carriers) reported by Stoykovich et al. and Morrill et al. demonstrated that treatment with KD for 10 months reduced (1) fasting glucose levels by 24-25%, (2) fasting insulin by 67-85.3%, (3) homeostatic model assessment for insulin resistance (HOMA-IR) by 75-88.8%, respectively. Furthermore, a randomised controlled trial conducted by Fortier et al. showed that administration of.
Applications in Specific Neurological Disorders
Epilepsy
The KD has been demonstrated as an effective treatment option for drug-resistant epilepsy, particularly in pediatric populations. Its efficacy is supported by numerous studies and long-term outcome data, showing improvements in seizure control for many patients. Neal et al. reported the first randomized, prospective, and controlled clinical trial for treatment-intractable childhood epilepsy in which 3-month administration of a KD resulted in a significant reduction in seizure frequency. The KD was also shown in smaller studies to reduce the onset and frequency of seizures in other childhood seizure syndromes such as Dravet syndrome, myoclonic-atonic epilepsy, and other conditions.
Alzheimer's Disease
Several clinical studies have investigated the effects of the KD or ketone supplements in patients with AD. The effectiveness of the KD has been analyzed in several animal models of Alzheimer's disease (AD), but the beneficial effects were shown to vary widely. Administration of BHB in the 3xTgAD mouse model enhanced energy use in the hippocampus and reduced oxidized proteins and lipids, suggesting correction of metabolic defects associated with AD.
Parkinson's Disease
Several pilot clinical studies have reported findings on the effect of nutritional ketosis on reducing PD symptoms. Consumption of a KD for up to 8 weeks resulted in small increases in cognitive abilities but not motor functions compared with a low-fat diet.
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Multiple Sclerosis
Several ongoing randomized controlled studies are listed on Clinicaltrials.gov that are testing safety, tolerability, and effectiveness of the KD as a therapeutic intervention for MS. Reports from several pilot studies suggest the KD may benefit patients with MS. For example, Brenton et al. demonstrated that patients on a modified KD for 6 months had no worsening symptoms and showed significant improvements in both fatigue and depression scores.
Autism Spectrum Disorder
Given the increasing prevalence of ASD and the limited effectiveness of current treatments, researchers have been exploring alternative therapeutic options, including the ketogenic diet. The study compared the effects of a ketogenic diet and a gluten-free, casein-free diet on autistic children.
Factors Affecting Success
Adherence to the Diet
Ensuring strict adherence to the ketogenic diet is crucial for its success in managing neurological disorders.
Ketosis Level
The degree of ketosis achieved can influence the efficacy of the KD in neurological disorders. Different individuals may require varying levels of ketone bodies for optimal therapeutic effect.
Individual Variability
The response to the KD can vary significantly among individuals.
Type and Severity of the Neurological Disorder
The efficacy of the KD may be influenced by the specific neurological disorder being treated and its severity.
Duration of the KD
The length of time an individual follows the ketogenic diet may impact its effectiveness in managing neurological disorders.
Nutritional Balance
Ensuring adequate intake of essential nutrients, such as vitamins, minerals, and protein, is important for the overall success of the KD in managing neurological disorders.
Age and Developmental Stage
The age and developmental stage of an individual may affect their response to the ketogenic diet. For example, younger children with epilepsy may have better seizure control on the diet compared to adolescents or adults.
Comorbid Conditions
The presence of comorbid conditions, such as diabetes, gastrointestinal disorders, or cardiovascular disease, can also affect the success of the ketogenic diet in managing neurological disorders.
Challenges and Considerations
Implementing the ketogenic diet (KD) can be challenging for individuals, especially those with neurological disorders, as it requires strict adherence to a high-fat, low-carbohydrate diet.
Potential Side Effects
The KD may cause gastrointestinal disturbances, such as constipation, diarrhea, and vomiting, particularly during the initial adaptation period. Moreover, long-term adherence to the KD has been associated with an increased risk of cardiovascular disease due to elevated levels of low-density lipoprotein (LDL) cholesterol and saturated fats.
Nutrient Deficiencies
The restrictive nature of the KD can lead to nutrient deficiencies, especially in vitamins and minerals that are abundant in carbohydrate-rich foods, such as B vitamins, calcium, and potassium.
Monitoring
Given the potential risks and challenges associated with the KD, careful monitoring by healthcare professionals is essential to ensure the safety and effectiveness of the diet in patients with neurological disorders.
Foods to Include and Avoid
Individuals following the ketogenic diet need to base their meals on these foods:
- Fatty fish, including salmon, tuna, and mackerel
- Nuts and seeds, such as walnuts, pumpkin seeds, almonds, and chia seeds
- Healthy oils, such as extra virgin olive oil or avocado oil
- Avocados
- Low carb vegetables
- Eggs
- Meat
- Butter and cream
- Unprocessed cheese
People eating a ketogenic diet need to avoid foods high in carbohydrates, such as:
- Fruit
- Grains and starches
- Sugary foods, such as cake, candy, or soda
- Legumes
- Diet or low fat products
- Condiments and sauces high in sugar content, such as ketchup, BBQ sauce, or teriyaki sauce
- Alcohol
- Sugar-free diet foods
- Tubers and root vegetables
- Unhealthy fats, including processed vegetable oils
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