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Ketogenic Diet and Alzheimer’s, Epilepsy and Parkinson’s

Neuro-protective and disease-modifying effects of the ketogenic diet

Abstract

The ketogenic diet has been in clinical use for over 80 years, primarily for the symptomatic treatment of epilepsy. A recent clinical study has raised the possibility that exposure to the ketogenic diet may confer long-lasting therapeutic benefits for patients with epilepsy. Moreover, there is evidence from uncontrolled clinical trials and studies in animal models that the ketogenic diet can provide symptomatic and disease-modifying activity in a broad range of neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, and may also be protective in traumatic brain injury and stroke. These observations are supported by studies in animal models and isolated cells that show that ketone bodies, especially β-hydroxybutyrate, confer neuroprotection against diverse types of cellular injury. This review summarizes the experimental, epidemiological and clinical evidence indicating that the ketogenic diet could have beneficial effects in a broad range of brain disorders characterized by the death of neurons. Although the mechanisms are not yet well defined, it is plausible that neuroprotection results from enhanced neuronal energy reserves, which improve the ability of neurons to resist metabolic challenges, and possibly through other actions including antioxidant and anti-inflammatory effects. As the underlying mechanisms become better understood, it will be possible to develop alternative strategies that produce similar or even improved therapeutic effects without the need for exposure to an unpalatable and unhealthy, high-fat diet.

Introduction

The ketogenic diet is a high-fat content diet in which carbohydrates are nearly eliminated so that the body has minimal dietary sources of glucose. Fatty acids are thus an obligatory source of cellular energy production by peripheral tissues and also the brain. Consumption of the ketogenic diet is characterized by elevated circulating levels of the ketone bodies acetoacetate, β-hydroxybutyrate and acetone, produced largely by the liver. During high rates of fatty acid oxidation, large amounts of acetyl-CoA are generated. These exceed the capacity of the tricarboxylic acid cycle and lead to the synthesis of the three ketone bodies within liver mitochondria. Plasma levels of ketone bodies rise, with acetoacetate and β-hydroxybutyrate increasing three-fold to four-fold from basal levels of 100 and 200 µmol/l, respectively (Musa-Veloso et al., 2002). In the absence of glucose, the preferred source of energy (particularly of the brain), the ketone bodies are used as fuel in extrahepatic tissues. The ketone bodies are oxidized, releasing acetyl-CoA, which enters the tricarboxylic acid cycle.

The ketogenic diet is an established and effective nonpharmacological treatment for epilepsy (Vining et al., 1998; Stafstrom, 2004; Sinha and Kossoff, 2005). Although the diet is useful in people of all ages, clinical experience suggests that it may be more valuable in children, if only because adults have greater difficulty adhering to it. Importantly, the diet is often effective in pharmacoresistant forms of common epilepsies as well as in the difficult to treat catastrophic epilepsy syndromes of infancy and early childhood such as West Syndrome, Lennox–Gastaut Syndrome, and Dravet Syndrome (Crumrine, 2002; Trevathan, 2002; Caraballoet al., 2005).

Recently, there has been interest in the potential of the ketogenic diet in the treatment of neurological disorders other than epilepsy, including Alzheimer’s disease and Parkinson’s disease. Studies in these neurodegenerative disorders have led to the hypothesis that the ketogenic diet may not only provide symptomatic benefit, but could have beneficial disease-modifying activity applicable to a broad range of brain disorders characterized by the death of neurons. Here, we review evidence from clinical studies and animal models that supports this concept.

Ketogenic diet

The classic ketogenic diet is a high-fat diet developed in the 1920s to mimic the biochemical changes associated with periods of limited food availability (Kossoff, 2004). The diet is composed of 80–90% fat, with carbohydrate and protein constituting the remainder of the intake. The diet provides sufficient protein for growth, but insufficient amounts of carbohydrates for the body’s metabolic needs. Energy is largely derived from the utilization of body fat and by fat delivered in the diet. These fats are converted to the ketone bodies β-hydroxybutyrate, acetoacetate, and acetone, which represent an alternative energy source to glucose. In comparison with glucose, ketone bodies have a higher inherent energy (Pan et al., 2002; Cahill and Veech, 2003). In adults, glucose is the preferred substrate for energy production, particularly by the brain. Ketone bodies are, however, a principal source of energy during early postnatal development (Nehlig, 2004). In addition, ketone bodies, especially acetoacetate, are preferred substrates for the synthesis of neural lipids. Ketone bodies readily cross the blood–brain barrier either by simple diffusion (acetone) or with the aid of monocarboxylic transporters (β-hydroxybutyrate, acetoacetate), whose expression is related to the level of ketosis (Pan et al., 2002; Pierre and Pellerin, 2005).

Today, several types of ketogenic diets are employed for treatment purposes. The most frequently used is the traditional ketogenic diet originally developed by Wilder in 1921, which is based on long-chain fatty acids (Wilder, 1921). In the 1950s, a medium-chain triglyceride diet was introduced, which produces greater ketosis (Huttenlocher et al., 1971). This modification has not been widely accepted because it is associated with bloating and abdominal discomfort and is no more efficacious than the traditional ketogenic diet. A third variation on the diet, known as the Radcliffe Infirmary diet, represents a combination of the traditional and medium-chain triglyceride diets (Schwartz et al., 1989). Its efficacy is also similar to the traditional ketogenic diet.

Although the ketogenic diet was a popular treatment approach for epilepsy in the 1920s and 1930s, its medical use waned after the introduction of phenytoin in 1938. The recognition that the diet may be an effective therapeutic approach in some drug-resistant epilepsies, particularly in children, has led to a resurgence of interest in the last 15 years. The popularization of various low carbohydrate diets for weight loss, such as the Atkins diet (Acheson, 2004), probably also has increased interest in the dietary therapy of epilepsy. In fact, a modified form of the Atkins diet, which is easier to implement than the various forms of the traditional ketogenic diet, may be an effective epilepsy treatment approach (Kossoff et al., 2006).

Clinical studies
Epilepsy

At present, strong evidence exists that the ketogenic diet protects against seizures in children with difficult-to-treat epilepsy (Freeman et al., 1998). Recent reports have raised the possibility that the diet may also improve the long-term outcome in such children (Hemingway et al., 2001; Marsh et al., 2006). In these studies, children with intractable epilepsy who remained on the ketogenic diet for more than 1 year and who experienced a good response to the diet, often had positive outcomes at long-term follow-up 3–6 years after the initiation of diet. Forty-nine percent of the children in this cohort experienced a nearly complete (≥ 90%) resolution in seizures. Surprisingly, even those children who remained on the diet for 6 months or less (most of these children terminated the diet because of an inadequate response) may have obtained a long-term benefit from exposure to the diet. Thirty-two percent of these children had a ≥ 90% decrease in their seizures and 22% became seizure free even without surgery. The diet also allowed a decrease or discontinuation of medications without a relapse in seizures. Of course, in the absence of a control group, it is not possible to be certain that the apparent good response in these children is simply the natural history of the epilepsy in the cohort studied, although these children had, by definition, intractable epilepsy before starting the diet. In any case, the results raise the possibility that the ketogenic diet, in addition to its ability to protect against seizures, may have disease-modifying activity leading to an improved long-term outcome. It is noteworthy that none of the currently marketed antiepileptic drugs has been demonstrated clinically to possess such a disease-modifying effect (Schachter, 2002; Benardo, 2003). Determining whether the ketogenic diet truly alters long-term outcome will require prospective controlled trials.

Alzheimer’s disease

Recent studies have raised the possibility that the ketogenic diet could provide symptomatic benefit and might even be disease modifying in Alzheimer’s disease. Thus, Reger et al. (2004) found that acute administration of medium-chain triglycerides improves memory performance in Alzheimer’s disease patients. Further, the degree of memory improvement was positively correlated with plasma levels of β-hydroxybutyrate produced by oxidation of the medium-chain triglycerides. If β-hydroxybutyrate is responsible for the memory improvement, then the ketogenic diet, which results in elevated β-hydroxybutyrate levels, would also be expected to improve memory function. When a patient is treated for epilepsy with the ketogenic diet, a high carbohydrate meal can rapidly reverse the antiseizure effect of the diet (Huttenlocher, 1976). It is therefore of interest that high carbohydrate intake worsens cognitive performance and behavior in patients with Alzheimer’s disease (Henderson, 2004; Young et al., 2005).

It is also possible that the ketogenic diet could ameliorate Alzheimer’s disease by providing greater amounts of essential fatty acids than normal or high carbohydrate diets (Cunnane et al., 2002; Henderson, 2004). This is because consumption of foods or artificial supplements rich in essential fatty acids may decrease the risk of developing Alzheimer’s disease (Ruitenberg et al., 2001; Barberger-Gateau et al., 2002; Morris et al., 2003a,b).

Parkinson’s disease

One recently published clinical study tested the effects of the ketogenic diet on symptoms of Parkinson’s disease (VanItallie et al., 2005). In this uncontrolled study, Parkinson’s disease patients experienced a mean of 43% reduction in Unified Parkinson’s Disease Rating Scale scores after a 28-day exposure to the ketogenic diet. All participating patients reported moderate to very good improvement in symptoms. Further, as in Alzheimer’s disease, consumption of foods containing increased amounts of essential fatty acids has been associated with a lower risk of developing Parkinson’s disease (de Lau et al., 2005).

By Maciej GasiorMichael A. Rogawski, and Adam L. Hartman; May 2008

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