Article

Ketone Bodies as a Therapeutic for Alzheimer's Disease

Accera, Inc., Broomfield, Colorado 80021, USA.
Neurotherapeutics (Impact Factor: 5.05). 08/2008; 5(3):470-80. DOI: 10.1016/j.nurt.2008.05.004
Source: PubMed

ABSTRACT

An early feature of Alzheimer's disease (AD) is region-specific declines in brain glucose metabolism. Unlike other tissues in the body, the brain does not efficiently metabolize fats; hence the adult human brain relies almost exclusively on glucose as an energy substrate. Therefore, inhibition of glucose metabolism can have profound effects on brain function. The hypometabolism seen in AD has recently attracted attention as a possible target for intervention in the disease process. One promising approach is to supplement the normal glucose supply of the brain with ketone bodies (KB), which include acetoacetate, beta-hydroxybutyrate, and acetone. KB are normally produced from fat stores when glucose supplies are limited, such as during prolonged fasting. KB have been induced both by direct infusion and by the administration of a high-fat, low-carbohydrate, low-protein, ketogenic diets. Both approaches have demonstrated efficacy in animal models of neurodegenerative disorders and in human clinical trials, including AD trials. Much of the benefit of KB can be attributed to their ability to increase mitochondrial efficiency and supplement the brain's normal reliance on glucose. Research into the therapeutic potential of KB and ketosis represents a promising new area of AD research.

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Available from: Samuel T Henderson, Feb 04, 2014
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    • "Ketogenic medical foods or exogenous ketones have proven problematic for reasons of cost, palatability, tolerability, and long-term safety. Ketogenic fats, such as medium-chain triglyceride oil (MCT oil), are poorly tolerated by the gastrointestinal system, but studies have shown that cognitive enhancement benefits can be observed from the mild ketosis in those individuals tolerant to MCT-based formulas (Henderson, 2008). Oral administration of BHB and AcAc in their free acid form is expensive and ineffective at producing sustained ketosis. "
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    ABSTRACT: Metabolic therapies that induce a state of mild ketosis from caloric restriction or the ketogenic diet offer neuroprotection against seizures and continue to emerge as a promising strategy for the metabolic management of Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Severe dietary restriction of calories or carbohydrates is typically needed to produce a level of ketosis that achieves therapeutic benefits. Interestingly, the strategy to use exogenous ketones or other metabolic intermediates as alternative fuels has not been exploited therapeutically. When administered orally in controlled dosages, ketone esters and other metabolic agents can improve glucose utilization and elevate plasma ketone levels comparable to levels achieved by the most rigorous ketogenic diets. Metabolic therapies in the form of a ketogenic diet or metabolic substrate supplementation offer a safe, convenient, and versatile new treatment approach for a variety of diseases, including seizure disorders and other neurodegenerative diseases.
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    • "Hence , somewhat higher plasma AcAc in older adults is needed in brain regions with a lower Ka to achieve the same net brain AcAc uptake as in younger adults . Diets or supplements that induce mild ketosis are reportedly therapeutically beneficial in both mild cognitive impairment and Alzheimer ' s disease , at least on a short - term basis ( Henderson , 2008 ; Krikorian et al . , 2012 ; Reger et al . "
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    ABSTRACT: The extent to which the age-related decline in regional brain glucose uptake also applies to other important brain fuels is presently unknown. Ketones are the brain's major alternative fuel to glucose, so we developed a dual tracer positron emission tomography protocol to quantify and compare regional cerebral metabolic rates for glucose and the ketone, acetoacetate. Twenty healthy young adults (mean age, 26 years) and 24 healthy older adults (mean age, 74 years) were studied. In comparison with younger adults, older adults had 8 ± 6% (mean ± SD) lower cerebral metabolic rates for glucose in gray matter as a whole (p = 0.035), specifically in several frontal, temporal, and subcortical regions, as well as in the cingulate and insula (p ≤ 0.01, false discovery rate correction). The effect of age on cerebral metabolic rates for acetoacetate in gray matter did not reach significance (p = 0.11). Rate constants (min(-1)) of glucose (Kg) and acetoacetate (Ka) were significantly lower (-11 ± 6%; [p = 0.005], and -19 ± 5%; [p = 0.006], respectively) in older adults compared with younger adults. There were differential effects of age on Kg and Ka as seen by significant interaction effects in the caudate (p = 0.030) and post-central gyrus (p = 0.023). The acetoacetate index, which expresses the scaled residuals of the voxel-wise linear regression of glucose on ketone uptake, identifies regions taking up higher or lower amounts of acetoacetate relative to glucose. The acetoacetate index was higher in the caudate of young adults when compared with older adults (p ≤ 0.05 false discovery rate correction). This study provides new information about glucose and ketone metabolism in the human brain and a comparison of the extent to which their regional use changes during normal aging.
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    • "MCTs can be rapidly metabolized to induce metabolic ketosis and ketogenic diets have been employed as therapy for a variety of brain disorders, including epilepsy and neurodegeneration [4] [5] [6]. Such diets lead to the formation of ketone bodies which can then be used as an alternative to glucose for energy requirements [4] [5] [6] [7]. Experimental animal studies using dietary supplementation with MCT formulations or coconut oil have provided somewhat conflicting results. "
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    ABSTRACT: Dietary supplementation has been studied as an approach to ameliorating deficits associated with aging and neurodegeneration. We undertook this pilot study to investigate the effects of coconut oil supplementation directly on cortical neurons treated with amyloid-β (Aβ) peptide in vitro. Our results indicate that neuron survival in cultures co-treated with coconut oil and Aβ is rescued compared to cultures exposed only to Aβ. Coconut oil co-treatment also attenuates Aβ-induced mitochondrial alterations. The results of this pilot study provide a basis for further investigation of the effects of coconut oil, or its constituents, on neuronal survival focusing on mechanisms that may be involved.
    No preview · Article · Oct 2013 · Journal of Alzheimer's disease: JAD
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