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


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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    • "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.
    Neurobiology of aging 12/2013; 35(6). DOI:10.1016/j.neurobiolaging.2013.11.027 · 5.01 Impact Factor
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    • "KD have been proposed as a neuroprotective approach for several brain disorders, particularly epilepsies, but also in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and psychiatric disorders such as depression and bipolar disease (El-Mallakh and Paskitti, 2001; Evangeliou et al., 2003; Van der Auwera et al., 2005; Vanitallie et al., 2005; Zhao et al., 2006; Tai and Truong, 2007; Henderson, 2008). We focused this study on two brain regions, the hippocampus and striatum, because these are commonly associated with the brain disorders mentioned. "
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    ABSTRACT: Aims: We investigated the effects of ketogenic diet (KD) on levels of tumor necrosis factor alpha (TNF-α, a classical pro-inflammatory cytokine), BDNF (brain-derived neurotrophic factor, commonly associated with synaptic plasticity), and S100B, an astrocyte neurotrophic cytokine involved in metabolism regulation. Main methods: Young Wistar rats were fed during 8weeks with control diet or two KD, containing different proportions of omega 6 and omega 3 polyunsaturated fatty acids. Contents of TNF-α, BDNF and S100B were measured by ELISA in two brain regions (hippocampus and striatum) as well as blood serum and cerebrospinal fluid. Key findings: Our data suggest that KD was able to reduce the levels of BDNF in the striatum (but not in hippocampus) and S100B in the cerebrospinal fluid of rats. These alterations were not affected by the proportion of polyunsaturated fatty acids offered. No changes in S100B content were observed in serum or analyzed brain regions. Basal TNF-α content was not affected by KD. Significance: These findings reinforce the importance of this diet as an inductor of alterations in the brain, and such changes might contribute to the understanding of the effects (and side effects) of KD in brain disorders.
    Life sciences 04/2013; 92(17-19). DOI:10.1016/j.lfs.2013.03.004 · 2.70 Impact Factor
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    • "Every day, an average human brain consumes approximately 16% of the total oxygen consumption and metabolizes approximately 110 to 145 g of glucose. Over 90% of used glucose is oxidized to ensure the supply of ATP which is vital for the cells and maintenance of synaptic transmission (Henderson, 2008). The determination of the brain glucose metabolism pattern is used in the differential diagnosis of dementia using Position Emission Tomography (PET) imaging with an analog of glucose; 18 fluorodeoxyglucose ( 18 FDG). "
    Pharmacology, 03/2012; , ISBN: 978-953-51-0222-9
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