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  • Beside its efficacy in the treatment of refractory epilepsy

    2018-10-22

    Beside its efficacy in the treatment of refractory epilepsy, the ketogenic diet has been suggested to be useful in the therapy of neurodegenerative and neuromuscular diseases including AD, Parkinson’s disease, amyotrophic lateral sclerosis and mitochondrial disorders [34]. The ketogenic diet is likely to have different mechanisms in different diseases [29].
    Rationale for the use of ketogenic diets in AD Energy deprivation is harmful to neurons and may contribute to the pathophysiology of AD since cftr inhibitor glucose uptake and metabolism have been shown to be impaired in AD. A decline in cerebral blood flow and mean cerebral oxygen utilization was found to be correlated with increasing severity of dementia [35]. Compared to elderly controls, individuals with senile dementia showed a decrease in regional glucose use in the posterior cingulate, temporal, cftr inhibitor parietal and prefrontal cortex [36] and this hypometabolism correlated significantly with measures of cognitive functioning [37]. The deficit in brain glucose metabolism is an early feature of AD and could be the consequence of a reduced need for glucose due to synaptic loss and neuronal cell death. However, brain glucose hypometabolism has also been observed in preclinical stages of AD long before the occurrence of cognitive deficits. Clinical studies have reported a decline in cerebral glucose utilization prior to the onset of clinically measurable cognitive decline and the diagnosis of AD [38,39]. Brain hypometabolism preceding the onset of clinical signs of AD may presymptomatically contribute to the risk of AD [40]. Early degeneration of the locus coeruleus, the noradrenergic brain stem nucleus, may be a reason for the compromised glucose metabolism in AD since the locus coeruleus stimulates glucose metabolism, at least in astrocytes (for review see Ref. [41]). Glucose metabolism has also been shown to decrease in healthily aging individuals, but the reduction is more pronounced in ApoE4 carriers than in matched non-carriers [42]. A low regional cerebral metabolic rate of glucose appears to occur early in the AD process long before the onset of clinical signs of dementia or neuronal loss and plaque deposition in the brain [43]. Brain hypometabolism has been suggested to indicate a risk for the future development of dementia [44]. A vicious circle may gradually develop in which latent presymptomatic brain hypometabolism leads to chronic brain energy deprivation, deteriorating neuronal function, further decline in demand for glucose and progression of cognitive impairment [40]. The reason why reduced brain glucose metabolism develops is unknown, but defective brain glucose transport, disrupted glycolysis, or impaired mitochondrial function may be involved (for a detailed account of the consequences of impaired energy metabolism in AD see Ref. [32]). Mitochondrial DNA is maternally inherited in humans, and it is therefore noteworthy that reduced brain glucose metabolism before the onset of cognitive decline is more pronounced in elderly individuals with a maternal family history of AD than in those with paternal or no family history [45]. The adult human brain represents about 2% of total body weight but requires approximately 20% of the entire body’s supply of energy. It relies almost exclusively on glucose as energy substrate and stores only small amounts of glycogen. Fatty acids cannot cross the blood–brain barrier and are not available as energy source in the brain. Although glucose is the brain’s major fuel, the ketone bodies β-hydroxybutyrate and acetoacetate produced by the liver from fatty acids can be used as replacement for glucose during starvation, fasting or demanding exercise [18,46]. Fasting or an intake of very small amounts of carbohydrates induces ketosis due to hepatic β-oxidation of long-chain fatty acids. In comparison to glucose, ketone bodies produce a larger amount of energy due to changes in mitochondrial ATP production that they induce [47,48]. Ketone bodies can bypass the block in glycolysis caused by impaired insulin function [49]. While glucose hypometabolism has repeatedly been demonstrated in patients with AD [24], the metabolism of ketone bodies was unchanged, at least in the early disease stages [50]. In a state of brain energy crisis, ketone bodies can be used as an auxiliary and alternative fuel for brain metabolism [16]. Since fuel hypometabolism in the AD brain appears to be specific to glucose, the administration of ketone bodies may overcome the reduction in glucose uptake and metabolism and improve the energy deficit in the brain. Both calorie restriction and consumption of a ketogenic diet reduce carbohydrate intake and lead to a compensatory rise in ketone bodies. This has been shown to improve mitochondrial function, reduce the expression of apoptotic and inflammatory mediators and increase the activity of neurotrophic factors [51]. Dietary carbohydrate reduction appears to have neuroprotective effects [52] and ketone bodies have been demonstrated to protect neurons against multiple types of neuronal injury and to have mitochondrial effects similar to those following calorie restriction or ketogenic diet [51]. In summary, an increase in ketone body supply, provided by a ketogenic diet or by the administration of ketone esters, would be expected to alleviate the impaired brain glucose metabolism preceding the onset of AD.