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  • br Clinical trials of ketogenic diets in AD Oral

    2018-11-06


    Clinical trials of ketogenic diets in AD Oral administration of medium chain triglycerides has been shown to induce ketosis in humans [66]. Due to their short fatty arginase inhibitors chain lengths, medium chain trigycerides do not underlie the regulation imposed on long chain fatty acids and they undergo obligatory oxidation. When fatty acids are oxidized at high rates, large amounts of acetyl coenzyme A are generated. Following the intake of a sufficiently large amount of medium chain triglycerides, the excess acetyl coenzyme A produced exceeds the capacity of the citric acid cycle and leads to the synthesis of ketone bodies in liver mitochondria [67]. In contrast to the ketogenic diet, medium chain triglycerides are oxidized regardless of the consumption of other nutrients, and a restriction of carbohydrate or protein intake is therefore not necessary. The effects of an increase in plasma ketone body levels on cognitive functions were investigated in older adults with memory disorders [66]. Elevation of ketone levels was induced using an oral dose of medium chain triglycerides. On separate days, 20 subjects with AD or mild cognitive impairment imbibed a drink containing emulsified medium chain triglycerides or placebo. A significant increase in β-hydroxybutyrate levels was observed 90min after administration when cognitive testing was performed. The increase in β-hydroxybutyrate was moderated by ApoE genotype [66]. In ApoE4-positive participants, β-hydroxybutyrate levels continued to rise between the 90 and 120-min blood sampling in the treatment condition, while levels in ApoE4-negative subjects remained constant [66]. The administration of medium chain triglycerides facilitated performance on the AD Assessment Scale-Cognitive Subscale in ApoE4-negative participants, but not in ApoE4-positive participants. Higher ketone values were associated with greater improvement in paragraph recall under medium chain triglyceride treatment relative to placebo across all participants [66]. Future studies need to assess the therapeutic benefits of medium chain triglycerides and the mediation by ApoE-4 status in patients with AD. An oral ketogenic compound, AC-1202, was administered to individuals with probable AD in order to assess if chronic induction of mild ketosis can improve cognitive performance [68,69]. AC-1202 is a form of medium chain triglycerides and elevates serum ketone bodies even in the presence of dietary carbohydrates. Daily administration of AC-1202 over 90days was evaluated in 152 patients with a diagnosis of mild to moderate AD in a randomized, placebo-controlled, double-blind, parallel-group study. The participants were on a normal diet and continued taking their usual AD medications. Primary cognitive end points were mean change from baseline in the AD Assessment Scale-Cognitive subscale (ADAS-Cog), and global scores in the AD Cooperative Study — Clinical Global Impression of Change (ADCS-CGIC). AC-1202 was compared to placebo in several population groups, including intention-to-treat (ITT), per protocol, and dosage compliant groups. The results were also stratified by ApoE4 carriage status. AC-1202 significantly increased serum ketone bodies two hours after administration compared to placebo [68,69]. Each population group showed a significant difference between AC-1202 and placebo in mean change from baseline in ADAS-Cog score on days 45 and 90. Effects were most notable in subjects who did not carry the ApoE4 allele, patients with the ApoE4 genotype did not benefit. Adverse events were more frequently observed in participants receiving AC-1202 and concerned mainly transient, mild to moderate gastrointestinal effects [68,69]. In summary, the oral ketogenic compound AC-1202 was found to have memory-enhancing effects after 45 and 90days of treatment. This medium-chain triglyceride preparation of fractionated coconut oil (caprylic trigyceride) has been approved for the treatment of AD in the USA [70].