Effect of an Oral Nutritional Supplement for improving brain energetics and cognition in Mild Cognitive Impairment
10 min read
/
ABSTRACT
Brain glucose uptake is about 10% below normal in Mild Cognitive Impairment (MCI) and deteriorates further in Alzheimer disease (AD). It is now clear that in contrast to glucose, uptake of the brain’s main alternative fuel – ketones (acetoacetate and beta-hydroxybutyrate) – remains normal in both MCI and mild-moderate AD. Furthermore, evidence is accumulating that an endogenous or exogenous source of ketones can at least partially bypass brain glucose hypometabolism and improve brain energy metabolism in both MCI and mild-moderate AD. The key question now is whether improved brain energy metabolism also improves cognitive performance in MCI or AD.The objective of the randomized, placebo-controlled Benefic trial (NCT02551419) was to assess whether counteracting the brain glucose deficit with an Oral Nutritional Supplement containing a ketogenic medium chain triglyceride (kMCT-ONS), BrainXpert Energy complex, could improve cognitive performance over 6 months in Mild Cognitive Impairment. Following screening with a comprehensive cognitive battery, n=122 MCI
were recruited (amnestic and non-amnestic MCI combined). An overall sample size of n=82 for both arms combined was required to have the necessary power to detect at least a moderate e—ect size on cognitive outcomes of episodic memory and executive function. Outcomes in all five main cognitive domains were assessed immediately before and at the end of the intervention.
The ONS was lactose-free skim milk emulsion containing 15 g kMCT twice/day (active arm; n=39 completers) or an energy equivalent placebo providing 12 g non-ketogenic vegetable oil twice/day (n=44 completers). The formulation and organoleptic properties of the ONS were identical for both active and placebo arms.
Brain ketone and glucose PET were done before and at the end of the 6-month intervention on sub-groups of both arms (n=19/arm pre- and post-intervention). The plasma ketone response was assessed before and after the intervention in a different sub-group (n=10/arm pre- and post-intervention). Plasma cardiometabolic and inflammatory marker profiles were also assessed. Data were analyzed by ANCOVA using pre-intervention cognitive score plus age, sex, education and apolipoprotein E4 status combined as covariates. Raw scores as well as normalized Z-scores for five tests in three cognitive domains improved post-intervention on the kMCT arm only (p¢0.01). Specifically, on the kMCT-ONS, trial 1 of the:
•Free and Cued Recall Test showed a +1 word improvement (+0.5 ¦ Z-score),
•Correct answers on the Verbal Fluency Test increased by 2 words (+0.3 ¦ Z-score) but decreased by 1 word on placebo (-0.1 ¦ Z-score),
•Correct answers on the Boston Naming Test increased by 1.1, • Time taken on the Stroop Colour Naming Test decreased by 1 sec (p=0.09),
• Errors on the Trail Making Test decreased by 0.9 on the kmct-ONS but increased by 0.8 on placebo (p=0.02).
Global brain ketone uptake doubled on the kMCT-ONS only and directly as the increase in plasma ketones (r = +0.87, p<0.01). Moderate e—ect sizes (partial ª = 0.06 - 0.14) were seen for several cognitive outcomes on the kMCT-ONS only. Free and cued recall, Trail-making, and Boston Naming test scores all correlated significantly and directly as the increase in plasma or global brain ketone uptake on kMCT-ONS (r = +0.23 - +0.33, p = 0.013 – 0.042). Increased uptake of ketones in multiple brain white matter fascicles was significantly positively correlated with faster processing speed on the kMCT-ONS (r = +0.47 – +0.61, p = 0.014 – 0.047; n=16). Plasma ketone response to a single 15-gram dose of the kMCT-ONS did not change significantly at the end vs. before the 6-month intervention; ketones did not increase at all on the placebo arm. Changes in anthropometry (weight, BMI) and plasma markers of cardiometabolic health (insulin, glucose, cholesterol) were not clinically significant post-intervention on either arm. Amongst the plasma inflammatory markers, only interleukin 8 increased on the kMCT-ONS (+3 pg/ml; interaction p = 0.002 vs. post-placebo; n=17). Average drop-out rate on both arms was 31%. In completers, protocol adherence was 89% over six months.
were recruited (amnestic and non-amnestic MCI combined). An overall sample size of n=82 for both arms combined was required to have the necessary power to detect at least a moderate e—ect size on cognitive outcomes of episodic memory and executive function. Outcomes in all five main cognitive domains were assessed immediately before and at the end of the intervention.
The ONS was lactose-free skim milk emulsion containing 15 g kMCT twice/day (active arm; n=39 completers) or an energy equivalent placebo providing 12 g non-ketogenic vegetable oil twice/day (n=44 completers). The formulation and organoleptic properties of the ONS were identical for both active and placebo arms.
Brain ketone and glucose PET were done before and at the end of the 6-month intervention on sub-groups of both arms (n=19/arm pre- and post-intervention). The plasma ketone response was assessed before and after the intervention in a different sub-group (n=10/arm pre- and post-intervention). Plasma cardiometabolic and inflammatory marker profiles were also assessed. Data were analyzed by ANCOVA using pre-intervention cognitive score plus age, sex, education and apolipoprotein E4 status combined as covariates. Raw scores as well as normalized Z-scores for five tests in three cognitive domains improved post-intervention on the kMCT arm only (p¢0.01). Specifically, on the kMCT-ONS, trial 1 of the:
•Free and Cued Recall Test showed a +1 word improvement (+0.5 ¦ Z-score),
•Correct answers on the Verbal Fluency Test increased by 2 words (+0.3 ¦ Z-score) but decreased by 1 word on placebo (-0.1 ¦ Z-score),
•Correct answers on the Boston Naming Test increased by 1.1, • Time taken on the Stroop Colour Naming Test decreased by 1 sec (p=0.09),
• Errors on the Trail Making Test decreased by 0.9 on the kmct-ONS but increased by 0.8 on placebo (p=0.02).
Global brain ketone uptake doubled on the kMCT-ONS only and directly as the increase in plasma ketones (r = +0.87, p<0.01). Moderate e—ect sizes (partial ª = 0.06 - 0.14) were seen for several cognitive outcomes on the kMCT-ONS only. Free and cued recall, Trail-making, and Boston Naming test scores all correlated significantly and directly as the increase in plasma or global brain ketone uptake on kMCT-ONS (r = +0.23 - +0.33, p = 0.013 – 0.042). Increased uptake of ketones in multiple brain white matter fascicles was significantly positively correlated with faster processing speed on the kMCT-ONS (r = +0.47 – +0.61, p = 0.014 – 0.047; n=16). Plasma ketone response to a single 15-gram dose of the kMCT-ONS did not change significantly at the end vs. before the 6-month intervention; ketones did not increase at all on the placebo arm. Changes in anthropometry (weight, BMI) and plasma markers of cardiometabolic health (insulin, glucose, cholesterol) were not clinically significant post-intervention on either arm. Amongst the plasma inflammatory markers, only interleukin 8 increased on the kMCT-ONS (+3 pg/ml; interaction p = 0.002 vs. post-placebo; n=17). Average drop-out rate on both arms was 31%. In completers, protocol adherence was 89% over six months.
Conclusions:
The Benefic Trial was powered to assess outcomes of memory and executive function in Mild Cognitive Impairment and demonstrated that this Oral Nutritional Supplement containing a ketogenic medium chain triglyceride (kMCT-ONS), BrainXpert Energy complex, improved several cognitive outcomes that were positively correlated with the improved brain energy status achieved by the enhanced supply of ketones. Hence, there was a direct mechanistic link between raising brain ketones with the kMCT-ONS and improving cognitive performance in MCI. The consistent plasma ketone response suggests there was no metabolic adaptation or loss of response to an oral dose of kMCT-ONS after daily consumption over six months. These results demonstrate e¬cacy, safety, acceptability, and feasibility of long-term use of BrainXpert Energy complex twice daily dose to improve cognitive performance in MCI.
Disclosures: Financial support for the Benefic Trial was provided by the Alzheimer Association USA, FRQS, Université de Sherbrooke and Nestlé Health Science. Abitec provided the kMCT (Captex 355) and placebo oil (high oleic acid sunflower oil). The ONS for both arms was prepared under contract at INAF, Université Laval, Québec, QC, Canada. SCC has consulted for or received travel honoraria or test products for research from Nestlé Health Science, Bulletproof, Cerecin, and Abitec. SCC is the founder and director of the consulting company, Senotec Ltd.
References:
• Cunnane SC, et al. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease. Ann N Y Acad Sci 2016;1367(1):12-20. https://pubmed.ncbi.nlm.nih.gov/26766547/
• Fortier M, et al. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimer’s & Dementia 2019;15: 625-634
https://pubmed.ncbi.nlm.nih.gov/31027873/
• Cunnane SC, et al. Brain energy rescue: an emerging therapeutic concept for
neurodegenerative disorders of ageing. Nat Rev Drug Discov 2020; 24. doi: 10.1038/s41573-020-0072-x. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/32709961/
Disclosures: Financial support for the Benefic Trial was provided by the Alzheimer Association USA, FRQS, Université de Sherbrooke and Nestlé Health Science. Abitec provided the kMCT (Captex 355) and placebo oil (high oleic acid sunflower oil). The ONS for both arms was prepared under contract at INAF, Université Laval, Québec, QC, Canada. SCC has consulted for or received travel honoraria or test products for research from Nestlé Health Science, Bulletproof, Cerecin, and Abitec. SCC is the founder and director of the consulting company, Senotec Ltd.
References:
• Cunnane SC, et al. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease. Ann N Y Acad Sci 2016;1367(1):12-20. https://pubmed.ncbi.nlm.nih.gov/26766547/
• Fortier M, et al. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimer’s & Dementia 2019;15: 625-634
https://pubmed.ncbi.nlm.nih.gov/31027873/
• Cunnane SC, et al. Brain energy rescue: an emerging therapeutic concept for
neurodegenerative disorders of ageing. Nat Rev Drug Discov 2020; 24. doi: 10.1038/s41573-020-0072-x. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/32709961/
