MCT preparations for improving cognitive function

Abstract

The present invention provides a composition for improving at least one of cognitive functions, such as episodic memory, executive function, or language skills; supporting memory and / or recall; providing energy and / or ketones to the brain; and / or preventing and / or treating mild cognitive impairment (MCI) in an individual. [Solution] A composition is provided comprising medium-chain triglycerides (MCT), wherein the MCT comprises octanoic acid and decanoic acid, and the composition contains protein in a weight ratio of at least 0.8 g per 1.0 g of MCT, and / or carbohydrates in a weight ratio of at least 1 g per 1.0 g of MCT, and / or lipids in a weight ratio of at least 0.1 g per 1.0 g of MCT.

Description

[Background technology]

[0001]

[0001] The present disclosure relates in general to compositions comprising medium-chain triglycerides (MCTs), and further comprising a food matrix containing at least a portion of said MCTs. Such compositions may improve cognitive function, support memory and / or regeneration, provide energy and / or ketones to the brain, and / or prevent and / or treat mild cognitive impairment (MCI).

[0002]

[0002] The two main types of ketones, β-hydroxybutyrate (BHB) and acetoacetate (AcA), are important alternative energy sources for extrahepatic tissues such as the brain, heart, or skeletal muscle. Furthermore, there is growing evidence suggesting that ketones may also play a direct or indirect role in signal transduction. Products aimed at increasing blood ketones may have therapeutic effects in several conditions, including but not limited to epilepsy, neurological and neurodegenerative diseases, heart failure, congenital metabolic disorders, obesity, type 2 diabetes, cancer, exercise capacity, and non-alcoholic fatty liver disease (NAFLD), such as non-alcoholic steatohepatitis (NASH).

[0003]

[0003] BHB and AcA are actively transported to the brain by monocarboxylic acid transporter 1 (MCT1), and as a result, the concentration in the brain is directly proportional to the concentration in the blood. Therefore, products that make plasma ketone concentrations more sustained have a longer effect (longer plasma ketone half-life T) compared with products that have a shorter period of time to raise blood ketones (shorter half-life T). k 1 / 2 It is expected that it will have )

[0004]

[0004] Medium-chain triglycerides (MCTs) are efficient ketone precursors when administered orally as a bolus. MCTs are rapidly digested, and the free medium-chain fatty acids (MCFAs) produced by digestion are efficiently absorbed by the portal vein without going through the normal digestion and absorption process of long-chain fatty acids, and are transported to the liver where most of them are metabolized into ketones. These specific formulations may affect the efficiency of ketone body production and gastrointestinal tolerability.

[0005]

[0005] Brain energy rescue is a promising strategy for reducing cognitive decline in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Impairment in certain cognitive functions, such as episodic memory and language skills, is a precursor to MCI and AD. If there is a high risk of early-onset or late-onset AD, brain glucose uptake is already reduced before the onset of mild cognitive deficits associated with MCI. Therefore, there is a deficit of about 10% in brain energy (glucose) before the onset, and this deficit is sufficient to contribute to cognitive decline in MCI. [Overview of the project]

[0006]

[0006] Surprisingly and unexpectedly, the inventors discovered that intervention with a ketogenic diet, such as medium-chain triglyceride supplements (kMCTs), statistically and clinically significantly improved several specific cognitive functions, including episodic memory and language skills. This indicates a mechanistic relationship between the improvement of cognitive function by ketones and the improvement of brain energy state.

[0007]

[0007] Accordingly, in non-limiting embodiments, the present disclosure provides a method for improving cognitive functions, including at least one of episodic memory, executive function, and language skills, in an individual. The method may include administering a composition comprising medium-chain triglycerides (MCTs) to an individual in a daily dose containing about 15 g to about 45 g of MCTs. The daily dose may include at least two servings of the composition, each serving containing about 15 g of MCTs. The daily dose may also include two servings of the composition.

[0008]

[0008] MCT may contain 51% to 90% by weight of octanoic acid. MCT may contain 51% to 70% by weight of octanoic acid. MCT may contain 71% to 90% by weight of octanoic acid. MCT may contain 60% by weight of octanoic acid. MCT may further contain decanoic acid.

[0009]

[0009] The composition may be administered to an individual for at least about 6 months.

[0010]

[0010] The individual may be 65 years of age or older. The individual may have mild cognitive impairment (MCI). The individual may have at least one of the following: memory impairment, cognitive impairment including lack of sound decision-making ability and impaired judgment, depression, or anxiety disorder. The individual may have or be suffering from a brain energy deficiency state or disease, neurological condition, and / or cognitive impairment.

[0011]

[0011] The composition may further contain at least one of pyridoxine (vitamin B6), folic acid (vitamin B9), or cobalamin (vitamin B12).

[0012]

[0012] The composition may further contain protein at a weight ratio of at least 0.1 g of protein per 1.0 g of MCT. The composition may further contain protein at a weight ratio of at least 0.4 g of protein per 1.0 g of MCT. Each serving of the composition may contain approximately 6.5 g of protein.

[0013]

[0013] The composition may optionally further contain (i) carbohydrates in a weight ratio of at least 0.1 g per 1.0 g of MCT, and / or (ii) lipids other than MCT in a weight ratio of at least 0.1 g per 1.0 g of MCT.

[0014]

[0014] The composition may be in a form selected from the group consisting of beverages, mayonnaise, salad dressings, margarine, low-fat spreads, dairy products, cheese spreads, processed cheese, dairy desserts, flavored milk, cream, fermented dairy products, cheese, butter, condensed milk products, ice cream mixes, soy products, pasteurized liquid eggs, bakery products, confectionery products, candy bars, chocolate bars, high-fat bars, liquid emulsions, spray-dried powders, freeze-dried powders, UHT puddings, pasteurized puddings, gels, jellies, yogurts, foods having fat-based or water-containing fillings, and combinations thereof.

[0015]

[0015] The composition may be an oral nutritional composition, a nutritional supplement, an oral nutritional supplement, a medical food, a supplement, a food product, or a food for special medical purposes (FSMP).

[0016]

[0016] The composition may be in the form of a solid powder, powder stick, capsule, or solution.

[0017]

[0017] In other embodiments, the composition is used in a method to support memory and / or recall in an individual, a method to provide energy and / or ketones to the brain of an individual, or a method to prevent and / or treat mild cognitive impairment (MCI) in an individual.

[0018]

[0018] In some embodiments, the composition may be administered to individuals having a condition selected from the group consisting of epilepsy, neurological disorders, neurodegenerative diseases, heart failure, congenital metabolic disorders, obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cancer, cerebral energy deficiency, migraine, memory impairment, age-related memory impairment, brain injury, stroke, amyloid lateral sclerosis, multiple sclerosis, cognitive impairment, mild cognitive impairment (MCI), post-intensive care cognitive impairment, age-related cognitive impairment, Alzheimer's disease, Parkinson's disease, Huntington's disease, congenital metabolic disorders, bipolar disorder, schizophrenia, and combinations thereof.

[0019]

[0019] Additional features and advantages will be described in the following detailed description of the invention and in the drawings, and will become apparent therefrom. [Brief explanation of the drawing]

[0020] [Figure 1] This table shows the raw scores of neurophysiological tests performed before (PRE) and after (POST) intervention, according to the experimental examples disclosed herein. [Figure 2] This table shows the normalized Z-scores of pre-intervention (PRE) and post-intervention (POST) neurophysiological tests according to the experimental examples disclosed herein. [Figure 3] This table shows the clinical chemistry and metabolic parameters before (PRE) and after (POST) interventions according to the experimental examples disclosed herein. [Figure 4] This plot shows the change from baseline (0) in raw scores in the first trial of the RL / RI-16 test (Figure 4), with the active drug group having higher scores compared to the placebo group (p=0.054). [Figure 5] This plot shows the change from baseline (0) in raw scores on the verbal fluency (category) test (Figure 5), with the active drug group having higher scores compared to the placebo group (p=0.005). [Figure 6] This plot shows the change from baseline (0) in raw scores on the Boston Name Scale (total correct answers; Figure 6), with the active drug group having higher scores compared to the placebo group (p=0.018). [Figure 7] This graph shows the correlation between changes in plasma β-hydroxybutyrate (BHB) or changes in plasma total ketones (BHB + acetacetate) for the following: Synthetic Z-score for episodic memory (r=+0.229, p=0.042), Test 1 of the RL / RI-16 test (r=+0.232, p=0.039), Verbal fluency (category) test (r=+0.325, p=0.013), and Boston Name Test (total correct answers; r=+0.229, p=0.042). [Figure 8]Graph showing plasma total ketones during a 4-hour metabolic test before and after 6 months of administration of 2×15 g / day of MCT. 2×15 g of MCT was consumed at this time (arrow). Data are mean ± standard deviation. [Figure 9] Table showing subgroup analysis of participants who adhered to the protocol. [Figure 10] Table showing subgroup analysis of participants in whom MCI included an element of amnesia. [Figure 11] Table showing subgroup analysis of ApoE4(-) participants. [Figure 12] Table showing subgroup analysis of ApoE4(+) participants. [Figure 13] Table showing composite scores for different neurocognitive function domains before (PRE) and after (POST) intervention according to the experimental examples disclosed herein. [Figure 14] Ketone PET image showing an increase in ketone uptake in the brain after intervention according to the experimental examples disclosed herein. [Figure 15] Graph showing CMRket of placebo and MCT before (PRE) and after (POST) intervention according to the experimental examples disclosed herein. [Figure 16] Table summarizing cognitive tests according to the experimental examples disclosed herein. [Figure 17] Table summarizing significant changes in cognitive tests according to the experimental examples disclosed herein. [Figure 18] Table showing more details of significant changes (Figure 17) in cognitive tests according to the experimental examples disclosed herein. <able>

Mode for Carrying Out the Invention

[0021]

[0036] Definition

[0037] The following are some definitions. However, definitions may also be found in the "Embodiments" section below, and the above heading "Definitions" does not mean that such disclosures in the "Embodiments" section are not definitions.

[0022]

[0038] All percentages are expressed by weight relative to the total weight of the composition unless otherwise specified. Similarly, all ratios are expressed by weight unless otherwise specified. As used herein, “about,” “approximately,” and “substantially” are understood to mean a number within a range, for example, within -10% to +10% of the reference figure, preferably within -5% to +5%, more preferably within -1% to +1%, and most preferably within -0.1% to +0.1% of the reference figure.

[0023]

[0039] Furthermore, all numerical ranges in this specification should be understood to include all integers, whole numbers, or fractions within that range. Moreover, these numerical ranges should be interpreted as supporting claims that cover any number or subset of a number within that range. For example, a disclosure of 1 to 10 should be interpreted as supporting ranges such as 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, and 3.5 to 9.9.

[0024]

[0040] Where used herein and in the appended claims, singular words include plural forms unless the context clearly indicates otherwise. Thus, references to “one,” “a,” and “the” (“a,” “an,” and “the”) generally include the plural forms of the respective terms. For example, when referring to “an ingredient” or “a method,” there are multiple such “ingredients” or “methods.” The term “and / or” used in the context of “X and / or Y” should be interpreted as “X” or “Y” or “X and Y.” Similarly, “at least one of X or Y” should be interpreted as “X” or “Y” or “both X and Y.”

[0025]

[0041] Similarly, the terms “comprise,” “comprises,” and “comprising” should be interpreted as non-exclusive and potentially encompassing others. Likewise, the terms “include,” “including,” and “or” should all be interpreted as potentially encompassing others unless such interpretation is clearly prevented by the context. However, embodiments provided by this disclosure may not include any elements not specifically disclosed herein. Therefore, disclosures of embodiments defined using the term “comprising” are also disclosures of embodiments that “essentially consist of” and “consist of” the disclosed components. “Essentially consisting of” means that an embodiment or its components include more than 50% by weight of the individually identified components, preferably at least 75% by weight of the individually identified components, more preferably at least 85% by weight of the individually identified components, most preferably at least 95% by weight of the individually identified components, for example, at least 99% by weight of the individually identified components.

[0026]

[0042] As used herein, the term “example,” especially when followed by a list of terms, is merely illustrative and descriptive, and should not be considered exclusive or comprehensive. All embodiments disclosed herein can be combined with any other embodiments disclosed herein unless otherwise expressly indicated.

[0027]

[0043] The term "animal" includes, but is not limited to, rodents, aquatic mammals, domesticated animals such as dogs and cats, livestock such as sheep, pigs, cattle and horses, and mammals including, but not limited to, humans. Where "animal" or "mammal" or their plural forms are used, these terms also apply to any animal that can obtain the effects indicated or intended to be indicated by the context of that section, for example, an animal that benefits from ketones. The term "individual" is often used herein in reference to humans, but this disclosure is not limited to humans. Therefore, the term "individual" refers to any animal, mammal, or human that can benefit from the methods and compositions disclosed herein.

[0028]

[0044] Relative terms such as “improved,” “increased,” and “enhanced” describe the properties or effects of compositions containing MCT in a food matrix (disclosed herein) relative to compositions having the same formulation except for lower amounts of protein and / or carbohydrates. The terms “maintained” and “sustained” mean that individual characteristics such as neurological health, cognitive function, or motor ability are approximately the same as the average level of the previous week, the average level of the previous month, or the average level of the previous year.

[0029]

[0045] As used herein, the terms “to treat” and “to treat” mean administering a composition disclosed herein to an object having a condition for the purpose of attenuating, reducing or improving at least one symptom associated with that condition, and / or delaying, reducing or preventing the progression of that condition. The terms “to prevent” and “prevent” mean administering a composition disclosed herein to an object not exhibiting any symptoms of that condition, in order to suppress or prevent the onset of at least one symptom associated with that condition.

[0030]

[0046] As used herein, “cognitive function” means any mental process that involves symbolic operations, such as perception, memory (free recall), executive function, processing speed, attention, comprehension of conversation, speech production, language, reading comprehension, image creation, learning, and reasoning, preferably at least memory.

[0031]

[0047] The terms “food,” “food product,” and “food composition” mean a composition intended for consumption by an individual, such as a human, and which provides the individual with at least one nutrient. The term “food matrix” means the physical structure of a food composition, which may be liquid, solid, or semi-solid in various embodiments. “Food” and related terms include any food, feed, snack, nutritional supplement, treat, meal substitute, or complete food, whether intended for humans or animals. Animal food includes food or feed intended for any domesticated or wild animal. In preferred embodiments, animal food refers to a nutritionally complete food or meal composition, such as pelletized food, extruded food, or dried food. Examples of such animal food include extruded pet food, such as food for dogs and cats.

[0032]

[0048] The term "Foods for Special Medical Use (FSMPs)" refers to specially processed and prepared formula foods designed to meet the specific nutritional or dietary needs of individuals with dietary restrictions, digestive or malabsorption disorders, metabolic disorders, or certain diseases. Such foods are used alone or in combination with other foods under the guidance of a physician or clinical dietitian. FSMPs are foods for special purposes, not medicines, and are not typically consumed by healthy individuals. FSMPs are specifically developed by clinicians and dietitians based on scientific facts derived from extensive medical research.

[0033]

[0049] The term "oral nutritional supplements (ONS)" refers to sterile liquids, semi-solids, or powders that provide macronutrients and micronutrients. ONS are widely used in emergency and social health settings for individuals who cannot meet their nutritional requirements through oral diet alone.

[0034]

[0050] Triglycerides (also known as triacylglycerols or triacylglycerides) are esters derived from glycerol and three fatty acids. The fatty acids may be unsaturated or saturated. Fatty acids that are not bound to other molecules are called free fatty acids (FFAs).

[0035]

[0051] Medium-chain triglycerides (MCTs) are triglycerides in which all three fatty acid portions of the molecule are medium-chain fatty acids. As defined herein, medium-chain fatty acids (MCFAs) are fatty acids having 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms. Medium-chain fatty acids having 8 carbon atoms may be referred to herein as "C8 fatty acids" or "C8". Medium-chain fatty acids having 10 carbon atoms may be referred to herein as "C10 fatty acids" or "C10".

[0036]

[0052] The term "fatty acid portion" refers to the MCT portion derived from fatty acids in the esterification reaction with glycerol. As a non-limiting example, the esterification reaction between glycerol and octanoic acid alone produces MCT containing the octanoic acid portion. Another non-limiting example is the esterification reaction between glycerol and decanoic acid alone, which produces MCT containing the decanoic acid portion.

[0037]

[0053] Octanoic acid (also known as caprylic acid) is a saturated fatty acid with the formula CH3(CH2)6COOH.

[0038]

[0054] Decanoic acid (also known as capric acid) is a saturated fatty acid with the formula CH3(CH2)8COOH.

[0039]

[0055] Embodiment

[0056] One aspect of the present disclosure is a composition comprising medium-chain triglycerides (MCTs). The composition may be an oral nutritional composition, a dietary supplement, an oral nutritional supplement, a medical food, a supplement, a food product, or a food for special medical purposes (FSMP). The composition may be in the form of a solid powder, a powder stick, a capsule, or a solution.

[0040]

[0057] The composition preferably comprises a food matrix containing at least a portion of MCTs, and a particularly preferred non-limiting embodiment of the composition is a liquid, such as a beverage. The composition may also be in the form of a powder that is readily soluble in water before ingestion. In one embodiment, the composition is administered to an individual in a serving that provides at least about 5 g of MCTs, e.g., at least about 10 g of MCTs, e.g., about 15 g of MCTs. In one embodiment, the composition is administered to an individual in a daily dose containing about 15 g to about 45 g of MCTs; preferably, a daily dose containing about 30 g of MCTs. In one embodiment, at least two servings of the composition are administered daily, each serving containing about 15 g of MCTs; preferably, two servings of the composition are administered daily, although some embodiments may contain more than two servings of the composition.

[0041]

[0058] MCT contains three fatty acid moieties, each independently having 6-12, 6-11, 6-10, 7-12, 7-11, 7-10, 8-12, 8-11, or 8-10 carbon atoms. In one embodiment, at least a portion of the MCT contains one or more octanoic acid moieties. In one embodiment, at least a portion of the MCT contains one or more decanoic acid moieties. In one embodiment, at least a portion of the MCT contains one or more octanoic acid moieties and one or more decanoic acid moieties.

[0042]

[0059] In one embodiment, MCT contains 51% to 90% by weight of octanoic acid. In one embodiment, MCT contains 51% to 70% by weight of octanoic acid. In one embodiment, MCT contains 71% to 90% by weight of octanoic acid. In one embodiment, MCT contains 60% by weight of octanoic acid. In one embodiment, the weight ratio of octanoic acid to decanoic acid is 60:40.

[0043]

[0060] The composition may further contain protein. The weight ratio of protein to MCT is preferably at least about 0.1g of protein per 1.0g of MCT, preferably at least about 0.4g of protein per 1.0g of MCT, more preferably at least about 0.8g of protein per 1.0g of MCT, more preferably at least about 1.0g of protein per 1.0g of MCT, even more preferably at least about 1.5g of protein per 1.0g of MCT, and most preferably at least about 1.7g of protein per 1.0g of MCT.

[0044]

[0061] Optionally, the composition may further contain carbohydrates and / or other lipids in addition to MCT.

[0045]

[0062] If carbohydrates are present, the weight ratio of carbohydrates to MCT is preferably at least about 0.3g of carbohydrates per 1.0g of MCT, preferably at least about 1.0g of carbohydrates per 1.0g of MCT, more preferably at least about 2.0g of carbohydrates per 1.0g of MCT, even more preferably at least about 3.0g of carbohydrates per 1.0g of MCT, even more preferably at least about 4.0g of carbohydrates per 1.0g of MCT, and most preferably at least about 4.7g of carbohydrates per 1.0g of MCT.

[0046]

[0063] If lipids other than MCTs are present, the weight ratio of lipids other than MCTs to MCTs is preferably about 0.1g of lipids per 1.0g of MCTs, at least about 0.2g of lipids per 1.0g of MCTs, preferably at least about 0.3g of lipids per 1.0g of MCTs, at least about 0.4g of lipids per 1.0g of MCTs, at least about 0.6g of lipids per 1.0g of MCTs, at least about 0.8g of lipids per 1.0g of MCTs, or at least 1.0g of lipids per 1.0g of MCTs. In one embodiment, if lipids other than MCTs are present, the lipids other than MCTs may be present such that the ratio of lipids other than MCTs to MCTs is 0.1:2.0 to 2.0:1.0, preferably 0.1:1.0 to 1.0:2.0.

[0047]

[0064] MCT is preferably present in the composition in an amount of 1 to 50% by weight, for example, 1 to 30% by weight, 1 to 10% by weight, 2 to 10% by weight, 3 to 10% by weight, 4 to 10% by weight, 5 to 10% by weight, 6 to 10% by weight, 7 to 10% by weight, or 8 to 10% by weight. In embodiments where the composition is a liquid, the composition may contain at least about 40 g of MCT per liter of liquid, preferably at least about 50 g of MCT per liter of liquid, more preferably at least about 75 g of MCT per liter of liquid, even more preferably at least about 100 g of MCT per liter of liquid, and most preferably at least about 120 g of MCT per liter of liquid. The MCT may be present in the liquid in an amount of up to about 250 g of MCT per liter of liquid, preferably up to about 200 g of MCT per liter of liquid, more preferably up to about 175 g of MCT per liter of liquid, and most preferably up to about 150 g of MCT per liter of liquid.

[0048]

[0065] In embodiments where the composition is a liquid, the composition may contain at least about 52 g of protein per liter of liquid, preferably at least about 60 g of protein per liter of liquid, more preferably at least about 65 g of protein per liter of liquid, and most preferably at least about 68 g of protein per liter of liquid. In embodiments where the composition is a liquid, the composition may contain at least about 36 g of carbohydrates per liter of liquid, preferably at least about 50 g of carbohydrates per liter of liquid, more preferably at least about 75 g of carbohydrates per liter of liquid, even more preferably at least about 100 g of carbohydrates per liter of liquid, even more preferably at least about 150 g of carbohydrates per liter of liquid, and most preferably at least about 188 g of carbohydrates per liter of liquid.

[0049]

[0066] Preferably, the composition contains one or more natural materials that yield at least a portion of the MCT. Non-limiting examples of suitable natural materials for MCT include coconut, coconut oil, palm kernel, and palm kernel oil. For example, decanoic acid and octanoic acid account for about 5-8% and 4-10% of the fatty acid composition of coconut oil, respectively.

[0050]

[0067] Additionally or alternatively, at least a portion of MCTs can be synthesized by esterifying glycerol with one or more medium-chain fatty acids (MCFAs) having a tail consisting of 6 to 12 carbon atoms. For example, a homotriglyceride containing three fatty acid moieties, each having 8 carbon atoms, can be synthesized by esterifying glycerol with a C8 fatty acid (e.g., octanoic acid), and a homotriglyceride containing three fatty acid moieties, each having 10 carbon atoms, can be synthesized by esterifying glycerol with a C10 fatty acid (e.g., decanoic acid).

[0051]

[0068] In one embodiment, the composition comprises MCT containing at least one octanoic acid moiety or decanoic acid moiety, and the composition is free from or substantially free from any other triglycerides. As used herein, the term "free from any other triglycerides" means that the composition contains no triglycerides that do not contain at least one octanoic acid moiety or decanoic acid moiety. As used herein, the term "substantially free from any other triglycerides" means that the composition may contain other trace amounts of triglycerides, i.e., less than 5 mol%, preferably less than 3 mol%, more preferably less than 2 mol%, even more preferably less than 1 mol%, or most preferably less than 0.5 mol% of other triglycerides.

[0052]

[0069] After oral absorption, MCTs are metabolized into free fatty acids, and then further into ketones. Free fatty acids are first metabolized to β-hydroxybutyrate (BHB), and then to acetoacetate (AcA). Depending on the MCTs utilized, MCFAs and ketones are produced in body fluids in varying amounts, and these molecules can be used as an alternative energy source to glucose, or to supplement energy derived from glucose.

[0053]

[0070] Ketones can be transported to the brain, for example, by monocarboxylic acid transporter 1 (MCT1), where they are primarily metabolized by neurons. Free fatty acids, such as C8 and C10 free fatty acids, can reach the brain by diffusion, where they are primarily metabolized by astrocytes.

[0054]

[0071] Oral administration of the composition to a subject delivers one or more of ketones, C8 fatty acids, or C10 fatty acids to the subject's body fluids. The subject's exposure to ketones and / or specific fatty acids (e.g., C8 or C10 fatty acids) can be quantified by measuring the levels of ketones and / or specific fatty acids in the subject's plasma, for example, over 8 hours after oral administration. The subject's exposure to ketones and / or specific fatty acids can be calculated by determining the area under the curve (AUC) on a plot of ketone and / or fatty acid concentrations in body fluids (e.g., plasma) against time (e.g., over 8 hours or over 24 hours). Before analysis, the body fluids can be treated with an organic solvent to precipitate proteins and reconstituted with a solvent suitable for mass spectrometry (MS). The concentrations of ketone bodies and medium-chain fatty acids can be evaluated using liquid chromatography-LC-MS coupled with high-resolution mass spectrometry. In particular, the concentrations of β-hydroxybutyrate (BHB), acetoacetic acid (AcA), and specific fatty acids can be quantitatively measured using external calibration methodology.

[0055]

[0072] In one embodiment, the protein is selected from the group consisting of dairy proteins, plant proteins, animal proteins, artificial proteins, or combinations thereof.

[0056]

[0073] Examples of dairy proteins include casein, casein hydrolysates, casein salts (all forms including, for example, sodium caseinate, calcium caseinate, and potassium caseinate), whey hydrolysates, whey (all forms including, for example, concentrates, isolates, and desalted products), milk protein concentrates, and milk protein isolates. Examples of plant proteins include soy protein (all forms including, for example, concentrates and isolates), pea protein (all forms including, for example, concentrates and isolates), and canola protein (all forms including, for example, concentrates and isolates). Other commercially available plant proteins include wheat and fractionated wheat protein, corn and its fractions including zein, rice, oats, potatoes, peanuts, and any protein derived from kidney-shaped beans, buckwheat, lentils, and legumes. Examples of animal proteins include beef, poultry, fish, lamb, seafood, pork, eggs, or combinations thereof.

[0057]

[0074] In one embodiment, the protein source comprises a milk protein. In one embodiment, the milk protein is selected from the group consisting of casein, casein salts, casein hydrolysates, whey, whey hydrolysates, milk protein concentrates, milk protein isolates, or combinations thereof.

[0058]

[0075] The composition may further contain minerals; vitamins; salts; or one or more additional components such as functional additives, e.g., palatants, colorants, emulsifiers, antimicrobial agents, or other preservatives. Non-limiting examples of minerals suitable for the compositions disclosed herein include calcium, phosphorus, potassium, sodium, iron, chloride, boron, copper, zinc, magnesium, manganese, iodine, selenium, chromium, molybdenum, fluoride, and any combination thereof. Non-limiting examples of vitamins suitable for the compositions disclosed herein include water-soluble vitamins (such as thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin (vitamin B7), myo-inositol (vitamin B8), folic acid (vitamin B9), cobalamin (vitamin B12), and vitamin C) and fat-soluble vitamins (such as vitamins A, D, E, and K), including their salts, esters, or derivatives. Inulin, taurine, carnitine, amino acids, enzymes, coenzymes, and any combination thereof may be included in various embodiments.

[0059]

[0076] In one embodiment, the composition further comprises at least one of pyridoxine (vitamin B6), folic acid (vitamin B9), or cobalamin (vitamin B12). Folic acid (vitamin B9) supplementation is beneficial for memory, improved cognitive function, and psychomotor speed. Vitamin B 12 Deficiency is mainly associated with changes in absorption in the elderly. Vitamin B 12 Folic acid deficiency can cause symptoms such as low mood, fatigue, and irritability. Furthermore, folic acid and vitamin B 12 It is required for the synthesis of neurotransmitters.

[0060]

[0077] The composition may further contain one or more active ingredients that promote or maintain overall neurological health or further enhance cognitive function. Examples of such active ingredients include choline, phosphatidylserine, alpha-lipoic acid, CoQ10, acetyl-L-carnitine, omega-3 fatty acids, and herbal extracts (such as ginkgo biloba, Bacopa monniera, Convolvulus pluricaulis, and snowdrop).

[0061]

[0078] The composition may be in the form of a medical food. As used herein, the term “medical food” refers to a food product specifically formulated for the dietary management of a medical disease or condition. For example, a medical disease or condition may have specific nutritional requirements that cannot be met by a normal diet alone. Medical foods may be administered under medical supervision. Medical foods may be administered orally or as enteral nutrition. The term “enteral nutrition” refers to a product intended to deliver nutrients directly to the gastrointestinal tract of a subject through a feeding tube. Enteral nutrition may be administered, for example, through a feeding tube placed through the subject’s nose (such as a nasogastric tube, nasoduodenal tube, and nasojejunal tube) or through a feeding tube placed directly in the subject’s abdomen (such as a gastrostomy tube, gastrojejunostomy tube, or jejunal tube).

[0062]

[0079] The composition may be in the form of a nutritional composition or a nutritional supplement. The term "nutritional supplement" refers to a product intended to supplement the target person's normal diet.

[0063]

[0080] The composition may be in the form of a complete nutrition product. The term "complete nutrition product" refers to a product that can be the sole source of nutrition for the subject.

[0064]

[0081] In various embodiments, the composition may be in the form of a beverage, mayonnaise, salad dressing, margarine, low-fat spread, dairy products, cheese spread, processed cheese, dairy desserts, flavored milk, cream, fermented dairy products, cheese, butter, condensed milk products, ice cream mix, soy products, pasteurized liquid eggs, bakery products, confectionery products, candy bars, chocolate bars, high-fat bars, liquid emulsions, spray-dried powders, freeze-dried powders, UHT puddings, pasteurized puddings, gels, jellies, yogurts, or foods having fat-based or water-containing fillings.

[0065]

[0082] In one embodiment, the composition may be an infant formula. In yet another embodiment, the composition can be used to coat food, snacks, pet food, or pet treats.

[0066]

[0083] The compositions disclosed herein may be administered enterally or parenterally. Preferably, the compositions are administered enterally. For example, the compositions may be administered in the form of food products or dietary supplements. Enteral administration may be oral, gastric, and / or rectal. Preferably, the compositions are administered orally.

[0067]

[0084] The subject may be a human, dog, cat, horse, goat, cow, sheep, pig, deer, or mammal such as a primate. Preferably, the subject is a human. In one embodiment, the subject is an infant. The infant may be a human, such as a newborn (i.e., an infant less than 28 days old) or a premature infant (i.e., an infant born before the completion of a 37-week gestation period).

[0068]

[0085] In one embodiment, the subject is an aged subject. For example, the subject may be an aged subject that has reached 40%, 50%, 60%, 66%, 70%, 75%, or 80% of its estimated lifespan. The determination of lifespan may be based on actuarial tables, calculations, or estimates, and may also take into account past, present, and future influences, or factors known to have a positive or negative effect on lifespan. When determining lifespan, species, sex, size, genetic factors, environmental and stress factors, current and past health status, past and present nutritional status, and stress factors may be taken into consideration. An aged subject may be, for example, a human subject whose age is 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or over 100 years.

[0069]

[0086] In one embodiment, the subjects are those diagnosed with mild cognitive impairment or those suffering from memory complaints. The subjects may require improvement in cognitive functions, particularly episodic memory, executive function, and language. The subjects may have or suffer from brain energy deficiency or disease, neurological conditions, and / or cognitive impairments.

[0070]

[0087] All references in this specification to treatment include curative, palliative, and prophylactic treatments. Treatment may also include treatments that slow the progression of disease severity. Treatments in both humans and animals are within the scope of this disclosure.

[0071]

[0088] The free fatty acids and ketones produced from MCTs provide an alternative energy source to glucose, supplementing or replacing the energy of cells such as astrocytes, muscle cells, cardiomyocytes, or nerve cells.

[0072]

[0089] Brain tissue consumes a large amount of energy relative to its volume. In the average healthy individual, the brain obtains most of its energy from oxygen-dependent glucose metabolism. Typically, most of the brain's energy is used to assist in signal transduction by neurons or nerve cells, and the remaining energy is used to maintain cellular health. For example, energy deficiency in the brain caused by impaired glucose utilization can lead to neuronal hyperactivity, seizures, and cognitive impairment.

[0073]

[0090] Examples of brain energy deficiency states or diseases include migraines, memory impairment, age-related memory impairment, brain injury, neurorehabilitation, stroke and post-stroke, amyloid lateral sclerosis, multiple sclerosis, cognitive impairment, mild cognitive impairment (MCI), post-intensive care cognitive impairment, age-related cognitive impairment, Alzheimer's disease, Parkinson's disease, Huntington's disease, congenital metabolic disorders (such as glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase complex deficiency), bipolar disorder, schizophrenia, and / or epilepsy.

[0074]

[0091] As used herein, the term “neurological condition” refers to a disorder of the nervous system. A neurological condition may be the result of damage to the brain, spine, or nerves caused by disease or injury. Non-limiting examples of symptoms of a neurological condition include paralysis, weakness, poor coordination, loss of sensation, seizures, confusion, pain, and altered level of consciousness. A nervous system disorder can be determined in a subject by performing an assessment of their response to touch, pressure, vibration, limb position, heat, cold, pain, and reflexes.

[0075]

[0092] Some neurological conditions are lifelong, and their onset can occur at any point in life. Other neurological conditions, such as cerebral palsy, are present from birth. Some neurological conditions, such as Duchenne muscular dystrophy, generally manifest in early childhood, while other neurological conditions, such as Alzheimer's disease and Parkinson's disease, primarily affect older adults. Some neurological conditions develop suddenly due to injuries or diseases such as head injury, stroke, or cancer of the brain and spine.

[0076]

[0093] In one embodiment, the neurological condition is a result of traumatic brain injury. Additionally or alternatively, the neurological condition is a result of energy deficiency in the brain or muscles.

[0077]

[0094] Examples of neurological conditions include migraines, memory impairment, age-related memory impairment, brain injury, neurorehabilitation, stroke and post-stroke, amyloid lateral sclerosis, multiple sclerosis, cognitive impairment, mild cognitive impairment (MCI), post-intensive care cognitive impairment, age-related cognitive impairment, Alzheimer's disease, Parkinson's disease, Huntington's disease, congenital metabolic disorders (such as glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase complex deficiency), bipolar disorder, schizophrenia, and / or epilepsy.

[0078]

[0095] Migraine is a severe headache accompanied by other symptoms such as nausea, visual disturbances, and increased sensitivity to light or sound. Migraine may be preceded by an aura, the main symptom of which is a visual disturbance such as blurred vision (difficulty focusing), scotoma, flashes of light, or a zigzag pattern moving from the central field of vision to the edges.

[0079]

[0096] Stroke (also known as cerebrovascular disease (CVA) and cerebrovascular injury (CVI)) occurs when blood flow to the brain becomes insufficient, resulting in cell death. There are two main types of stroke: ischemic (caused by insufficient blood flow) and hemorrhagic (caused by bleeding). A stroke causes a part of the brain to stop functioning normally. Signs and symptoms of a stroke may include inability to move one side of the body, loss of sensation on one side of the body, difficulty understanding or speaking, a feeling that the world is spinning, or a loss of vision on one side. Signs and symptoms often appear immediately after a stroke.

[0080]

[0097] Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, Charcot's disease, and motor neuron disease, is characterized by the death of neurons that control voluntary muscles. ALS is characterized by progressively worsening weakness due to muscle stiffness, simple muscle contractions, and muscle wasting; this leads to difficulty speaking, swallowing, and ultimately breathing.

[0081]

[0098] Multiple sclerosis affects the nerves of the brain and spinal cord, causing a wide range of symptoms including problems with muscle movement, motor function and balance, numbness and tingling, blurred vision (typically unilateral visual field defects), and fatigue.

[0082]

[0099] Parkinson's disease is a degenerative disorder of the central nervous system that primarily affects the motor system. In the early stages of the disease, the most prominent symptoms are motor-related; these include resting tremor, rigidity, and difficulty walking and gaiting. Later in the course of the disease, cognitive and behavioral problems may develop, and dementia generally occurs in the advanced stages of the disease. Other symptoms include depressive symptoms and sensory, sleep, and emotional problems.

[0083]

[0100] Alzheimer's disease is a progressive neurodegenerative disease. It is the most common cause of dementia. Symptoms include memory loss and difficulties with thinking, problem-solving, or speech. The Mini-Mental State Examination (MMSE) is one example of a test used to diagnose Alzheimer's disease.

[0084]

[0101] Huntington's disease is a genetic condition that damages specific nerve cells in the brain. It affects muscle coordination, leading to impaired mental function and motor symptoms. Early symptoms often include minor mood or cognitive problems. This is often followed by a general lack of coordination and unsteady gait. As the disease progresses, uncoordinated, convulsive movements become more pronounced, along with impaired mental function and motor symptoms. Physical abilities gradually deteriorate to the point where coordinated movements become difficult. Mental function generally declines to the point of dementia.

[0085]

[0102] Congenital metabolic disorders are a variety of diseases caused by defective genes. Typically, the defective gene(s) result in a deficiency in an enzyme or transport protein, which inhibits the body's processing of a compound, leading to the accumulation of the compound's toxicity. Congenital metabolic disorders can affect any organ, and usually involve two or more organs. Symptoms tend to be nonspecific in many cases and are usually related to dysfunction or failure of major organs. The onset and severity of metabolic disorders may be exacerbated by environmental factors such as diet and co-existing diseases.

[0086]

[0103] Glucose transporter 1 (Glut1) deficiency syndrome is a genetic metabolic disorder involving the GLUT1 protein, which transports glucose across the blood-brain barrier, the boundary separating microvascular tissue from brain tissue. The most common symptom is seizures (epilepsy), which usually begin within the first few months of life. Further possible symptoms include varying degrees of cognitive impairment, as well as motor disorders characterized by ataxia, dystonia, and chorea. Glut1 deficiency syndrome can be caused by mutations in the SLC2A1 gene, which produces the GLUT1 protein.

[0087]

[0104] Pyruvate dehydrogenase complex deficiency (PDCD) is a neurodegenerative disease associated with mitochondrial metabolic abnormalities and disruption of carbohydrate metabolism. PDCD is characterized by lactic acid buildup and various neurological disorders. The signs and symptoms of this condition usually first appear shortly after birth, but can vary considerably among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acidosis, which can cause nausea, vomiting, severe respiratory distress, and abnormal heartbeat. Other symptoms include neurological problems; mental function and delayed development of motor skills such as sitting and walking; intellectual disability; seizures; hypotonia (low pressure); poor coordination; and difficulty walking. Some affected individuals may have abnormal brain structures, such as underdeveloped corpus callosum (the tissue connecting the left and right hemispheres of the brain), atrophy of the lateral part of the brain known as the cerebral cortex, or multiple damaged tissue areas (lesions) in parts of the brain.

[0088]

[0105] In PDCD, one of the proteins in the pyruvate dehydrogenase complex (PDC) is deficient. The pyruvate dehydrogenase complex contains three enzymes identified as E1, E2, and E3, with the E1 enzyme containing subunits identified as α and β. The most common form of PDCD is caused by an abnormal gene in the E1α subunit (PDHA1 gene) located on the X chromosome. Some cases of PDCD are caused by genetic mutations in other pyruvate dehydrogenase complex subunits, such as the PDHX, PDHB, DLAT, PDP1, and DLD genes.

[0089]

[0106] Bipolar disorder is a brain disorder characterized by abnormal shifts in mood, energy levels, activity levels, and ability to perform daily tasks. It is characterized by periods of elevated mood and periods of depression. Bipolar disorder can be diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the World Health Organization's International Statistical Classification of Diseases and Related Health Problems.

[0090]

[0107] Schizophrenia is a chronic and serious disorder characterized by abnormal interpretation of reality and resulting brain damage. It can manifest as a combination of hallucinations, auditory hallucinations, delusions, and highly confused thoughts and behaviors. Schizophrenia can be diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the World Health Organization's International Statistical Classification of Diseases and Related Health Problems.

[0091]

[0108] Epilepsy is a neurological disorder characterized by disruption of the activity of nerve cells in the brain, resulting in seizures or abnormal behaviors, sensations, and sometimes periods of loss of consciousness.

[0092]

[0109] The terms "cognitive impairment" and "cognitive disorder" refer to disorders that cause impairment in cognition, particularly those that primarily affect learning, memory, perception, and / or problem-solving.

[0093]

[0110] Cognitive impairment can occur in patients after intensive care. It can also occur as part of aging, for example, as mild cognitive impairment (MCI).

[0094]

[0111] The term “cognition” refers to the entire set of mental functions and processes, including knowledge, attention, long-term and working memory, judgment and evaluation, reasoning and “calculation,” problem-solving and decision-making, language comprehension and language creation. The level and improvement of cognition can be readily assessed by those skilled in the art using any suitable neurological and cognitive tests known in the art, including cognitive tests designed to assess information processing speed, executive function and memory. Suitable examples of tests include the Mini-Mental State Examination (MMSE), CANTAB (Cambridge Neuropsychological Test Automated Battery), Alzheimer's Disease Assessment Scale Cognitive Test (ADAScog), Wisconsin Card Classification Task, Verbal and Visual Fluency Tests and Trailmaking Test, Wechsler Memory Scale (WMS), Immediate and Delayed Visual Reproduction Test (Trahan et al., Neuropsychology, 1988 19(3) p.173-89), and the Ray Auditory Language Learning Scale (RAVLT) (Ivnik, RJ. et al., Psychological Assessment: A Journal of Consulting and Clinical). Psychology, 1990(2): p.304-312), electroencephalography (EEG), magnetoencephalography (MEG), positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), computed tomography, and long-term enhancement are among the available methods.

[0095]

[0112] EEG, the measurement of electrical activity in the brain, is achieved by placing electrodes on the scalp at various landmarks and amplifying and recording brain signals. MEG is similar to EEG in that it measures magnetic fields, which are related to electric fields. MEG is used to measure spontaneous brain activity, including synchronization waves, in the nervous system.

[0096]

[0113] PET provides indicators of oxygen utilization and / or glucose metabolism. In this technique, a radioactive positron-emitting tracer is administered, and the brain's uptake of the tracer correlates with brain activity. These tracers emit gamma rays, which are detected by sensors surrounding the head, thereby obtaining a 3D map of brain activity. As soon as the tracer is taken up by the brain, radioactivity is detected in response to local cerebral blood flow. During activation, an increase in cerebral blood flow and neuronal glucose metabolism can be detected within seconds.

[0097]

[0114] A more suitable analysis may also be based on neuropsychological tests, clinical examinations, and individual complaints of cognitive decline (e.g., subjective memory loss). A more suitable examination may be based on assessments of motor skills, memory and attention, seizure susceptibility, and social engagement and / or social cognition.

[0098]

[0115] Memory impairment is the result of nerve damage to brain structures that impairs the storage, retention, and retrieval of memories. Memory impairment can progress with age (e.g., Alzheimer's disease) or it can result directly from, for example, head injury. The level and improvement of memory impairment can be readily assessed by those skilled in the art using any suitable tests known in the art, such as the Alzheimer's Disease Rating Scale Cognitive Test (ADAScog), the Mini-Mental State Examination (MMSE), computed tomography (CT) scans, magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and electroencephalography (EEG).

[0116] [Examples]

[0099]

[0117] The following non-limiting embodiments present scientific data to develop and support the concept of compositions, prepared by pre-mixing MCT with a liquid protein / food matrix, as provided by this disclosure, for improving cognitive function, supporting memory and / or regeneration, providing energy and / or ketones to the brain, and / or preventing and / or treating mild cognitive impairment (MCI).

[0100]

[0118] participants

[0119] Participants were males or females aged ≥55 years with mild cognitive impairment according to the Peterson criteria, which included (i) the presence of subjective memory impairment, (ii) objective evidence of cognitive impairment as assessed by the Neurocognitive Battery, (iii) absence of major depression (General Depression Rating Scale [GDS < 10 / 30]), and (iv) complete autonomy in daily living based on an instrumental activities of daily living score (based on the French version of the Functional Autonomy Measure System [SMAF-E]) ≤ 15 / 24. Exclusion criteria included a diagnosis of major neurocognitive disorder according to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders, use of cholinesterase inhibitors, major depression, a history of alcohol or substance abuse, cancer within the past two years, smoking, poorly controlled diabetes (fasting plasma glucose > 7 mM or glycated hemoglobin > 6.5%), obvious evidence of heart, liver or kidney disease, and vitamin B 12 This included deficiencies, poorly controlled hypertension, dyslipidemia, or thyroid disorders.

[0101]

[0120] Eligible participants first underwent a general cognitive assessment using the Montreal Cognitive Assessment (MoCA; score 18–26 / 30) and / or the Mini-Mental State Examination (MMSE; score 24–27 / 30). If eligible, they then underwent a detailed neurocognitive function battery to determine if they had deficits (≥1.5 SD below mean) in one or more cognitive domains compared to appropriate standard data. Participants were then classified as amnestic MCI (at least one score ≥1.5 SD below mean) or non-amnestic MCI (at least one score ≥1.5 SD below mean in cognitive domains other than episodic memory). Screening tests for all participants were reviewed by collaborating physicians and neuropsychologists prior to enrollment.

[0102]

[0121] A series of randomizations were performed in a 1:1 ratio to assign eligible participants to either the active drug or placebo treatment. 70 participants were randomized into seven blocks, each containing 10 participants. Prior to the initiation of the intervention, participants completed health and memory complaint questionnaires, and fasting blood samples were collected for metabolic and clinical chemistry measurements.

[0103]

[0122] Participants received either the active drug or placebo beverage during monthly visits and were instructed to keep a daily log to monitor compliance. Telephone follow-up was conducted as needed during the first month. During the monthly visits, participants consumed the test beverage at home with their usual breakfast, visited the laboratory 1-2 hours later, and had a blood sample taken during the visit. Participants were asked to return any unused bottles to assess compliance. Participants also met with a research nurse to discuss any concerns and any potential adverse events. The final 6-month visit took place 165 ± 9 days after the start of the intervention. Blood samples were taken 1-2 hours after consuming breakfast and the final dose of the assigned supplement at the metabolic kitchen. A neurocognitive function questionnaire was completed during the final week of the intervention.

[0104]

[0123] Participants were not informed of the beverage's composition and were instructed to consume 125 mL of the assigned beverage twice a day, usually with breakfast and again with dinner (a total of 250 mL / day). The daily dose was gradually increased from 50 mL to 125 mL per meal over the first two weeks.

[0105]

[0124] Cognitive Test

[0125] Eligibility was assessed using the MMSE and MoCA questionnaires to determine general cognitive status. Eligible participants then completed a 90-minute neurocognitive function battery assessing five key areas of cognitive function: episodic memory, executive function, processing speed, attention, and language. Episodic memory was assessed using the French version of the 16-item Free and Cued Word Learning and Recall Test (Rappel Libre / Rappel Indice [RL / RI-16]) and the Brief Visual Memory Test-Revised (BVMT-R). The Trailmaking Test from the Delis-Kaplan Executive Function System, the Stroop Color-Word Interference Test (Stroop), and the Verbal Fluency (VF) Test provided information on executive function, attention, and processing speed, respectively. The Number-Symbol Substitution Test and the forward and backward digit span of the Wechsler Adult Intelligence Scale provided information on processing speed and working memory, respectively. The Boston Names Test was a test of language ability. To minimize the learning effects that may occur in post-supplementary testing, the RL / RI-16 and BVMT-R tests used two types of validated word lists and stimulus pages. These tests are commonly used in clinical practice and were administered by trained evaluators using standardized testing procedures. Z-scores for each subtest were determined using a table of standardized scores from similar populations.

[0106]

[0126] Metabolic test

[0127] Participants in Phase 2 of the study were asked to participate in the same metabolic test for two days (Day 1 before the start of supplementation, and Day 2 at the end of the 6-month supplementation period). The objective of the study was to evaluate whether habitual intake of kMCT alters the plasma ketone response. Briefly, after a 12-hour overnight fast, participants were given a standardized breakfast (two slices of toast with raspberry jam, one slice of cheese, and two scrambled eggs; totaling 470 calories, 19.5g fat, 24.2g protein, and 55g carbohydrates) and a randomized single dose (125mL) of the beverage. Four hours later, a second dose of the same test beverage was given, but no food was provided. Forearm venous blood samples were collected in EDTA tubes at baseline and every 30 minutes during the 8-hour study period.

[0107]

[0128] result

[0129] The adjusted raw scores in the first free recall test of the RL / RI-16 test improved in the active group (multi-covariate model; p=0.042; Figures 1 and 4), and the difference remained significant after normalization for age, sex, and education (Z-score change was +0.51 in the active group compared to -0.1 in the placebo group, p=0.042; Figure 2). No significant changes were observed in either group in the Shortened Visual Memory Test-Revised (BVMT-R). After the intervention, scores in verbal fluency (category) were significantly higher in the active group (+1.9 words) compared to the placebo group (-1.0 words) (p≦0.005; Figures 1 and 5). Errors were significantly lower in all conditions of trail making (p=0.020) and the Stroop test (p=0.042), and both measures of executive function showed improvement after the intervention in the active group. The Boston Naming Scale also showed improvement in the active treatment group after intervention (+1.1 total correct answers), while the placebo group had 0.2 fewer total correct answers; p=0.018; Figure 6). Attention and processing speed scores did not change significantly after treatment in either group (data not shown). The post-intervention differences in several cognitive tests ranged from moderate (0.06) to large (0.14) effect sizes (partial η). 2This includes raw scores and Z-scores for verbal fluency (category), raw scores for the Trailmaking Test (total errors), Z-scores for the Stroop Test (errors, inhibition-switching), and raw scores for the Boston Names Test (Figures 1-2).

[0108]

[0130] In participants with ApoE4(-), amnesic MCI, and protocol adherence, the post-treatment differences in the active treatment group maintained a statistically significant difference compared to placebo in terms of total correct answers on the Category Verbal Fluency Test and the Boston Name Test. Improvements were observed in several subtests of the first free recall test of the RL / RI-16 test in these three subgroups (Figures 9-11). ApoE4(+) participants in the active treatment had better scores on the immediate recall of the RL / RI-16 (recalling 0.8 more words compared to placebo participants who recalled 0.9 fewer words; p=0.036); better scores on the Category Verbal Fluency Test (p=0.048); and fewer total errors on the Trailmaking Test (p=0.017; Figure 12).

[0109]

[0131] Changes in plasma ketones (BHB or total ketones) were significantly positively correlated with changes in several cognitive tests, including episodic memory, executive function, and language, with coefficients ranging from +0.229 to +0.325 and p-values ​​ranging from 0.042 to +0.0028 (Figure 7). These correlation analyses were limited to cognitive tests where differences between groups were observed in raw scores or Z-scores (Figures 1-2). While there were no changes in composite scores across different neurocognitive function domains (Figure 13), the composite Z-score for episodic memory showed a positive correlation with BHB concentration (r=+0.229, p=0.042; Figure 7).

[0110]

[0132] Metabolism and experimental results

[0133] After 6 months of supplementation, total plasma ketones, BHB, and AcA all significantly increased in the active treatment group (p<0.0001; Figure 3). There were no changes in body mass index or body weight in either group. After the intervention, glucose, cholesterol, and aspartate transaminase were significantly higher in the active treatment group, but remained within the clinical reference range at the inventors' facility. No other changes were observed in the chemical properties of the blood (Figure 3). There was no change in the plasma ketone response when comparing the response after intervention with 2 × 15 g kMCT or placebo to before the intervention (Figure 8).

[0111]

[0134] The results showed that in MCI patients, taking 30g / day of kMCT improved performance on widely used tests of episodic memory, executive function, and language over a 6-month period compared to the corresponding placebo. The active treatment group showed a moderate to large effect size (0.06–0.14 fractional η). 2 These improvements in cognitive function were observed, suggesting that these improvements are clinically relevant, particularly in executive function and language tests (Figures 1-2). Positive correlations between changes in plasma ketones and changes in performance in several cognitive domains (Figure 7) support the idea that ketones improve cognition in MCI by contributing to brain energy rescue.

[0112]

[0135] The results demonstrated that, using a liquid emulsion providing 30 g / day in two 15 g doses, kMCT exhibited good ketone bioavailability and, when administered over 6 months, resulted in cognitive improvements in MCI, regardless of age, sex, education, type of MCI, and ApoE4 status (Figures 2-3 and 9-13).

[0113]

[0136] The results also demonstrated the safety of habitual kMCT supplementation in the elderly population with MCI. The cardiometabolic outcomes were either unchanged or remained within the normal reference range for age (Figure 3), suggesting that concerns regarding saturated fat and weight gain associated with kMCT (or placebo fat) consumption, or other aspects of cardiovascular health, are not warranted in this population. Metabolic evaluation of plasma ketone responses in a subgroup (placebo n = 12 and active n = 10) in the second phase of the trial showed that the increase in ketones was maintained throughout the 6-month test period, suggesting no significant changes in ketone production or metabolism during this time frame (Figure 8). Furthermore, the elderly had at least as good a ketone response to a 15 g dose of kMCT as young adults, with transient peaks not exceeding 1.6 mM (combined BHB and AcA), a ketone level at least one order of magnitude lower than ketone levels associated with ketoacidosis.

[0114]

[0137] Figure 14 is a ketone PET image showing an increase in ketone uptake in the brain after intervention according to the experimental examples disclosed herein. Figure 15 is a graph showing the CMR of placebo and MCT before (PRE) and after (POST) intervention according to the experimental examples disclosed herein ket is a graph. Figure 16 is a table summarizing the cognitive tests according to the experimental examples disclosed herein. Figure 17 is a table summarizing the significant changes in the cognitive tests according to the experimental examples disclosed herein. Figure 18 is a table showing in more detail the significant changes (Figure 17) in the cognitive tests according to the experimental examples disclosed herein.

[0115]

[0138] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the subject matter and without sacrificing the intended advantages. Accordingly, such changes and modifications are intended to be encompassed by the appended claims.

Claims

1. A method for improving cognitive function of an individual, including at least one of episodic memory, executive function, or language skills, comprising the step of administering to the individual a composition containing medium-chain triglycerides (MCTs) in a daily dose containing about 15 g to about 45 g of MCTs and / or about 51% to about 90% by weight of MCTs containing octanoic acid.

2. A method for supporting memory and / or recall in an individual, comprising the step of administering to the individual a composition containing medium-chain triglycerides (MCTs) in a daily dose containing about 15 g to about 45 g of MCTs and / or about 51% to about 90% by weight of MCTs containing octanoic acid.

3. A method for providing energy and / or ketones to the brain of an individual, comprising the step of administering to the individual a composition containing medium-chain triglycerides (MCTs) in a daily dose containing about 15 g to about 45 g of MCTs.

4. A method for preventing and / or treating mild cognitive impairment (MCI), comprising the step of administering a composition containing medium-chain triglycerides (MCTs) to an individual in a daily dose containing about 15 g to about 45 g of MCTs.

5. The method according to any one of claims 1 to 4, wherein the daily dose comprises at least two servings of the composition, with each serving containing approximately 15 g of MCT.

6. The method according to claim 5, wherein the daily dose comprises two servings of the composition.

7. The method according to any one of claims 1 to 4, wherein the daily dose comprises three servings of the composition, with each serving containing approximately 15 g of MCT.

8. The method according to any one of claims 1 to 4, wherein the MCT contains about 51% to about 90% by weight of octanoic acid.

9. The method according to any one of claims 1 to 4, wherein the MCT contains about 51% to about 70% by weight of octanoic acid.

10. The method according to any one of claims 1 to 4, wherein the MCT contains about 71% to about 90% by weight of octanoic acid.

11. The method according to any one of claims 1 to 4, wherein the MCT contains about 60% by weight of octanoic acid.

12. The method according to any one of claims 8 to 11, wherein the composition further comprises decanoic acid.

13. The method according to claim 12, wherein the weight ratio of octanoic acid to decanoic acid is about 60:about 40.

14. The method according to any one of claims 1 to 4, wherein the composition is administered to the individual for at least six months.

15. The method according to any one of claims 1 to 4, wherein the individual is 65 years of age or older.

16. The method according to any one of claims 1 to 4, wherein the individual has mild cognitive impairment (MCI).

17. The method according to any one of claims 1 to 4, wherein the individual suffers from at least one of the following: memory impairment, cognitive impairment including lack of sound decision-making ability and impaired judgment, depression, or anxiety disorder.

18. The method according to any one of claims 1 to 4, wherein the individual has or is suffering from a state of brain energy deficiency or disease, neurological condition, and / or cognitive impairment.

19. The method according to any one of claims 1 to 4, wherein the individual has a condition selected from the group consisting of epilepsy, neurological disorders, neurodegenerative diseases, heart failure, congenital metabolic disorders, obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cancer, cerebral energy deficiency, migraine, memory impairment, age-related memory impairment, brain injury, stroke, amyloid lateral sclerosis, multiple sclerosis, cognitive impairment, mild cognitive impairment (MCI), post-intensive care cognitive impairment, age-related cognitive impairment, Alzheimer's disease, Parkinson's disease, Huntington's disease, congenital metabolic disorders, bipolar disorder, schizophrenia, and combinations thereof.

20. The method according to any one of claims 1 to 4, wherein the composition is in a form selected from the group consisting of beverages, mayonnaise, salad dressings, margarine, low-fat spreads, dairy products, cheese spreads, processed cheese, dairy desserts, flavored milk, cream, fermented dairy products, cheese, butter, condensed milk products, ice cream mixes, soy products, pasteurized liquid eggs, bakery products, confectionery products, candy bars, chocolate bars, high-fat bars, liquid emulsions, spray-dried powders, freeze-dried powders, UHT puddings, pasteurized puddings, gels, jellies, yogurts, foods having fat-based or water-containing fillings, and combinations thereof.

21. The method according to any one of claims 1 to 4, wherein the composition is a liquid.

22. The method according to any one of claims 1 to 4, wherein the composition is a powder.

23. The method according to any one of claims 1 to 4, wherein the composition further comprises at least one of pyridoxine (vitamin B6), folic acid (vitamin B9), or cobalamin (vitamin B12).

24. The method according to any one of claims 1 to 4, wherein the composition further comprises protein in a weight ratio of at least 0.1 g of protein per 1.0 g of MCT.

25. The method according to any one of claims 1 to 4, wherein the composition further comprises protein in a weight ratio of at least 0.4 g of protein per 1.0 g of MCT.

26. The method according to any one of claims 1 to 4, wherein the composition contains protein in a weight ratio of at least 1.7 g of protein per 1.0 g of MCT.

27. The method according to claim 5, wherein each serving of the composition contains approximately 6.5 g of protein.

28. The method according to any one of claims 1 to 4, wherein the composition further comprises at least one raw material selected from the group comprising (i) carbohydrates in a weight ratio of at least 0.1 g per 1.0 g of MCT, and / or (ii) lipids other than MCT in a weight ratio of at least 0.1 g per 1.0 g of MCT.

29. The method according to claim 28, wherein the MCT is at least about 40 g per liter of the composition.

30. The method according to claim 28, wherein the carbohydrate content is at least about 36 g per liter of the composition.

31. The method according to claim 28, wherein the protein is at least about 52 g per liter of the composition.

32. The method according to claim 28, wherein the at least one raw material contains carbohydrates in a weight ratio of at least 4.7 g of carbohydrates per 1.0 g of MCT.

33. The method according to claim 28, wherein the at least one raw material contains lipids other than MCT in a weight ratio of at least 0.3 g of lipids per 1.0 g of MCT.

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