omega-3 fatty acids and choline as neuroprotective agents in patients not suffering from dementia

Abstract

The present invention relates to omega-3 fatty acids and choline as neuroprotective agents for individuals not suffering from dementia. A method of reducing, treating, or preventing cognitive aging in an individual not suffering from dementia, the method comprising administering to the individual a therapeutically effective amount of a composition comprising omega-3 fatty acids and choline. The method can achieve one or more of the following beneficial effects: reducing brain atrophy, increasing or maintaining the number of synapses, increasing amyloid beta phagocytosis, or reducing or maintaining neuroinflammation in the individual not suffering from dementia. The method can prevent dementia in an individual at risk, such as an elderly person. The composition can be administered to the individual at a daily dose providing 5.5 mg / day to 5,500 mg / day choline, such as 85 mg / day to 3,500 mg / day choline.

Description

[0001] This application is for the invention entitled "A Neuroprotective Agent for Patients Without Dementia," filed on September 29, 2017. This is a divisional application of PCT / EP2017 / 074731 concerning “-3 fatty acids and choline”, which entered the Chinese national phase on March 7, 2019, and has application number 201780055067.7. Background Technology

[0002] This disclosure relates generally to compositions and methods for mitigating cognitive aging in individuals who do not have dementia. More specifically, this disclosure relates to mitigating cognitive aging by administering a composition comprising a combination of omega-3 fatty acids and choline.

[0003] Population aging has always been a significant demographic event. Due to increased life expectancy, the elderly population is growing faster than the overall population, and the proportion of elderly people relative to other population groups is increasing dramatically due to declining birth rates. For example, in 1950, at least one in twelve people was at least 60 years old, and in 2000, at least one in ten people was 60 years of age or older. By the end of 2050, the number of people aged 60 or older worldwide is projected to be one in five.

[0004] Older or aging individuals often experience some degree of cognitive impairment, including a decline in cognitive function that worsens with age; and age-related changes in brain morphology and cerebrovascular function are commonly observed. Cognitive decline is consistently reported as aging across a range of cognitive domains, including processing speed, attention, episodic memory, spatial ability, and executive function. Brain imaging studies have shown that these normally age-related cognitive declines are associated with a reduction in the volume of gray and white matter in the brain, with the frontal striatum system being most affected by aging. This reduction in cortical volume can be attributed to numerous harmful cellular processes associated with normal aging, such as the accumulation of free radical damage over time leading to oxidative damage, chronic low-grade inflammation, homocysteine ​​buildup (which, when elevated, is a risk factor for cognitive impairment and dementia), and reduced mitochondrial efficiency. In addition to direct cellular damage, the brain is also indirectly impaired by damage to microvascular structures. Clearly, the pathology of aging and dementia involves the complexity of these interacting factors, which are interconnected. For example, mitochondrial dysfunction leads to increased oxidative stress, and oxidative stress can trigger inflammation and vascular damage.

[0005] Furthermore, cognitive decline is an early predictor of Alzheimer's disease and begins before the onset of dementia. In this context, the Cognitive Composite Score represents a reliable method for assessing pre-dementia cognitive decline. Substantial evidence suggests that maintaining brain health and preventing age-related cognitive decline can prevent or delay the progression of dementia due to Alzheimer's disease and other age-related neuropathologies.

[0006] Nutrition, education, physical activity, and cognitive training have recently been demonstrated as potential interventions to prevent age-related cognitive decline. A wealth of clinical, epidemiological, and individual evidence supports individual nutritional factors that reduce the risk of dementia and age-related neurodegeneration. However, the results of formal trial testing of nutritional interventions have been mixed (Schmitt et al., Nutrition Reviews 68: S2–S5 (2010)).

[0007] Some long-term studies have not observed any cognitive benefits when using a combination of B6, B12 and folic acid as an intervention. McMahon et al. ((2006) N Engl J Med, 354(26), 2764-2772) found that taking supplements containing folic acid (1000 µg), vitamin B12 (500 µg) and B6 (10 mg) for 2 years had no effect on cognition in adults over 65 years of age. Similarly, Hankey et al. ((2013)(stroke, 44(8), 2232-2239)) found that daily supplementation with folic acid (2000µg), vitamin B6 (25mg), and vitamin B12 (500µg), as measured by MMSE, in cognitively unimpaired patients who had previously experienced a stroke or transient ischemic attack, resulted in a decrease in mean tHcy over a median period of 2.8 years, but had no effect on the incidence of cognitive impairment or cognitive decline.

[0008] Several short-term studies have also failed to show the effect of the combination of B6, B12 and folic acid on improving cognitive function. Lewerin et al. ((2005) Am J Clin Nutr, 81(5), 1155-1162) found that supplementation with folic acid (800µg), vitamin B12 (500µg) and vitamin B6 (3mg) for 4 months had no effect on cognition in older adults (median age 76 years). Summary of the Invention

[0009] Unbound by theory, the inventors believe that previous nutritional interventions attempting to reduce the risk of dementia and age-related neurodegeneration focused on the isolated administration of nutrients, rather than intelligently combining them to significantly enhance effects through nutrient interactions. Furthermore, studies investigating the effects of combined components on cognitive function have used mixtures of components all targeting the same mechanism (e.g., a mixture of folic acid, B12, and B6 targeting Hcy levels, or a mixture of vitamins C and E targeting oxidative damage), which may explain the inconsistency between this evidence and single-component studies. Therefore, this disclosure relates overall to a multi-intervention approach, whereby each nutritional intervention targets different risk factors associated with cognitive decline.

[0010] Therefore, in one general embodiment, this disclosure provides a method for mitigating, treating, or preventing cognitive aging in a non-dementia individual who has a need for or is at risk of developing cognitive aging. The method includes administering to the individual a therapeutically effective amount of a composition comprising omega-3 fatty acids and choline. The composition may be administered at a daily dose providing 5.5 mg / day to 5,500 mg / day of choline.

[0011] In one implementation scheme, the individual is a middle-aged or elderly person, such as an elderly person.

[0012] In one implementation, the individual has a low DHA status at baseline. In one implementation, the individual has a Clinical Dementia Scale (CDR) score of 0.5 at baseline. In one implementation, the individual has a plasma homocysteine ​​level of at least 12 µmol / L at baseline. In one implementation, the individual has a Cardiovascular Risk Factors, Ageing, and Dementia (CAIDE) risk score of 10 to 15 at baseline. In one implementation, the individual is amyloid-positive on a PET scan at baseline. In one implementation, the individual has a genotype indicating a risk of cognitive decline.

[0013] In one embodiment, the composition is administered orally to the individual daily for at least one month.

[0014] In one embodiment, the composition comprises a nitric oxide-releasing compound, such as citrulline.

[0015] In one embodiment, the ω-3 fatty acid comprises a fatty acid selected from docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof.

[0016] In one embodiment, choline is provided by a component selected from the group consisting of choline chloride, tartrate choline, citicoline (CDP choline), L-α-glycerophosphate choline (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof.

[0017] In one embodiment, the composition comprises one or more B vitamins selected from the group consisting of vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9 and vitamin B12; optionally comprising all of vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9 and vitamin B12.

[0018] In one embodiment, the composition comprises one or more antioxidants selected from the group consisting of vitamin C, vitamin D, vitamin E, and selenium.

[0019] In another embodiment, this disclosure provides a method for mitigating, treating, or preventing cognitive aging in a non-dementia individual who is in need of or at risk of cognitive aging, the method comprising administering to the individual a therapeutically effective amount of a composition comprising omega-3 fatty acids and choline. The omega-3 fatty acids may comprise fatty acids selected from docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof. Choline may be provided by a compositional component selected from choline chloride, tartrate choline, citicoline (CDP-choline), L-α-glycerophosphate choline (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof. The composition may be administered to the individual at a daily dose providing 5.5 mg / day to 5,500 mg / day of choline.

[0020] In another embodiment, the present invention provides a method for achieving one or more beneficial effects selected from the group consisting of reducing brain atrophy, increasing or maintaining the number of synapses, increasing or maintaining amyloid β-phagocytosis, and reducing neuroinflammation in a non-dementia individual in need of such effects. This disclosure also provides a method for achieving one or more beneficial effects selected from the group consisting of improving neuronal fluidity, stimulating neuronal plasticity and activity, improving anti-inflammatory potential, and reducing reactive oxygen species (ROS) and / or targeted nitric oxide release. This disclosure also provides methods for achieving one or more beneficial effects selected from the group consisting of supporting or maintaining cognitive performance, supporting or maintaining brain performance, slowing brain aging, supporting active thinking and brain health, supporting or maintaining a healthy brain, enhancing memory, enhancing executive function, enhancing attention, maintaining cognitive health, maintaining brain cell health, etc. Such beneficial effects are preferably achieved by the methods defined herein, preferably for mitigating, treating, or preventing cognitive aging in a non-dementia individual in need of or at risk of such effects. These methods include administering to the individual a therapeutically effective amount of a composition comprising ω-3 fatty acids and choline. The ω-3 fatty acids may comprise fatty acids selected from the group consisting of docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof. Choline can be provided by a compositional ingredient selected from the following: choline chloride, tartrate choline, citicoline (CDP choline), L-α-glycerophosphate choline (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof. The composition can be administered to an individual at a daily dose providing 5.5 mg / day to 5,500 mg / day of choline.

[0021] In another embodiment, this disclosure provides a composition comprising a combination of omega-3 fatty acids and choline. The composition comprises an amount of the combination that can effectively reduce cognitive aging in non-dementia individuals. The composition may be a food product comprising proteins, carbohydrates, fats, and combinations thereof. The composition may be a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, and diluent. The omega-3 fatty acids may comprise fatty acids selected from docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and mixtures thereof. Choline may be provided by a compositional component selected from choline chloride, tartrate choline, citicoline (CDP-choline), L-α-glycerophosphate choline (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof. The daily dose of the composition may provide choline from 5.5 mg / day to 5,500 mg / day.

[0022] In another embodiment, this disclosure provides a method for preparing a food composition for mitigating cognitive aging in non-dementia individuals. The method includes adding an effective amount of a combination of omega-3 fatty acids and choline to at least one ingredient selected from the group consisting of proteins, carbohydrates, and fats. The omega-3 fatty acids may comprise fatty acids selected from docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and mixtures thereof. Choline may be provided by a compositional ingredient selected from choline chloride, choline tartrate, citicoline (CDP-choline), L-α-glycerophosphate choline (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof.

[0023] In another embodiment, the present invention provides a method for preparing a pharmaceutical composition for alleviating cognitive aging in non-dementia individuals, the method comprising adding an effective amount of a combination of omega-3 fatty acids and choline to at least one component selected from the group consisting of: a pharmaceutically acceptable carrier, a diluent, and an excipient. The omega-3 fatty acids may comprise fatty acids selected from: docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof. Choline may be provided by a compositional component selected from: choline chloride, tartrate choline, citicoline (CDP-choline), L-α-glycerophosphate choline (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof.

[0024] In another embodiment, this disclosure provides a method for preventing dementia in an individual at risk. The method includes administering to the individual a therapeutically effective amount of a composition comprising omega-3 fatty acids and choline. The dementia to be prevented may be selected from Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, and combinations thereof. The omega-3 fatty acids may comprise fatty acids selected from docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and mixtures thereof.

[0025] In another embodiment, this disclosure provides a method for improving the cognitive abilities of a non-dementia individual (e.g., an individual in need of such an individual), the method comprising administering to the individual a therapeutically effective amount of a composition comprising omega-3 fatty acids and choline. The omega-3 fatty acids may comprise fatty acids selected from docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof. Choline may be provided by a compositional component selected from choline chloride, tartrate choline, citicoline (CDP-choline), L-α-glycerophosphate choline (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof.

[0026] The advantage of one or more embodiments provided in this disclosure is that they can mitigate cognitive aging in non-dementia individuals, such as older adults.

[0027] Another advantage of one or more embodiments provided in this disclosure is the use of ω-3 fatty acids (such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) to modulate neuronal membrane fluidity, stimulate neuroplasticity, provide anti-neuroinflammatory effects and / or reduce oxidative stress in the brain, in combination with choline to reduce homocysteine ​​levels in plasma, and optionally in combination with nitric oxide-releasing compounds (such as arginine or citrulline) to protect signal transduction pathways.

[0028] Another advantage of one or more embodiments provided in this disclosure is the use of a larger amount of choline compared to known nutritional interventions for cognitive aging.

[0029] Another advantage of one or more embodiments provided in this disclosure is the reduction of brain atrophy and neuroinflammation in non-dementia individuals, as well as the increase or maintenance of amyloid β-phagocytosis and synapse number. In this case, one or more beneficial effects thereby achieved are selected from improving neuronal fluidity, stimulating neuronal plasticity and activity, improving anti-inflammatory potential, reducing reactive oxygen species (ROS) and / or targeted nitric oxide release, or other beneficial effects selected from those described herein.

[0030] Other features and advantages are described herein and will become apparent from the following figures and detailed descriptions. Attached Figure Description

[0031] Figure 1 This is a table listing the treatments used in the experimental embodiments disclosed herein.

[0032] Figure 2 This is a graph showing the results obtained from neurons + astrocytes in the experimental embodiments disclosed herein (T3 = DHA + EPA + choline). Detailed Implementation

[0033] definition

[0034] The following provides some definitions. However, definitions may be located in the “Implementation” section below, and the title “Definitions” above does not imply that such disclosures in the “Implementation” section are not definitions.

[0035] All percentages expressed herein are by weight of the total weight of the composition unless otherwise stated. As used herein, “about,” “approximately,” and “substantially” should be understood to refer to a number within a range of values, such as -10% to +10% of the mentioned number, preferably -5% to +5%, more preferably -1% to +1%, and most preferably -0.1% to +0.1%. All numerical ranges herein should be understood to include all integers or fractions within the range. Furthermore, these numerical ranges should be understood to support claims that involve any value or subset of values ​​within the range. For example, disclosures of 1 to 10 should be understood to support ranges of 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0036] As used in this disclosure and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly specifies otherwise. Thus, for example, reference to “component” includes two or more components.

[0037] The terms “comprising,” “including,” and “containing” are to be interpreted as inclusive rather than exclusive. Similarly, the terms “comprising,” “including,” and “or” should be considered inclusive unless the context explicitly prohibits this interpretation. However, the compositions disclosed herein may not contain any elements not specifically disclosed herein. Therefore, the disclosure of embodiments using the term “comprising / including” includes both embodiments “consisting substantially of the specified components” and embodiments “consisting of the specified components.” A composition “consisting substantially of the specified components” contains at least 50% by weight of the reference component, preferably at least 75% by weight, more preferably at least 85% by weight, and most preferably at least 95% by weight of the reference component.

[0038] The term “and / or” as used in the context of “X and / or Y” should be interpreted as “X” or “Y” or “X and Y”. In the context of its use herein, the terms “example” and “such as” (especially when followed by a list of terms) are merely exemplary and illustrative and should not be considered exclusive or comprehensive.

[0039] The terms “food,” “food product,” and “food composition” mean a product or composition intended for ingestion by an individual (e.g., a human) and to provide that individual with at least one nutrient. The compositions of this disclosure (including the various embodiments described herein) may comprise, consist of, or substantially consist of the elements described herein, as well as any other or optional ingredients, components, or elements described herein or that may be used in a diet.

[0040] "Prevention" includes reducing the risk and / or severity of a condition or disorder. The terms "treatment," "mitigation," and "relief" include both preventative or preventive treatment (preventing and / or delaying the development of a target pathological condition or disorder) and curative, therapeutic, or disease-modifying treatment, including therapeutic measures that cure, delay, or reduce symptoms of a diagnosed pathological condition or disorder and / or halt its progression; and include treatment of patients at risk of contracting or suspected of contracting the disease, as well as treatment of patients who are ill or have been diagnosed with a disease or medical condition. This term does not necessarily mean that an individual is treated until fully recovered. These terms also refer to health maintenance and / or promotion in individuals who are not ill but may be prone to developing unhealthy conditions. These terms are also intended to include intensifying or otherwise enhancing one or more major preventative or therapeutic measures. The terms "treatment," "mitigation," and "relief" are also intended to include dietary management or prevention of a disease or disorder, or dietary management used to prevent a disease or disorder. Treatment may be related to a patient or physician.

[0041] The term "individual" refers to any animal, including humans, that may suffer from cognitive aging and thus benefit from one or more of the methods disclosed herein. Generally, an individual is a human, bird, bovine, canine, equine, feline, goat, wolf, rodent, sheep, and pig. "Companion animal" is any domesticated animal, including but not limited to cats, dogs, rabbits, guinea pigs, ferrets, hamsters, mice, gerbils, horses, cattle, goats, sheep, donkeys, pigs, etc. Preferably, the individual is a human or a companion animal, such as a dog or cat.

[0042] In a human context, the term "middle-aged and older" refers to individuals who are at least 60 years old from birth, preferably 63 years or older, more preferably 65 years or older, and most preferably 70 years or older. In a human context, the term "older adult" refers to individuals who are at least 45 years old from birth, preferably 50 years or older, more preferably 55 years or older, and includes middle-aged and older individuals.

[0043] For other animals, “older adult” means having exceeded 50% of the average lifespan of its particular species and / or breed. An animal is considered “middle-aged or older” if it exceeds 66% of its average lifespan, preferably exceeding 75% of its average lifespan, and more preferably exceeding 80% of its average lifespan. Middle-aged or older cats or dogs are at least about 7 years old from birth.

[0044] Cognitive aging is a decline in cognitive abilities that progresses with age (e.g., as one ages into middle or old age), and may include age-related changes in brain morphology and / or cerebrovascular function. Cognitive aging does not include cognitive impairment caused by underlying conditions other than aging, such as head injuries or depression.

[0045] “Cognitive ability” is defined as the intellectual processes that enable a person to perceive, understand, or comprehend ideas. Cognitive ability encompasses the quality of knowing, which includes all aspects of perception, recognition, assumption, sensation, thinking, reasoning, memory, and imagination. Loss of cognitive ability is difficulty in processing new information or situations or in responding to them. Cognitive impairment can manifest in many ways, such as short-term memory loss, decreased learning ability, reduced learning speed, weakened attention, decreased motor performance, and / or dementia, etc. Non-limiting examples of specific cognitive domains that include abilities that decline with age include: (i) attention: processing speed, and selective and segmented attention; (ii) learning and memory: delayed free recall, source memory, prospective memory, and episodic memory; (iii) language: language fluency, visual naming, and word lookup; (iv) visuospatial ability: visual construction skills; and (v) executive functions: planning, decision-making, reasoning, and cognitive flexibility.

[0046] As used herein, "effective amount" is the amount in an individual that prevents defects, treats diseases or medical conditions, or more generally, the amount that alleviates symptoms, manages disease progression, or provides nutritional, physiological, or medical benefits. The relative terms "improvement," "enhancement," "enhancement," etc., refer to the effects of the compositions disclosed herein relative to compositions lacking one or more ingredients and / or containing one or more ingredients in different amounts but otherwise identically.

[0047] Implementation Plan

[0048] In one aspect of this disclosure, the composition comprises a combination of omega-3 fatty acids and choline; and preferably, the composition comprises an amount of the combination that effectively reduces cognitive aging and / or improves cognitive function in non-dementia individuals. In another aspect, a method for reducing cognitive aging and / or improving cognitive function in non-dementia individuals includes administering (e.g., orally) an effective amount of the composition to the individual.

[0049] In one embodiment, the composition is administered to an individual at a daily dose providing 0.01 to 10.0 times the recommended daily amount (RDA) of choline, for example, 0.15 to 6.0 times the RDA of choline. In this regard, the RDA of choline is 550 mg / day, therefore the composition can be administered at a daily dose providing 5.5 mg / day to 5,500 mg / day of choline (e.g., 85 mg / day to 3,500 mg / day of choline). However, this disclosure is not limited to a specific daily dose of choline.

[0050] This composition can enhance cognitive function in non-dementia individuals susceptible to or experiencing cognitive decline due to aging. The composition can prevent, reduce, or delay cognitive decline in non-dementia individuals susceptible to or experiencing cognitive decline due to aging. In some embodiments, these methods include identifying individuals as having or at risk of cognitive aging prior to administration. For example, the method may include determining that the individual needs cognitive improvement prior to administration. The composition can reduce brain atrophy and neuroinflammation, and increase amyloid β-phagocytosis and the number of synapses.

[0051] For example, this disclosure provides a method for treating cognitive aging in non-dementia individuals (e.g., those with cognitive aging) who require it, the method comprising administering to the individual a therapeutically effective amount of a composition comprising omega-3 fatty acids and choline. As another example, this disclosure provides a method for preventing cognitive aging in non-dementia individuals at risk (e.g., older adults or middle-aged individuals who do not yet have cognitive aging), the method comprising administering to the individual a therapeutically effective amount of a composition comprising omega-3 fatty acids and choline. Yet another example, this disclosure provides a method for improving the cognitive abilities of non-dementia individuals (e.g., those who require it), the method comprising administering to the individual a therapeutically effective amount of a composition comprising omega-3 fatty acids and choline.

[0052] “Non-dementia” individuals have a clinical dementia score of up to 0.5. The CDR measures dementia severity and is a global dementia score assessed by semi-structured interviews with informed subjects, ranging from 0 to 3 (0, 0.5, 1, 2, and 3) (Hughes et al., Br. J. Psychiatry 140:566-72 (1982)). Clinicians synthesize cognitive and functional abilities based on six domains: memory, orientation, judgment and problem-solving, community affairs, family and interests, and personal care. The scale exhibits good inter-rater consistency.

[0053] The non-dementia individual does not have any of Alzheimer's disease, vascular dementia, Lewy body dementia, or frontotemporal dementia. In some implementations, the non-dementia individual is a healthy aging individual. In other implementations, the non-dementia individual has an age-related cognitive impairment phenotype. For example, when compared with a control individual without the phenotype, the non-dementia individual may have one or more of the following phenotypes: decreased memory, short-term memory loss, slowed learning speed, decreased learning ability, reduced problem-solving skills, reduced attention span, decreased motor performance, or increased confusion.

[0054] A non-limiting example of a non-demented individual at risk of cognitive aging is a human who has spontaneous memory complaints but has a Mini-Mental State Examination (MMSE) score of at least 24 and demonstrates independence in basic daily activities (as indicated by an Activities of Daily Living (ADL) score of at least 4). An MMSE score used for this purpose may be, for example, 24 to 30, more preferably 26 to 30.

[0055] The MMSE is a very short, easily managed / executable mental state test that has proven to be a highly reliable and effective tool for detecting and tracking the progression of cognitive impairment associated with neurodegenerative diseases. The MMSE is a fully structured scale consisting of 30 points divided into seven categories: location orientation (state, county, town, hospital, and floor), time orientation (year, quarter, month, day, and date), recall (immediately repeating three words), attention and focus (subtracting 7 consecutively from 100, or spelling words backwards), recall (recalling three previously repeated words), language (saying two object names, repeating phrases, reading aloud and understanding sentences, writing sentences, and following three-step commands), and visual constructs (copying designs) (Folstein et al., J. Psychiat. Res. 12:189-198 (1975)).

[0056] MMSE scores are based on the number of items completed correctly, with lower scores indicating poorer performance and more severe cognitive impairment. The total score ranges from 0 to 30.

[0057] The Activities of Daily Living (ADL) is an information-based scale widely used to assess the activities of daily living in people with and without Alzheimer's disease (AD). This tool assesses abilities across a variety of performance levels. The ADL demonstrates the sensitivity of individuals with mildly impaired sensitivity to changes compared to unimpaired controls and can identify functional changes (Galasko et al., Alzheimer Dis. Assoc. Disord. 11 Suppl. 2: S33-9 (1997)).

[0058] As previously stated, substantial evidence suggests that maintaining brain health and preventing age-related cognitive decline can prevent or delay the development of dementia. Therefore, the methods disclosed herein for treating or preventing cognitive aging may ultimately prevent dementia, such as Alzheimer's disease. Thus, another aspect of this disclosure is a method for preventing dementia in individuals at risk. This method involves administering a therapeutically effective amount of the composition disclosed herein to the individual. The dementia to be prevented may be selected from: Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, and combinations thereof. These methods preferably include administering the composition as described herein.

[0059] In one embodiment, the individual has a low DHA status at baseline (erythrocyte ω-3 index <4.8%). In one embodiment, the individual has a Clinical Dementia Scale (CDR) score of 0.5 at baseline. In one embodiment, the individual has a high plasma homocysteine ​​level at baseline. As used herein, a "high" plasma homocysteine ​​level is defined as a plasma homocysteine ​​level of at least 12 µmol / L. In another embodiment, the individual has a CAIDE (Cardiovascular Risk Factors, Aging, and Dementia) risk score of 10–15 at baseline. In another embodiment, the individual is amyloid-positive on a PET scan at baseline. In another embodiment, the individual has a genotype indicating a risk of cognitive decline (e.g., the brain protein E (APOE) genotype).

[0060] In various embodiments, the ω-3 fatty acid comprises 1 to 50% by weight of the composition, preferably 1 to 30% by weight, and most preferably 1 to 15% by weight. Preferably, the ω-3 fatty acid comprises at least one of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), and more preferably comprises both EPA and DHA, each having anti-inflammatory properties. The daily dose of the composition preferably provides 0.5 g to 1.0 g of DHA and / or 0.5 g to 1.0 g of EPA daily, more preferably 0.7 g to 1.0 g of DHA and / or 0.6 mg to 0.75 g of EPA daily, and most preferably about 770 mg of DHA and / or about 700 mg of EPA daily.

[0061] Omega-3 fatty acids may comprise blends of one or more sources of omega-3 fatty acids, and each of these sources may be natural (e.g., fish oil) or synthetic (i.e., formed through human-manipulated chemical processes rather than those of natural origin). The term "fish oil" refers to a crude or purified fatty or oily extract rich in omega-3 fatty acids obtained from marine individuals, preferably cold-water fish such as, but not limited to, salmon, tuna, mackerel, herring, sea bass, striped bass, halibut, catfish, sardines, shark, shrimp, and clams, or any combination thereof.

[0062] Non-limiting examples of suitable sources of choline that may be used in a composition include choline chloride, tartrate choline, citicoline (CDP choline), L-α-glycerophosphate choline (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof.

[0063] In one embodiment, the composition may optionally comprise a nitric oxide-releasing compound. A nitric oxide-releasing compound refers to any compound that causes or may cause the release of nitric oxide in an individual. The nitric oxide-releasing compound preferably comprises one or more of arginine, citrulline, ornithine, or a peptide or protein containing at least one of these amino acids, more preferably arginine and / or citrulline, and even more preferably citrulline, which provides beneficial effects on the cardiovascular system, particularly in improving blood flow, endothelial function, and blood pressure. In various embodiments, the nitric oxide-releasing compound is present in amounts from 1% to 20% by weight of the composition, preferably from 1% to 15% by weight, and more preferably from 1% to 10% by weight. In one embodiment, the daily dose of the composition provides 0.5 g to 10.0 g of the nitric oxide-releasing compound (e.g., citrulline) daily, preferably from 1.0 g to 5.0 g daily, more preferably from 2.0 g to 4.0 g daily, and most preferably about 3.0 g daily.

[0064] The composition may also contain one or more of vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folic acid), and vitamin B12 (cobalamin), or salts, conjugates, or derivatives having B vitamin activity. The composition may contain one or more of these additional B vitamins at 0.1 to 40 times the RDA, preferably 1 to 20 times the RDA, more preferably 1 to 10 times the RDA. In one embodiment, the composition further contains all of vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folic acid), and vitamin B12 (cobalamin).

[0065] In this case, the composition may further comprise, for example, at least one B vitamin selected from: vitamin B6, vitamin B9 and / or vitamin B12, wherein the composition is preferably administered to an individual at a daily dose that provides at least 0.01 to 100 times the recommended daily intake (RDA) of vitamin B6, such as 10 to 80 times the RDA of vitamin B6, and / or 0.01 to 5.0 times the RDA of vitamin B9, such as 1.0 to 2.5 times the RDA of vitamin B9, and / or 0.1 to 40 times the recommended daily intake (RDA) of vitamin B12.

[0066] Typically, the daily amount of vitamin B12 in the compositions of the present invention is 0.1 to 40 times the daily RDA of vitamin B12, preferably 10 to 40 times, more preferably 10 to 30 times, or even more preferably 10 to 25 times, and most preferably about 12 to 21 times the daily RDA of vitamin B12. In this regard, the US RDA of vitamin B12 for humans aged 14 years and older is 2.4 micrograms per day, such that the daily dose of the composition administered to an individual provides about 0.002 mg to about 0.4 mg of vitamin B12 per day, preferably 0.02 mg to 0.07 mg of vitamin B12 per day, more preferably 0.03 mg to 0.05 mg of vitamin B12 per day. Furthermore, the RDA for vitamin B6 is 1.3 mg / day, and the RDA for vitamin B9 is 0.4 mg / day.

[0067] The composition may also contain 40 to 500 times, for example 40 to 50 times or even 50 to 500 times the recommended daily intake (RDA) of vitamin B12. This daily dose can therefore provide approximately 200 times the RDA of vitamin B12 daily, for example, 100 to 300 times or preferably 150 to 250 times the recommended daily intake (RDA) of vitamin B12 daily. In this case, the daily dose of the composition administered to an individual can provide 0.1 mg to 1.5 mg of vitamin B12 daily, preferably 0.2 mg to 1.2 mg of vitamin B12 daily, more preferably 0.4 mg to 1.0 mg of vitamin B12 daily, and most preferably approximately 0.5 mg of vitamin B12 daily.

[0068] In some embodiments, the composition may also contain one or more antioxidants to prevent oxidative damage and inflammation-related damage. Non-limiting examples of suitable antioxidants include vitamin C, vitamin D, vitamin E, selenium, and combinations thereof. The composition may contain 0.0001% to 25% by weight of an antioxidant (if present); preferably 0.0001% to about 15% by weight; more preferably 0.001% to 5% by weight; and most preferably 0.001% to 2% by weight.

[0069] In some embodiments, the composition is a food composition for humans and / or pets, such as companion individuals. The food composition may contain one or more additional substances, such as minerals, another vitamin, salt, or functional additives, such as flavorings, colorings, emulsifiers, or antimicrobial compounds or other preservatives. Non-limiting examples of suitable minerals include calcium, phosphorus, potassium, sodium, iron, chlorine, boron, copper, zinc, magnesium, manganese, and iodine. Non-limiting examples of suitable additional vitamins include fat-soluble vitamins A, D, E, and K.

[0070] In other embodiments, the composition is a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, diluents, or excipients. Generally, pharmaceutical compositions are prepared by mixing ω-3 fatty acids and choline with one or more excipients, buffers, binders, plasticizers, colorants, diluents, compressants, lubricants, flavoring agents, or wetting agents.

[0071] The composition may have an acute effect that can be observed in less than a month. In addition, or alternatively, the composition may have a long-term effect, and thus various embodiments include administering the composition to an individual (e.g., orally) for a period of at least one month; preferably at least two months, more preferably at least three, four, five, or six months; and most preferably at least one year. During this period, the composition may be administered to the individual at least one day per week; preferably at least two days per week, more preferably at least three, four, five, or six days per week; and most preferably seven days per week. The composition may be administered daily in a single dose or daily in multiple individual doses.

[0072] Unless otherwise described, any embodiments defined herein, and in particular the components of the said compositions, may be combined with each other. This also relates to the characteristics and beneficial effects of the methods and treatments using such compositions as defined herein.

[0073] Example

[0074] Example 1

[0075] The following non-limiting examples are experimental examples demonstrating that embodiments of the compositions comprising ω-3 fatty acids and choline provided in this disclosure can alleviate cognitive aging in non-dementia individuals.

[0076] Specifically, this experimental study compared the effects of selected components, used alone and in combination, on synapse formation in human iPSC-derived neuronal cultures + astrocytes. Cells were grown for two weeks (neurons + astrocytes), then the culture medium was replaced with a custom-designed medium. Treatment lasted 48 hours (n=8), followed by immunocytochemistry + high-content imaging + image analysis. Figure 1 Provide a table showing the processing. For example... Figure 2As shown, at high concentrations, the combination of DHA+EPA and choline (T3) significantly increased the number of synapses.

[0077] Example 2

[0078] The following non-limiting examples are illustrations of compositions in the embodiments provided in this disclosure for mitigating cognitive aging in non-dementia individuals.

[0079]

[0080] Example 3

[0081] A study will be conducted with the primary objective of demonstrating the efficacy of a 4-year intervention using the compositions listed in Example 2 to prevent cognitive decline as measured by a comprehensive neuropsychological assessment. The overall study cohort will consist of non-demented adults aged 70 years and older with subjective memory problems, with a subgroup defined by another subgroup of the study cohort who had low DHA status at baseline (erythrocyte ω-3 index <4.8%) and a Clinical Dementia Scale (CDR) score of 0.5 at baseline.

[0082] The trial design will be a placebo-controlled, double-blind, randomized, multicenter, 2-parallel study. Subjects will be randomly assigned to one of two treatment groups (placebo or BPB).

[0083] Subjects were randomly assigned to take either one of the study products: the representative composition of Example 2 or the placebo product. Both the effective study product and the placebo study product consisted of a sachet containing a powdered beverage mixture to be reconstituted in cold water and two soft gel capsules.

[0084] In the representative composition of Example 2, the softgel capsules provide DHA and EPA. The powdered beverage contains the remaining active ingredients along with auxiliary ingredients (sucrose, flavoring agents, and sweeteners).

[0085] In the placebo product, the softgel capsules contain a mixture of vegetable oils that do not contain DHA and EPA but have similar fatty acid profiles to those in the active capsules. The powdered beverage does not contain any active ingredient and is matched to the carbohydrate content of the active powdered beverage. It is composed of sucrose / starch, polydextrose, protein, flavoring agents, natural colorings, and sweeteners to closely resemble the taste, texture, and appearance of the active powdered beverage.

[0086] Take the survey product once a day: take one powdered beverage and two capsules at the same time of day.

[0087] During the study, participants were not allowed to take any additional dietary supplements containing B vitamins (thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folic acid (B9), cobalamin (B12), DHA, EPA).

[0088] The primary endpoint will be the change in the composite score of cognitive assessment over 4 years. The composite score combines scores from the following neuropsychological tests: learning test, orientation score, digit substitution test, and category naming test. The primary outcome will be viewed in three groups (overall study group; low DHA status at baseline, CDR 0.5).

[0089] The study will also examine secondary end values ​​that support the primary objective, particularly

[0090] (i) The therapeutic effect on plasma nutrient levels and biomarkers (e.g., homocysteine, erythrocyte (RBC) DHA status) associated with BPB intervention;

[0091] (ii) Treatment efficacy as measured by separate analysis of test results used in the composite score and additional neuropsychological test scores: MMSE total score;

[0092] (iii) Connect-the-dots test, logical memory test, verbal fluency test, Structural test, and number span test;

[0093] (iv) Treatment efficacy as measured by changes in CDR-SOB (Clinical Dementia Scale-Box Sum) scores; and conversion rates to mild cognitive impairment (MCI) and dementia;

[0094] (v) Therapeutic effects on participants' reported functional and quality-of-life outcomes: cognitive function tools; EQ-5D-5L; and applied cognitive ability tools;

[0095] (vi) Treatment efficacy in subgroups defined by the following subject characteristics: high plasma homocysteine ​​level at baseline (plasma homocysteine ​​≥12µmol / L), CAIDE (cardiovascular risk factors, aging and dementia) risk score at baseline, amyloid positivity on PET scan at baseline, and genotype.

[0096] In addition, for this purpose, biomarkers will be measured, specifically (i) MRI-derived total brain and hippocampal atrophy, and high signal accumulation of total white matter, arterial spin labeling imaging, and resting-state fMRI in representative study population subgroups (up to 500 subjects per arm); (ii) amyloid / Tau PET in representative study population subgroups (up to 500 subjects per arm); and (iii) plasma markers, namely plasma BDNF, plasma Aβ40-42 and Tau protein, asymmetric dimethylarginine, homocysteine, plasma inflammatory markers (sCAM, E-selectin, TNFα, IL1, IL6, IL10, CRP), and plasma markers of oxidative stress response (oxidized low-density lipoprotein (oxLDL), F2-isoprostane).

[0097] Secondary exploratory endpoints will include physical function (SPPB), frailty (Fried), anxiety, and depression (Geriatric Depression Scale (GDS), Neuropsychiatric Questionnaire (NPI Q)), collection and storage of blood and DNA for future research; and effect modifications through genetics (single nucleotide polymorphisms, such as ApoE-ε4, MTHFR, CBS, FAD1 / 2, and other specific genes identified through novel scientific discoveries) or medicine (disease states, such as diabetes, cardiovascular disease, and hypertension).

[0098] It should be understood that various changes and modifications to the currently preferred embodiments described herein will be apparent to those skilled in the art. These changes and modifications can be made without departing from the spirit and scope of the subject matter of the invention and without diminishing its intended advantages. Therefore, these changes and modifications are intended to be covered by the appended claims.

Claims

1. A method for mitigating, treating, or preventing cognitive aging in a non-dementia individual who is in need of or at risk of cognitive aging, the method comprising administering to the individual a therapeutically effective amount of a composition comprising omega-3 fatty acids and choline.

2. The method according to claim 1, wherein the individual is a middle-aged or elderly person.

3. The method according to claim 1 or 2, wherein the individual is an elderly person.

4. The method according to claims 1 to 3, wherein the composition is administered orally to the individual daily for at least one month.

5. The method according to any one of claims 1 to 4, wherein the composition further comprises a nitric oxide-releasing compound.

6. The method of claim 5, wherein the nitric oxide-releasing compound comprises citrulline.

7. The method according to any one of claims 1 to 6, wherein the ω-3 fatty acid comprises fatty acids selected from docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof.

8. The method according to any one of claims 1 to 7, wherein the choline is provided by a compositional component selected from: choline chloride, tartrate choline, citicoline, L-α-glycerophosphate choline, lecithin, phosphatidylcholine, and mixtures thereof.

9. The method according to any one of claims 1 to 8, wherein the composition comprises one or more B vitamins selected from the group consisting of vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, and vitamin B12.

10. The method according to any one of claims 1 to 9, wherein the composition comprises one or more antioxidants selected from the group consisting of vitamin C, vitamin D, vitamin E and selenium.

11. The method according to any one of claims 1 to 10, wherein the individual has a low DHA status at baseline.

12. The method according to any one of claims 1 to 11, wherein the individual has a Clinical Dementia Scale (CDR) score of 0.5 at baseline.

13. The method according to any one of claims 1 to 12, wherein the individual has a low plasma homocysteine ​​level of at least 12 µmol / L at baseline.

14. The method according to any one of claims 1 to 13, wherein the individual has a cardiovascular risk factor, aging, and dementia (CAIDE) risk score of 10 to 15 at baseline.

15. The method according to any one of claims 1 to 14, wherein the individual is amyloid-positive on a baseline PET scan.

16. The method according to any one of claims 1 to 15, wherein the individual has a genotype indicating a risk of cognitive decline.

17. The method according to any one of claims 1 to 16, wherein the composition is administered to the individual at a daily dose of 5.5 mg / day to 5,500 mg / day of the choline.

18. The method according to any one of claims 1 to 17, wherein the composition is administered to the individual at a daily dose providing 0.002 mg to 0.4 mg of vitamin B12 per day, preferably 0.02 mg to 0.07 mg of vitamin B12 per day, more preferably 0.03 mg to 0.05 mg of vitamin B12 per day.

19. The method according to any one of claims 1 to 18, wherein the application results in improved neuronal fluidity, stimulation of neuronal plasticity and activity, improvement of anti-inflammatory potential, support or maintenance of cognitive performance, support or maintenance of brain performance, slowing brain aging, supporting active thinking and brain health, supporting or maintaining a healthy brain, enhancing memory, enhancing executive function, enhancing attention, maintaining cognitive health, and maintaining brain cell health.

20. A method for mitigating, treating, or preventing cognitive aging in a non-dementia individual who is in need of or at risk of cognitive aging, the method comprising administering to the individual a therapeutically effective amount of a composition comprising omega-3 fatty acids and choline.

21. A method for achieving one or more beneficial effects selected from the following in a non-dementia individual in need: reducing brain atrophy, increasing or maintaining the number of synapses, increasing or maintaining amyloid β-phagocytosis, and reducing neuroinflammation, said method comprising administering to said individual a therapeutically effective amount of a composition comprising ω-3 fatty acids and choline.

22. A composition comprising a combination of omega-3 fatty acids and choline; and said composition comprising an amount of said combination that effectively reduces cognitive aging in non-dementia individuals.

23. The composition of claim 22, wherein the composition comprises 1% to 50% by weight of the ω-3 fatty acid of the composition and choline in an amount of 5.5 mg / day to 5,500 mg / day.

24. The composition according to claim 22 or 23, wherein the composition is a food product comprising ingredients selected from: proteins, carbohydrates, fats, and combinations thereof.

25. The composition according to claim 22 or 23, wherein the composition is a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, and diluent.

26. The composition according to any one of claims 22 to 25, wherein the composition is used to alleviate, treat, or prevent cognitive aging in non-dementia individuals who have a need for or are at risk of such aging.

27. The composition according to any one of claims 22 to 26, wherein the composition is used to improve neuronal fluidity, stimulate neuronal plasticity and activity, improve anti-inflammatory potential, support or maintain cognitive performance, support or maintain brain performance, slow brain aging, support active thinking and brain health, support or maintain a healthy brain, enhance memory, enhance executive function, enhance attention, maintain cognitive health, and maintain brain cell health.

28. A method for preparing a food composition for mitigating cognitive aging in non-dementia individuals, the method comprising adding an effective amount of a combination of omega-3 fatty acids and choline to at least one ingredient selected from: protein, carbohydrates and fat.

29. A method for preparing a pharmaceutical composition for alleviating cognitive aging in non-dementia individuals, the method comprising adding an effective amount of a combination of ω-3 fatty acids and choline to at least one component selected from: a pharmaceutically acceptable carrier, a diluent, and an excipient.

30. A method for preventing dementia in an individual at risk, the method comprising administering to the individual a therapeutically effective amount of a composition comprising omega-3 fatty acids and choline.

31. The method of claim 30, wherein the dementia prevented is selected from Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, and combinations thereof.

32. A method for improving the cognitive abilities of a non-dementia individual, the method comprising administering to the individual a therapeutically effective amount of a composition comprising omega-3 fatty acids and choline.

Images