Ω3 fatty acids and choline as neuroprotectant in patients with no dementia

Abstract

To provide a method for attenuating, treating or preventing cognitive aging in an individual who doe not have dementia.SOLUTION: A method includes a step of administering to the individual a therapeutically effective amount of a composition containing ω3 fatty acid and choline. The method can achieve a benefit that is one or more of decreasing brain atrophy, increasing or maintaining the number of synapses, increasing amyloid-β phagocytosis, or decreasing or maintaining neuroinflammation in the non-demented individual. The method can prevent dementia in an individual at risk thereof, for example an elderly human. The composition can be administered to the individual in a daily dose that provides 5.5 mg / day to 5,500 mg / day of the choline, for example 85 mg / day to 3,500 mg / day of the choline.SELECTED DRAWING: None

Description

Background Art

[0001]

[0001] The present disclosure generally relates to compositions and methods for reducing cognitive aging in non-demented individuals. More specifically, the present disclosure relates to reducing cognitive aging by administering a composition comprising a combination of ω3 fatty acids and choline.

[0002]

[0002] The aging of the population is a significant demographic event. As the life expectancy increases and the increase in the elderly population exceeds the increase in the total population, the proportion of the elderly population to the remaining population has increased significantly due to the decline in the birth rate. For example, in the 1950s, one in twelve people was over 60 years old, while at the end of the 2000s, one in ten people was over 60 years old. By the end of the 2050s, it is predicted that one in five people worldwide will be over 60 years old.

[0003]

[0003] Elderly and aging individuals often have some degree of cognitive impairment, such as a decline in cognitive function associated with aging, and morphological and cerebrovascular functional changes in the brain associated with aging are generally observed. The decline in cognitive function has been reported to date as being associated with aging across the entire range of cognitive domains, including processing speed, attention, episodic memory, spatial ability, and executive function. Brain imaging analysis has shown that these normal age-related declines in cognitive function are associated with a decrease in the volume of both gray and white matter in the brain, and it has been found that the fronto-striatal system is most severely damaged with aging. Such a decrease in cortical volume can be attributed to, for example, the accumulation of damage by free radicals that cause oxidative damage over time, chronic low-grade inflammation, the accumulation of homocysteine (an increased amount of homocysteine is a risk factor for cognitive impairment and dementia), and the decline of mitochondrial function, among many harmful cellular processes associated with normal aging. In addition to direct cellular damage, the brain also suffers indirect damage from injury to the microvascular structure. It is clear that aging, and indeed the pathology of dementia, encompasses complex interactions between these factors, and each effect is correlated. For example, mitochondrial dysfunction results in increased oxidative stress, which can trigger inflammation and vascular damage.

[0004]

[0004] Furthermore, the decline in cognitive function is an early predictor of Alzheimer's pathology and begins before the onset of dementia. In this case, the overall score for cognition becomes a reliable means of assessing pre-dementia decline in cognitive function. A lot of evidence suggests that maintaining brain health and preventing age-related decline in cognitive function can prevent or delay the progression of dementia due to Alzheimer's disease and other age-related neuropathologies.

[0005]

[0005] In recent years, nutritional intake, learning, exercise, and cognitive exercise have attracted attention as intervention methods that can prevent age-related decline in cognitive function. There is a lot of clinical, epidemiological, and individual evidence supporting the existence of individual nutritional factors that reduce the risk of dementia and age-related neurodegeneration. However, in formal trials regarding nutritional interventions, the results are complex (Schmitt et al., Nutrition Reviews 68:S2~S5(2010)).

[0006]

[0006] Although several long-term trials have been conducted, no benefits to cognitive function were observed in interventions using combinations of B6, B12, and folate. According to McMahon et al. (2006) N Engl J Med, 354(26), 2764~2772, even after adults aged 65 and above had taken supplements containing folate (1000 μg), vitamin B12 (500 μg), and vitamin B6 (10 mg) for two years, no effect on cognitive function was confirmed. Similarly, according to Hankey et al. (2013) (Stroke, 44(8), 2232~2239), for patients who had experienced a stroke or transient ischemic attack but whose cognitive function was not impaired, when taking folic acid (2000 μg), vitamin B6 (25 mg), and vitamin B12 (500 μg) daily, as measured by the MMSE over 2.8 years (median), the mean tHcy decreased, but there was no effect on the incidence of cognitive impairment or decline in cognitive function.

[0007]

[0007] In several short-term trials as well, combinations of B6, B12, and folate were unable to show an effect in improving cognitive function. According to Lewerin et al. (2005) Am J Clin Nutr, 81(5), 1155~1162, even after supplementing with folic acid (800 μg), vitamin B12 (500 μg), and vitamin B6 (3 mg) for four months, there was no effect on the cognitive function of elderly adults (median age 76 years).

Summary of the Invention

[0008]

[0008] While not being bound by theory, the inventors believe that conventional nutritional interventions that attempt to reduce the risk of dementia and age-related neurodegeneration have focused on administering nutrients alone and have not intelligently combined them to enhance the degree of effect through the interaction of nutrients. Furthermore, in studies that have tested the effects of mixed components on cognitive function, mixtures of components that all target the same mechanism have been used (e.g., a mixture of folate, B12, and B6 that targets Hcy concentration, or a mixture of vitamins C and E that targets oxidative damage), and this may be the reason why this evidence shows the same contradictions as studies on single components. Accordingly, the present disclosure broadly relates to multiple intervention approaches in which each nutritional intervention targets different risk factors associated with cognitive decline.

[0009]

[0009] Accordingly, in a broad embodiment, the present disclosure provides a method for reducing, treating, or preventing cognitive aging in an individual who needs to reduce, treat, or prevent cognitive aging or who is at risk of cognitive aging but does not have dementia. The method includes administering to the individual a composition comprising ω3 fatty acids and choline in a therapeutically effective amount. The composition can be administered in a daily dose that provides 5.5 mg / day to 5,500 mg / day of choline.

[0010]

[0010] In one embodiment, the individual is an elderly adult, such as an elderly human.

[0011]

[0011] In one embodiment, the individual has a low DHA state at baseline. In one embodiment, the individual has a Clinical Dementia Rating (CDR) of 0.5 at baseline. In one embodiment, the individual has a plasma homocysteine concentration of at least 12 μmol / L at baseline. In one embodiment, the individual has a Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score of 10 - 15 at baseline. In one embodiment, the individual is amyloid positive on an amyloid PET scan at baseline. In one embodiment, the individual has a genotype indicating a risk of cognitive decline.

[0012]

[0012] In one embodiment, the composition is orally administered to the individual daily for at least one month.

[0013]

[0013] In one embodiment, the composition comprises a nitric oxide-releasing compound, such as citrulline.

[0014]

[0014] In one embodiment, the ω3 fatty acid comprises a fatty acid selected from the group consisting of docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof.

[0015]

[0015] In one embodiment, the choline is provided by a component selected from the group consisting of choline chloride, choline bitartrate, cytidine diphosphate choline (CDP-choline), L-α-glycerophosphocholine (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof.

[0016]

[0016] 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, and optionally comprises all of vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, and vitamin B12.

[0017]

[0017] In one embodiment, the composition comprises one or more antioxidants selected from the group consisting of vitamin C, vitamin D, vitamin E, and selenium.

[0018]

[0018] In another embodiment, the present disclosure provides a method for reducing, treating, or preventing cognitive aging in an individual who needs or is at risk of cognitive aging and who is 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 omega-3 fatty acids can include fatty acids selected from the group consisting of docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof. Choline can be provided by a component selected from the group consisting of choline chloride, choline bitartrate, citicoline (CDP-choline), L-α-glycerophosphocholine (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof. The composition can be administered to the individual in a daily dose that provides 5.5 mg / day to 5,500 mg / day of choline.

[0019] In another embodiment, the present disclosure provides a method of obtaining one or more benefits selected from the group consisting of reduction of brain atrophy, increase or maintenance of synapse number, increase or maintenance of amyloid-β phagocytosis, and decrease of neuroinflammation, in an individual who does not have dementia that requires such benefits. The present disclosure also provides a method of obtaining one or more benefits selected from the group consisting of improvement of neuronal fluidity, stimulation of neuroplasticity and activity, improvement of anti-inflammation, and reduction of reactive oxygen species (ROS) and / or targeted nitric oxide release. The present disclosure also provides a method of obtaining one or more benefits selected from supporting or maintaining cognitive performance, supporting or maintaining brain performance, slowing down brain aging, maintaining activated consciousness and brain adaptability, supporting or maintaining a healthy brain, enhancing memory, enhancing executive function, enhancing attention, maintaining cognitive health, maintaining the health of brain cells, etc. Any of such benefits can be achieved by the methods defined herein, preferably methods that reduce, treat or prevent, or reduce, treat or prevent cognitive aging in individuals who do not have dementia but are at risk of cognitive aging. The method includes administering to the individual a composition comprising ω3 fatty acids and choline in a therapeutically effective amount. The ω3 fatty acids may include fatty acids selected from the group consisting of docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof. Choline can be provided by a component selected from the group consisting of choline chloride, choline bitartrate, citicoline (CDP-choline), L-α-glycerophosphocholine (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof. The composition can be administered to the individual in a daily dose that provides 5.5 mg / day to 5,500 mg / day of choline.

[0020]

[0020] In another embodiment, the present disclosure provides a composition comprising a combination of ω3 fatty acids and choline. The composition comprises the combination in an amount effective to reduce cognitive aging in individuals who do not have dementia. The composition can be a food product comprising a component selected from the group consisting of proteins, carbohydrates, fats, and combinations thereof. The composition can be a pharmaceutical composition comprising a component selected from the group consisting of pharmaceutically acceptable carriers, diluents, and excipients. The ω3 fatty acids can comprise a fatty acid selected from the group consisting of docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof. Choline can be provided by a component selected from the group consisting of choline chloride, choline bitartrate, cytidine diphosphate choline (CDP-choline), L-α-glycerophosphocholine (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof. The daily dose of the composition can provide 5.5 mg / day to 5,500 mg / day of choline.

[0021]

[0021] In another embodiment, the present disclosure provides a method for manufacturing a food composition for reducing cognitive aging in individuals who do not have dementia. The method comprises the step of adding an effective amount of a combination of ω3 fatty acids and choline to at least one component selected from the group consisting of proteins, carbohydrates, and fats. The ω3 fatty acids can comprise a fatty acid selected from the group consisting of docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof. Choline can be provided by a component selected from the group consisting of choline chloride, choline bitartrate, cytidine diphosphate choline (CDP-choline), L-α-glycerophosphocholine (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof.

[0022]

[0022] In another embodiment, the present disclosure provides a method for manufacturing a pharmaceutical composition for reducing cognitive aging in non-demented individuals, the method comprising the step of adding an effective amount of a combination of ω3 fatty acids and choline to at least one component selected from the group consisting of pharmaceutically acceptable carriers, diluents, and excipients. The ω3 fatty acids may include fatty acids selected from the group consisting of docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof. Choline can be provided by a component selected from the group consisting of choline chloride, choline bitartrate, cytidine diphosphate choline (CDP-choline), L-α-glycerophosphocholine (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof.

[0023]

[0023] In another embodiment, the present disclosure provides a method for preventing dementia in an individual at risk of dementia. The method comprises the step of administering to the individual a therapeutically effective amount of a composition comprising ω3 fatty acids and choline. The dementia to be prevented may be selected from the group consisting of Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, and combinations thereof. The ω3 fatty acids may include fatty acids selected from the group consisting of docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof.

[0024]

[0024] In another embodiment, the present disclosure provides a method for improving cognitive ability in a non-demented individual (e.g., an individual in need of improving cognitive ability), the method comprising the step of administering to the individual a therapeutically effective amount of a composition comprising ω3 fatty acids and choline. The ω3 fatty acids may include fatty acids selected from the group consisting of docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof. Choline can be provided by a component selected from the group consisting of choline chloride, choline bitartrate, cytidine diphosphate choline (CDP-choline), L-α-glycerophosphocholine (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof.

[0025]

[0025] The benefits according to one or more embodiments provided by the present disclosure are to reduce cognitive aging in individuals who are not demented (e.g., elderly humans).

[0026]

[0026] Other benefits according to one or more embodiments provided by the present disclosure include using omega-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to regulate neuronal cell membrane fluidity, stimulate neuroplasticity, provide an anti-neuroinflammatory effect, and / or reduce brain oxidative stress, in combination with choline, to reduce plasma homocysteine concentration, and optionally in combination with a nitric oxide-releasing compound such as arginine or citrulline to protect signaling pathways.

[0027]

[0027] Still other benefits according to one or more embodiments provided by the present disclosure are to use a greater amount of choline compared to known nutritional interventions for cognitive aging.

[0028]

[0028] Still other benefits according to one or more embodiments provided by the present disclosure are to reduce brain atrophy and neuroinflammation, and increase or maintain amyloid-β phagocytosis and synapse number in individuals who are not demented. In this regard, one or more of the benefits obtained by the present invention are selected from the group consisting of improvement of neuronal cell membrane fluidity, stimulation of neuroplasticity and activity, improvement of anti-inflammatory properties, reduction of reactive oxygen species (ROS) and / or targeted nitric oxide release, or other benefits disclosed herein.

[0029]

[0029] Further features and benefits are described herein and will become apparent from the following drawings and the mode for carrying out the invention.

[0030]

Brief Description of the Drawings

[0030]

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0031]

[0032] Definitions

[0033] Several definitions are shown below. However, there may be cases where the definitions are in the section "Embodiments" below, and the above heading "Definitions" does not mean that such disclosure in the "Embodiments" section is not a definition.

[0032]

[0034] All percentages described in this specification are based on the total weight of the composition unless otherwise specified. As used herein, "about," "approximately," and "substantially" refer to numbers within a numerical range, for example, within a range of -10% to +10% of the reference number, preferably within a range of -5% to +5% of the reference number, more preferably within a range of -1% to +1% of the reference number, and most preferably within a range of -0.1% to +0.1% of the reference number. All numerical ranges in this specification should be understood to include all integers or fractions within that range. Furthermore, these numerical ranges should be interpreted as being provided to support claims directed to any number or subset of numbers within this range. For example, the 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, 3.5 to 9.9, etc.

[0033]

[0035] As used in this disclosure and the appended claims, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated. Thus, for example, references to "a component" or "the component" include two or more components.

[0034]

[0036] The terms "comprise", "comprises", and "comprising" are to be construed inclusively rather than exclusively. Similarly, the terms "include", "including", and "or" are all to be construed as inclusive as long as such construction is not clearly precluded by the context. However, the compositions disclosed herein may not contain elements not specifically disclosed herein. Accordingly, the disclosure of embodiments using the term "comprising" includes the disclosure of embodiments "consisting essentially of" and "consisting of" the specified components. A "consisting essentially of" composition means containing at least 50% by weight of the referenced component, preferably at least 75% by weight of the referenced component, more preferably at least 85% by weight of the referenced component, and most preferably at least 95% by weight of the referenced component.

[0035]

[0037] In the context of "X and / or Y", the term "and / or" should be construed as "X" or "Y" or "X and Y". As used herein, the terms "example" and "such as" are merely illustrative and for the purpose of explanation when followed particularly by a listing of terms, and should not be judged as exclusive or inclusive.

[0036]

[0038] The terms "food", "food product", and "food composition" mean a product or composition intended for ingestion by an individual such as a human and for providing at least one nutrient to such individual. The compositions of the present disclosure include many of the embodiments described herein, and can contain, consist of, or consist essentially of the elements disclosed herein, as well as any additional or optional formulations, ingredients, or elements described herein or useful in other dietary therapies.

[0037]

[0039] "Prevention" includes reducing the risk and / or severity of a condition or disease. The terms "treatment", "treating", "reducing" and "alleviating" include both prevention or prophylactic treatment (preventing and / or delaying the onset of a targeted condition or disorder) and curative, therapeutic or disease-modifying treatment, e.g., treatment means for curing, delaying, alleviating symptoms, and / or halting the progression of a diagnosed condition or disorder, as well as treatment of patients at risk of a disease or suspected of having a disease, and patients in poor health or diagnosed with a disease or medical symptom. The term does not necessarily mean that the subject is treated until cured. These terms also mean the maintenance and / or enhancement of health in individuals who do not have a disease but are prone to an unhealthy condition. These terms are also intended to include the synergistic effect or enhancement of one or more primary preventive or therapeutic means. The terms "treatment", "treating", "reducing" and "alleviating" are further intended to include dietary therapy for a disease or symptom, or dietary therapy for the prophylaxis or prevention of a disease or symptom. Treatment may be related to the patient or to the physician.

[0038]

[0040] The term "individual" means any animal, including a human, that has the potential to experience cognitive aging and can therefore benefit from one or more of the methods disclosed herein. Generally, an individual is a human or an animal such as a bird, cow, dog, horse, cat, goat, wolf, mouse, sheep, or pig. A "companion animal" is any domesticated animal, including but not limited to cats, dogs, rabbits, guinea pigs, ferrets, hamsters, mice, rats, horses, cows, goats, sheep, donkeys, pigs, etc. Preferably, the individual is a companion animal such as a dog or a cat or a human.

[0039]

[0041] In the context of humans, the term "elderly" means an age of at least 60 years old, preferably 63 years old or older, more preferably 65 years old or older, and most preferably 70 years old or older. In the context of humans, the term "older adult" means an age of at least 45 years old, preferably 50 years old or older, more preferably 55 years old or older, and includes individuals who are elderly.

[0040]

[0042] In the case of other animals, "older adult" refers to an animal that has exceeded 50% of its average lifespan in its individual species and / or line within the species. An animal is considered "elderly" when it has exceeded 66% of its average life expectancy, preferably when it has exceeded 75% of its average life expectancy, and more preferably when it has exceeded 80% of its average life expectancy. An elderly cat or dog is at least about 7 years old.

[0041]

[0043] "Cognitive aging" is a decline in cognitive ability that progresses with age, such as becoming elderly, and may include age-related changes in brain morphology and / or cerebrovascular function. Cognitive aging does not include a decline in cognitive ability caused by underlying conditions other than aging, such as head trauma or depression.

[0042]

[0044] "Cognitive ability" is defined as the intellectual process by which an individual becomes conscious, perceives, or understands an idea. Cognitive ability encompasses the quality of cognition, which includes all aspects of perception, recognition, conception, sensation, thinking, reasoning, memory, and imagination. A decline in cognitive ability means that it is difficult to cope with or react to new information or situations. Cognitive impairment can manifest in many forms, particularly, for example, as a decline in short-term memory, learning ability, learning speed, attention, motor ability, and / or dementia. Non-limiting examples of specific cognitive domains that include abilities that decline with age are: (i) attention: processing speed, as well as selective and divided attention; (ii) learning and memory: delayed free recall, source memory, prospective memory, and episodic memory; (iii) language: speech fluency, visual naming, and word finding; (iv) visuospatial ability: visual construction skills; and (v) executive function: planning, decision-making, reasoning, and mental flexibility.

[0043]

[0045] As used herein, "effective amount" means an amount that prevents a deficiency, treats a disease or medical condition in an individual, or more generally, reduces symptoms, manages disease progression, or provides nutritional, physiological or medical benefits to an individual. Relative terms such as "improved", "increased", "enhanced", etc. related to the effects of the compositions disclosed herein are used when compared to compositions that lack one or more components and / or have different amounts of one or more components but are otherwise identical in other components.

[0044]

[0046] Embodiments

[0047] In one aspect of the present disclosure, the composition comprises a combination of ω3 fatty acids and choline, and preferably the composition comprises an effective amount of the combination to reduce cognitive aging and / or improve cognitive ability in an individual who does not have dementia. In another aspect, a method for reducing cognitive aging and / or improving cognitive ability in an individual who does not have dementia comprises administering to the individual an effective amount of the composition (e.g., orally).

[0045]

[0048] In one embodiment, the composition is administered to an individual in a daily dose that provides from 0.01 to 10.0 times the recommended dietary allowance (RDA) of choline, such as from 0.15 to 6.0 times the RDA of choline. In this regard, the RDA of choline is 550 mg / day, and thus the composition can be administered in a daily dose that provides from 5.5 mg / day to 5,500 mg / day of choline, such as from 85 mg / day to 3,500 mg / day of choline. However, the present disclosure is not limited to a specific daily dose of choline.

[0046]

[0049] The composition can increase cognitive function in individuals who are not suffering from or are prone to developing cognitive decline caused by the aging process. The composition can prevent, reduce, or delay cognitive decline in individuals who are not suffering from or are prone to developing cognitive decline caused by the aging process. In some embodiments, the method includes identifying an individual having cognitive aging or at risk of cognitive aging prior to administration. For example, the method can include identifying an individual in need of improvement in cognitive ability prior to administration. The composition can reduce brain atrophy and neuroinflammation and increase the number of synapses and the phagocytosis of amyloid-β.

[0047]

[0050] For example, the present disclosure provides a method of treating cognitive aging in an individual who is not suffering from dementia (e.g., having cognitive aging) in need of treatment, the method comprising administering to the individual a composition comprising ω3 fatty acids and choline in a therapeutically effective amount. As another example, the present disclosure provides a method of preventing cognitive aging in an individual who is not suffering from dementia at risk of cognitive aging (e.g., an elderly or aged individual who does not yet have cognitive aging), the method comprising administering to the individual a composition comprising ω3 fatty acids and choline in a therapeutically effective amount. In yet another example, the present disclosure provides a method of improving cognitive ability in an individual who is not suffering from dementia (e.g., an individual in need of improvement in cognitive ability), the method comprising administering to the individual a composition comprising ω3 fatty acids and choline in a therapeutically effective amount.

[0048]

[0051] Individuals who are "not demented" have a Clinical Dementia Rating (CDR) of up to 0.5. The CDR is a globally used method for measuring the severity of dementia, scoring dementia on a scale of 0 to 3 (0, 0.5, 1, 2, and 3), which is evaluated by semi-structured interviews of subjects and informants. See Hughes et al., Br. J. Psychiatry 140:566-72 (1982). Clinicians comprehensively evaluate cognitive and functional abilities based on six domains, including memory, orientation, judgment and problem-solving, activities in the community, activities and hobbies at home, and self-care. This scale shows good agreement among evaluators.

[0049]

[0052] Individuals who are not demented do not have any of Alzheimer's disease, vascular dementia, Lewy body dementia, or frontotemporal dementia. In some embodiments, the individuals who are not demented are healthy elderly individuals. In other embodiments, the individuals who are not demented have a phenotype associated with age-related cognitive impairment. For example, an individual who is not demented may have a phenotype that includes one or more of a decrease in the ability to remember, loss of short-term memory, decrease in learning speed, decrease in learning ability, decrease in problem-solving ability, decrease in attention duration, decrease in motor ability, or increase in confusion, when compared to a control individual who does not have such a phenotype.

[0050]

[0053] Non-limiting examples of individuals who are not demented but at risk of cognitive aging are humans who have a naturally occurring memory impairment, but are independent in basic daily activities as indicated by a Mini-Mental State Examination (MMSE) score of at least 24 and an Activities of Daily Living (ADL) score of at least 4. The MMSE score for solving the problems of the present invention may be, for example, 24-30, more preferably 26-30.

[0051]

[0054] The MMSE is a very reliable and proven effective means, and is a very simple and easily controllable / implementable mental function evaluation method for detecting and tracking the progression of cognitive impairment related to neurodegenerative diseases. The MMSE is a fully structured scale consisting of 30 points, which is classified into the following seven categories: orientation to place (state, county, town, hospital and floor), orientation to time (year, season, month, day of the week and date), registration (immediately repeat three words), attention and concentration (subtract 7 continuously from 100 or spell the word "world" backwards), recall (recall the three words repeated previously), language (answer the names of two items, repeat a phrase, read aloud and understand a passage, write a passage, follow a three-step command), and construction of visual information (copy a figure). See Folstein et al., J. Psychiat. Res. 12:189~198 (1975).

[0052]

[0055] In the MMSE, the number of items answered correctly is scored, and the lower the score, the worse the performance and the greater the cognitive impairment. The total score ranges from 0 to 30.

[0053]

[0056] ADL is a means widely used as an informant-based activities of daily living scale for evaluating the activities of daily living of people with or without AD. This means evaluates a wide range of abilities. ADL shows sensitivity to changes in moderately impaired individuals compared to non-disabled controls and can capture functional changes. See Galasko et al., Alzheimer Dis. Assoc. Disord. 11 Suppl. 2:S33~9 (1997).

[0054]

[0057] As described above in the specification of the present application, a lot of evidence suggests that the onset of dementia can be prevented or delayed by maintaining brain health and preventing cognitive decline due to aging. Therefore, the method for treating or preventing cognitive aging disclosed in this specification can also specifically prevent dementia such as Alzheimer's disease. Accordingly, another aspect of the present disclosure is a method for preventing dementia in an individual at risk of dementia. The present invention relates to a method comprising the step of administering to an individual a therapeutically effective amount of the composition disclosed herein. The dementia to be prevented can be selected from the group consisting of Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, and combinations thereof. The method of the present invention preferably comprises the step of administering the composition described herein.

[0055]

[0058] In one embodiment, the individual has a low DHA status at baseline (erythrocyte ω3 index less than 4.8%). In one embodiment, the individual has a clinical dementia rating (CDR) of 0.5 at baseline. In one embodiment, the individual has a high plasma homocysteine concentration at baseline. As used herein, "high" plasma homocysteine concentration means that homocysteine in plasma is 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 amyloid scan at baseline. In another embodiment, the individual has a genotype that indicates a risk of cognitive decline (e.g., apolipoprotein E (APOE) genotype).

[0056]

[0059] In various embodiments, the ω3 fatty acid is 1 to 50% by weight of the composition, preferably 1 to 30% by weight of the composition, and most preferably 1 to 15% by weight of the composition. Preferably, the ω3 fatty acid contains at least one of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), more preferably both EPA and DHA, each of which has anti-inflammatory properties. The daily dose of the composition preferably provides 0.5 g to 1.0 g of DHA per day and / or 0.5 g to 1.0 g of EPA per day, more preferably 0.7 g to 1.0 g of DHA per day and / or 0.6 mg to 0.75 g of EPA per day, and most preferably about 770 mg of DHA per day and / or about 700 mg of EPA per day.

[0057]

[0060] The ω3 fatty acid may include a mixture of one or more ω3 fatty acid resources, and each of the one or more ω3 fatty acid resources may be of natural origin (e.g., fish oil) or a synthetic (i.e., formed by an artificial chemical process as opposed to something of natural origin). The term "fish oil" means a crude or purified lipid or oily extract rich in ω3 fatty acids and obtained from marine organisms, preferably cold-water fish such as salmon, tuna, mackerel, herring, snapper, sea bream, saury, eel, and sardines, as well as sharks, shrimp, and bivalves, or any combination thereof.

[0058]

[0061] Non-limiting examples of suitable resources of choline that can be used in the composition include choline chloride, choline bitartrate, citicoline (CDP choline), L-α-glycerophosphocholine (α-GPC), lecithin, phosphatidylcholine, and mixtures thereof.

[0059]

[0062] In one embodiment, the composition can optionally contain a nitric oxide-releasing compound. The term "nitric oxide-releasing compound" means any compound(s) that can cause or result in the release of nitric oxide in an individual. The nitric oxide-releasing compound preferably contains 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 a beneficial effect on the cardiovascular system particularly by improving blood flow, endothelial function, and blood pressure. In various embodiments, the nitric oxide-releasing compound is 1 to 20% by weight of the composition, preferably 1 to 15% by weight of the composition, more preferably 1 to 10% by weight of the composition. In one embodiment, the daily dose of the composition provides 0.5 g to 10.0 g, preferably 1.0 g to 5.0 g, more preferably 2.0 g to 4.0 g, and most preferably about 3.0 g per day of a nitric oxide-releasing compound (such as citrulline).

[0060]

[0063] The composition can further contain at least one vitamin B, such as, for example, 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 one or more of their salts, conjugates, or derivatives having vitamin B activity. The composition can contain one or more of these additional vitamins B in an amount of 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).

[0061]

[0064] In this context, the composition may further comprise at least one B vitamin selected from, for example, vitamin B6, vitamin B9 and / or vitamin B12, and the composition is preferably administered to an individual in a daily dose that provides at least 0.01 to 100 times the recommended daily allowance (RDA), for example 10 to 80 times the RDA of vitamin B6, and / or 0.01 to 5.0 times the RDA, for example 1.0 to 2.5 times the RDA of vitamin B9, and / or 0.1 to 40 times the recommended daily allowance (RDA) of vitamin B12.

[0062]

[0065] Typically, the amount of vitamin B12 in the composition of the present invention is 0.1 to 40 times the RDA of vitamin B12 per day, 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 RDA of vitamin B12 per day. In this regard, the RDA of vitamin B12 in the United States is 2.4 μg per day for humans 14 years of age and older, and in such individuals, a daily dose of the composition can be administered that 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. Further, the RDA of vitamin B6 is 1.3 mg / day and the RDA of vitamin B9 is 0.4 mg / day.

[0063]

[0066] The composition can also contain 40 to 500 times the RDA of vitamin B12, for example 40 to 50 times, or even 50 to 500 times. The daily dose can provide about 200 times the recommended daily requirement (RDA) per day, for example 100 to 300 times the RDA per day, or preferably 150 to 250 times the RDA of vitamin B12. In this context, an individual can be administered a daily dose of the composition that provides 0.1 mg to 1.5 mg of vitamin B12 per day, preferably 0.2 mg to 1.2 mg of vitamin B12 per day, more preferably 0.4 mg to 1.0 mg of vitamin B12 per day, and most preferably about 0.5 mg of vitamin B12 per day.

[0064]

[0067] In some embodiments, the composition can further comprise one or more antioxidants for protecting against oxidative damage and damage induced by inflammation. Non-limiting examples of suitable antioxidants include vitamin C, vitamin D, vitamin E, selenium, and combinations thereof. When the composition contains an antioxidant, it can contain the antioxidant in an amount of 0.0001% to 25% by weight, 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.

[0065]

[0068] In some embodiments, the composition is a food composition for humans and / or pets (e.g., companion animals). The food composition may contain one or more additional substances such as, for example, minerals, other vitamins, salts, or functional additives such as, for example, flavorings, colorants, emulsifiers, or antibacterial compounds, or other preservatives. Non-limiting examples of suitable minerals include calcium, phosphorus, potassium, sodium, iron, chloride, boron, copper, zinc, magnesium, manganese, and iodine. Non-limiting examples of suitable additional vitamins include fat-soluble vitamins such as vitamin A, D, E, and K.

[0066]

[0069] In another embodiment, the composition is a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, diluents, or excipients. Generally, the pharmaceutical composition is prepared by mixing omega-3 fatty acids and choline with one or more of an excipient, buffer, binder, plasticizer, colorant, diluent, compression agent, lubricant, flavoring, or wetting agent.

[0067]

[0070] The composition can have acute effects that can be confirmed in less than 1 month. Additionally or alternatively, the composition can also have long-term effects. In various embodiments, the composition is administered to an individual over a period of at least 1 month, preferably at least 2 months, more preferably at least 3, 4, 5, or 6 months, most preferably at least 1 year (e.g., by oral administration). During this period, the composition can be administered to the individual at least 1 day per week, preferably at least 2 days per week, more preferably at least 3, 4, 5, or 6 days per week, most preferably 7 days per week. The composition can be administered once a day or in multiple individual doses per day.

[0068]

[0071] Any of the embodiments defined herein, and any of the components of the composition described in particular, may be combined with each other, unless otherwise specified. This also applies to the features and benefits of the methods and treatments defined herein using such compositions.

[0072]

Examples

[0069]

[0073] Example 1

[0074] The following non-limiting examples are experimental examples that support the reduction of cognitive aging in non-demented individuals according to embodiments of the composition comprising ω3 fatty acids and choline provided by the present disclosure.

[0070]

[0075] Specifically, in the experiment, a test was conducted to compare the effects of only the selected components and their combinations on synapse formation in human iPSC-derived neural cultures + astrocytes. The cells were grown for 2 weeks (neurons + astrocytes), and then the medium was replaced with a custom-made medium. The treatment was carried out for 48 hours (n = 8), followed by immunocytochemistry + high-content imaging + image analysis. Figure 1 shows a table representing the treatment. As shown in Figure 2, the combination of DHA + EPA and choline (T3) strongly increased the number of synapses at high concentrations.

[0071]

[0076] Example 2

[0077] The following non-limiting examples illustrate the compositions in the embodiments provided by the present disclosure for reducing cognitive aging in individuals without dementia.

[0072]

Table 1

[0073]

[0078] Example 3

[0079] The main purpose of the test implementation is to show the effectiveness of the intervention with the composition described in Example 2 for four years to prevent cognitive function decline measured by the composite score of neuropsychological evaluation. The entire test population consists of non-demented adults over 70 years old with subjective concerns about memory. Among them, a subgroup of the test population defined by a low DHA state (erythrocyte ω3 index < 4.8%) at baseline and another subgroup of the test population with a clinical dementia rating (CDR) of 0.5 at baseline are established.

[0074]

[0080] The test design is a placebo-controlled, double-blind, randomized, multi-site, two-parallel-group test. The subjects are randomly assigned to one of two dosing groups (placebo and BPB).

[0075]

[0081] The subjects are randomly assigned to either one of the investigational products, i.e., the representative composition of Example 2, or a placebo product. The investigational products for the active and placebo consist of one sachet containing a powdered beverage mixture reconstituted with cold water and two soft gel capsules.

[0076]

[0082] In the representative composition of Example 2, the soft gel capsules provide DHA and EPA. The powdered beverage contains the remaining active ingredients along with auxiliary components (sucrose, flavoring, and sweetener).

[0077]

[0083] In the placebo product, the soft gel capsules contain a mixture of DHA- and EPA-free vegetable oils but have a fatty acid profile similar to that of the active capsules. The powdered beverage contains no active ingredients and has a carbohydrate content that matches that of the active powdered beverage. It is composed of sucrose / starch, polydextrose, protein, flavoring agents, natural colorants, and sweeteners to approximate the taste, texture, and appearance of the active powdered beverage as closely as possible.

[0078]

[0084] Have the investigational product taken once a day, i.e., take one cup of the powdered beverage and two capsules at the same time of day.

[0079]

[0085] During the trial, do not have the participants take 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, and EPA.

[0080]

[0086] The primary endpoint is the change in the composite score of the cognitive ability assessment after 4 years. The composite score is the sum of the following neuropsychological test scores: learning test, recognition score, digit symbol substitution test, category naming test. Observe the main results in three groups: the full test group, the low DHA status group, and the baseline CDR = 0.5 group.

[0081]

[0087] Also test secondary endpoints that support the primary objective. Specifically: (i) The treatment effect on plasma nutrient concentrations and biomarkers (e.g., homocysteine, DHA status of red blood cells (RBC)) related to the BPB intervention; (ii) The treatment effect measured by the individual analysis of the test results used in the composite score, as well as the scores of additional neuropsychological tests (MMSE total score); (iii) Trail Making Test, Logical Memory Test, Letter Fluency, Stroop test, and Digit Span; (iv) Treatment effect measured by change in CDR-SOB (Clinical Dementia Rating-Sum of Boxes) score, and conversion rates to mild cognitive impairment (MCI) and dementia; (v) Treatment effects on function and quality of life based on participant outcome reports: Cognitive Function Instrument; EQ-5D-5L, and Applied Cognition-ABilities instruments; (vi) Treatment effects in subgroups defined by the following subject characteristics: High plasma homocysteine concentration at baseline (plasma homocysteine ≥ 12 μmol / L), CAIDE (Cardiovascular Risk Factors, Aging and Dementia) risk score at baseline, amyloid positivity by amyloid PET scan at baseline, and genotype.

[0082]

[0088] Furthermore, in this regard, the following biomarkers were specifically measured: (i) MRI-based whole brain and hippocampal atrophy, and accumulation of total white matter hyperintensities, imaging by Arterial Spin LaBeling, Resting State fMRI in a representative subset of the study population (up to 500 subjects per arm); (ii) amyloid / tau PET in a representative subset of the study population (up to 500 subjects per arm); (iii) plasma markers, namely plasma BDNF, plasma Aβ40-42 and tau protein, asymmetric dimethylarginine, homocysteine, plasma inflammatory markers (sCAMs, E-selectin, TNFα, IL1, IL6, IL10, CRP), and plasma markers of oxidative stress (oxidized low density lipoprotein (oxLDL), F2-isoprostane).

[0083]

[0089] Secondary test endpoints include physical function (SPPB), frailty (Fried), anxiety and depression status (Geriatric Depression Scale (GDS), Neuropsychiatric inventory questionnaire (NPI-Q)), blood and deoxyribonucleic acid (DNA) collection and preservation for future research, and changes in effects caused by genes (single nucleotide polymorphisms (e.g., ApoE-ε4, MTHFR, CBS, FAD1 / 2, other specific genes identified by new scientific discoveries)) or medical conditions (disease states (e.g., diabetes, cardiovascular disease, hypertension)).

[0084]

[0090] It should be understood that various changes and modifications to the preferred embodiments of the invention 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 of the invention and without sacrificing the intended benefits. Accordingly, such changes and modifications are intended to be included within the scope of the appended claims.

Claims

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

2. The method of claim 1 , wherein the individual is an elderly adult.

3. The method of claim 1 or 2, wherein the individual is an elderly human.

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

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

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

7. 7. The method of any one of claims 1 to 6, wherein the omega-3 fatty acids comprise fatty acids selected from the group consisting of docosahexaenoic acid, eicosapentaenoic acid, and mixtures thereof.

8. 8. The method of any one of claims 1 to 7, wherein the choline is provided by a component of the composition selected from the group consisting of choline chloride, choline bitartrate, citicoline, L-α-glycerophosphocholine, lecithin, phosphatidylcholine and mixtures thereof.

9. 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 of 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 of any one of claims 1 to 10, wherein the individual has a low DHA status at baseline.

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

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

14. 14. The method of any one of claims 1 to 13, wherein the individual has a Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score of 10-15 at baseline.

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

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

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

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

19. 19. The method of any one of claims 1-18, wherein said administration results in improving neuronal membrane fluidity, stimulating neuroplasticity and activity, improving anti-inflammatory properties, supporting or maintaining cognitive performance, supporting or maintaining brain performance, slowing brain aging, supporting active consciousness and brain adaptability, supporting or maintaining a healthy brain, enhancing memory, enhancing executive function, enhancing attention, maintaining healthy cognition, and maintaining brain cell health.

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

21. A method of obtaining one or more of the benefits selected from the group consisting of reduced brain atrophy, increased or maintained synaptic number, increased or maintained amyloid-β phagocytosis, and reduced neuroinflammation in an individual without dementia in need of said benefit, comprising the step of administering to said individual a therapeutically effective amount of a composition comprising an omega-3 fatty acid and a choline.

22. A composition comprising a combination of omega-3 fatty acids and choline, the composition comprising said combination in an amount effective to reduce cognitive aging in a non-demented individual.

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

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

25. 24. The composition of claim 22 or 23, wherein the composition is a pharmaceutical composition comprising a component selected from the group consisting of pharma- ceutically acceptable carriers, diluents and excipients.

26. 26. The composition of any one of claims 22 to 25 for use in reducing, treating or preventing cognitive ageing in a non-demented individual in need thereof or at risk of cognitive ageing.

27. 27. The composition of any one of claims 22 to 26, for use in improving neuronal membrane fluidity, stimulating neuroplasticity and activity, improving anti-inflammatory properties, supporting or maintaining cognitive performance, supporting or maintaining brain performance, slowing brain aging, maintaining active consciousness and brain adaptability, supporting or maintaining a healthy brain, enhancing memory, enhancing executive function, enhancing attention, maintaining healthy cognition, and maintaining brain cell health.

28. 1. A method for producing a food composition for reducing cognitive aging in a non-demented individual, comprising the step of 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 proteins, carbohydrates and lipids.

29. 1. A method for producing a pharmaceutical composition for reducing cognitive aging in a non-demented individual, comprising the step of 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 pharma- ceutical acceptable carriers, diluents and excipients.

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

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

32. 1. A method for improving cognitive performance in a non-demented individual, comprising administering to the individual a therapeutically effective amount of a composition comprising an omega-3 fatty acid and a choline.

Images