Tea polyphenols as a brain function improver

Abstract

To provide novel brain function improving agent and the like.SOLUTION: There is provided a brain function improving agent comprising tea polyphenol as an active ingredient. The brain function is evaluated by Cognitrax.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a brain function improving agent containing tea polyphenols, and a composition containing the same, particularly a food and drink composition. [Background technology]

[0002] In recent years, as the aging of the population progresses, cognitive impairment of the brain associated with aging has become a social problem, and various researches are being conducted on foods, ingredients, etc. that are effective in preventing or improving cognitive impairment. The presence or absence of cognitive impairment in humans can be diagnosed by a cognitive function test (screening test), and various cognitive function tests have been proposed. Therefore, in the evaluation of cognitive function, an appropriate test is appropriately selected from known cognitive function tests according to the purpose of the test and performed. Patent Document 1 proposes improving cognitive function using a composition containing docosahexaenoic acid, uridine, etc., and describes the use of a mini-mental state test as a standard test for evaluating cognitive ability.

[0003] Other known methods for testing cognitive function include the Hasegawa Dementia Scale-Revised and the Cognitrax test. Patent Document 2 describes a method for evaluating the effectiveness of green tea ingredients for mild cognitive impairment using the Cognitrax test.

[0004] Patent Document 3 discloses that green tea leaf powder containing theanine and catechin is effective in maintaining the cognitive function of healthy individuals or improving mild cognitive impairment through the Cognitrax test. On the other hand, Non-Patent Document 1 discloses that epigallocatechin gallate can regulate cerebral blood flow parameters in the frontal lobe of healthy adults, but is unrelated to cognitive function. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2015-143248 A [Patent Document 2] JP 2020-038156 A [Patent Document 3] JP 2020-037540 A [Non-patent literature]

[0006] [Non-Patent Document 1] Wightman et al., "Epigallocatechin gallate, cerebral blood flow parameters, cognitive performance and mood in healthy humans: a double-blind, placebo-controlled, crossover investigation", Hum Psychopharmacol. 2012 Mar;27(2):177-86. Summary of the Invention [Problem to be solved by the invention]

[0007] However, because brain functions are extremely complex and various functions interact with each other, there is a demand for drugs, supplements, and food and beverage products such as beverages and tea leaf products that are specifically designed to improve specific brain functions, in particular functional foods.

[0008] The present invention has been made in consideration of the above problems, and aims to provide a novel brain function improver or a composition containing the same, particularly a food and drink composition. [Means for solving the problem]

[0009] Cognitive function testing methods differ not only in sensitivity and specificity, but also in the cognitive functions evaluated due to differences in evaluation methods. For example, the Revised Hasegawa Dementia Scale and the Mini-Mental State Examination, which evaluate cognitive function by totaling the scores of individual items such as reciting numbers backwards and calculation problems, have biases in the test content and point allocation, and the types of dementia that are easy to detect (Alzheimer's type, cerebrovascular type, etc.) are different. It has also been reported that it is difficult to detect abnormalities in subjects with mild symptoms of cognitive decline.

[0010] Unlike the conventional Revised Hasegawa Dementia Scale and Mini-Mental State Examination, the Cognitrax test has the advantage of being able to individually determine areas of impaired function.

[0011] The inventors discovered that even when assessed using the same Cognitrax test, matcha and each of the components contained in it contribute to improving cognitive functions in different ways, and thus completed the present invention.

[0012] That is, the present invention includes the following inventions. [1] A brain function improving agent comprising tea polyphenols as an active ingredient, the brain function being evaluated by a Cognitrax test. [2] The brain function improving agent according to [1], wherein the tea polyphenols are catechins. [3] The brain function improving agent according to [2], wherein the catechins include one or more selected from the group consisting of epigallocatechin gallate (EGCG), epicatechin gallate (ECG), gallocatechin gallate (GCG), catechin gallate (CG) and epicatechin (EC). [4] The brain function improving agent according to [3], wherein the tea polyphenols contain epigallocatechin gallate and the epigallocatechin gallate content is 40% by mass or more. [5] The brain function improver according to any one of [1] to [4], further comprising 1 mass % or less of caffeine. [6] The brain function improving agent according to any one of [1] to [5], wherein the brain function is sustained attention, reaction speed, or impulsivity as evaluated by the sustained processing test in the Cognitrax test, or working memory or sustained attention as evaluated by the 4-part sustained processing test. [7] The brain function improving agent according to [6], wherein sustained attention, reaction speed or impulsivity, or working memory or sustained attention are brain functions not assessed by the Revised Hasegawa Dementia Scale or the Mini-Mental State Examination. [8] The brain function improving agent according to any one of [1] to [7], wherein an effective amount of catechin is 100 to 400 mg per day. [9] The brain function improving agent according to [8], wherein the effective amount of catechin is a single dose.

[10] The brain function improving agent according to any one of [6] to [9], wherein the improvement in sustained attention, reaction speed, or impulsivity is a reduction in the number of incorrect responses in the sustained processing test of the Cognitrax test compared to when matcha is administered.

[11] The brain function improving agent according to any of [6] to

[10] , wherein the sustained processing test is an examination of the time required to respond when a specific letter is displayed while letters are displayed randomly.

[12] The brain function improving agent according to any one of [6] to

[11] , wherein the improvement in working memory or connectivity attention is a decrease in mean correct response time in the 4-part sustained processing test of the Cognitrax test compared to when matcha is administered.

[13] The brain function improving agent described in

[12] , wherein the 4-part sustained processing test is a test of memory for two pictures prior to randomly displayed pictures.

[14] A composition comprising the brain function improving agent according to any one of [1] to

[13] .

[15] The composition described in

[14] , which is in the form of a beverage, food, supplement or pharmaceutical.

[16] The composition according to

[14] or

[15] , which is in the form of a liquid, powder, tablet or capsule.

[17] The composition according to any one of

[14] to

[16] , for improving working memory or sustained attention as assessed by the 4-part sustained processing test of the Cognitrax test. Effect of the Invention

[0013] Essentially, by consuming only tea polyphenols, it is possible to improve brain function that could not be assessed by the Revised Hasegawa Dementia Scale or Mini-Mental State Examination. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Hereinafter, the embodiments or implementations of the present invention will be described in detail, however, the present invention is not limited to these and various modifications are possible without departing from the gist of the present invention.

[0015] (brain function improver) In one embodiment, there is provided a brain function improving agent comprising tea polyphenols, wherein the brain function is a brain function assessed by a Cognitrax test.

[0016] Dementia symptoms are diverse, including memory impairment, impaired judgment, disorientation, language disorder (aphasia), apraxia, agnosia, and impaired executive function. Mild cognitive impairment (MCI) is a gray zone stage between a healthy state and dementia. In other words, it is a state in which a problem with one of the cognitive functions (memory, decision-making, reasoning, execution, etc.) does not interfere with daily life.

[0017] The Cognitrax test is a cognitive function testing technology developed by CNS Vital Signs, a US company (Gualtieri CT, Johnson LG: Reliability and validity of a computerized neurocognitive test battery, CNS Vital Signs. Arch Clin Neuropsychol 2006;21:623-643.), and has the following characteristics, for example: -Measures a wide range of functional areas, including memory, attention, processing speed, and executive function. The results are quantified and displayed in comparison with age-standard values. -10 types of tests are provided, and you can select the test depending on the purpose of the inspection. By monitoring individual values ​​over time, it is possible to detect changes in memory and cognitive function. - Accurate and reliable measurements with millisecond sensitivity. Very low learning or ceiling effect.

[0018] The ten tests in the Cognitrax test are: 1. Verbal Memory Test (Verbal Memory (VBM)) 2. Visual Memory Test (VIM) 3. Finger Tapping Test (FTT) 4.SDC Test (Symbol Digit Coding (SDC)) 5. Stroop Test (ST) 6. Shifting Attention Test (SAT) 7. Continuous Performance (CPT) 8. Perception of Emotion (POET) 9. Reasoning Test (NVRT) 10. Four Part Continuous Performance (FPCPT)

[0019] The brain function is preferably sustained attention, reaction speed or impulsivity as assessed by the sustained processing test in the Cognitrax test, or working memory or sustained attention as assessed by the 4-part sustained processing test.

[0020] The sustained processing test measures sustained attention over long periods of time. In the test, subjects are asked to respond only to the letter "B" that appears among randomly displayed letters on a screen, and to ignore all other letters. The results are an assessment of sustained attention, choice response speed, and / or impulsivity.

[0021] As used herein, "sustained attention assessed by the sustained processing test in the Cognitrax test" refers to a brain function that is a part of cognitive function, the ability to maintain a consistent reaction behavior during sustained or repetitive activities, and cannot be assessed by the Hasegawa Dementia Scale-Revised or the Mini-Mental State Examination. In other words, "sustained attention assessed by the sustained processing test in the Cognitrax test" is different from attention assessed by the Hasegawa Dementia Scale-Revised or the Mini-Mental State Examination (e.g., the ability assessed by a calculation problem in which 7 is repeatedly subtracted from 100) or other cognitive functions.

[0022] As used herein, "reaction speed assessed by the sustained processing test in the Cognitrax test" refers to a brain function that is a part of cognitive function, such as reaction speed, such as the time from when a question is presented to when a response (pressing a button), and cannot be assessed by the Revised Hasegawa Dementia Scale or the Mini-Mental State Examination, which do not assess reaction speed. In other words, "reaction speed assessed by the sustained processing test in the Cognitrax test" is different from the cognitive function assessed by the Revised Hasegawa Dementia Scale or the Mini-Mental State Examination.

[0023] As used herein, "impulsivity assessed by the sustained processing test in the Cognitrax test" refers to a part of cognitive function, in which when an uncontrollable impulse or impaired control of the impulse occurs, the desire manifests itself as an action, resulting in unplanned, explosive, and impulsive behavior (impulsive behavior), but this behavioral characteristic, i.e., the tendency to exhibit impulsive behavior, is a brain function that cannot be evaluated by the Revised Hasegawa Dementia Scale or the Mini-Mental State Examination, which do not assess such tendencies. In other words, "impulsivity assessed by the sustained processing test in the Cognitrax test" is different from the cognitive function assessed by the Revised Hasegawa Dementia Scale or the Mini-Mental State Examination.

[0024] An example of improvement in sustained attention, reaction speed, or impulsivity is a reduction in the number of incorrect responses in the sustained processing test of the Cognitrax test when administered matcha tea compared to matcha tea. Matcha tea, which is used as a comparison to confirm the effects of brain function improvers, is expected to contain about half the amount of tea polyphenols, especially catechins, which are the active ingredients. For example, if the brain function improver contains 220 mg of epigallocatechin gallate, this is equivalent to 4 g of matcha tea, so the matcha used as a comparison will contain a total of about 2 g, and the epigallocatechin gallate contained in it will be about 110 mg.

[0025] The Four-Part Sustained Processing Test measures working memory and sustained attention. It consists of four parts: Part 1 tests simple reaction speed, Part 2 is a modified sustained processing test, Part 3 tests memory for the previous picture, and Part 4 tests memory for the previous two pictures.

[0026] As used herein, "working memory assessed by the 4-part sustained processing test of the Cognitrax test" refers to a part of cognitive function, a memory function (function) temporarily required for the purpose of performing a task while performing the task, and the mechanism (structure) or system (structure) that supports it, that is, a function of working memory, and refers to a brain function that cannot be evaluated by the Revised Hasegawa Brief Intelligence Scale or the Mini-Mental State Examination. In other words, "working memory assessed by the 4-part sustained processing test of the Cognitrax test" is different from the working memory function and other cognitive functions evaluated by the Revised Hasegawa Brief Intelligence Scale or the Mini-Mental State Examination.

[0027] An example of an improvement in working memory or sustained attention is a reduction in the average response time in the 4-part sustained processing test of the Cognitrax test when administered matcha tea compared to matcha tea. Matcha tea, which is used as a comparison to confirm the effects of brain function improvers, is expected to contain about half the amount of tea polyphenols, especially catechins, which are the active ingredients. For example, if the brain function improver contains 220 mg of epigallocatechin gallate, this is equivalent to 4 g of matcha, so the comparison target matcha will be about 2 g in total, and the epigallocatechin gallate contained in it will be about 110 mg.

[0028] As used herein, "sustained attention as assessed by the 4-part sustained processing test of the Cognitrax test" refers to a brain function that is a part of cognitive function, the ability to maintain a consistent reaction behavior during sustained or repetitive activities, and cannot be assessed by the Hasegawa Dementia Scale-Revised or the Mini-Mental State Examination. In other words, "sustained attention as assessed by the 4-part sustained processing test of the Cognitrax test" is different from cognitive function as assessed by the Hasegawa Dementia Scale-Revised or the Mini-Mental State Examination.

[0029] The tea polyphenols, which are the active ingredients of the brain function improving agent, may be derived from one or more kinds of tea selected from the group consisting of tea leaves, unfermented tea, semi-fermented tea, fermented tea, and post-fermented tea. Any one of these may be used alone, or two or more of these may be used as an extract, or a mixture of the extracts may be used.

[0030] Examples of non-fermented teas include green teas such as sencha, bancha, gyokuro, kamairicha, tencha, and roasted tea; examples of semi-fermented teas include oolong teas such as tieguanyin, ogonkei, suisen, and baozhongcha; examples of fermented teas include black teas such as Darjeeling and uva; and examples of post-fermented teas include pu-erh tea.

[0031] Furthermore, this tea polyphenol can be purified to increase the content of tea polyphenols, especially catechins, by purification means such as solvent extraction, resin adsorption, and filtration such as ultrafiltration and reverse osmosis filtration to obtain tea polyphenols. Commercially available tea polyphenol preparations can also be used. For example, TheaFran 30A (manufactured by Itoen Co., Ltd.) is a tea polyphenol preparation in which green tea is subjected to hot water extraction treatment and the extract is dried to have a catechin concentration of about 30%, and TheaFran 90S (manufactured by Itoen Co., Ltd.) is a tea polyphenol preparation in which an extract obtained by hot water extraction treatment of green tea is separated in an adsorption column using water and low- and high-concentration alcohol, and dried to have a tea polyphenol concentration of about 85 to 99.5%. Other commercially available tea polyphenol preparations include "Polyphenon" manufactured by Mitsui Norin Co., Ltd., "Sunphenon" manufactured by Taiyo Kagaku Co., Ltd., and "Sun Oolong" manufactured by Suntory Co., Ltd. TheaFran 90S is preferable because it contains 90% or more by mass of tea polyphenols.

[0032] It is preferable that the brain function improver does not substantially contain tea-derived components other than tea polyphenols, such as theanine and caffeine. Theafuran 90S may contain 1% by mass or less of caffeine, but the caffeine contained in the brain function improver at about 1% by mass does not affect the effect of the brain function improver.

[0033] The tea polyphenol may be catechins. Catechins are polyphenols that are abundant in plants such as tea plants. It is known that catechins are contained in green tea leaves at about 8 to 20% by mass. The components contained in green tea leaves vary depending on the variety of tea plant, the cultivation method and cultivation environment, the time of plucking of tea leaves (first harvest, second harvest, etc.) and the part (bud, leaf, stem), and the processing conditions of tea leaves (steaming, rolling, drying, etc.). For example, in covered tea such as gyokuro and tencha cultivated in a shaded environment, the proportion of epigallocatechin gallate in the catechins is high. From the viewpoint of efficiency, it is preferable to extract the active ingredient from tea leaves in which the content of the desired catechin compound has increased. Isolation of catechins can be carried out using a known method. Synthetic catechins may be used.

[0034] As used herein, "catechins" refers to any one or more catechins selected from the group consisting of four epicatechins (epicatechin (EC), epicatechin gallate (ECG), epigallocatechin (EGC), epigallocatechin gallate (EGCG)) and four non-epicatechins (catechin (C), gallocatechin (GC), catechin gallate (CG), gallocatechin gallate (GCG)).

[0035] The active ingredient may be a combination of two or more of the catechins. For example, the catechin is preferably one or more selected from the group consisting of epigallocatechin gallate (EGCG), epicatechin gallate (ECG), gallocatechin gallate (GCG), catechin gallate (CG) and epicatechin (EC). Among these catechin compounds, when epigallocatechin gallate (EGCG) is used alone or in combination with other catechin compounds, an active ingredient containing more epigallocatechin gallate (EGCG) than other catechin compounds is preferred. The content of epigallocatechin gallate (EGCG) in tea polyphenols is preferably 30% by mass or more, 40% by mass or more, 50% by mass or more, 60% by mass or more, 70% by mass or more, 80% by mass or more, or 90% by mass or more.

[0036] The brain function improving agent may be in the form of a powder, however, the dosage form of the brain function improving agent is not limited to powder and may be in other forms.

[0037] The brain function improving agent is enclosed in an appropriate container depending on the dosage form. In the case of a powder, it can be enclosed in a bag, a box, or a similar container. For example, the brain function improving agent may be enclosed in a package such as a tea bag, and examples of the shape of such a package include a square type, a triangular pyramid type (so-called Tetra Pak (registered trademark)), a rounded bag, a W-chamber type, etc. In addition, the brain function improving agent may be filled in a type of bag that is dripped like coffee by pouring water or hot water into the bag body.

[0038] The container may be made of any material known to those skilled in the art. Examples of the material include plastics and metals, and more specifically, polyester, nylon, polycarbonate, cellophane, polyethylene, polypropylene, aluminum, paper, cellulose fibers, natural fibers, polylactic acid, etc. For example, the container may be made of a cloth filter made of synthetic fibers or a nonwoven fabric filter.

[0039] The container may comprise a laminate film, preferably such a laminate film comprises an internal aluminium layer.

[0040] The brain function improving agent can be administered to a subject suffering from or suspected of having mild cognitive impairment, more specifically, to a human who needs to improve working memory or sustained attention. The age of the subject is not particularly limited, but is preferably middle-aged or elderly, 50 to 69 years old.

[0041] When the brain function improving agent is substantially composed of tea polyphenols, the dosage of the brain function improving agent is adjusted so that the effective amount of tea polyphenols is, for example, about 250 to 1000 mg per day, preferably about 600 mg to 1000 mg, more preferably about 800 mg. When Theafuran 90S is used as an active ingredient, the effective amount of epigallocatechin gallate (EGCG) is calculated from the effective amount of tea polyphenols described above to be about 100 to 400 mg per day, preferably about 150 to 250 mg, more preferably about 200 mg. The dosage described above may be a single dosage once a day, or may be multiple dosages 2 to 3 times a day. The dosage described above may be appropriately increased or decreased depending on the age, pathology, and symptoms of the subject.

[0042] It is preferable that tea polyphenols as an active ingredient are mixed alone in the brain function improving agent, but they may be combined with other active ingredients known to improve brain function as long as the effect of improving brain function is not impaired. However, theanine and caffeine, which are tea-derived ingredients, inhibit the effect of tea polyphenols in improving brain function when combined with tea polyphenols, so it is preferable to exclude theanine and caffeine as much as possible.

[0043] (composition)

[0044] In one embodiment, a composition comprising a brain function improving agent is provided.

[0045] The dosage form of the brain function improving agent or the composition containing it is not particularly limited, and the administration route can be appropriately determined by a person skilled in the art depending on the dosage form and the degree of brain function improving agent to be improved, for example, oral administration or parenteral administration (intravenous, intraarterial, subcutaneous, intradermal, intramuscular, or intraperitoneal injection, transdermal, nasal, transmucosal, etc.). Oral administration is preferred.

[0046] The composition may contain an excipient other than tea polyphenol as an active ingredient. The excipient may be a solid excipient generally used in pharmaceutical preparations. Examples of the excipient include starches such as corn starch, wheat flour, and rice flour, sugars such as lactose, sucrose, mannitol, sorbitol, and white sugar, dextrin, precipitated silica, gelatin, cellulose, and methylcellulose. One or more of these excipients may be appropriately selected and used.

[0047] The composition may be in the form of a powder.

[0048] A composition containing a brain function improver is prepared by adding and mixing tea polyphenols and, optionally, fats and oils, seasonings, flavors, etc., as necessary, to an excipient. The composition may be prepared and provided as a liquid, powder, capsule, or tablet, in which case it is easy to provide as a supplement, etc. As used herein, "liquid" refers to a liquid preparation based on a liquid medium such as water or oil, including syrup, etc. As used herein, "tablet" refers to the dosage form of not only tablets but also tablets including pills. For tablets, the form may be such that the contents cannot be distinguished by taste, such as sugar-coated tablets. Capsules that are generally used for pharmaceuticals, etc., can be used, and both hard capsules and soft capsules can be used. Hard capsules can be prepared by filling a sample into a capsule coating formed using, for example, gelatin, hydroxypropyl methylcellulose, etc. Soft capsules can be obtained by sandwiching a sample between sheets of gelatin to which a plasticizer such as glycerin has been added, and then pressing and molding.

[0049] The size and content of the capsules and tablets, as well as the number of servings per time, can be set so that the subject can take them without difficulty. In general, the intake conditions can be set so that the daily intake of tea polyphenols is about 250-1000mg, preferably about 600mg-1000mg, more preferably about 800mg. When the brain function improving agent is substantially composed of tea polyphenols, the dosage of tea polyphenols is adjusted to, for example, about 250-1000mg, preferably about 600mg-1000mg, more preferably about 800mg per day.

[0050] The composition is preferably provided in the form of a food or drink, particularly a food for specified health uses or a functional food. The composition is expected to be taken by subjects suffering from or suspected of having mild cognitive impairment, more specifically, by people who need to improve their working memory or sustained attention, and therefore the composition can be used to improve the brain function of such subjects, particularly the working memory or sustained attention evaluated by the 4-part sustained processing test of the Cognitrax test, and preferably brain functions not evaluated by the Revised Hasegawa Dementia Scale or the Mini-Mental State Examination.

[0051] The active ingredient, tea polyphenols, can be added to food and drink by sprinkling or placing it on the surface of the food or drink, or by mixing and dissolving it in the food or drink.

[0052] As used herein, "food and drink" refers to processed foods, beverages, fruits and vegetables, and other items that are consumed. Examples of beverages include, but are not limited to, milk beverages, lactic acid bacteria beverages, soy milk; tea beverages such as green tea, black tea, barley tea, roasted green tea, brown rice tea, and blended tea; soft drinks, nutritional beverages, sports beverages, fruit beverages, vegetable juices, dairy beverages, alcoholic beverages, jelly beverages, and carbonated beverages; and other beverages and drink preparations. In the case of tea beverages, it is preferable to reduce the caffeine or theanine, or both, content relative to the tea polyphenol content, or to eliminate the caffeine or theanine, or both.

[0053] Examples of containers for filling the beverage include, but are not limited to, commonly used containers such as plastic bottles, cans, paper bottles, jars, etc. It is preferable to use a container that can be sealed after being filled.

[0054] Examples of foods include sweets such as cookies, biscuits, chocolate, cakes, puddings, ice cream, sherbet, waffles, wafers, pancakes, donuts, popcorn, castella, caramel, candy, chewing gum, and Japanese sweets; breads such as white bread, sweet bread, and other breads; noodles such as udon, hiyamugi, somen, buckwheat, Chinese noodles, spaghetti, macaroni, rice vermicelli, and harusame; processed meat foods such as hamburger steaks, ham, bacon, and sausages; and instant foods such as curry, ramen, and soup, but are not limited to these.

[0055] Among foods and beverages, it is preferable to incorporate tea polyphenols into tea-related foods and beverages such as tea drinks, granulated tea, tea bags, and packed tea (leaf).

[0056] Alternatively, the composition may be prepared in the form of granules, emulsion, cream, etc., and provided as food such as seasoning, sauce, dressing, etc. Such foods can be easily handled by providing them in small portions appropriately packaged according to the amount to be taken per serving.

[0057] The number of times of ingestion per day, the time of ingestion (morning / afternoon, morning / afternoon / evening, relative to meals), the amount of ingestion per time, and the amount of ingestion per day are appropriately set, so the green tea composition may be prepared in an easy-to-ingest form based on the ingestion conditions set. Tea polyphenols are preferably ingested in the morning. The composition may be orally ingested for about 10 weeks or more, preferably about 12 weeks or more.

[0058] The rate of people whose symptoms progress from mild cognitive impairment to dementia is said to be about 10% on average per year, which means that about 40% will progress to dementia after 5 years, so it is very important to prevent dementia by dealing with mild cognitive impairment early. Therefore, providing the market with green tea-related foods in a form that is effective in maintaining cognitive function or improving mild cognitive impairment is significant in terms of health and medical care.

[0059] (Treatment method) In one embodiment, there is provided a method for improving brain function in a subject, the method comprising administering to the subject a brain function-improving agent comprising tea polyphenols, wherein the brain function is working memory or sustained attention as assessed by the 4-part sustained processing test of the Cognitrax test.

[0060] The subjects to whom the brain function improving agent is administered are those who suffer from or are suspected of having mild cognitive impairment, more specifically, those who need to improve their working memory or sustained attention. The age of the subjects is not particularly limited, but is preferably middle-aged or elderly, aged 50 to 69 years.

[0061] When the brain function improving agent is substantially composed of tea polyphenols, the dosage of the brain function improving agent is adjusted so that the effective amount of tea polyphenols is, for example, about 250 to 1000 mg per day, preferably about 600 mg to 1000 mg, more preferably about 800 mg. When Theafuran 90S is used as an active ingredient, the effective amount of epigallocatechin gallate (EGCG) is calculated from the effective amount of tea polyphenols described above to be about 100 to 400 mg per day, preferably about 150 to 250 mg, more preferably about 200 mg. The dosage described above may be a single dosage once a day, or may be multiple dosages 2 to 3 times a day. The dosage described above may be appropriately increased or decreased depending on the age, pathology, and symptoms of the subject.

[0062] The timing of administration is not limited, but it is preferable to administer it in the morning. The administration period is about 10 weeks or more, preferably about 12 weeks or more. Such long-term administration is particularly preferable when improving working memory or sustained attention evaluated by a four-part sustained processing test.

[0063] As long as the effect of tea polyphenols in improving brain function is not impaired, it may be used in combination with drugs known to improve brain function. EXAMPLES

[0064] The present invention will be described in more detail below using examples and comparative examples, but the present invention is not limited to the following examples.

[0065] Preparation of brain function improver The brain function improver used was THEA-FLAN 90S (Itoen Co., Ltd., Tokyo), which contains tea polyphenols isolated from green tea extract. THEA-FLAN 90S contains more than 90% polyphenols, and the catechin content of THEA-FLAN 90S (482 mg) when taken per day was 336.4 mg and the caffeine content was 2.7 mg. The breakdown of catechins in THEA-FLAN 90S was 216.9 mg EGCG, 96.4 mg (-)-epicatechin gallate (ECG), 3.2 mg (-)-epigallocatechin (EGC), 1.7 mg (-)-epicatechin (EC), 12.5 mg (-)-gallocatechin gallate (GCG), 4.0 mg (-)-catechin gallate (CG), 1.0 mg (-)-gallocatechin (GC), and 0.8 mg (-)-catechin (C). The brown capsule made of pork gelatin No. 1 was filled with THEA-FLAN 90S for use in this study. The placebo was the same capsule filled with brown-colored cornstarch. Both the catechin capsule and the placebo capsule used cornstarch as an excipient. The capsules were manufactured by Sansho Pharmaceutical Co., Ltd. (Shizuoka Prefecture). Hereinafter, capsules filled with THEA-FLAN 90S will be simply referred to as catechin capsules.

[0066] subject Subjects were recruited from healthy Japanese men and women aged 50-69 years who self-reported cognitive decline. The MMSE-J was administered to 60 potentially eligible subjects. Subjects were included if they met the following criteria: 1) You can reliably take 3 capsules per day for 12 consecutive weeks. 2) MMSE-J score is 24 or higher. 3) Being a non-smoker.

[0067] In addition, subjects who met any of the following criteria were excluded. 1) Currently taking any medication or receiving outpatient treatment. 2) History or comorbidity of severe liver, kidney, endocrine, cardiovascular, gastrointestinal, pulmonary, hematological, or metabolic disease. 3) History of drug and / or food allergies. 4) Using health foods and / or supplements that may affect cognitive function. 5) Taking medications that may affect cognitive function. 6) People with extremely unbalanced dietary habits or extremely irregular lifestyle habits related to eating and sleeping. 7) People suspected of having insomnia. 8) People with a history of mental illness or alcoholism. 9) Anyone currently participating in another clinical trial or who has participated within the past 3 months. 10) People with irregular employment schedules, such as night shifts. 11) Those who are judged by the investigator to be unsuitable for this study.

[0068] The subjects were randomly assigned to the placebo or catechin group using a random number table, with age, sex, and MMSE-J score as allocation factors. Subjects performed both serial sevens and backward tasks on the MMSE-J, and allocation was based on the backward task score. The randomization process was carried out by HUMA R&D CORP. (a contract research organization) in Japan.

[0069] Study design The study was conducted with a double-blind, placebo-controlled, parallel-group design. Primary endpoints included MMSE-J and Cognitrax results. Secondary endpoints included serum levels of Aβ(1-40), Aβ(1-42), sAPPα, APP770, and BDNF.

[0070] Subjects were instructed to take three placebo or catechin capsules per day for 12 weeks, taking the capsules after breakfast. If they did not eat breakfast, they were instructed to take them in the morning. Intake records were made on a computer using HUMA R&D CORP.'s Web input system. Subjects were not asked to limit their intake of other polyphenols (green tea, black tea, oolong tea, etc.) or to deviate from their usual diet. During the study period, subjects were prohibited from taking other health foods, supplements, or drugs that may affect cognitive function. In addition, they were instructed to avoid excessive exercise, dietary restrictions, binge eating, and heavy drinking. There were no particular restrictions on other types of health foods and supplements, but subjects were instructed to avoid taking these products as much as possible. If any of these products were taken, the type and amount were recorded on a record sheet. In addition, if they were taking medication, they were asked to record the name and dosage of the medication. Other than these restrictions, they were told to maintain their usual lifestyle. In addition, subjects filled out a diary to record their intake status and the presence or absence of adverse events, respiratory infections, abdominal pain, etc.

[0071] Mini-Mental State Examination In this study, we used the Japanese version of the Mini-Mental State Examination (MMSE-J, Nippon Bunka Kagakusha). The MMSE-J consists of 11 items, including orientation to time, orientation to place, memorization, attention and calculation, recall, naming, repetition, three-step command, reading, writing, and drawing, and the total score of these items is used for evaluation. In this study, two tests of attention and calculation from the above items, namely the backward spelling task and the serial sevens task, were used. The score of the backward spelling task was used to assign subjects to the placebo or catechin group.

[0072] Cognitrax Trials Cognitrax is a cognitive function testing service developed by the US company CNS Vital Signs (Morrisville, North Carolina) to measure both reaction time and number of responses. Test details are shown in Table 1. [Table 1-1] [Table 1-2] [Table 1-3]

[0073] Blood Biomarkers On the day of the study, subjects were placed on a diet restriction from 6 hours before arriving at the hospital until the completion of the study. Serum collection tubes were used to estimate BDNF levels, and disodium ethylenediaminetetraacetate tubes were used to measure Aβ(1-40), Aβ(1-42), sAPPα, and APP770. After collection, blood was centrifuged at 3000 rpm and dispensed into 1.5 ml Eppendorf tubes. Measurements were performed using the kits at the following dilution rates: Aβ(1-42) blood samples were diluted 4-fold with the Human Amyloid-β(FL) Assay Kit-IBL; sAPPα blood samples were diluted 4-fold with the sAPPα(high sensitivity) Assay Kit-IBL; APP770 blood samples were diluted 50-fold with the Human APP770 Assay Kit-IBL; BDNF blood samples were diluted 20-fold with the Human BDNF ELISA Kit (Quantikine-R&D Systems). Measurements below the range of the kit were excluded due to imprecision. Table 9 shows the number of samples analyzed for each biomarker. Measurements were performed by Skylight Biotech Co., Ltd.

[0074] statistical analysis Each value is presented as the mean ± standard deviation (SD). Normality was tested with the Shapiro-Wilk test. If no significant difference was found, a t-test was used, and if a significant difference was found, a Mann-Whitney U test was used. Statistical analyses were performed at baseline, during the single-dose study, and at week 12. Data were analyzed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). To account for the multiplicity of tests, the significance level of differences between conditions was adjusted to p < 0.05 / 3 = 0.017 by Bonferroni correction.

[0075] result Ultimately, 52 patients were enrolled in the study. After allocation to each group, one patient in the placebo group and one patient in the catechin group violated the exclusion criteria. Three patients in the catechin group dropped out during the study period for personal reasons. The final analysis included 25 patients in the placebo group (12 men, 13 women) and 22 patients in the catechin group (12 men, 10 women). The clinical characteristics of the patients in this study are shown in Table 2.

[0076] [Table 2]

[0077] MMSE-J (Interactive Test) The mean MMSE-J (backwards task) scores before the intervention (baseline) were 27.6±1.8 in the placebo group and 27.8±1.3 in the catechin group. The mean scores after the intervention were 28.0±2.0 in the placebo group and 28.0±1.7 in the catechin group. No significant differences were observed between the groups before and after the intervention.

[0078] Cognitrax Test (PC-based cognitive function test) The cognitive tests of Cognitrax were conducted in the following order: Verbal Memory Test (VBM), Visual Memory Test (VIM), Finger-tapping Test (FTT), Symbol Digit-coding Test (SDC), Stroop Test (ST), Shifting Attention Test (SAT), Continuous Performance Test (CPT), Perception of Emotions Test (POET), Non-verbal Reasoning Test (NVRT), and 4-part Continuous Performance Test (FPCPT). After that, VBM and VIM were repeated, and the results of the first VBM and VIM test were used to evaluate immediate memory, and the results of the second VBM and VIM test were used to evaluate delayed memory. There was an interval of about 50 minutes between the first VBM / VIM and the second VBM / VIM. Performance in memory-related tasks was evaluated using the results of VBM and VIM (Table 3). Performance in attention-related tasks was evaluated using the results of ST, SAT, CPT, and FPCPT parts 1 and 2 (Table 4). Performance in facial expression recognition-related tasks was evaluated using the results of POET (Table 5). Performance in working memory-related tasks was evaluated using the results of FPCPT parts 3 and 4 (Table 6). Performance in visual information processing-related tasks was evaluated using the results of SDC and NVRT (Table 7). Performance in motor function-related tasks was evaluated using the results of FTT (Table 8).

[0079] Administration of tea catechins did not significantly affect VBM or VIM results, either after a single dose or after chronic ingestion. [Table 3] VBM, Verbal Memory test; VIM, Visual Memory test. Values ​​are shown as mean ± standard deviation.

[0080] After a single dose, the catechin group made significantly fewer errors in the Continuous Processing Test (CPT) than the placebo group. No significant differences were observed in other attention-related tests. [Table 4-1] [Table 4-2] ST, Stroop Test; SAT, Shifting Attention Test; CPT, Continuous Performance Test; FPCPT, Four-Part Continuous Performance Test. *p < 0.05 / 3 = 0.017 vs. placebo group. P values ​​were calculated using the Mann-Whitney U test with Bonferroni correction. Values ​​are presented as mean ± standard deviation.

[0081] Perception of positive emotions (calmness, happiness) and negative emotions (sadness, anger) were assessed using the Perception of Emotions Test (POET), which assesses positive and negative emotions in total and positive and negative emotions separately. Using the POET, no significant differences were found between the placebo and catechin groups in the facial expression recognition task, either after a single dose or after chronic tea catechin intake. [Table 5] POET, Perception of Emotions test. Values ​​are shown as mean ± standard deviation.

[0082] After repeated administration of tea catechins, the mean time to respond correctly in FPCPT part 4, which tests memory for the previous two pictures, was significantly lower in the catechin group than in the placebo group. In FPCPT part 3, which tests memory for the previous picture, no significant differences were found between the placebo and catechin groups. Daily intake of tea catechins for 12 weeks significantly reduced the mean time to respond correctly in the 4-part sustained processing test compared to placebo. [Table 6] FPCPT, Four-Part Continuous Performance Test. Values ​​are presented as mean ± standard deviation. *p < 0.05 / 3 = 0.017 vs placebo group. P values ​​were calculated using the Mann-Whitney U test with Bonferroni correction.

[0083] No significant differences were observed between the placebo and catechin groups in the SDC and NVRT.Catechin had no effect on visual information processing tasks after single or long-term administration. [Table 7] SDC, Symbol Digit Coding Test; NVRT, Non-Verbal Reasoning Test. Values ​​are shown as mean ± standard deviation.

[0084] Using the FTT, no significant differences were found in the mean number of strokes for the right and left hands between the placebo and catechin groups. Catechin had no effect on motor function tasks after single administration or long-term ingestion. [Table 8] FTT, Finger Tapping Test Values ​​are shown as mean ± standard deviation.

[0085] The first VBM and VIM performed represented immediate memory, and the last represented delayed memory. There was a 50-minute interval between the first and last VBM and VIM performed.

[0086] No significant differences were observed between the placebo and catechin groups in serum concentrations of amyloid-β1-40 or amyloid-β1-42 and the Aβ1-40 / Aβ1-42 ratio.No significant differences were observed between the placebo and catechin groups in the secreted form of amyloid-β precursor protein α (sAPPα) or the level of amyloid-β precursor protein (APP) 770.No significant differences were observed between the placebo and catechin groups in serum concentrations of brain-derived neurotrophic factor (BDNF).

[0087] [Table 9] Values ​​are shown as mean ± standard deviation.

[0088] Comparative Example A similar randomized, double-blind, parallel-group comparative study was also conducted on catechin, caffeine, and matcha containing catechin. Samples were prepared in the same manner as capsules filled with catechin, filling capsules with theanine (50.3 mg), caffeine (72.5 mg), and catechin (171 mg) in amounts equivalent to 2 g of matcha. Of the catechins included, 110 mg was derived from epigallocatechin gallate.

[0089] Similar to the catechin study, healthy Japanese men and women aged 50 to 69 years were recruited as subjects, and 62 subjects who did not meet the exclusion criteria were assigned to either a placebo or matcha group.

[0090] Subjects took nine capsules of either placebo or matcha tea per day after breakfast for 12 weeks. As a result, the sustained processing test of the Cognitrax test did not show a reduction in incorrect responses (single administration), as was seen with catechin, and the four-part sustained processing test did not show a reduction in mean correct response time (12 weeks of administration).

Claims

1. A brain function improving agent containing tea polyphenols as an active ingredient, the tea polyphenols containing 40% by mass or more of epigallocatechin gallate (EGCG), the content of epigallocatechin gallate (EGCG) being greater than the content of other catechins, the other catechins further containing one or more selected from the group consisting of epigallocatechin gallate (EGCG), epicatechin gallate (ECG), gallocatechin gallate (GCG), catechin gallate (CG) and epicatechin (EC), and the catechins contained in the brain function improving agent are A brain function improver, the brain function of which is 1% by mass or less of phene, the brain function improver is substantially free of theanine, and the brain function is sustained attention, reaction speed or impulsivity as evaluated by the sustained processing test in the Cognitrax test, or working memory or sustained attention as evaluated by the 4-part sustained processing test (however, the total amount of epigallocatechin gallate (EGCG) and gallocatechin gallate (GCG) in the tea polyphenols is not 59-72% by mass, and the active ingredient is not epigallocatechin gallate (EGCG) alone).

2. The brain function improving agent described in claim 1, wherein the epigallocatechin gallate (EGCG) content in tea polyphenols is 50% by mass or more, 60% by mass or more, 70% by mass or more, 80% by mass or more, or 90% by mass or more.

3. The brain function improving agent according to claim 1, wherein sustained attention, reaction speed or impulsivity, or working memory or sustained attention is a brain function not assessed by the Revised Hasegawa Dementia Scale or the Mini-Mental State Examination.

4. 3. The brain function improving agent according to claim 1, wherein the effective amount of epigallocatechin gallate is 100 to 400 mg per day.

5. The brain function improving agent according to claim 4, wherein the effective amount of epigallocatechin gallate is a single dose.

6. 2. The brain function improving agent according to claim 1, wherein the improvement in sustained attention, reaction speed or impulsivity is a reduction in the number of incorrect responses in the sustained processing test of the Cognitrax test compared to when matcha is administered.

7. The agent for improving brain function according to claim 1, wherein the sustained processing test is a test of the time required to respond when a specific letter is displayed among letters displayed randomly.

8. 2. The brain function improving agent according to claim 1, wherein the improvement in working memory or connectivity attention is a decrease in the mean correct response time in the four-part sustained processing test of the Cognitrax test compared to when matcha is administered.

9. 2. The brain function improving agent according to claim 1, wherein the four-part sustained processing test is a test of memory for two pictures displayed randomly.

10. A composition for improving sustained attention, reaction speed or impulsivity as assessed by the sustained processing test in the Cognitrax test, or working memory or sustained attention as assessed by the 4-part sustained processing test, comprising the brain function improving agent according to any one of claims 1 to 9.

11. The composition according to claim 10, in the form of a beverage, food, supplement or medicine.

12. 12. The composition according to claim 10 or 11, in the form of a liquid, powder, tablet or capsule.

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