Composition for preventing and / or improving the progression of mild cognitive impairment-like symptoms

Abstract

The problem that this invention aims to solve is to provide a composition for preventing and / or improving the progression of mild cognitive impairment-like symptoms. [Solution] At least one of sulforaphane, glucoraphanin, sulforaphene, and glucoraphenin is included as a contributing ingredient in a composition for preventing and / or improving the progression of mild cognitive impairment-like symptoms. At least one selected from cruciferous plants, their extracts or fractions, and their pulverized products is included in a composition for preventing and / or improving the progression of mild cognitive impairment-like symptoms. Broccoli sprouts and / or broccoli seeds are preferred as the cruciferous plants.

Description

Technical Field

[0001] The present invention relates to a composition for preventing and / or improving the progression of mild cognitive impairment-like symptoms.

Background Art

[0002] In Japan, with the progress of an aging society, it is predicted that one in five people aged 65 or older will develop dementia by 2025, and one in four by 2036. Preventing this is an urgent social issue, and the search for effective methods to maintain and improve cognitive function has been actively conducted.

[0003] As one such method, obtaining an effect by ingesting as food has also been widely studied, and various active ingredients have been proposed. For example, phytochemicals (such as carotenoids, flavonoids, isothiocyanates, etc.) contained in fruits, vegetables, grains, beans, and other plants are known to bring beneficial health effects (Non-Patent Documents 1 and 2). Regarding sulforaphane, which is one of the isothiocyanates, and its precursor glucoraphanin, various physiological actions related to cognitive function have been frequently reported. Specifically, it has been reported that sulforaphane improves spatial learning and spatial memory, and visual cognitive memory ability that have decreased due to specific pathological conditions or specific stimuli, and also that working memory and processing speed are improved in humans who have ingested sulforaphane (Patent Documents 1 to 8, Non-Patent Documents 3 to 10).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

[0005] [Non-licensed Document 1] Tan, BL et al., (2019). Molecules 24:1801. doi: 10.3390 / molecules24091801 [Non-licensed Document 2] Rapposelli, S. et al., (2022). Molecules 27:624. doi: 10.3390 / molecules [Non-licensed Document 3] Nouchi, R., et al. Nutrients 13(2). 2021 [Non-licensed Document 4] Nouchi, R., et al. Frontiers in Aging Neuroscience 14. 2022 [Non-licensed Document 5] Shimizu, S., et al., 2022. Int J Mol Sci 23(15). PMID: 35955572 [Non-licensed Document 6] Gao J., et al., 2018. Neuroscience. 2018 Sep 15;388:357-366. PMID: 30086367 [Non-licensed Document 7] Dwivedi S. et al., 2016. Mol Neurobiol. 2016 Oct;53(8):5310-23. PMID: 26433376 [Non-licensed Document 8] Lee S., et al., 2014. Pharmacol Res. 2014 Jul;85:23-32. PMID: 24836869 [Non-Patent Document 9] Lee S. et al., 2018. Mol Nutr Food Res. 2018 Jun;62(12):e1800240. PMID: 29714053 [Non-Patent Document 10] Wang G. et al., 2016. Cell Physiol Biochem. 2016;39(3):901-7. PMID: 27497670 [Overview of the project] [Problems that the invention aims to solve]

[0006] However, it has not been clarified whether sulforaphane and similar substances are effective in improving symptoms or preventing progression in people who already have mild cognitive impairment-like symptoms. Furthermore, studies to date have only examined the effects of short-term intake of sulforaphane and similar substances in healthy elderly individuals, and the effects of long-term intake have not been clarified. The problem that this invention aims to solve is to provide a novel composition for preventing and / or improving the progression of mild cognitive impairment-like symptoms. [Means for solving the problem]

[0007] Based on the above, the inventors of the present invention, after diligent study, found that at least one of sulforaphane, glucoraphanin, sulforaphene, and glucoraphenin can be a contributing component to a composition for preventing and / or improving the progression of mild cognitive impairment-like symptoms, and thus completed the present invention. In other words, the present invention can be defined as follows: One aspect of the composition for preventing progression and / or improving mild cognitive impairment-like symptoms according to the present invention contains at least one selected from sulforaphane, glucoraphanin, sulforaphene, and glucoraphenin as a contributing component. Here, when the contributing component contains glucoraphanin and / or glucoraphenin, the composition of the present invention preferably further contains a component having myrosinase activity. The component having myrosinase activity is preferably at least one selected from extracts or fractions of the plant body and / or seeds of Brassica rapa, and pulverized products thereof. Another aspect of the composition for preventing progression and / or improving mild cognitive impairment-like symptoms according to the present invention contains at least one selected from cruciferous plants, extracts thereof, fractions thereof, and pulverized products thereof. The cruciferous plant is preferably broccoli sprout and / or broccoli seeds. In the present invention, prevention of progression and / or improvement of mild cognitive impairment-like symptoms is prevention of decline and / or improvement of any one or more of immediate free recall ability, delayed free recall ability, and delayed cued recall ability. The composition for preventing progression and / or improving mild cognitive impairment-like symptoms according to the present invention is preferably ingested by a human presenting mild cognitive impairment-like symptoms. Also, it is preferably ingested continuously for a period of 3 months or more.

Effects of the Invention

[0008] The present invention provides a new composition for preventing progression and / or improving mild cognitive impairment-like symptoms (hereinafter, also referred to as "the composition according to the present invention"). <​​​​​​​​Graph showing the change over time of the MPI score (mild cognitive impairment-like symptoms) in the简易认知机能スケール (MCI-Screen test) according to <统计解析1>. a: Measured value, b: Amount of change. Error bars represent the mean ± standard error. [Figure 2] Graph showing the change over time of the immediate free recall score (raw points) in the简易认知机能スケール (MCI-Screen test) according to <统计解析1>. a: Measured value, b: Amount of change. Error bars represent the mean ± standard error. [Figure 3] Graph showing the change over time of the immediate free recall score (age-adjusted) in the简易认知机能スケール (MCI-Screen test) according to <统计解析1>. a: Measured value, b: Amount of change. Error bars represent the mean ± standard error. [Figure 4] Graph showing the change over time of the delayed free recall score (age-adjusted) in the简易认知机能スケール (MCI-Screen test) according to <统计解析1>. a: Measured value, b: Amount of change. Error bars represent the mean ± standard error. [Figure 5] Graph showing the change over time of the delayed cued recall score (raw points) in the简易认知机能スケール (MCI-Screen test) according to <统计解析(1)>. a: Measured value, b: Amount of change. Error bars represent the mean ± standard error. [Figure 6] Graph showing the change over time of the delayed cued recall score (age-adjusted) in the简易认知机能スケール (MCI-Screen test) according to <统计解析1>. a: Measured value, b: Amount of change. Error bars represent the mean ± standard error. [Figure 7] Graph showing the change over time (measured value) of the MPI score (mild cognitive impairment-like symptoms) in the简易认知机能スケール (MCI-Screen test) according to <统计解析2>. Error bars represent the mean ± standard error. [Figure 8] Graph showing the change over time (measured value) of the immediate free recall score (raw points) in the简易认知机能スケール (MCI-Screen test) according to <统计解析2>. Error bars represent the mean ± standard error. [Figure 9] It should be noted that some of the terms like "简易认知机能スケール" might need to be further clarified or accurately translated based on the specific context in the relevant field, as it seems to be a specific Japanese term that might not have a direct one-to-one English equivalent without more background information. Here, a rough approximation is provided.This graph shows the temporal changes (measured values) in the immediate free recall score (age-adjusted) of the simplified cognitive function scale (MCI-Screen test), based on <Statistical Analysis 2>. Error bars represent the mean ± standard error. [Figure 10] This graph shows the temporal changes (measured values) in the delayed free recall score (age-adjusted) of the simplified cognitive function scale (MCI-Screen test), based on <Statistical Analysis 2>. Error bars represent the mean ± standard error. [Figure 11] This graph shows the time-dependent changes (measured values) in the number of delayed cue recall scores (raw scores) in the simplified cognitive function scale (MCI-Screen test), based on <Statistical Analysis 2>. Error bars represent the mean ± standard error. [Figure 12] This graph shows the temporal changes (measured values) in the delayed cue recall score (age-adjusted) of the simplified cognitive function scale (MCI-Screen test), based on <Statistical Analysis 2>. Error bars represent the mean ± standard error. [Modes for carrying out the invention]

[0010] <Composition according to the present invention> The compositions according to the present invention are compositions for preventing and / or improving the progression of mild cognitive impairment-like symptoms. These compositions contain at least one of sulforaphane, glucoraphanin, sulforaphene, and glucoraphenine as contributing components.

[0011] <Sulforaphane and glucoraphanin> Glucoraphanin is a type of glucosinolate and a precursor to sulforaphane. It is hydrolyzed by the enzyme myrosinase to produce sulforaphane. When mammals such as humans ingest glucoraphanin, it is converted to sulforaphane by enzymes in intestinal bacteria and absorbed from the intestinal tract. Glucoraphanin is known to be abundant in cruciferous plants, and in the present invention, glucoraphanin may be included in the preparation or food composition in a purified state, or in one or more states selected from cruciferous plants, their extracts or fractions thereof, and their pulverized products. The structural formulas of glucoraphanin and sulforaphane are shown below.

[0012] [ka]

[0013] [ka]

[0014] <Sulforaphene and glucoraphenin> Glucorafenine is a type of glucosinolate and a precursor of sulforaphene. It is hydrolyzed by the enzyme myrosinase to produce sulforaphene. When mammals such as humans ingest glucorafenine, it is converted to sulforaphene by enzymes of intestinal bacteria and absorbed from the intestinal tract. Glucorafenine is known to be abundant in cruciferous plants, especially radishes, radish leaves, and seeds. In the present invention, glucorafenine may be contained in the preparation or food composition in a purified state, or in one or more states selected from cruciferous plants, their extracts or fractions thereof, and their pulverized products. The structural formulas of glucorafenine and sulforaphene are shown below.

[0015] [ka]

[0016] [ka]

[0017] Because glucoraphenin is structurally similar to glucoraphanin, it is expected to have similar effects and properties. For example, glucoraphenin has been reported to contribute to the activity of the second-phase enzyme, which is an indicator of the activation of the transcription factor Nrf2 (NF-E2-related-factor 2) (Barillari et al., J Agric Food Chem. 55(14), 5505-11, 2007). Furthermore, Nrf2 is known to be activated in response to stress, such as oxidative stress (Itoh et al., Genes Dev. 1999 Jan 1;13(1), :76-86, 1999), and increases the gene expression of antioxidant enzymes (Ishii et al., J Biol Chem. 2000 May 26;275(21), :16023-9, 2000), increases the gene expression of detoxification metabolic enzymes (Itoh et al., Biochem Biophys Res Commun. 1997 Jul 18;236(2), :313-22, 1997), and reduces the gene expression of cytokines that cause inflammation (Kobayashi et al., Nat Commun. 2016 May 23;7, :11624, 2016, and Itoh et al., Mol Cell Biol. 2004). (Jan;24(1), :36-45, 2004.) has been reported, and these effects are common to those of glucoraphanin. From the above, it can be inferred that glucoraphanin has similar effects on cognitive function as glucoraphanin and sulforaphane.

[0018] Generally, when glucosinolates are ingested in the form of vegetables, chewing in the mouth breaks down the tissue, causing the glucosinolates in the vegetables to react with myrosinase, and the isothiocyanates converted from glucosinolates are absorbed into the body. However, in many processed foods, the myrosinase is inactivated by heating during the manufacturing process. Therefore, when glucosinolates are ingested in such processed foods, conversion to isothiocyanates in the mouth hardly occurs. The same is true when glucosinolates are ingested in the form of supplements that do not require chewing. In such cases, conversion to isothiocyanates is carried out by myrosinase present in intestinal bacteria in the body, but the conversion efficiency by intestinal bacteria is very low. Therefore, if the composition according to the present invention contains glucoraphanin and / or glucoraphenin, it is preferable to further contain myrosinase or a component having myrosinase activity. This increases the efficiency of converting glucoraphanin to sulforaphane and glucoraphenin to sulforaphene, making it easier to obtain the desired effect when the composition of the present invention is ingested.

[0019] The enzyme activity of myrosinase relative to the amount of glucoraphanin (myrosinase activity (UNIT) / glucoraphanin (mg)), or the enzyme activity of myrosinase relative to the amount of glucoraphenin (myrosinase activity (UNIT) / glucoraphenin (mg)), should have a lower limit of 0.0001 (UNIT / mg) or higher, preferably 0.001 (UNIT / mg) or higher, and an upper limit of 0.022 (UNIT / mg) or lower, preferably 0.01 (UNIT / mg) or lower.

[0020] Furthermore, the myrosinase may be chemically synthesized or naturally occurring, and is not particularly limited, but natural is preferred, and plant-derived is even more preferred. Examples of such plants include plants of the Brassicaceae family.

[0021] For information on the form in which a component having myrosinase activity is included in an orally administered composition, please refer to Japanese Patent No. 7057070. The components having myrosinase activity are not particularly limited, but extracts from Brassicaceae plants and / or seeds of Brassicaceae plants are preferred. This is because Brassicaceae plants are rich in myrosinase. Examples of Brassicaceae plants include mustard greens, cabbage, broccoli, kale, watercress, komatsuna, bok choy, radish sprouts, cauliflower, Chinese cabbage, rapeseed, mustard greens, kohlrabi, etc., with mustard greens being particularly preferred. One or more of these plants may be used. In addition, all or part of the plant body (flowers, leaves, stems) or seeds of these plants may be used. Furthermore, the Brassicaceae plant used as a component possessing myrosinase activity may also be included in the composition of the present invention in addition to containing a contributing component that exhibits an effect of preventing and / or improving the progression of mild cognitive impairment-like symptoms.

[0022] The means for obtaining extracts from Brassicaceae plants and their seeds are not particularly limited as long as myrosinase activity is maintained, but since myrosinase is inactivated at high temperatures, it is preferable to use low-temperature extraction methods. An example is water extraction at room temperature or below. The means for powdering can be pulverized after drying. The means for drying are not particularly limited as long as myrosinase activity is maintained, but since myrosinase is inactivated at high temperatures, it is preferable to use low-temperature drying methods. Examples include vacuum freeze-drying and cold-air drying. The means for pulverization can be any commonly used method, such as using a pin mill or jet mill.

[0023] The extract obtained in this manner can be, for example, powdered and included in the composition of the present invention. The powder is not particularly limited, but from the viewpoint of facilitating the exercise of enzyme activity, it is preferable that the volume average diameter is 500 μm or less, more preferably 300 μm or less, and even more preferably 50 to 300 μm. The means of pulverization are not particularly limited, but sieving with a mesh is preferred. The mesh opening is preferably 500 μm or less, more preferably 300 μm or less, and even more preferably 50 to 300 μm.

[0024] Myrosinase of powdered Brassicaceae plants and / or Brassicaceae seed extracts The activity level is preferably 25.0 units / g or higher, and more preferably 40.0 units / g or higher.

[0025] The amount of extracts from Brassicaceae plants and / or seeds of Brassicaceae plants included in the composition of the present invention as components having myrosinase activity is not particularly limited, but may be, for example, 2 to 20% by mass of the total composition.

[0026] <Brassicaceae plants> The Brassicaceae plants contained in other embodiments of the composition of the present invention are not particularly limited, but examples include broccoli, kale, cabbage, cauliflower, mustard greens, rapeseed, mustard greens, radish, radish leaves, Japanese mustard greens, Japanese mustard greens, Chinese cabbage, Brussels sprouts, Petit Vert, snow radish, and plants produced by appropriately crossbreeding these. The plant body can be the growing body of the plant (buds, leaves, stems, roots, or flowers, etc.), sprouts (germinating bodies), or seeds, and is not particularly limited. Of these, broccoli, which belongs to the genus Brassica in the Brassicaceae family, is more preferred. Furthermore, broccoli sprouts or seeds are particularly preferred due to their high content of sulforaphane and glucoraphanin.

[0027] <Broccoli sprout extract> When extracting at least one of sulforaphane and glucoraphanin from broccoli sprouts, the extraction can be performed at any number of days after germination, as long as the sprouts have not yet grown into mature plants where the content per unit weight decreases significantly. However, it is preferable to use sprouts that are 1 to 10 days after germination, more preferably 1 to 3 days after. Furthermore, it is preferable to use broccoli sprouts in which the content of at least one of sulforaphane and glucoraphanin is preferably 50 to 350 mg / 100g (wet weight), more preferably 150 to 330 mg / 100g (wet weight), and even more preferably 250 to 300 mg / 100g (wet weight).

[0028] <Acquisition of contributing components> At least one of sulforaphane, glucoraphanin, sulforaphene, and glucoraphenin can be obtained from cruciferous plants, including broccoli sprouts, by well-known methods. Furthermore, isolated and purified sulforaphane, glucoraphanin, sulforaphene, and glucoraphenin are commercially available and can also be used. Examples of commercially available products include, but are not limited to, sulforaphane (Funakoshi Co., Ltd.) and L-Sulforaphene (Cayman Chemical Company).

[0029] <Extraction of glucoraphanin and glucorafenin> For example, glucoraphanin and glucorafenin can be obtained by extracting a part or the whole of a plant, either as is or after drying and grinding, with a solvent. Examples of solvents include water, lower monohydric alcohols (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, etc.), liquid polyhydric alcohols (glycerin, propylene glycol, 1,3-butylene glycol, etc.), lower esters (ethyl acetate, etc.), hydrocarbons (benzene, hexane, pentane, etc.), ketones (acetone, methyl ethyl ketone, etc.), ethers (diethyl ether, tetrahydrofuran, dipropyl ether, etc.), acetonitrile, etc., and one or more of these can be used.

[0030] Considering that the compositions of the present invention are preferably administered or ingested orally, water, ethanol, or aqueous ethanol are particularly preferred as the extraction solvent. Examples of preferred extraction methods include, for example, extraction with hot water (90-100°C) for 10-50 minutes, or extraction with 0-100% by volume of aqueous ethanol at room temperature or heated for 1-10 days, after which the extract may be further fractionated and purified. In addition, glucoraphanin and glucoraphenin may be extracted by supercritical fluid extraction.

[0031] <How to obtain sulforaphane from glucoraphanin> The method for obtaining sulforaphane from glucoraphanin is not limited to reacting glucoraphanin with myrosinase. For example, one method involves crushing, grinding, pulverizing, shearing, or juicing cruciferous plants containing glucoraphanin without heating to react the glucoraphanin with endogenous myrosinase and metabolize it into sulforaphane, or by adding myrosinase to glucoraphanin to metabolize it into sulforaphane. Sulforaphane can be obtained from raw materials containing sulforaphane metabolized from glucoraphanin by these methods, using the same method as for glucoraphanin (for example, the extraction method mentioned above).

[0032] <Method for obtaining sulforaphene from glucoraphenin> The method for obtaining sulforaphene from glucoraphanin is the same as the method for obtaining sulforaphane from glucoraphanin described above.

[0033] <Measurement of glucoraphanin and glucorafenin concentrations> The concentration of glucoraphanin in the composition of the present invention can be measured by methods well known to those skilled in the art. For example, high-performance liquid chromatography (HPLC) can be used, and a specific method is the method of Fahey et al. (Fahey et al., Proc. Natl. Acad. Sci. USA, 94, This can be done according to (10367-10372, 1997), etc. The concentration of glucoraphenin can be measured in the same way as glucoraphanin.

[0034] <Measurement of sulforaphane and sulforaphene concentrations> The concentrations of sulforaphane and sulforaphene in the composition can be measured by methods well known to those skilled in the art. For example, high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) can be used. Specific methods include those by Han et al. (Han et al., Int. J. Mol. Sci., 12, 1854-1861, 2011.) and Baenas et al. (Baenas et al., food Res. Int., 100(Pt1), 497-503, 2017.).

[0035] <Composition for preventing and / or improving the progression of mild cognitive impairment-like symptoms> Mild cognitive impairment (MCI) is a condition that has not yet progressed to dementia. While memory loss is present, there is no other cognitive impairment besides memory loss, and it does not significantly impact daily life (see: Ministry of Health, Labour and Welfare, "Comprehensive Promotion of Dementia Measures" https: / / www.mhlw.go.jp / content / 12300000 / 000519620.pdf, e-HealthNet https: / / www.e-healthnet.mhlw.go.jp / information / dictionary / alcohol / ya-033.html). The following criteria are used for its diagnosis (Japanese Society of Neurology, "Dementia Disease Treatment Guidelines 2017" https: / / www.neurology-jp.org / guidelinem / nintisyo_2017.html); • There is a decline in cognitive function compared to before. This may be noted by the individual, an informant, or a skilled clinician. • There is impairment in one or more cognitive function areas, including memory, executive function, attention, language, and visuospatial cognition. • Daily living activities are performed independently. However, they may take longer, be less efficient, or result in more mistakes than before. • It is not dementia. In this specification, mild cognitive impairment-like symptoms encompass the symptoms of mild cognitive impairment and symptoms similar thereto. The compositions according to the present invention can be suitably used to prevent and / or improve the progression of mild cognitive impairment-like symptoms. Here, prevention of symptom progression includes preventing the worsening of symptoms, delaying the worsening of symptoms, and reducing the degree of symptom worsening. Furthermore, improvement of symptoms "Good" includes restoring symptoms that have already progressed, and returning to the state before the symptoms progressed. When the composition according to the present invention is taken continuously over a long period of time, it is possible to obtain the effect of preventing the progression of the aforementioned symptoms and / or improving them even after, for example, three months or more, and more preferably 18 months or more, from the start of intake.

[0036] In this specification, prevention and / or improvement of the progression of mild cognitive impairment-like symptoms may specifically mean preventing and / or improving the decline of one or more of the group consisting of immediate free recall ability, delayed free recall ability, and delayed cue recall ability. The ability to immediately recall and reproduce what one has just seen or heard is the ability to do so without any assistance. Delayed free recall refers to the ability to recall and reproduce, without any assistance, things that have been seen or heard after a certain period of time. Delayed cue recall refers to the ability to recall and replay things seen or heard after a certain period of time, provided with some kind of cue.

[0037] <Target recipients / Target recipients> The subjects to whom the composition of the present invention is administered (recipients) and those to whom it is ingested (intakers) are not particularly limited as long as they are animals, but are usually humans. Furthermore, the subjects are preferably humans who do not have dementia, more preferably humans with normal cognitive function and humans exhibiting symptoms similar to mild cognitive impairment, and even more preferably humans exhibiting symptoms similar to mild cognitive impairment. Humans exhibiting symptoms similar to mild cognitive impairment include humans who have been diagnosed with mild cognitive impairment and humans who exhibit the same symptoms even if they have not been diagnosed. Furthermore, the subjects may be adults, children, infants, neonates, etc., but are usually elderly. Furthermore, there are no particular limitations on gender.

[0038] <Form of composition> The composition of the present invention can be administered as a nascent agent or ingested as a food composition. Specifically, it can be a nascent agent or food composition for human or animal use, or a material or preparation used in combination with such nascent agent or food composition. The food composition includes foods, functional foods, foods for specified health uses, foods for the sick, and supplements that are based on the concept of preventing and / or improving the progression of mild cognitive impairment-like symptoms and, if necessary, display this information. Examples of display methods include, but are not limited to, "prevents the progression of mild cognitive impairment-like symptoms," "improves mild cognitive impairment-like symptoms," and "maintains the ability to recall." These displays can be affixed to containers and packaging in known methods, displayed or distributed in advertisements, price lists, or transaction documents related to the product, or information containing these can be provided by electromagnetic means (such as the internet).

[0039] <agent> Preferably, the composition of the present invention can be administered orally as a formulation, for example, by tablet, coated tablet, capsule, granule, powder, solution, syrup, or emulsion. However, parenteral administration is not excluded, and may also be administered by local tissue administration, subcutaneous, intradermal, intramuscular, or intravenous injection, rectal administration, or intranasal administration by volatilizing the active ingredient. These oral / parenteral formulations can be formulated using known excipients that are commonly used in pharmaceutical and other formulation technology fields, such as excipients, binders, disintegrants, lubricants, colorants, flavoring agents, solubilizers, suspending agents, and coating agents. Furthermore, the composition of the present invention may be in the form of a pharmaceutical or quasi-drug.

[0040] <Food Composition> Examples of the food composition in which the composition of the present invention can be consumed include beverages (juice, etc.). Examples include general foods such as coffee, black tea, tea, carbonated drinks, sports drinks, and green juice, as well as confectionery (gum, candy, caramel, chocolate, cookies, snacks, jelly, gummies, tablets, etc.), noodles (soba, udon, ramen, etc.), dairy products (milk, ice cream, yogurt, etc.), seasonings (miso, soy sauce, etc.), and soups, as well as health foods (tablets, capsules, etc.) and nutritional supplements (supplements, energy drinks, etc.). Depending on the type, various ingredients can be blended. For example, food additives such as glucose, fructose, sucrose, maltose, sorbitol, corn starch, dextrin, stevioside, corn syrup, lactose, citric acid, tartaric acid, malic acid, succinic acid, lactic acid, L-ascorbic acid, dl-α-tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, cellulose, gum arabic, carrageenan, casein, gelatin, pectin, agar, B vitamins, nicotinamide, calcium pantothenate, amino acids, calcium salts, colorants, flavorings, and preservatives can be used as desired.

[0041] <Contributing Components> A contributing component is a substance whose effect is on the physiological function of the body. In Foods for Specified Health Uses and Foods with Function Claims, the contributing components are the so-called "active ingredients" and "functional active ingredients." In the case of pharmaceuticals and quasi-drugs, they are the so-called "active ingredients." As mentioned above, glucoraphanin and glucoraphenin are hydrolyzed by the enzyme myrosinase and enzymes from intestinal bacteria to sulforaphane and sulforaphene, respectively. Therefore, when an ingestor ingests sulforaphane, glucoraphanin, sulforaphene, or glucoraphenin, or cruciferous plants containing these, not only sulforaphane and sulforaphene absorbed from the intestinal tract, but also glucoraphanin and glucoraphenin can be said to be contributing components in the composition of the present invention.

[0042] <Content of contributing components> When used as an agent, the composition of the present invention is not particularly limited, but it preferably contains at least one of sulforaphane, glucoraphanin, sulforaphene, and glucoraphenin in a total of 0.03% by mass or more, more preferably 0.5% by mass or more, and particularly preferably 5% by mass or more. Furthermore, when the composition of the present invention is used as a food composition, it is not particularly limited, but it is preferable that it contains at least one of sulforaphane, glucoraphanin, sulforaphene, and glucoraphenin in a total of 0.01% by mass or more, more preferably 0.04% by mass or more, and particularly preferably 0.25% by mass or more.

[0043] <Dosage / Intake> The dosage or intake of the composition of the present invention will vary depending on the sex, symptoms, age, and method of administration when the recipient is a human. However, at least one of sulforaphane, glucoraphanin, sulforaphene, or glucoraphenin should be at least 24 mg per day for an adult (weighing about 60 kg), and at least 30 mg is preferable from the viewpoint of ensuring that the effect is fully exerted. This daily amount can be administered / ingested all at once or divided into several doses, and the timing may be before, after, or between meals. Furthermore, while the administration / intake period is not particularly limited, it is preferable to take it continuously for at least 3 months, more preferably for at least 18 months. Continuously means preferably every day, but it is not necessarily every day, and days when intake is missed are acceptable, and it means taking it for at least 50%, more preferably 70%, even more preferably 80%, and especially preferably 90% of the intake period. The composition of the present invention is for long-term continuous use. It can be ingested, thereby exerting a long-term effect of preventing the progression of mild cognitive impairment-like symptoms and / or improving them. The aforementioned daily dosage / intake amount varies depending on the form of the composition, but it refers to the recommended daily intake indicated, or the amount contained in one bottle of a single-serving beverage that is typically consumed in one go.

[0044] Another aspect of one aspect of the present invention is the use of at least one selected from sulforaphane, glucoraphanin, sulforaphene, and glucoraphenine in the manufacture of a composition for preventing and / or improving the progression of mild cognitive impairment-like symptoms. Another aspect of one aspect of the present invention is the use of at least one selected from sulforaphane, glucoraphanin, sulforaphene, and glucoraphenine in preventing and / or improving the progression of mild cognitive impairment-like symptoms. Another aspect of one aspect of the present invention is at least one selected from sulforaphane, glucoraphanin, sulforaphene, and glucoraphenine, used for preventing and / or improving the progression of mild cognitive impairment-like symptoms. Another aspect of one embodiment of the present invention is a method for preventing and / or improving the progression of mild cognitive impairment-like symptoms, comprising administering at least one selected from sulforaphane, glucoraphanin, sulforaphene, and glucoraphenin to a target.

[0045] Another aspect of another embodiment of the present invention is the use of at least one selected from Brassicaceae plants, their extracts or fractions, and their pulverized products in the preparation of a composition for preventing and / or improving the progression of mild cognitive impairment-like symptoms. Another aspect of another embodiment of the present invention is the use of at least one selected from Brassicaceae plants, their extracts or fractions, and their pulverized products in preventing and / or improving the progression of mild cognitive impairment-like symptoms. Another aspect of another embodiment of the present invention is at least one selected from Brassicaceae plants, extracts or fractions thereof, and pulverized materials thereof, used for preventing and / or improving the progression of mild cognitive impairment-like symptoms. Another aspect of another aspect of the present invention is a method for preventing and / or improving the progression of mild cognitive impairment-like symptoms, comprising administering to a subject at least one selected from Brassicaceae plants, extracts or fractions thereof, and pulverized materials thereof.

[0046] Furthermore, "administering to the target of..." may be synonymous with "having the target of... ingest." Ingestion may be voluntary (ad libitum intake) or compulsory (forced intake). [Examples]

[0047] The following randomized, placebo-controlled, double-blind, parallel-group comparative trial was conducted to examine the effect of the test food on mild cognitive impairment-like symptoms. <Target audience> This study targeted individuals aged 60 and over who met the following screening criteria in the memory tests conducted during the Iwaki Health Promotion Project health checkups from 2014 to 2017 and were suspected of having memory impairment (including those who were found to have mild cognitive impairment in subsequent detailed examinations). However, individuals who met the following exclusion criteria were excluded. Screening criteria: All of the following 1-3 must be met. 1. The individual or their family acknowledges cognitive impairment in the questionnaire. 2. MMSE Question 5: Delayed playback score of 2 or less 3. The WMS-R Logical Memory Test II must meet the following criteria. For those with 16 years or more of education, the score should be 8 points or less; for those with 10-15 years, the score should be 4 points or less; and for those with 9 years or less, the score should be 2 points or less. Exclusion criteria: Must meet any of the following criteria 1-5. 1. Patients with serious illnesses, including cancer, diabetes, and hypertension, who are deemed unable to continue this study until its completion. 2. Patients taking cholinesterase inhibitors (limited to use as a treatment for dementia) 3. Patients with allergies to the ingredients contained in the test food. 4. Patients who have psychosis or co-occurring psychiatric symptoms and are deemed unable to participate in the study. 5. Individuals diagnosed with dementia at the start of the trial.

[0048] <Grouping and Intervention> Participants were randomly assigned to two groups, a test group (GLR group) and a placebo group (control group), using a gender-adjusted stratified randomization method (12 or 13 participants in each group). Participants were kept unaware of which group they belonged to. As an intervention, participants consumed either the assigned test food (a supplement containing a mixture of broccoli sprout extract and mustard greens extract powder) or the placebo food, three tablets per day for 42 months, starting from the beginning of the study. The GLR group received 24 mg / day of glucoraphanin and 120 mg / day of mustard greens extract. The placebo food replaced the broccoli sprout extract in the test food with corn starch and crystalline cellulose.

[0049] <Assessment of mild cognitive impairment-like symptoms> Before the intervention, and at 3, 6, 18, 30, and 42 months after the intervention, participants will use the "Mind Health Check (registered trademark, English name: MCI-Screen)" simple cognitive function scale provided by Millennia Corporation, https: / / www.millennia-corporation.jp / ninchi / about.html The following was conducted: In the "Brain Health Check (registered trademark)," the Memory Performance Index (MPI) score, a scale for detecting mild cognitive impairment, was evaluated (Table 1). The MPI score has been shown to be a scale capable of screening mild cognitive impairment with high accuracy; a decrease in the MPI score indicates a decrease in mild cognitive impairment symptoms, while an increase indicates improvement.

[0050] [Table 1]

[0051] Statistical analysis of the evaluation values ​​was performed in two ways, with different subjects being analyzed.

[0052] <Statistical analysis 1> Statistical analysis was performed on the evaluation values ​​of participants who completed the entire trial period (10 in the GLR group and 9 in the control group). These participants included individuals with normal cognitive function and those diagnosed with mild cognitive impairment before the start of the intervention. To assess the overall effect of the intervention, the change from baseline (the difference between the measured value at each measurement point and the mean value at month 0 of the intervention for each group) was used as the dependent variable. A linear mixed model was used to compare each participant using random effects, group (control group or GLR group), time point (measurement points: 0, 3, 6, 18, 30, 42 months after intervention), group-time point interaction, baseline measured value, and baseline-time point interaction as fixed effects. Standardized values ​​were used for the change from baseline and time point data. For comparisons between two groups at each measurement point (0, 3, 6, 18, 30, 42 months after intervention), the Mann-Whitney U test was used with the measured values. All statistical analyses were performed using R (ver. 4.3.2).

[0053] <Results and Discussion 1> (1) Mild cognitive impairment-like symptoms The results regarding mild cognitive impairment-like symptoms are shown in Figure 1 and Table 2. A comparison of measured values ​​between the control group and the GLR group before the intervention (measurement point 0 months) showed no significant difference between the two groups. A linear mixed model comparison of the change from baseline between the control group and the GLR group showed that the GLR group significantly outperformed the control group. Furthermore, a comparison of measured values ​​at each measurement point showed that the GLR group was significantly higher than the control group at 30 months and 42 months. This indicates that glucoraphanin intake suppressed the decline in mild cognitive impairment-like symptoms. In addition, regarding the change from baseline (mean / SD), the control group also showed an increase of +8.4 / 9.8 at 3 months after intervention and +9.5 / 9.8 at 6 months after intervention, but the GLR group showed an even greater increase, at +10.4 / 7.2 at 3 months after intervention and +11.8 / 11.4 at 6 months after intervention. This indicates an improvement in cognitive function, i.e., an improvement in mild cognitive impairment-like symptoms.

[0054] [Table 2]

[0055] The results for the number of immediately recalled free-play points (raw scores) are shown in Figure 2 and Table 3. A comparison of measured values ​​between the control group and the GLR group before the intervention (measurement point 0 months) showed no significant difference between the two groups. A linear mixed model comparison of the change from baseline between the control group and the GLR group showed that the GLR group significantly outperformed the control group. Furthermore, a comparison of measured values ​​at each measurement point showed that the GLR group tended to have significantly higher values ​​than the control group at 3 months and 18 months, and significantly higher values ​​at 30 months and 42 months. In other words, this indicates that glucoraphanin intake maintained immediate free regeneration capacity and suppressed its decline.

[0056] [Table 3]

[0057] The results for the immediate free recall score (age-adjusted) are shown in Figure 3 and Table 4. A comparison of measured values ​​between the control group and the GLR group before the intervention (measurement point 0 months) showed no significant difference between the two groups. A linear mixed model comparison of the change from baseline between the control group and the GLR group showed that the GLR group significantly outperformed the control group. Furthermore, a comparison of measured values ​​at each measurement point showed that the GLR group tended to have significantly higher values ​​than the control group at 18 months, and significantly higher values ​​at 30 months and 42 months. In other words, this indicates that glucoraphanin intake maintained immediate free regeneration capacity and suppressed its decline.

[0058] [Table 4]

[0059] The results for delayed free recall (age-adjusted) are shown in Figure 4 and Table 5. A comparison of measured values ​​between the control group and the GLR group before the intervention (measurement point 0 months) showed no significant difference between the two groups. A linear mixed model comparison of the change from baseline between the control group and the GLR group showed that the GLR group significantly outperformed the control group. This indicates that glucoraphanin intake maintained delayed free regeneration capacity and suppressed its decline.

[0060] [Table 5]

[0061] The results regarding the number of delayed cue playback points are shown in Figure 5 and Table 6. A comparison of measured values ​​between the control group and the GLR group before the intervention (measurement point 0 months) showed no significant difference between the two groups. A linear mixed model comparison of the change from baseline between the control group and the GLR group showed that the GLR group significantly outperformed the control group. This indicates that glucoraphanin intake maintained delayed cue regeneration capacity and suppressed its decline.

[0062] [Table 6]

[0063] The results for delayed cue retrieval scores are shown in Figure 6 and Table 7. A comparison of measured values ​​between the control group and the GLR group before the intervention (measurement point 0 months) showed no significant difference between the two groups. A linear mixed model comparison of the change from baseline between the control group and the GLR group showed that the GLR group significantly outperformed the control group. This indicates that glucoraphanin intake maintained delayed cue regeneration capacity and suppressed its decline.

[0064] [Table 7]

[0065] <Statistical analysis 2> Statistical analysis was performed on the evaluation scores of participants who completed the entire trial period and were diagnosed with mild cognitive impairment before the start of the intervention (6 in the GLR group and 6 in the control group). To assess the overall effect of the intervention, a linear mixed model was used, with the absolute value of the outcome (the measured value at each measurement point in each group) as the dependent variable. Each participant was compared using a random effect, group (control group or GLR group), time point (measurement points: 0, 3, 6, 18, 30, 42 months after intervention), and group-time point interaction as fixed effects. Standardized values ​​were used for the time point data. For comparisons between two groups at each measurement point (0, 3, 6, 18, 30, 42 months after intervention), the Mann-Whitney U test was used with the measured values. All statistical analyses were performed using R (ver. 4.3.2).

[0066] <Results and Discussion 2> (1) Mild cognitive impairment-like symptoms The results regarding mild cognitive impairment-like symptoms are shown in Figure 7 and Table 8. A comparison of measured values ​​between the control group and the GLR group before the intervention (measurement point 0 months) showed no significant difference between the two groups. A linear mixed model comparison of the measured values ​​of the control group and the GLR group showed that the GLR group outperformed the control group. Furthermore, a comparison of the measured values ​​of the two groups at each measurement point showed that the GLR group tended to have higher values ​​than the control group at 30 months, and significantly higher values ​​at 42 months. In other words, this indicates that glucoraphanin intake suppressed the decline of mild cognitive impairment-like symptoms. This suggests that cognitive function improved, i.e., mild cognitive impairment-like symptoms improved, in individuals diagnosed with mild cognitive impairment.

[0067] [Table 8]

[0068] The results for the immediate free playback score (raw score) are shown in Figure 8 and Table 9. A comparison of measured values ​​between the control group and the GLR group before the intervention (measurement point 0 months) showed no significant difference between the two groups. A linear mixed model comparison of the measured values ​​of the control group and the GLR group showed that the GLR group outperformed the control group. Furthermore, in the comparison of measured values ​​between the two groups at each measurement point, the GLR group was significantly higher than the control group at 3 months, 30 months, and 42 months. In other words, this indicates that in individuals diagnosed with mild cognitive impairment, glucoraphanin intake maintained immediate free regeneration ability and suppressed its decline.

[0069] [Table 9]

[0070] The results for the immediate free recall score (age-adjusted) are shown in Figure 9 and Table 10. A comparison of measured values ​​between the control group and the GLR group before the intervention (measurement point 0 months) showed no significant difference between the two groups. A linear mixed model comparison of the measured values ​​of the control group and the GLR group showed that the GLR group significantly outperformed the control group. Furthermore, in the comparison of measured values ​​between the two groups at each measurement point, the GLR group was significantly higher than the control group at 30 months and 42 months. In other words, this indicates that in individuals diagnosed with mild cognitive impairment, glucoraphanin intake maintained immediate free regeneration ability and suppressed its decline.

[0071] [Table 10]

[0072] The results for delayed free recall (age-adjusted) are shown in Figure 10 and Table 11. A comparison of measured values ​​between the control group and the GLR group before the intervention (measurement point 0 months) showed no significant difference between the two groups. A linear mixed model comparison of the measured values ​​of the control group and the GLR group showed that the GLR group significantly outperformed the control group. Furthermore, in the comparison of measured values ​​between the two groups at each measurement point, the GLR group tended to have higher values ​​than the control group at 30 months and 42 months. In other words, it was shown that in individuals diagnosed with mild cognitive impairment, glucoraphanin intake maintained delayed free recall ability and suppressed its decline.

[0073] [Table 11]

[0074] The results regarding the number of delayed cue playback points are shown in Figure 11 and Table 12. A comparison of the measured values ​​of the control group and the GLR group before the intervention (measurement point 0 months) showed no significant difference between the two groups. A comparison of the measured values ​​of the control group and the GLR group using a linear mixed model showed that the GLR group significantly outperformed the control group. Furthermore, in the comparison of the measured values ​​of the two groups at each measurement point, the GLR group showed a higher slope compared to the control group at 30 months and 42 months. A positive trend was observed. Specifically, in individuals diagnosed with mild cognitive impairment, glucoraphanin intake was shown to maintain delayed cue recall ability and suppress its decline.

[0075] [Table 12]

[0076] The results for delayed cue retrieval scores are shown in Figure 12 and Table 13. A comparison of measured values ​​between the control group and the GLR group before the intervention (measurement point 0 months) showed no significant difference between the two groups. A linear mixed model comparison of the measured values ​​of the control group and the GLR group showed that the GLR group significantly outperformed the control group. Furthermore, in the comparison of measured values ​​between the two groups at each measurement point, the GLR group tended to have higher values ​​than the control group at 30 months and 42 months. In other words, this indicates that in individuals diagnosed with mild cognitive impairment, glucoraphanin intake maintained delayed cue recall ability and suppressed its decline.

[0077] [Table 13] [Industrial applicability]

[0078] The fields in which this invention is useful are the health food business and the pharmaceutical and quasi-drug businesses.

Claims

1. A composition for preventing and / or improving the progression of mild cognitive impairment-like symptoms, A composition containing at least one selected from sulforaphane, glucoraphanin, sulforaphene, and glucoraphenine as a contributing component.

2. The composition according to claim 1, wherein the contributing component further contains a component having myrosinase activity, in the case where the contributing component includes glucoraphanin and / or glucoraphenin.

3. The composition according to claim 2, wherein the component having myrosinase activity is at least one selected from extracts or fractions thereof of mustard plants and / or seeds, and pulverized thereof.

4. A composition for preventing and / or improving the progression of mild cognitive impairment-like symptoms, A composition containing at least one selected from Brassicaceae plants, their extracts or fractions thereof, and their pulverized products.

5. The composition according to claim 4, wherein the Brassicaceae plant is broccoli sprouts and / or broccoli seeds.

6. The composition according to claim 1 or 4, wherein the prevention and / or improvement of the progression of mild cognitive impairment-like symptoms is the prevention and / or improvement of a decline in one or more of the group consisting of immediate free recall ability, delayed free recall ability, and delayed cue recall ability.

7. The composition according to claim 1 or 4, to be ingested by a person exhibiting symptoms similar to mild cognitive impairment.

8. The composition according to claim 1 or 4, which is ingested continuously for a period of three months or more.

Images