Compositions and their use

Abstract

The present invention relates to compositions and their use. More specifically, the present invention relates to compositions for promoting, supporting or optimizing a subject's re-myelination, and / or brain structure, and / or brain connectivity, and / or one or more of cognitive potential, learning potential, and intellectual potential, and / or cognitive function.

Description

[0001] This application is a divisional application, and the parent application is an application with a filing date of December 13, 2016, an application number of 201680072954.0, and an invention name of “Compositions and their uses”. Technical Field

[0002] The present invention relates to a composition for promoting, supporting or optimizing remyelination, and / or brain structure, and / or brain connectivity, and / or one or more of cognitive potential, learning potential, and intellectual potential, and / or cognitive function of an individual. Background Art

[0003] Breastfeeding is recommended for all infants. However, in some cases, breastfeeding is not enough or possible for medical reasons. In these cases, infant formula may be used as a substitute for breast milk. However, research shows that infant formula does not always have the same effects on the body as breast milk.

[0004] In recent studies, it has been shown that the brain structure of the entire brain of infants who are exclusively breastfed, in particular the amount and / or spatiotemporal distribution of myelinated material, may differ from that of infants fed infant formula, and that these differences may be associated with enhanced intelligence, learning, and / or cognitive function in breastfed infants, particularly in later life, even when accounting for confounding factors ("Breastfeeding and early white matter development: a cross-sectional study", Deoni et al, NeuroImage 82, (2013), 77-86). The study also clearly demonstrated that there is an association, particularly a temporal association, between remyelination, particularly the trajectory of remyelination, and brain structure.

[0005] Previous longitudinal structural studies of the brain of breastfed and formula-fed infants are not available, and identified differences in cognitive function and ability are often attributed solely to factors such as socioeconomic status and maternal education. Since infant brain MRI has become a practice of Deoni et al., possible differences in brain structure between breastfed and formula-fed infants have neither been considered nor measured in the way that is currently possible.

[0006] The correlation of brain structure, in particular the amount and / or spatial distribution of myelinated material throughout the brain, is well documented for cognitive function and intelligence. Essentially, myelin in the brain provides insulating sheets along neurons, thereby allowing nerve impulses to be conducted faster. However, brain structure, in particular the amount and / or spatial distribution of myelin throughout the brain, affects brain connections, for example, by what pathways and how to quickly and effectively transmit messages in the form of nerve impulses within the brain, particularly between different brain regions. This intercerebral communication can play a role in cognitive function and learning, and may affect and may even be used for physiological limitations, intelligence, cognition and / or learning potential and regulate cognitive function.

[0007] Therefore, there is a need to find ways to promote, support or optimize remyelination, particularly the trajectory of remyelination, and / or brain structure, particularly the amount and / or spatial distribution of myelinated material throughout the brain, and / or brain connectivity in individuals, particularly formula-fed individuals.

[0008] Additionally, there is a need to find ways to optimize the intellectual potential and / or cognitive potential and / or learning potential and / or cognitive function of individuals, particularly formula-fed individuals.

[0009] Surprisingly, the inventors have now discovered a composition comprising vitamins that can promote, support or optimize remyelination, in particular the trajectory of remyelination, and / or the amount and / or spatial distribution of myelinated material in brain structures, in particular throughout the brain, in an individual, in particular a formula-fed individual.

[0010] More particularly, the inventors have discovered a composition comprising vitamins that can promote, support or optimize remyelination, in particular the trajectory of remyelination, and / or brain structure, in particular the amount and / or spatial distribution of myelinated material throughout the brain, in individuals fed infant formula, and can make one or more of the above more consistent or closer to those observed in breastfed, more particularly exclusively breastfed individuals.

[0011] The findings result from a nutritional analysis of the results of a longitudinal cognitive and brain imaging study in which remyelination, particularly the trajectory of remyelination, and / or brain structure, particularly the amount and / or spatial distribution of myelinated material throughout the brain, particularly as determined by remyelination and the trajectory of remyelination, of breastfed and infant formula fed individuals was examined and compared. Additional details and results of the study are given in the Examples included herein. Summary of the invention

[0012] The invention is set forth in the claims and described in detail in the detailed description included herein.

[0013] The present invention encompasses a synthetic nutritional composition comprising vitamins useful for promoting, supporting or optimizing one or more of the following:

[0014] ● Remyelination, particularly the trajectory of remyelination, in individuals, particularly those who are formula-fed,

[0015] - The amount and spatial distribution of myelinated material in brain structures, particularly the entire brain, and / or specific brain regions.

[0016] Brain connections,

[0017] Intellectual potential,

[0018] ●Cognitive potential,

[0019] ●Learning potential,

[0020] ●Cognitive function.

[0021] More particularly the individual may be a human infant or child, and even more particularly a formula-fed human infant or child.

[0022] The synthetic nutritional composition may be a composition selected from infant formulas, growing-up milks, compositions for infants intended to be added to or diluted with human breast milk, and foodstuffs intended for consumption by infants and / or children alone or in combination with human breast milk.

[0023] The composition can optimize remyelination, particularly remyelination trajectories, and / or brain structures, and / or brain connections in an individual, particularly a formula-fed individual, and bring them closer by any amount to those observed or measured for breastfed individuals, particularly exclusively breastfed individuals, either in the brain as a whole or in one or more brain regions when compared to a composition in which all other components are identical except for the content of one or more vitamins.

[0024] The vitamin may be any vitamin. Particularly effective vitamins may be folic acid and / or vitamin B12.

[0025] The composition may further comprise one or more of the following ingredients:

[0026] a phospholipid, in particular a phospholipid of formula (I) as defined herein or a mixture of compounds of formula (I), more particularly phosphatidylcholine, phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine, sphingomyelin, or mixtures thereof,

[0027] ● minerals, in particular iron and / or zinc and / or copper and / or calcium and / or phosphorus and / or magnesium,

[0028] Choline,

[0029] ●Fatty acid derivatives, wherein the fatty acid derivatives are compounds containing fatty acids other than phospholipids, wherein the fatty acid derivatives can be selected from free fatty acids, monoacylglycerols, diacylglycerols, triacylglycerols, cholesterol esters and combinations thereof, and wherein the fatty acids can contain docosahexaenoic acid and / or arachidonic acid and / or stearic acid and / or nervonic acid.

[0030] If the composition additionally comprises one or more of these ingredients, it may be more effective.

[0031] Particularly beneficial concentrations of the above ingredients are set forth in the claims and in the detailed description included herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 - Shown is a graph of the mean whole brain (whole white matter) myelination trajectory of breastfed infants and toddlers compared to the mean whole brain (whole white matter) myelination trajectory of infants and toddlers fed two commercial formulas containing different levels of folic acid.

[0033] Figure 1a - Shown is a graph of the mean regional myelination trajectory of breastfed infants and toddlers compared to the mean regional myelination trajectory of infants and toddlers fed two commercial formulas containing different levels of folic acid.

[0034] Figure 1b - is a brain image showing myelinated brain areas associated with folate.

[0035] Figure 2 - is a brain image showing myelinated brain areas associated with vitamin B12.

[0036] Figure 2a - is a brain image showing myelinated brain areas associated with iron.

[0037] Figure 2b - is a brain image showing myelinated brain areas associated with zinc.

[0038] Figure 2c - is a brain image showing myelinated brain areas associated with calcium.

[0039] Figure 2d - is a brain image showing myelinated brain areas associated with phosphorus.

[0040] Figure 2e - is a brain image showing myelinated brain areas associated with magnesium.

[0041] Figure 2f - is a brain image showing myelinated brain areas associated with sphingomyelin.

[0042] Figure 2g - is a brain image showing myelinated brain areas associated with phosphatidylinositol.

[0043] Figure 2h - is a brain image showing myelinated brain areas associated with phosphatidylcholine.

[0044] Figure 2i - is a brain image showing myelinated brain areas associated with choline.

[0045] Figure 2j - is a brain image showing myelinated brain areas associated with docosahexaenoic acid.

[0046] Figure 2k - is a brain image showing myelinated brain areas associated with arachidonic acid.

[0047] Figure 3 : Shown are the effects of neuraminic acid on neuronal cell density and astrocyte density.

[0048] Figure 4 : Shown are the effects of stearic acid on neuronal cell density and astrocyte density.

[0049] Figure 5 : Shown are the effects of octanoic acid on neuronal cell density and astrocyte density.

[0050] Figure 6 : Shown are the effects of sphingomyelin on the number of neurospheres and neuronal proliferation.

[0051] Figure 7 : Relative abundance of major SM species in ingredients, infant formula, bovine milk and human milk are shown. (Error bars represent standard deviation when n=3).

[0052] Figure 8 : Relative fatty acid abundance of SM fractions from ingredients, infant formula, bovine milk and human milk is shown. (Error bars represent standard deviation when n=3).

[0053] Fig. 9 : Myelination trajectories in different brain regions in children aged 5 years or older fed Formula 3 (green) or Formula 6 (blue).

[0054] Fig.10 : Myelination trajectories in different brain regions in children aged 5 years or older who were fed Formula 6 (blue) or breastfed (breastfed for at least 90 days) (purple).

[0055] Fig.11: Myelination trajectories in different brain regions in children aged 5 years or older who were fed Formula 3 (green) or breastfed (breastfed for at least 90 days) (purple).

[0056] Fig.12 : The effect of DHA on MBP, NF and / or MBP / NF at day 18 and / or day 30 is shown.

[0057] Fig.13 : The effect of stearic acid on A2B5, MBP, MAG, NF, MBP / NF and / or MAG / NF at day 14, day 18 and / or day 30 is shown.

[0058] Fig.14 : The effect of vitamin B12 on A2B5, NF, MBP / NF and / or MAG at day 12, day 18 and / or day 30 is shown.

[0059] Fig.15 : The effects of folic acid on A2B5, NF, MAG, MAG / NF and / or MBP / NF at day 12, day 18 and / or day 30 are shown.

[0060] Fig.16 : The effects of choline on A2B5, MAG and / or MBP at day 12, day 18 or day 30 are shown.

[0061] Fig.17 : The effect of iron on A2B5, MBP, MAG, NF and / or MAG / NF at day 12, day 18 and / or day 30 is shown.

[0062] Fig.18 : The effect of zinc on MBP, NF and / or MBP / NF at day 12, day 18 and / or day 30 is shown.

[0063] Fig.19 : The effect of phosphorus on MAG, NF and / or MAG / NF at day 12, day 18 and / or day 30 is shown.

[0064] Fig. 20 : The effect of magnesium on A2B5, MBP, NF, MAG, MBP / NF and / or MAG / NF at day 22, day 18 and / or day 30 is shown.

[0065] Fig.21 : The effect of copper on A2BF, MAG and / or MAG / NF at day 12 and / or day 18 is shown.

[0066] Fig. 22 : Shown are the effects of phosphatidylcholine on A2B5 at day 12 and on MAG at day 18.

[0067] Fig.23 : The effects of phosphatidylinositol on A2B5, MBP, MAG, NF, MAG / NF at day 12, day 18 and / or day 30 are shown.

[0068] Fig.24 : The effect of phosphatidylserine on A2B5, NF and / or MAG / NF at day 12 and / or day 18 is shown.

[0069] Fig.25 : The effect of sphingomyelin on A2B5, MAG and / or MBP at day 12, day 18 and / or day 30 is shown.

[0070] Fig.26 : Shown are the effects of ceramide on A2B5 at day 12 and on MAG at day 18.

[0071] Fig. 27 : The effects of galactosylceramide on A2B5, MBP, NF and / or MBP / NF at day 12 and / or day 30 are shown.

[0072] Fig.28 : Shown are the effects of glycosylated ceramide on A2B5 at day 12 and on NF at days 12 and 18.

[0073] Fig.29 : Shown are the effects of D-erythroceramide on A2B5 at day 12 and on MAG at day 18.

[0074] Fig.30 : Shown are the effects of ceramide-1-phosphate on A2B5 at day 12 and on NF and MAG at day 18.

[0075] Fig.31 : The effects of monosialoganglioside-3 (GM3) on A2B5, MBP, MAG and / or MBP / NF at day 12, day 18 and / or day 30 are shown.

[0076] Fig.32 : The effects of disialoganglioside 3 (GD3) on A2B5, MBP, NF and / or MAG at day 12, day 18 and / or day 30 are shown.

[0077] Fig.33 : The fatty acid profiles of phosphatidylinositol (PI), phosphatidylcholine, phosphatidyl (PC), phosphatidylserine (PS) and sphingomyelin used in Example 7 are shown.

[0078] Fig.34: Shown are the effects of vitamin B12 on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0079] Fig.35 : Shown are the effects of ARA on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0080] Fig.36 : Shown are the effects of stearic acid on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0081] Fig.37 : Shown are the effects of zinc on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0082] Fig.38 : Shows the effect of phosphatidylinositol on MAG and MBP mRNA expression.

[0083] Fig.39 : Shown are the effects of GD3 on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0084] Fig.40 : Shown are the effects of DHA on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0085] Fig.41 : Shown are the effects of neuraminic acid on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0086] Fig.42 : Shown are the effects of iron on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0087] Fig.43 : Shown are the effects of phosphatidylcholine on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0088] Fig.44 : Shown are the effects of phosphatidylserine on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0089] Fig.45 : Shown are the effects of folic acid on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0090] Fig.46: Shown are the effects of choline on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0091] Fig.47 : Shown are the effects of ceramide on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0092] Fig.48 : Shown are the effects of galactosylceramide on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0093] Fig.49 : Shows the effect of glycosylated ceramide on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0094] Fig.50 : Shown are the effects of ceramide-1-phosphate on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0095] Fig.51 : Shows the effect of D-erythroceramide on MAG and MBP mRNA expression and on the co-expression of MBP and BetaIII.

[0096] Fig.52 : Shows the effect of sphingomyelin on the co-expression of MBP and BetaIII.

[0097] Fig.53 : Shows the effect of GM3 on the co-expression of MBP and BetaIII.

[0098] Fig.54 : shows the experimental procedure of the maturation experiment.

[0099] Fig.55 : shows the experimental procedure of myelination experiment. DETAILED DESCRIPTION

[0100] In one aspect of the invention, there is provided a synthetic composition comprising vitamins which can be used to promote, support or optimize remyelination, particularly remyelination trajectory, and / or brain structure, and / or brain connectivity, and / or intellectual potential and / or cognitive potential and / or learning potential and / or cognitive function in an individual, particularly a formula-fed individual.

[0101] By promoting, supporting and / or optimizing remyelination, particularly remyelination trajectory, and / or brain structure, and / or intellectual potential and / or cognitive potential and / or learning potential and / or cognitive function in an individual, particularly a formula-fed individual. The composition of the present invention can prevent, reduce the risk and / or alleviate suboptimal remyelination, particularly suboptimal remyelination trajectory, and / or suboptimal brain structure, and / or suboptimal brain connectivity, and / or suboptimal intellectual potential and / or suboptimal cognitive potential and / or suboptimal learning potential and / or suboptimal cognitive function in the individual. This can be non-therapeutic or therapeutic.

[0102] As used herein, the term "facilitates" refers to a factor or factors that cause a process to occur.

[0103] As used herein, the term "support" refers to the factor or factors that maintain a process once it begins to occur.

[0104] As used herein, the term subject refers to a mammal, particularly a cat, dog or human, more particularly the term refers to a human, even more particularly a human infant or child, and even more particularly a human infant or child fed infant formula and / or growing-up milk.

[0105] As used herein, the term "infant" refers to a human infant up to 12 months of age, and includes premature infants and very premature infants, infants with low birth weight (i.e., a newborn weighing less than 2500 g (5.5 pounds) whether due to prematurity or fetal growth restriction), and infants who are small for gestational age (SGA) (i.e., an infant whose birth weight is below the 10th percentile for infants of the same gestational age).

[0106] As used herein, the term "child" refers to a human between 1 and 18 years old, more specifically between 1 and 10 years old, even more specifically between 1 and 5 years old, and even more specifically between 1 and 2 years old.

[0107] As used herein, the term "formula-fed infant or child" refers to an infant or child who is fed infant formula and / or growing-up milk.

[0108] As used herein, the term "breastfed individual" refers to a mammal, particularly a cat, dog or human, more particularly the term refers to a human, even more particularly a human infant or child, and even more particularly a human infant or child fed human breast milk, particularly from a nourished mother.

[0109] As used herein, the term "remyelination" refers to the process of developmental myelination, particularly the myelination of exposed axons in the brain of an individual during growth and development. It is a process that begins in the womb and continues after birth, particularly in specific brain regions, and is most abundant in the first 5 years of life of a human individual, particularly the first 2 or 3 years of life of a human individual, and more particularly the first year of life of a human individual.

[0110] As used herein, the term "remyelination trajectory" refers to the extent of remyelination or accumulation of new myelin (as measured, for example, by the myelin water fraction) as a function of time, particularly during infancy and childhood, particularly early childhood, more particularly during the first 5 years of life of a human individual, more particularly during the first 2 or 3 years of human life, even more particularly during the first year or first 6 months of human life when infant formula may be the sole form of nutrition for some infants.

[0111] As used herein, the term "brain structure" refers to the structure of gray and white matter of the brain, and within a specific brain region, and in particular to myelinated white matter of the brain, and within a specific brain region, as determined by remyelination, in particular the remyelination trajectory (i.e., by the restructuration of myelin deposition). More particularly, the term refers to the amount and / or spatial distribution of myelinated material throughout the brain, and / or in a specific brain region, and even more particularly to the amount and / or spatiotemporal distribution of myelinated material throughout the brain, and / or in a specific brain region.

[0112] As used herein, the term "intelligence potential" refers to the possible intelligence and intelligence that an individual can obtain as determined by physiological factors. In particular, intelligence potential can refer to fluid intelligence.

[0113] As used herein, the term "fluid intelligence" refers to an individual's neural potential and / or an individual's ability to solve novel or abstract problems as determined by physiological factors. This is different from crystallized intelligence, which is determined at least in part by learned or culturally adapted knowledge.

[0114] As used herein, the term "cognitive potential" refers to the possible cognitive and / or mental abilities or mental capacity that an individual may acquire as determined by physiological factors. In particular, the term may refer to one or more of the following: information processing potential, perceptual potential, attention potential, thinking potential, reasoning potential, comprehension and memory potential, psychomotor potential (including gross motor and fine motor potential), visual potential (including visual reception potential), auditory potential, language potential (including expressive and receptive language potential), memory and recall potential, concentration potential, executive function potential (including problem solving, decision making and inhibition potential).

[0115] As used herein, the term "learning potential" refers to the possible ability or capacity that an individual has to learn (e.g., how easily and / or quickly an individual can acquire knowledge or skills through experience, study, or being taught), as determined by physiological factors, and the possible ability that an individual has to adapt to environmental factors, as determined by physiological factors.

[0116] As used herein, the term "learning" refers to acquiring knowledge or skills through experience, learning, or by being taught.

[0117] As used herein, the term "cognition" refers to the intellectual process by which a person knows, perceives, or understands ideas; therefore, the ability to think and understand. Cognition includes all aspects of information processing, perception, attention, thinking, reasoning, comprehension, and memory, as well as psychomotor, language, memory, concentration, executive function, and problem-solving abilities.

[0118] Since human breast milk is the gold standard in infant nutrition, the re-myelination trajectory measured or observed in breast milk of breastfed individuals, more particularly exclusively breastfed individuals, particularly well-nourished or well-nourished mothers, may be considered optimal. Therefore, if a composition of the present invention causes the re-myelination trajectory of an individual, particularly a formula-fed individual, to meet or be closer to the re-myelination trajectory measured or observed in breast milk of breastfed individuals, more particularly exclusively breastfed individuals, particularly well-nourished or well-nourished mothers, then the composition may be considered to optimize the myelination trajectory of the individual.

[0119] If the distance between the trajectory of the individual and any equivalent / same measurement point on the trajectory of the breastfed individual is at most 50%, in particular at most 25%, more particularly at most 20%, then the remyelination trajectory of the individual can be considered to be consistent with or closer to the remyelination trajectory measured or observed in the breast milk of a breastfed, more particularly fully breastfed individual, in particular a well-nourished or well-nourished mother. Non-limiting examples within the range of at most 50% include 50%, 40%, 30%, 25%, 20%, 10%, 5%, 1%, 0.5% and 0.01%. In particular, the trajectory will be considered bioequivalent.

[0120] The myelination trajectory can be measured at any combination of time points. Particularly, the time points are within the first 5 years of human life, more particularly the first 2 or 3 years of human life, and even more particularly the first year or first 6 months of human life.

[0121] The remyelination trajectory can be determined by repeatedly measuring any marker of myelination in an individual over time. In particular, the remyelination trajectory can be measured by measuring the individual's myelin-associated water fraction (myelin water fraction) and / or myelin-associated water pools (myelin water pools) at different time points, in particular over the first 5 years of life of a human individual, more particularly the first 2 or 3 years of life of a human individual, and even more particularly the first year or first 6 months of life of a human individual. The individual's myelin-associated water fraction and / or myelin-associated water pools can be measured using multi-component relaxation (MCR) magnetic resonance imaging (MRI) techniques, in particular using the mcDESPOT technique (Deoni et al., 2008). In particular, the remyelination trajectory can be determined by measuring myelin-associated pools using the mcDESPOT technique (Magn. Reson. Med. 2008 60: 1372-1387, the subject matter of which is hereby incorporated by reference).

[0122] If the composition of the present invention makes one or more individuals, especially formula-fed individuals, in standardized cognitive tests (including intelligence tests, school performance tests and / or neurodevelopmental tests), for example, scores on the Mullen Early Learning Scales meet or are closer to scores measured or observed in breast milk of breastfed, more especially fully breastfed individuals, especially well-nourished or nutritious mothers, then the composition can be considered to optimize the cognitive function and / intelligence of the individual. If the difference between one or more of the standardized neurodevelopmental test scores of the individual (e.g., Mullen's T score) and one or more of the standardized neurodevelopmental test scores of the breastfed individual is less than one standard deviation, more particularly less than half of the standard deviation of the standardized test scores, for example, less than 10 points, more particularly less than 5 points of Mullen's T score, particularly less than 2 points, the cognitive and neurodevelopmental function of the individual can be considered to be in line with or closer to the cognitive and neurodevelopmental function measured in the breastfed individual. The standardized neurodevelopmental test scores (e.g., Mullen's T score) are measured at the same time point in the individual and the breastfed individual.

[0123] The Mullen score may be measured at any suitable time point, particularly within the first 5 years, 3 years of human life, more particularly within the first 2 years of human life, even more particularly within the first year or first 6 months of human life.

[0124] In terms of promoting, supporting or optimizing cognitive potential, learning potential and / or intellectual potential, the compositions of the present invention may have short-term or long-term effects on cognitive function (including the development of cognitive function, and / or learning) and on preventing or minimizing any neurocognitive deficits, impairments or delays.

[0125] Such short-term effects may become apparent within only a few days, weeks or months.

[0126] Such long-term effects may become apparent only within a few years (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 years).

[0127] A composition comprising vitamins, such as vitamin B12 and / or folic acid, is particularly effective in supporting, promoting or optimizing remyelination, in particular remyelination trajectories, and / or brain structures in the following brain regions: cerebellum, visual cortex, motor and somatosensory cortex. Thus, the vitamins are particularly effective in promoting, supporting or optimizing visual potential, motor function (including coordination and execution of motor potential), and psychomotor potential.

[0128] In one embodiment of the invention, the cognitive potential is selected from the group consisting of visual potential, motor function (including coordination and execution of movements), and psychomotor potential.

[0129] In promoting, supporting or optimizing visual potential, motor function (including coordination and execution of motor potential), and psychomotor potential, the composition of the present invention may have short-term or long-term effects, such as an enhancing effect on visual acuity, motor function (including coordination and execution of movement), and psychomotor function. The short-term effect may become apparent only within a few days, weeks or months.

[0130] Such long-term effects may become apparent only within a few years (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 years).

[0131] In an embodiment of the invention, a composition comprising vitamins enhances vision and / or motor function (including coordination and execution of movements), and psychomotor function in an individual.

[0132] As used herein, the term vitamin may refer to any vitamin. Non-limiting examples of vitamins include: vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin K, vitamin C, vitamin D, niacin, biotin, pantothenic acid, folic acid, vitamin B12, and combinations thereof.

[0133] Particularly effective vitamins may be folic acid, vitamin B12 and vitamin B6, especially folic acid and vitamin B12, especially folic acid.

[0134] In an embodiment of the present invention, the vitamin is vitamin B12, folic acid and / or a combination thereof.

[0135] Vitamins may be included in the compositions of the invention in amounts ranging from 0.001% up to 99.999% of the composition.

[0136] Folic acid may be included in the composition of the invention in an amount of 0.001% up to 99.999% of the composition.

[0137] Folic acid may in particular be included in an amount higher than 50 mcg / 100 g of the dry composition, more particularly 50 to 500 mcg / 100 g of the dry composition.

[0138] In one embodiment, the composition of the present invention comprises folic acid in an amount selected from: above 50mcg, above 65mcg, above 70mcg, above 100mcg, above 110mcg, above 160mcg, in the range of 50mcg to 500mcg, in the range of 50mcg to 400mcg, in the range of 110mcg to 500mcg, in the range of 70mcg to 170mcg, in the range of 110mcg to 400mcg, in the range of 110mcg to 400mcg, in the range of 110mcg to 350mcg, wherein all weights are based on 100g of dry composition.

[0139] In one embodiment, the composition according to the invention comprises an amount of folic acid such that the total daily intake derived from the nutritional composition of the invention will not exceed 400 mcg.

[0140] Folic acid may be incorporated into the nutritional composition of the invention as such or in the form of its physiologically acceptable salts (folates) or mixtures thereof.

[0141] Vitamin B12 may be included in the compositions of the present invention in an amount of 0.001% up to 99.999% of the composition.

[0142] In particular vitamin B12 may be included in the composition in an amount selected from: above 0.01 mcg, in particular above 0.04 mcg, in particular above 0.05 mcg, wherein all weights are based on 100 g of dry composition.

[0143] In one embodiment, the composition of the present invention comprises vitamin B12 in an amount selected from: above 0.01mcg, above 0.5mcg, above 0.7, above 5, in the range of 0.1mcg to 10mcg, 0.4mcg to 5mcg, 0.5mcg to 2mcg, 1mcg to 1.5mcg, 4mcg to 8.5mcg, 5mcg to 8mcg, wherein all weights are based on 100g of dry composition.

[0144] In one embodiment, the composition according to the invention comprises an amount of vitamin B12 such that the total daily intake from the nutritional composition of the invention will not exceed 7.6 mcg / 100 g dry composition (77.6 mcg / Kg dry composition).

[0145] Vitamin B12 may be incorporated into the nutritional composition of the present invention as such or in the form of its physiologically acceptable salt or mixture thereof, or through any source comprising vitamin B12. In particular, vitamin B12 may be incorporated into the composition in its pure form, such as cyanocobalamin, hydroxocobalamin, and any combination thereof.

[0146] It may be particularly advantageous if the composition according to the invention further comprises one or more of the following ingredients: minerals and / or phospholipids and / or fatty acid derivatives and / or choline.

[0147] When the composition of the present invention comprises vitamins, particularly folic acid and / or vitamin B12, and one or more of these ingredients, it may have an improved effect in promoting remyelination, particularly remyelination trajectory, and / or brain structure, and / or brain connectivity, and / or cognitive potential, and / or intellectual potential, and / or learning potential, and / or cognitive function in individuals, particularly individuals fed with formula foods. For example, this may be because the ingredients achieve remyelination in the same and / or separate complementary brain regions. The improved effect may be synergistic.

[0148] In one embodiment, the composition of the invention further comprises minerals and / or choline and / or phospholipids and / or derivatives of fatty acids.

[0149] As used herein, the term mineral refers to any mineral. Non-limiting examples of minerals include: iron, zinc, calcium, phosphorus, copper, magnesium, iodine, manganese, chloride, potassium, sodium, selenium, chromium, and combinations thereof. Minerals are typically added in the form of salts.

[0150] Particularly effective minerals may be iron, zinc, calcium, phosphorus, copper and magnesium, especially iron.

[0151] In one embodiment, the composition of the invention comprises iron and / or zinc and / or calcium and / or phosphorus and / or copper and / or magnesium, in particular iron and zinc, more in particular iron.

[0152] In one embodiment, the nutritional composition according to the invention comprises iron.Iron may be comprised in the composition of the invention in an amount of up to 99.999% of the composition.

[0153] In particular, iron may be contained in the composition in an amount higher than 5 mg / 100 g of dry composition.

[0154] In one embodiment, the composition according to the invention comprises iron in an amount selected from: above 4 mg, above 9 mg, in the range of 5 to 40 mg, in the range of 9 to 40 mg, in the range of 5 and 20 mg, in the range of 9 to 20 mg, in the range of 5 to 15 mg, in the range of 9 to 15 mg, in the range of 3.5 to 7 mg, wherein all weights are based on 100 g of dry composition.

[0155] Iron may be incorporated into the compositions of the present invention in the form of a physiologically acceptable salt, such as ferric citrate, ferric phosphate, ferric pyrophosphate, ferrous ascorbate, ferrous carbonate, ferrous citrate, ferrous fumarate, ferrous gluconate, ferrous lactate, ferrous sulfate, or mixtures thereof.

[0156] Iron may be incorporated into the compositions of the invention in the form of a physiologically acceptable iron complex (such as, for example, sodium iron EDTA salt) or a mixture thereof.

[0157] If iron is added to the composition in the form of a ferrous salt or complex (e.g., the ferrous salts listed above), the Fe2+ is more bioavailable and therefore may be more beneficial.

[0158] In one embodiment, the composition according to the invention comprises iron at a level such that the total daily intake from the nutritional composition of the invention will not exceed 40 mg.

[0159] In one embodiment, the nutritional composition according to the invention comprises zinc.Zinc may be comprised in the composition of the invention in an amount of up to 99.999% of the composition.

[0160] In particular zinc may be included in the composition in an amount higher than 0.08 mg, higher than 0.3 mg, higher than 0.5 mg, wherein all weights are based on 100 g of dry composition.

[0161] In one embodiment, the composition according to the invention comprises zinc in an amount selected from: within the range of 0.5 mg to 8 mg, 2 mg to 5.5 mg, 2.5 mg to 4.5 mg, 3 mg to 4 mg, 4 mg to 7.5 mg, 6 mg to 7.5 mg, wherein all weights are based on 100 g of dry composition.

[0162] In one embodiment, the composition according to the invention comprises a level of zinc such that the total daily intake from the nutritional composition of the invention will not exceed 302.4 mg / day, or will not exceed 245 mg / day, or will not exceed 166 mg / day, or will not exceed 98.9 mg / day, or will not exceed 95.6 mg / day.

[0163] Zinc may be incorporated into the composition of the invention in the form of a physiologically acceptable salt and / or by comprising any source of zinc, more particularly Zn2, such as, for example: zinc nitrate, zinc sulfate, zinc gluconate, zinc acetate or mixtures thereof, or in the form of a physiologically acceptable zinc complex, such as, for example, zinc picolinate or mixtures thereof.

[0164] In one embodiment, the composition according to the invention comprises copper.Copper may be comprised in the composition of the invention in an amount of up to 99.999% of the composition.

[0165] In particular copper may be included in the composition in an amount greater than 10mcg, greater than 40mcg, greater than 60mcg, wherein all weights are based on 100g dry weight of the composition.

[0166] In one embodiment, the composition according to the invention comprises copper in an amount selected from: above 100mcg, ranging from 100mcg to 850mcg, 180mcg to 650mcg, 200mcg to 400mcg, 210mcg to 300mcg, 210mcg to 240mcg, 450mcg to 850mcg, 800mcg to 840mcg, wherein all weights are based on 100g dry weight of the composition.

[0167] In one embodiment, the composition according to the invention comprises copper at a level such that the total daily intake from the nutritional composition of the invention will not exceed 1426 mcg / day, or will not exceed 488 mcg / day.

[0168] Copper can be incorporated into the composition of the invention as such or in the form of a physiologically acceptable salt, and / or via any source comprising copper, more particularly Cu2+. For example, copper can be incorporated into the composition as: copper sulfate and / or copper gluconate and / or copper carbonate, and / or copper citrate, and / or copper-lysine complex.

[0169] In one embodiment, the composition according to the invention comprises magnesium.Magnesium may be comprised in the composition according to the invention in an amount of up to 99.999% of the composition.

[0170] In particular magnesium may be included in the composition in an amount higher than 0.2 mg, higher than 0.35 mg, higher than 0.5 mg, wherein all weights are based on 100 g dry weight of the composition.

[0171] In one embodiment, the composition according to the invention comprises magnesium in an amount selected from: ranging from 0.35 mg to 90 mg, ranging from 25 mg to 70 mg, 30 mg to 65 mg, 35 mg to 60 mg, 40 mg to 50 mg, 35 mg to 55 mg, wherein all weights are based on 100 g of dry composition.

[0172] In one embodiment, the composition according to the invention comprises magnesium at a level such that the total daily intake from the nutritional composition of the invention will not exceed 110 mg / day, or will not exceed 65 mg / day.

[0173] Magnesium can be incorporated into the composition of the invention as such or in the form of a physiologically acceptable salt and / or via any source containing magnesium, more particularly Mg2+. For example, magnesium carbonate, magnesium chloride, magnesium oxide, magnesium sulfate, magnesium gluconate, magnesium hydroxide, magnesium citrate, magnesium orthophosphate.

[0174] In one embodiment, the composition according to the invention comprises calcium.Calcium may be comprised in the composition according to the invention in an amount of up to 99.999% of the composition.

[0175] In particular calcium may be included in the composition in an amount higher than 0.84 mg, higher than 2.52 mg, higher than 4.62 mg, wherein all weights are based on 100 g dry weight of the composition.

[0176] In one embodiment, the composition according to the invention comprises calcium in an amount selected from: in the range of 84 mg to 760 mg, in the range of 200 mg to 550 mg, in the range of 250 mg to 450 mg, in the range of 280 mg to 520 mg, 350 mg to 650 mg, 400 mg to 600 mg, wherein all weights are based on 100 g of dry composition.

[0177] In one embodiment, the composition according to the invention comprises calcium at a level such that the total daily intake from the nutritional composition of the invention will not exceed 482 mg / day, or will not exceed 477 mg / day.

[0178] Calcium can be incorporated into the composition of the invention as is or in the form of a physiologically acceptable salt and / or from any source containing calcium, more particularly Ca2+. For example, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium glycerophosphate, calcium lactate, calcium hydroxide, calcium orthophosphate.

[0179] In one embodiment, the composition according to the invention comprises phosphorus.Phosphorus may be comprised in the composition according to the invention in an amount of up to 99.999% of the composition.

[0180] In particular phosphorus may be contained in the composition in an amount higher than 1.7 mg / 100 g, higher than 14.3 mg / 100 g, higher than 27.3 mg / 100 g dry weight of the composition.

[0181] In one embodiment, the composition according to the invention comprises phosphorus in an amount selected from: ranging from 17 mg to 516 mg, ranging from 129 mg to 400 mg, ranging from 140 mg to 390 mg, ranging from 150 mg to 370 mg, 160 mg to 365 mg, ranging from 270 mg to 350 mg, 200 mg to 360 mg, wherein all weights are based on 100 g of dry composition.

[0182] In one embodiment, the composition according to the invention comprises phosphorus at a level such that the total daily intake from the nutritional composition of the invention will not exceed 863 mg / day, or will not exceed 787 mg / day.

[0183] Phosphorus may be incorporated into the composition of the invention as such or in the form of a physiologically acceptable salt, and / or via any source comprising phosphorus (eg calcium phosphate, calcium hydrogen phosphate).

[0184] A composition comprising minerals, particularly one or more of iron, zinc, copper, calcium, magnesium and phosphorus, is particularly effective in supporting, promoting or optimizing remyelination, particularly remyelination trajectories, and / or brain structures in one or more of the following brain regions: cerebellum, visual cortex, motor and somatosensory cortex, corpus callosum, frontal cortex, temporal lobe white matter, internal capsule, prefrontal cortex, motor cortex. These brain regions are associated with motor function (including coordination and execution of movement), visual function, hemispheric interaction, executive function, working memory, problem solving, social-emotional function, language, auditory function, problem solving and / or working memory.

[0185] In one embodiment, the compositions of the invention comprise choline.

[0186] The term "choline" identifies a quaternary ammonium salt containing an N,N,N-trimethylethanolammonium cation having the structure shown below:

[0187]

[0188] choline

[0189] Unless otherwise indicated, in the context of the present invention the term "choline" shall be intended to identify all choline present in the nutritional composition of the present invention in free form (or as a salt thereof).

[0190] Choline may be included in the compositions of the invention in an amount of up to 99.999% of the composition.

[0191] In particular choline may be included in the composition in an amount higher than 30 mg / 100 g dry composition.

[0192] In one embodiment, the composition according to the invention comprises choline in an amount selected from: above 10 mg, above 50 mg, above 100 mg, above 111 mg, above 170 mg, in the range of 30 mg and 1000 mg, in the range of 30 mg to 700 mg, in the range of 50 mg and 1000 mg, in the range of 50 mg to 700 mg, in the range of 50 mg and 500 mg, in the range of 100 mg to 400 mg, in the range of 170 mg to 300 mg, in the range of 120 mg to 200 mg, wherein all weights are based on 100 g of dry composition.

[0193] In one embodiment, the composition according to the invention comprises choline in free form (or as a salt thereof) or derived from a structure comprising it, at a level such that the total daily intake derived from the nutritional composition of the invention will not exceed 1 g.

[0194] Choline may be incorporated into the composition of the invention as such or in the form of a physiologically acceptable salt such as choline chloride, choline citrate, choline bitartrate or mixtures thereof.

[0195] A composition comprising choline is particularly effective in supporting, promoting or optimizing remyelination, particularly remyelination trajectories, and / or brain structures in the following brain regions: cerebellum, visual cortex, thalamus, parietal cortex, and frontal lobe. These brain regions are associated with motor function (including coordination and execution of movement), vision, working memory and / or executive function and / or social-emotional reasoning and / or spatial reasoning.

[0196] In one embodiment, the composition of the present invention comprises a phospholipid metabolic precursor or a metabolite thereof.

[0197] As used herein, the term "phospholipid" refers to any phospholipid, in particular a compound of formula (I)

[0198]

[0199] in,

[0200] R 1 is O;

[0201] X is NH or O;

[0202] R 2 is a C2-C44 saturated or unsaturated, linear or branched acyl group;

[0203] R 3 is a substituent of formula (II) or formula (III):

[0204] R 5 -O-CH 2

[0205] (II)

[0206]

[0207] Among them, R 5 is a C2-C44 saturated or unsaturated, linear or branched acyl group; and

[0208] R 6 is a C2-C44 saturated alkyl or alkenyl group; and

[0209] R 4 is selected from: C5 or C6 substituted or unsubstituted cyclic alkyl or alkenyl groups, or

[0210] —(CH2)n—R 7 , wherein n is an integer in the range of 1 to 4, in particular 1 to 2, and R 7 is -N(CH3)3+, NH3+ or a substituent of formula (IV), and

[0211]

[0212] Especially R 4 is a C6 cyclic alkyl or alkyl or alkenyl group substituted by one or more hydroxyl groups, more particularly R 4 Derived from inositol (C6H12O6), and even more particularly inositol, i.e. R 4 for:

[0213]

[0214] As used herein, the term "acyclic" refers to a group that is not cyclic, ie, does not contain a closed chain of atoms.

[0215] Non-limiting examples of phospholipids include phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine, sphingomyelin, and phosphatidylcholine.

[0216] In an embodiment of the present invention, the phospholipid is selected from the group consisting of: phosphatidylcholine, phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine, sphingomyelin and / or combinations thereof.

[0217] Phosphatidylinositol is a compound of formula (V)

[0218]

[0219] Where R 8 is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group, and R 9 is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group.

[0220] More specifically R 8 and R 9 is independently a C13 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group which, together with its adjacent carbonyl group, corresponds to a C14 to C44 saturated or unsaturated fatty acid residue, and even more particularly R 8 and R 9 Each is independently a C13 to C23 branched or unbranched acyclic alkyl or acyclic alkenyl group, which together with its adjacent carbonyl group corresponds to a C14 to C24 saturated or unsaturated fatty acid residue.

[0221] More specifically R 8 and R 9 is a C13 to C23 branched or unbranched acyclic alkyl or acyclic alkenyl group, which together with its adjacent carbonyl group is a C14 to C24 saturated or unsaturated fatty acid residue, wherein the fatty acid from which the fatty acid residue is derived is selected from: C14:0, C15:0, C16:0, C18:0, C20:0, C20:3, C20:4, C21:0, C22:0, C23:0, C24:0, C18:1n-9, C18:2n-6 and C24:1n-9. Even more particularly C18:0, C18:1n-9, C18:2, C20:3 and C20:4.

[0222] As will be appreciated by the skilled artisan. As used herein, the term phosphatidylserine refers to phosphatidyl-L-serine.

[0223] Phosphatidylserine is a compound of formula (VI)

[0224]

[0225] Where R 10 is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group, and R 11is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group.

[0226] More specifically R 10 and R 11 is independently a C13 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group which, together with its adjacent carbonyl group, corresponds to a C14 to C44 saturated or unsaturated fatty acid residue, and even more particularly R 10 and R 11 Each is independently a C13 to C23 branched or unbranched acyclic alkyl or acyclic alkenyl group, which together with its adjacent carbonyl group corresponds to a C14 to C24 saturated or unsaturated fatty acid residue.

[0227] More specifically R 10 and R 11 is a C13 to C23 branched or unbranched acyclic alkyl or acyclic alkenyl group, which together with its adjacent carbonyl group is a C14 to C24 saturated or unsaturated fatty acid residue, wherein the fatty acid from which the fatty acid residue is derived is selected from: C14:0, C15:0, C16:0, C18:0, C20:0, C20:3, C20:4, C21:0, C22:0, C23:0, C24:0, C18:1n-9, C18:2n-6 and C24:1n-9. Even more particularly C18:0, C18:1n-9, C20:4 and C22:6.

[0228] Phosphatidylethanolamine is a compound of formula (VII)

[0229]

[0230] Where R 12 is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group, and R 13 is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group.

[0231] More specifically R 12 and R 13 is independently a C13 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group which, together with its adjacent carbonyl group, corresponds to a C14 to C44 saturated or unsaturated fatty acid residue, and even more particularly R 12 and R 13 Each is independently a C13 to C23 branched or unbranched acyclic alkyl or acyclic alkenyl group, which together with its adjacent carbonyl group corresponds to a C14 to C24 saturated or unsaturated fatty acid residue.

[0232] As used herein, the term "sphingomyelin" refers to a lipid molecule, or a mixture of lipid molecules, in which sphingosine or a sphingosine backbone is esterified with a fatty acid residue at the amino group (-NH2) via an amide bond, and in which the hydroxyl group at position 1 of the sphingosine backbone is linked to a phosphorylcholine moiety.

[0233] In particular, the sphingomyelin is a compound of formula (VIII) or a mixture of compounds of formula (VIII)

[0234]

[0235] in

[0236] R 14 is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group, R 15 is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group.

[0237] More specifically, R 14 It is a C13 to C43 branched or unbranched acyclic alkyl group, or an acyclic alkenyl group, which together with the adjacent carbonyl group corresponds to a C14 to C44 saturated or unsaturated fatty acid residue.

[0238] Non-limiting examples of C14 to C44 saturated or unsaturated fatty acids from which the fatty acid residue can be derived include: C14:0, C15:0, C16:0, C18:0, C20:0, C21:0, C22:0, C23:0, C24:1, C25:0, C28:1, C30:2, C30:1, C30:0, C32:3, C32:2, C32:1, C32:0, C33:1, C34:3, C34:2, C34:1, C34:0. :0, C35:2, C35:0, C36:4, C36:3, C36:2, C36:1, C36:0, C37:1, C37:0, C38:4, C38:3, C38:1, C38:0, C39:1 , C39:0, C40:2, C40:1, C40:0, C41:2, C41:1, C41:0, C42:47, C42:3, C42:2, C42:1, C42:0, C44:3, C44:1.

[0239] Even more specifically, R 14It is a C13 to C23 branched or unbranched acyclic alkyl or acyclic alkenyl group, which together with the adjacent carbonyl group corresponds to a C14 to C24 saturated or unsaturated fatty acid residue, wherein the fatty acid from which the fatty acid residue is derived is selected from: C14:0, C15:0, C16:0, C18:0, C20:0, C21:0, C22:0, C23:0, C24:0, C18:1n-9, C18:2n-6 and C24:1n-9.

[0240] Even more particularly, the sphingomyelin is a mixture of compounds of formula (VIII), wherein the mixture is such that the fatty acid residues (R 14 The total amount of fatty acids (together with the adjacent carbonyl groups) is mainly saturated fatty acids, and the least dominant is unsaturated fatty acids. More particularly the mixture will be such that 80% to 96% of the fatty acid residues in the mixture are saturated fatty acids, particularly C14, C15, C16, C18, C20, C22, C23, C24 saturated fatty acids, more particularly C16, C18, C20, C22 and C24.

[0241] Phosphatidylcholine is a compound of formula (IX)

[0242]

[0243] Where R 16 is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group, and R 17 is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group.

[0244] More specifically, R 16 and R 17 is independently a C13 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group which, together with its adjacent carbonyl group, corresponds to a C14 to C44 saturated or unsaturated fatty acid residue, and even more particularly, R 16 and R 17 Each is independently a C13 to C23 branched or unbranched acyclic alkyl or acyclic alkenyl group, which together with its adjacent carbonyl group corresponds to a C14 to C24 saturated or unsaturated fatty acid residue.

[0245] More specifically, R 16 and R 17is a C13 to C23 branched or unbranched acyclic alkyl or acyclic alkenyl group, which together with its adjacent carbonyl group is a C14 to C24 saturated or unsaturated fatty acid residue, wherein the fatty acid from which the fatty acid residue is derived is selected from the group consisting of: C14:0, C15:0, C16:0, C16:1, C18:0, C20:0, C20:1, C20:3, C20:4, C21:0, C22:0, C22:6, C23:0, C24:0, C18:1n-9, C18:2n-6 and C24:1n-9. Even more particularly C14:0, C16:0, C18:0, C18:1n-9, C18:2n-6, C20:1, C20:3, C20:4 and C22:6.

[0246] The phospholipids, their metabolic precursors and / or their metabolites may be contained in the composition of the invention in an amount of up to 99.999% of the composition.

[0247] In particular sphingomyelin, its metabolic precursors and / or metabolites may be contained in the composition in an amount of up to 99.999% of the composition.

[0248] More particularly the composition will comprise sphingomyelin in an amount higher than 200 mg / kg dry weight of the composition, more particularly in the range of 200 mg / kg to 2.5 g / kg dry weight of the composition.

[0249] In one embodiment, the composition comprises sphingomyelin in an amount selected from: greater than 200 mg / kg, greater than 300 mg / kg, in the range of 200 mg / kg to 2.5 g / kg, in the range of 200 mg / kg to 2 g / kg, in an amount in the range of 300 mg / kg to 1.5 g / kg or 400 mg / Kg to 1 g / Kg, in the range of 200 mg / kg to 850 mg / kg, or 300 mg / kg to 820 mg / kg. All weights are based on the dry weight of the composition.

[0250] In particular, phosphatidylcholine, its metabolic precursors and / or metabolites may be contained in the composition in an amount of up to 99.999% of the composition.

[0251] More particularly the composition will comprise phosphatidylcholine in an amount higher than 200 mg / kg dry weight of the composition, more particularly in the range of 200 mg / kg to 2.5 g / kg dry weight of the composition.

[0252] In one embodiment, the composition comprises phosphatidylcholine in an amount selected from: greater than 200 mg / kg, greater than 300 mg / kg, greater than 400 mg / kg, in the range of 200 mg / kg to 2.5 g / kg, in the range of 200 mg / kg to 2 g / kg, in an amount in the range of 300 mg / kg to 1.5 g / kg or 400 mg / Kg to 1 g / Kg, 500 mg / Kg to 1.3 g / Kg. All weights are based on the dry weight of the composition.

[0253] In particular, phosphatidylinositol, its metabolic precursors and / or metabolites may be contained in the composition in an amount of up to 99.999% of the composition.

[0254] More particularly the composition will comprise phosphatidylinositol in an amount higher than 50 mg / kg of dry weight of the composition, more particularly in the range of 200 mg / kg to 1.5 g / kg of dry weight of the composition.

[0255] In one embodiment, the composition comprises phosphatidylinositol in an amount selected from: greater than 200 mg / kg, greater than 300 mg / kg, in the range of 200 mg / kg to 2.5 g / kg, in the range of 200 mg / kg to 2 g / kg, in the range of 250 mg / kg to 800 mg / kg, or 400 mg / Kg to 1.5 g / Kg, or 400 mg / kg to 800 mg / kg. All weights are based on the dry weight of the composition.

[0256] In particular, phosphatidylserine, its metabolic precursors and / or metabolites may be contained in the composition in an amount of up to 99.999% of the composition.

[0257] More particularly the composition will comprise phosphatidylserine in an amount higher than 50 mg / kg dry weight of the composition, higher than 200 mg / kg dry weight of the composition, more particularly in the range of 150 mg / kg to 1.5 g / kg dry weight of the composition, 200 mg / kg to 1 g / kg dry weight of the composition.

[0258] In one embodiment, the composition comprises phosphatidylserine in an amount selected from: greater than 150 mg / kg, greater than 200 mg / kg, greater than 300 mg / kg, in the range of 200 mg / kg to 2.5 g / kg, in the range of 200 mg / kg to 2 g / kg, in the range of 250 mg / kg to 1000 mg / kg, or 400 mg / Kg to 1 g / Kg. All weights are based on the dry weight of the composition.

[0259] In particular, phosphatidylethanolamine, its metabolic precursors and / or metabolites may be contained in the composition in an amount of up to 99.999% of the composition.

[0260] More particularly the composition will comprise phosphatidylethanolamine in an amount higher than 150 mg / kg dry weight of the composition, higher than 200 mg / kg dry weight of the composition, more particularly in the range of 150 mg / kg to 1.5 g / kg dry weight of the composition.

[0261] In one embodiment, the composition comprises phosphatidylethanolamine in an amount selected from: greater than 170 mg / kg, greater than 180 mg / kg, greater than 200 mg / kg, in the range of 200 mg / kg to 2.5 g / kg, in the range of 200 mg / kg to 2 g / kg, in the range of 250 mg / kg to 800 mg / kg, or 200 mg / Kg to 1 g / Kg. All weights are based on the dry weight of the composition.

[0262] In one embodiment, the composition of the invention comprises phospholipids including phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine, sphingomyelin and phosphatidylcholine such that the total concentration does not exceed 15.4 g / kg.

[0263] If one or more metabolic precursors and / or metabolites of phospholipids are used in the composition instead of or in combination with phospholipids, the amount of the compound is such that the level of phospholipids physiologically delivered by the composition complies with those listed above. Determining the appropriate amount is well within the capabilities of those skilled in the art.

[0264] As used herein, the term metabolic precursor and / or metabolite of one or more phospholipids does not include choline.

[0265] Non-limiting examples of metabolic precursors and / or metabolites of phospholipids, in particular sphingomyelin, phosphatidylcholine, phosphatidylinositol, phosphatidylserine and / or phosphatidylethanolamine, are: galactosylceramide, glycosylated ceramide, sphingosine, sphingosine-1-phosphate, ceramide, D-erythro-dihydroceramide and ceramide-1-phosphate, and gangliosides.

[0266] Particularly effective phospholipids may be phosphatidylcholine, phosphatidylserine, phosphatidylinositol and / or sphingomyelin, in particular sphingomyelin.

[0267] In an embodiment of the present invention, the phospholipid is a metabolic precursor and / or metabolite of phosphatidylcholine, phosphatidylserine, phosphatidylinositol, sphingomyelin and / or any one of the above and / or a combination of any one of the foregoing. In particular, the phospholipid is sphingomyelin, its metabolic precursor and / or metabolite.

[0268] Particularly effective metabolic precursors and / or metabolites of phospholipids, in particular sphingomyelin, may be ceramides and gangliosides and gangliosides as well as ceramide-1-phosphate and d-erythro-dihydroceramide.

[0269] The term "ceramide" indicates a lipid molecule in which sphingosine or a sphingosine backbone is esterified and acylated with a fatty acid residue via an amide bond. When the term ceramide is used in the present specification, it may identify a single ceramide species as well as a mixture of single ceramide species.

[0270] In particular, the ceramide is a compound of formula (IXa) or a mixture of compounds of formula (IXa)

[0271]

[0272] in,

[0273] R 16a is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group,

[0274] R 17a is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group.

[0275] More specifically, R 16a It is a C13 to C43 branched or unbranched acyclic alkyl group, or an acyclic alkenyl group, which together with the adjacent carbonyl group corresponds to a C14 to C44 saturated or unsaturated fatty acid residue.

[0276] Non-limiting examples of C14 to C44 saturated or unsaturated fatty acids from which the fatty acid residue can be derived include: C14:0, C15:0, C16:0, C18:0, C20:0, C21:0, C22:0, C23:0, C24:1, C25:0, C28:1, C30:2, C30:1, C30:0, C32:3, C32:2, C32:1, C32:0, C33:1, C34:3, C34:2, C34:1, C34:0. :0, C35:2, C35:0, C36:4, C36:3, C36:2, C36:1, C36:0, C37:1, C37:0, C38:4, C38:3, C38:1, C38:0, C39:1 , C39:0, C40:2, C40:1, C40:0, C41:2, C41:1, C41:0, C42:47, C42:3, C42:2, C42:1, C42:0, C44:3, C44:1.

[0277] Even more specifically, R 16aIt is a C13 to C23 branched or unbranched acyclic alkyl or acyclic alkenyl group, which together with the adjacent carbonyl group corresponds to a C14 to C24 saturated or unsaturated fatty acid residue, wherein the fatty acid from which the fatty acid residue is derived is selected from: C14:0, C15:0, C16:0, C18:0, C20:0, C21:0, C22:0, C23:0, C24:0, C18:1n-9, C18:2n-6 and C24:1n-9, more particularly selected from C16:0, C18:0, C20:0, C22:0 and C24:0.

[0278] Even more particularly, the ceramide is a mixture of compounds of formula (IXa) wherein the mixture is such that the fatty acid residues (R 16a The total amount of fatty acids (together with the adjacent carbonyl groups) is predominantly saturated fatty acids, and the least predominant is unsaturated fatty acids. More particularly the mixture will be such that 80% to 96% of the fatty acid residues in the mixture are saturated fatty acids, particularly C14, C15, C16, C18, C20, C22, C23, C24 saturated fatty acids, more particularly C16, C18, C20, C22 and C24.

[0279] As used herein, the term "ganglioside" indicates an oligosaccharide amide lipid molecule comprising a residue of ceramide of formula IXa as defined herein. When the term ganglioside is used in this specification, it may identify a single ganglioside species as well as a mixture of single ganglioside species comprising a residue of ceramide of formula IXa as defined herein.

[0280] Particularly effective gangliosides may be monosialoganglioside-3 (GM3) ganglioside and / or disialoganglioside 3 (GD3) ganglioside.

[0281] Ceramide-1-phosphate and d-erythro-dihydroceramide comprise the residue of ceramide of formula IXa as defined herein.

[0282] Gangliosides and / or ceramides and / or ceramide-1-phosphate and / or d-erythro-dihydroceramide may be included in the composition in any amount.

[0283] Concentrations in the range of 2 mg / 100 g to 11.5 mg / 100 g GD3 and / or GM3 may be particularly effective.

[0284] Sphingomyelin can be synthesized from ceramide and phosphatidylcholine, and therefore it may be particularly beneficial if ceramide and / or one or more gangliosides are used in combination with a phosphatidylcholine metabolic precursor or a metabolite thereof.

[0285] The phospholipids, its metabolic precursors and / or metabolites included in the compositions of the present invention can be natural, synthetic or mixtures thereof. The metabolic precursors and / or metabolites can be used in the compositions of the present invention in their pure form or substantially pure form. Alternatively, they can be added in the form of a source comprising them.

[0286] Any source of phospholipid metabolic precursors and / or metabolites thereof suitable for ingestion by an individual for whom the composition is intended to be consumed may be used in the present invention.

[0287] In particular, phospholipid metabolic precursors or metabolites thereof will be from natural sources, non-limiting examples of which include eggs, soybeans, bovine brains and / or mammalian milk or extracts thereof. Non-limiting examples of soybean sources include soy lecithin food additives, and non-limiting examples of mammalian milk include cow's milk, camel's milk, sheep's milk, goat's milk, including skim milk. Non-limiting extracts of milk include protein extracts (e.g., whey proteins and caseins), milk fat globule membranes (MFGM) and extracts containing them.

[0288] A particularly useful source of phospholipid metabolic precursors or metabolites thereof, in particular sphingomyelin, which can be used in the present invention may be a bovine milk whey protein concentrate enriched with α-lactalbumin and / or non-pure α-lactalbumin, which has been extracted from milk whey protein, in particular bovine milk whey protein.

[0289] α-lactalbumin is a high quality, easily digestible whey protein, e.g. by human infants, and is the major protein found in HM. Since α-lactalbumin and / or α-lactalbumin enriched milk fractions have a high content of essential amino acids, particularly tryptophan, they are ideal for use in low protein infant formulas. Although α-lactalbumin itself is a protein, non-pure sources may contain sphingomyelin.

[0290] In one embodiment, the phospholipid metabolic precursors or metabolites thereof, in particular sphingomyelin, are used in the form of a whey protein concentrate enriched in α-lactalbumin or as α-lactalbumin.

[0291] In a more particular embodiment, a bovine whey protein concentrate enriched in α-lactalbumin or α-lactalbumin having a phospholipid content, in particular a sphingomyelin content, higher than 500 mg / 100 g, 900 mg / 100 g, 1000 mg / 100 g dry weight of the composition is used.

[0292] Another particularly useful source of phospholipid metabolic precursors or metabolites thereof may be milk fat globule membrane (hereinafter referred to as MFGM) or extracts containing them, in particular MFGM or extracts containing them from bovine milk. It may be particularly beneficial if MFGM or extracts containing them contain at least 1%, 2%, 5%, 10%, 20%, 30%, 40% phospholipids and / or at least 0.1%, 0.2%, 0.5% to 5%, 0.8% to 3%, 1% to 2%, 1.6%, 1.9%, 1.8% of phosphatidylcholine, phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine and / or sphingomyelin. MFGM may further contain magnesium, phosphorus and / or calcium, in particular in concentrations ranging from 0.05% to 2%, 0.1% to 0.4%.

[0293] A composition comprising phospholipids and / or metabolic precursors and / or metabolites thereof, in particular sphingomyelin, phosphatidylcholine and / or phosphatidylinositol, is particularly effective in supporting, promoting or optimizing remyelination, in particular remyelination trajectories, and / or brain structures in one or more of the following brain regions: cerebellum, visual cortex, corpus callosum, internal capsule, frontal lobe, parietal lobe, temporal lobe, motor cortex, frontal cortex. These brain regions are associated with one or more of the following: vision, motor function (including coordination and execution of movement), hemispheric interaction, language function, auditory function (including listening and attention), working memory, executive function (including problem solving, social processing, and behavioral interaction, spatial reasoning, and language).

[0294] In one embodiment, the composition of the invention comprises a fatty acid derivative.

[0295] Fatty acid derivatives may be included in the compositions of the invention in an amount of up to 99.999% of the composition.

[0296] As used herein, the term "fatty acid derivative" refers to a compound containing fatty acids, in particular free fatty acids, and / or monoacylglycerol (hereinafter referred to as MAG), and / or diacylglycerol (hereinafter referred to as DAG), and / or triacylglycerol (hereinafter referred to as TAG) and / or cholesterol ester, other than phospholipids. More particularly, the term refers to MAG, DAG, TAG and / or cholesterol ester. Even more particularly, the term refers to TAG.

[0297] As used herein, the term "MAG" refers to a glycerol molecule in which one of the OH groups forms an ester bond with a fatty acid. In particular, as used herein, the term "MAG" refers to a compound of formula (X)

[0298]

[0299] in,

[0300] R18 , R 19 or R 20 Two of them are H, and R 18 , R 19 or R 20 One of the groups is a C4 to C44 saturated or unsaturated acyl group.

[0301] More specifically, R 18 R 19 or R 20 Two of them are H, and R 18 , R 19 or R 20 One of the is a C10 to C24 saturated or unsaturated acyl group, and even more particularly a C14 to C24 saturated or unsaturated acyl group.

[0302] As used herein, the term "DAG" refers to a glycerol molecule in which two of the OH groups form ester bonds with two fatty acids. In particular, as used herein, the term "DAG" refers to a compound of formula (X)

[0303] Among them, R 18 , R 19 or R 20 One of them is H, and R 18 , R 19 or R 20 In one embodiment, two of the acyl groups are C4 to C44 saturated or unsaturated acyl groups. More particularly, they are C10 to C24 saturated or unsaturated acyl groups, and even more particularly, they are C14 to C24 saturated or unsaturated acyl groups. The two C4 to C44 saturated or unsaturated acyl groups may be the same or different.

[0304] As used herein, the term "TAG" refers to a glycerol molecule in which three of the OH groups form ester bonds with three fatty acids. In particular, as used herein, the term "TAG" refers to a compound of formula (X)

[0305] Among them, all R 18 , R 19 or R 20 is a C4 to C44 saturated or unsaturated acyl group, more particularly a C10 to C24 saturated or unsaturated acyl group, and even more particularly a C14 to C24 saturated or unsaturated acyl group. The three C4 to C44 saturated or unsaturated acyl groups may all be the same, all different, or two may be the same and one different.

[0306] As used herein, the term "cholesterol ester" refers to a compound of formula (XI)

[0307]

[0308] in,

[0309] R 21 is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group.

[0310] More specifically, R 21 is a C9 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group which, together with the adjacent carbonyl group, corresponds to a C10 to C44 saturated or unsaturated fatty acid residue, and even more particularly a C14 to C24 saturated or unsaturated fatty acid residue.

[0311] As used herein, the term "fatty acid" refers to a compound of formula (XII)

[0312]

[0313]

[0314] in

[0315] R 22 is a C2 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group.

[0316] More specifically, R 22 It is a C9 to C43 branched or unbranched acyclic alkyl or acyclic alkenyl group, and even more particularly a C13 to C23 branched or unbranched acyclic alkyl or acyclic alkenyl group.

[0317] Non-limiting examples of C10 to C44 saturated or unsaturated fatty acids that may be included in the fatty acid derivative (i.e., the fatty acid derivative may be a free fatty acid or a MAG, DAG, TAG and / or cholesterol ester whose fatty acid residue is derived from a fatty acid) include: C10:0, C12:0, C14:0, C15:0, C16:0, C16:1n-7, C18:0, C18:1n-7, C18:1n-9, C18:2n-6, C20:3n-3, C20:0, C20:1n-9, C20:2n-6, C20:3n-6, C20:4n-6, 20:5n-3, C21:0, C22:0, C22:1n-9, C22:6n-3, C23: 0, C24:1, especially 24:1n-9, C25:0, C28:1, C30:2, C30:1, C30:0, C32:3, C32:2, C32:1, C32:0, C33:1, C34:3, C34:2, C34:1, C34:0, C35:2, C35:0, C36:4, C36:3, C36:2, C36:0 :1, C36:0, C37:1, C37:0, C38:4, C38:3, C38:1, C38:0, C39:1, C39:0, C40:2, C40:1 , C40:0, C41:2, C41:1, C41:0, C42:47, C42:3, C42:2, C42:1, C42:0, C44:3, C44:1. In particular, the fatty acids will be selected from: C10:0, C12:0, C14:0, C16:0, C16:1n-7, C18:0, C18:1n-7, C18:1n-9, C18:2n-6, 18:3n-3, C20:0, C20:1n-9, C20:2n-6, C20:3n-6, C20:4n-6, 20:5n-3, C22:0, C22:1n-9, C22:6n-3, C24:1, 24:1n-.

[0318] Any fatty acid derivative suitable for ingestion by an individual for whom the composition is intended to be consumed may be used in the present invention.

[0319] In particular, fatty acid derivatives will come from natural sources, non-limiting examples of which include eggs, algae, fish oil, molds, yeasts, seeds, plants such as soybeans, and animal sources such as bovine brains, and / or mammalian milk or extracts thereof. Non-limiting examples of soybean sources include soy lecithin food additives, and non-limiting examples of mammalian milk include cow's milk, camel's milk, sheep's milk, goat's milk, including skim milk. Non-limiting extracts of milk include protein extracts, milk fat globule membranes (MFGM) and extracts containing them. Fatty acid derivatives can also come from palm oil, tallow, lard, cottonseed oil, peanut oil.

[0320] It may be particularly advantageous if the fatty acid derivative comprises a saturated or unsaturated fatty acid selected from the group consisting of C20:4n-6, C22:6n-3, C24:1n-9, C16:0, C18:1n-9 and C18.0. In particular, a saturated or unsaturated fatty acid of C20:4n-6 and / or C22:6n-3 and / or C18:0, more particularly 22:6n-3 and / or C18:0 may be particularly beneficial.

[0321] A composition comprising phospholipids, particularly sphingomyelin, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, and more particularly sphingomyelin, may be particularly effective when used in combination with one or more of these fatty acids.

[0322] C20:4n-6 is arachidonic acid (hereinafter referred to as ARA or AA). C22:6n-3 is docosahexaenoic acid (hereinafter referred to as DHA). 24:1n-9 is nervonic acid. C18.0 is stearic acid. C16:0 is palmitic acid. C18:1n-9 is oleic acid.

[0323] In one embodiment, the composition according to the invention comprises fatty acid derivatives containing DHA and / or ARA and / or nervonic acid and / or stearic acid, in particular fatty acid derivatives containing DHA and / or ARA and / or stearic acid. Most particularly fatty acid derivatives containing DHA and / or stearic acid.

[0324] Fatty acid derivatives comprising DHA and / or ARA and / or nervonic acid and / or stearic acid may be included in the composition of the present invention in an amount of up to 99.999% of the composition.

[0325] Fatty acid derivatives, in particular comprising DHA and / or ARA and / or nervonic acid and / or stearic acid, may be comprised in the composition of the invention in an amount of 15 to 350 mg / 100 g dry weight of the composition, more in particular 30 to 300 mg / 100 g dry weight of the composition.

[0326] In one embodiment, the composition according to the invention comprises fatty acid derivatives containing DHA and / or ARA and / or nervonic acid and / or stearic acid in an amount selected from: above 15 mg / 100 g, above 30 mg / 100 g, above 50 mg / 100 g, above 55 mg / 100 g, within the range of 30 mg / 100 g and 300 mg / 100 g, within the range of 30 mg / 100 g to 200 mg / 100 g or 30 mg / 100 g to 150 mg / 100 g, within the range of 50 mg / 100 g to 300 mg / 100 g. In the range of 50 mg / 100 g to 200 mg / 100 g, in the range of 50 mg / 100 g to 150 mg / 100 g, in the range of 150 mg / 100 g to 350 mg / 100 g, in the range of 60 mg / 100 g to 350 mg / 100 g, in the range of 60 mg / 100 g to 120 mg / 100 g, in the range of 100 mg / 100 g to 110 mg / 100 g. All concentrations are by dry weight of the composition.

[0327] Fatty acid derivatives including stearic acid occur in natural sources such as palm oil, tallow, lard, cottonseed oil, peanut oil.

[0328] Fatty acid derivatives containing nervonic acid are present in natural sources, such as seed oils of Cardaminegracea, Heliphila longifola, Thlaspi perfoliatum, Tropaeolum speciosum, Lunaria biennis, Lunaria annua, and Malania oleifera; the fungi Neocallismastix frontalis, Erysiphe graminis, and Sphaerotheca humuli; the bacterium Pseudomonas atlantica; the yeast Saccharomyces cerevisiae, and the marine diatom Nitzschia cylindrus.

[0329] Fatty acid derivatives comprising DHA and / or ARA are present in natural sources such as, for example, eggs, algae, fungi or fish oils and plants.

[0330] The oil comprising fatty acid derivative can have various sources, and this fatty acid derivative comprises DHA and / or ARA, and comprises other polyunsaturated fatty acids (PUFA), particularly EPA (eicosapentaenoic acid) usually.Preferably, the fatty acid derivative comprising DHA provides with the form of the fish oil comprising the fatty acid derivative containing DHA and / or ARA.Fish oil comprises 5 % by weight or more usually, and is preferably 10 % by weight or more fatty acid derivative comprising DHA and / or ARA.It is also possible to obtain the oil containing the fatty acid derivative comprising DHA and / or ARA obtained in a large number from algae or microorganism usually.For example, can use from comprising 10 % by weight or more, the oil of the algae gathering of for example 20 % by weight or more fatty acid derivative.

[0331] If the nutritional composition according to the invention comprises fatty acid derivatives containing ARA and DHA, the ingredients may be contained in the composition according to the invention, for example, in an amount such that the weight ratio of DHA:ARA is in the range of 4:1 to 1:4, for example 3:1 to 1:3, for example 2:1 to 1:2, for example 1.5:1 to 1:1.5, in particular 1.1:1 to 1:1.1.

[0332] It may also be beneficial if the composition of the present invention comprises a mixture of fatty acid derivatives, wherein the mixture is such that the weight ratio of unsaturated fatty acids and / or fatty acid residues to saturated fatty acids and / or fatty acid residues in the composition of the present invention is in the range of 1:1 to 1:2, 1:1.2 to 1:1.9, 1:1.25 to 1:1.5, 1:3 to 1:4.

[0333] In addition, when a large amount of fatty acid ester derivatives comprising DHA and / or ARA are included in the composition of the present invention, it may be particularly beneficial if the total amount of fatty acid derivatives comprising saturated long-chain fatty acids, particularly C20 / 24, is increased. These saturated long-chain fatty acids can be important components of myelin, enabling it to surround and coat axons. The weight ratio of DHA and / or AA to these unsaturated long-chain fatty acids in the composition of the present invention can be, for example, in the range of 1:1 to 1:10, 1:2 to 1:9, 1:3 to 1:4.5, 1:3.5 to 1:4.5.

[0334] Compositions of the invention comprising fatty acid derivatives (e.g., fatty acid derivatives comprising DHA and / or AA) may be particularly effective in supporting, promoting or optimizing remyelination, particularly remyelination trajectories, and / or brain structures in one or more of the following brain regions: cerebellum, internal capsule, parietal lobe, motor and sensory cortex (including coordination and execution of movement), visual cortex, frontal cortex. This brain region is associated with visual function, motor function and psychomotor function (including coordination and execution of motor function), and / or executive function, and social-emotional function.

[0335] Those skilled in the art can identify appropriate amounts of the above nutrients, their metabolic precursors or metabolites according to the nature, purpose, target individual and dosage of the composition (e.g., how many times a day the composition will be taken by an individual). Generally, the effective dose will depend on the age, body shape and health status of the individual, on the lifestyle of the individual, on the amount of the nutrients in the composition, and may depend on the sex of the individual.

[0336] An effective dose may be any dose that promotes, supports or optimizes remyelination, particularly remyelination trajectory, and / or brain structure, and / or brain connectivity, and / or intellectual potential and / or cognitive potential and / or learning potential and / or cognitive function in an individual.

[0337] For infant formula or growing-up milk, one can base the amounts or ratios of the compounds or nutrients (eg, vitamins) disclosed herein on those found in human breast milk, particularly produced by a well-nourished mother for an infant or child of the same age.

[0338] Determination of an effective dosage is well within the capability of those skilled in the art based on the information herein and the knowledge in the art.

[0339] In one embodiment, the composition according to the invention comprises: vitamins, in particular vitamin B12 and / or folic acid; phospholipids, in particular phosphatidylcholine, and / or and / or phosphatidylserine, and / or phosphatidylinositol, and / or sphingomyelin and / or metabolic precursors or metabolites of any of the foregoing; minerals, in particular iron and / or zinc and / or calcium and / or magnesium and / or phosphorus and / or copper; and choline; and fatty acid derivatives, in particular fatty acid derivatives comprising DHA and / or AA and / or nervonic acid and / or stearic acid.

[0340] Particularly beneficial concentrations / amounts of the ingredients in the composition may be an amount of sphingomyelin of at least 300 mg / kg or 420 mg / kg, particularly more than 800 mg / kg, more particularly more than 900 mg / kg; an amount of phosphatidylcholine of at least 1000 mg / kg; an amount of phosphatidylserine of at least 900 mg / kg; an amount of phosphatidylinositol of at least 700 mg / kg; an amount of folic acid of at least 140 mg / kg, more particularly at least 160 mg / kg; an amount of vitamin B12 of at least 2.34 mcg / 100 g, particularly more than 5 mcg / 100 g, more particularly 7 mcg / 100 g; an amount of iron of at least 6 mg / 100 g or at least 8.6 mg / 100 g, more particularly 11.5 mg / 100 g, even more. In particular, more than 16 mg / kg; the amount of choline is at least 124 mg / kg, more particularly 140 mg / kg; the amount of fatty acid derivatives containing DHA is at least 89 mg / 100 g; the amount of fatty acid derivatives containing AA is at least 89 mg / 100 g or at least 175 mg / 100 g; the amount of zinc is at least 4 mg / 100 g or at least 4.7 mg / 100 g, more particularly 7 mg / 100 g; the amount of calcium is at least 200 mg / 100 g or at least 500 mg / 100 g; the amount of phosphorus is at least 140 mg / 100 g or at least 350 mg / 100 g; the amount of copper is at least 250 mcg / 100 g or at least 600 mcg / 100 g; the amount of magnesium is at least 30 mg / 100 g or at least 50 mg / 100 g. All weights are calculated on a dry weight basis of the composition.

[0341] For any analytical technique used to measure the concentration of one or more of the above-mentioned components, concentrations that fall within the established error range should be considered to fall within the concentration ranges listed herein.

[0342] In one embodiment, the composition according to the invention comprises: vitamin B12 and / or folic acid; sphingomyelin and / or metabolic precursors or metabolites thereof; iron, zinc; choline and fatty acid derivatives comprising DHA and / or AA.

[0343] In one embodiment, the composition according to the invention comprises fatty acid derivatives comprising DHA and / or ARA; vitamin B12 and / or folic acid; sphingomyelin and iron.

[0344] In a more specific embodiment, the composition according to the invention comprises fatty acid derivatives comprising DHA at a concentration of 102 mg / 100 g, fatty acid derivatives comprising ARA at a concentration of 102 mg / 100 g, vitamin B12 at a concentration of 5.4 mcg / 100 g, folic acid at a concentration of 169 mcg / 100 g, sphingomyelin at a concentration of 81.4 mg / 100 g and iron at a concentration of 6.7 mg / 100 g.

[0345] The composition of the present invention may be any type of composition suitable for direct administration to an individual.

[0346] In particular the composition will be a synthetic nutritional composition.

[0347] As used herein, the term "synthetic nutritional composition" refers to a synthetic composition for nourishing an individual. The nutritional composition may be taken enterally, parenterally or intravenously. In particular, the composition will be taken enterally, more particularly orally.

[0348] In an embodiment of the present invention, the composition will be a synthetic nutritional composition selected from the group consisting of growing-up milks, infant formulas, or compositions for infants intended to be added to or diluted with human breast milk (hereinafter referred to as "HM") (e.g., HM fortifiers), or foodstuffs intended for consumption by infants and / or children alone or in combination with HM (e.g., complementary foods).

[0349] The compositions of the present invention may also contain any other ingredients or excipients known for use in the type of composition involved (eg, infant formula).

[0350] Non-limiting examples of such ingredients include: proteins, amino acids, carbohydrates, oligosaccharides, lipids, prebiotics or probiotics, nucleotides, nucleosides, other vitamins, minerals, and other micronutrients.

[0351] In a typical embodiment of the invention, the composition will comprise a protein source, a lipid source, and a carbohydrate source.

[0352] For example, such compositions may comprise protein in the range of about 2 g / 100 kcal to 6 g / 100 kcal, lipid in the range of about 1.5 g / 100 kcal to 3 g / 100 kcal and / or carbohydrate in the range of about 1.7 g / 100 kcal to 12 g / 100 kcal.

[0353] If the composition is liquid, its energy density may be between 60 kcal / 100 ml and 75 kcal / 100 ml.

[0354] If the composition is solid, its energy density may be between 60 kcal / 100 g and 75 kcal / 100 g.

[0355] The type of protein is not considered to be critical to the present invention. However, in the case of synthetic compositions for infants and / or children (e.g., infant formula or growing-up milk), the protein should support the growth of the infant and / or child so that the infant and / or child can follow a typical growth curve for their genetic background, birth weight and health status.

[0356] Non-limiting examples of proteins include casein, alpha-lactalbumin, whey, beta-lactoglobulin, soy protein, rice protein, corn protein, oat protein, barley protein, wheat protein, rye protein, pea protein, egg protein, sunflower protein, potato protein, fish protein, meat protein, lactoferrin, serum albumin, immunoglobulin, and combinations thereof.

[0357] Non-limiting examples of amino acids include leucine, threonine, tyrosine, isoleucine, arginine, alanine, histidine, isoleucine, proline, valine, cysteine, glutamine, glutamic acid, glycine, serine, arginine, lysine, methionine, phenylalanine, tryptophan, asparagine, aspartic acid, and combinations thereof.

[0358] Non-limiting examples of carbohydrates include lactose, sucrose, maltodextrin, starch, and combinations thereof.

[0359] Non-limiting examples of lipids include palm olein, high oleic sunflower oil, high oleic safflower oil, canola oil, fish oil, coconut oil, butterfat, and combinations thereof.

[0360] It may be particularly beneficial if the composition comprises fat in an amount of 25 g / 100 g to 30 g / 100 g dry weight of the composition.

[0361] Non-limiting examples of essential fatty acids include: linoleic acid (LA), alpha-linolenic acid (ALA). The composition of the present invention may also include gangliosides (monosialylganglioside-3 (GM3) and disialylganglioside 3 (GD3), and combinations thereof).

[0362] Non-limiting examples of prebiotics include: oligosaccharides optionally containing fructose, galactose, mannose; dietary fiber, in particular soluble fiber, soy fiber; inulin; and combinations thereof. Preferred prebiotics are fructooligosaccharides (FOS), galacto-oligosaccharides (GOS), isomalto-oligosaccharides (IMO), xylo-oligosaccharides (XOS), arabinoxolose (AXOS), manno-oligosaccharides (MOS), soy oligosaccharides, glycosylsucrose (GS), lactosucrose (LS), lactulose (LA), palatinose oligosaccharides (PAO), maltooligosaccharides, gums and / or their hydrolysates, pectins and / or their hydrolysates, and combinations of the foregoing.

[0363] Further examples of oligosaccharides are described in Wrodnigg, TM; Stutz, AE (1999) Angew. Chem. Int. Ed. 38:827-828 and WO 2012 / 069416 (incorporated herein by reference).

[0364] Non-limiting examples of probiotics include: Bifidobacterium, Lactobacillus, Lactococcus, Enterococcus, Streptococcus, Kluyveromyces, Saccharoymces, Candida, in particular selected from Bifidobacterium longum, Bifidobacterium lactis, Bifidobacterium animalis, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium adolescentis, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus paracasei, paracasei), Lactobacillus salivarius, Lactobacillus lactis, Lactobacillus rhamnosus, Lactobacillus johnsonii, Lactobacillus plantarum, Lactobacillus salivarius, Lactococcus lactis, Enterococcus faecium, Saccharomyces cerevisiae, Saccharomyces boulardii or a mixture thereof, preferably selected from Bifidobacterium longum NCC3001 (ATCC BAA-999), Bifidobacterium longum NCC2705 (CNCM I-2618), Bifidobacterium longum NCC490 (CNCM I-2170), Bifidobacterium lactis NCC2818 (CNCM I-3446), Bifidobacterium breve strain A, Lactobacillus paracasei NCC2461 (CNCM I-2116), Lactobacillus johnsonii NCC533 (CNCM I-1225), Lactobacillus rhamnosus GG (ATCC53103), Lactobacillus rhamnosus NCC4007 (CGMCC 1.3724), Enterococcus faecium SF 68 (NCC2768; NCIMB10415), and combinations thereof.

[0365] Non-limiting examples of nucleotides include cytidine monophosphate (CMP), uridine monophosphate (UMP), adenosine monophosphate (AMP), guanosine monophosphate (GMP), and combinations thereof.

[0366] Other suitable and desired ingredients of the nutritional compositions that can be used in the nutritional compositions of the present invention may be described in the guidelines issued by the Codex Alimentarius for the type of nutritional composition involved, such as infant formula, HM fortifier, follow-on formula or foodstuffs (e.g., complementary foods) intended for consumption by infants.

[0367] In an even more specific embodiment, the composition of the invention is an infant formula having the composition listed in Example 5 and specifically in Table 11a.

[0368] The synthetic nutritional composition used in the present invention, such as infant formula, can be prepared in any suitable manner. For example, infant formula can be prepared by blending a protein source, a carbohydrate source and a fat source in a suitable ratio. If an emulsifier is used, it can be included in the blend. Vitamins and any minerals can be added at this time, but in order to avoid thermal degradation, they are usually added a little later. Any lipophilic vitamins, emulsifiers and other substances can be dissolved in a fat source first and then blended. Water (preferably water through reverse osmosis) can then be mixed to form a liquid mixture. The liquid mixture can then be heat treated to reduce the amount of bacteria. For example, the liquid mixture can be rapidly heated to a temperature in the range of about 80°C to about 110°C for about 5 seconds to about 5 minutes. This can be done by steam injection or a heat exchanger (such as a plate heat exchanger). Then, the liquid mixture can be cooled to about 60°C to about 85°C, for example, by rapid cooling. The liquid mixture can then be homogenized; for example, in two stages: the first stage is carried out at about 7MPa to about 40MPa, and the second stage is carried out at about 2MPa to about 14MPa. The homogenized mixture can then be further cooled to add any heat-sensitive components; for example, vitamins and minerals. At this moment, the pH and solid content of the homogenized mixture are standardized. The homogenized mixture is transferred to a suitable drying device (such as a spray dryer or a freeze dryer) and converted into a powder. The water content of the powder should be less than about 5% by weight. If it is necessary to increase one or more probiotics, the probiotics can be cultured according to any suitable method, and then, for example, prepared by freeze drying or spray drying for addition to infant formula. Alternatively, bacterial products that have been made into suitable forms can be purchased from professional suppliers such as Danish Hansen Company (Christian Hansen) and Japanese Morinaga Milk Industry Co., Ltd. (Morinaga) for addition to food products (such as infant formula). Such bacterial products can be added to powdered infant formula by dry mixing.

[0369] As is apparent from the above disclosure, the compositions of the present invention can be used to promote, support or optimize remyelination, particularly remyelination trajectory, and / or brain structure, and / or brain connectivity and / or intellectual potential, and / or cognitive potential and / or learning potential and / or cognitive function in an individual, particularly a formula-fed individual.

[0370] In another aspect of the invention, there is provided a method for promoting, supporting or optimizing remyelination, in particular remyelination trajectory, and / or brain structure, and / or brain connectivity and / or intellectual potential, and / or cognitive potential and / or learning potential and / or cognitive function in an individual, in particular a formula-fed individual, the method comprising feeding the individual a composition comprising vitamins, in particular folic acid and / or vitamin B12 as defined herein.

[0371] In another aspect of the invention, a composition is provided comprising vitamins, in particular folic acid and / or vitamin B12 as defined herein, for the preparation of a composition for promoting, supporting and / or optimizing remyelination, in particular remyelination trajectory, and / or brain structure, and / or brain connectivity and / or intellectual potential, and / or cognitive potential and / or learning potential and / or cognitive function in an individual, in particular a formula-fed individual.

[0372] It may be particularly beneficial if the composition of the invention is administered to an infant of 9 months of age or younger, particularly 6 months of age or younger, more particularly 3 months of age or younger.

[0373] Non-limiting examples of 3 months of age or younger are up to 2 weeks of age, up to 1 month of age, up to 2 months of age, up to 3 months of age, 1 to 3 months of age.

[0374] The effects of the compositions of the invention described herein may have long-term health benefits. Dementia (e.g., Alzheimer's disease) results in a decline in the individual's ability to think and remember, as well as emotional and language problems. The risk of an individual suffering from dementia, particularly Alzheimer's disease, has been associated with the intellectual ability or intelligence of the person. Therefore, by optimizing the intelligence, cognition, and / or learning potential of an individual, the risk of an individual suffering from dementia, particularly Alzheimer's disease, may be reduced. The long-term effects may only become apparent in a few years (e.g., 40, 50, 60, 70, 80, 90 years).

[0375] In addition, various mental illnesses and / or neurological disorders (e.g., anxiety, depression, autism and schizophrenia) are related to brain structure, particularly related to the amount and / or spatial distribution of white matter of the whole brain. By promoting, supporting or optimizing individual remyelination, particularly remyelination track and / or brain structure, it is possible to prevent mental illnesses and / or neurological disorders (e.g., anxiety, depression, autism and schizophrenia), or reduce the risk of suffering from these diseases, or reduce the severity of the illness. The effect can only become apparent in a few years (e.g., 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 20 years, 30 years, 40 years, 50 years, 60 years, 70 years, 80 years, 90 years).

[0376] Unless otherwise indicated, all percentages expressed herein are by weight.

[0377] In the context of the present invention, the term "comprising" or "including" does not exclude other possible elements. The composition mentioned in the present invention (including the multiple embodiments described herein) may include the following elements, be composed of or consist essentially of the following elements: the basic elements and necessary restrictions described herein, and any other or optional (or as required) ingredients, components or restrictions described herein.

[0378] As will be apparent to the skilled artisan, the same benefits disclosed herein can be obtained by taking the vitamins, particularly folic acid and / or vitamin B12 directly, as opposed to in the form of a composition. Thus, the vitamins, particularly folic acid and / or vitamin B12 can be used directly in any of the methods or uses described herein in place of the compositions of the invention.

[0379] As will be further apparent to the skilled person, it may be particularly beneficial if the vitamins, in particular folic acid and / or vitamin B12, are administered separately, sequentially and / or simultaneously with, i.e. consumed: choline; and / or minerals, in particular iron and / or zinc and / or calcium and / or phosphorus and / or magnesium and / or copper; fatty acid derivatives, in particular fatty acid derivatives comprising docosahexaenoic acid and / or arachidonic acid and / or nervonic acid and / or stearic acid; and / or phospholipids, in particular phosphatidylcholine, phosphatidylserine, phosphatidylinositol and / or sphingomyelin and / or sphingomyelin and / or metabolic precursors or metabolites of any of the foregoing.

[0380] All details of the invention apply equally to the composition comprising vitamins, in particular folic acid and / or vitamin B12, and to the direct use of vitamins, in particular folic acid and / or vitamin B12.

[0381] It should be understood that all features of the present invention disclosed herein can be freely combined, and that changes and modifications may be made to these features without departing from the scope of the present invention as defined in the claims. In addition, if there are known equivalents for specific features, these equivalents should be incorporated into this specification as if they were specifically mentioned in this specification.

[0382] As used herein, the terms "particularly (especially)" or "more particularly (more particularly)" should not be seen as limiting, but should be interpreted as being synonymous with "for example" or "especially".

[0383] The following are a series of non-limiting examples used to illustrate the present invention.

[0384] Experimental Section :

[0385] Methods, definitions, and materials

[0386] MRI (Magnetic Resonance Imaging): MRI brain scans of infants and children between 0 and 5 years of age were obtained using white matter imaging techniques. This technique provides a quantitative measure, myelin water fraction (MWF), which is a surrogate marker of myelin content in the brain. When mapped as a function of time in early childhood, a myelination trajectory can be generated.

[0387] Infant formula food composition: Six infant formulas were fed to the infants participating in the study and analyzed for their composition / levels of myelin-related nutrients.

[0388] The nutritional compositions were tested in standard commercial infant formulas from different brands / suppliers and revealed different levels of nutrients contained therein.

[0389] Cognitive abilities: Age-standardized (T) scores for gross motor, visual reception, and language (expressive and receptive) were derived from the Mullen Scales of Early Learning, which are standardized and validated measures of early cognitive development for infants and children 6 years of age or younger.

[0390] Nutrient analysis

[0391] The nutrients in each of the 6 infant formula compositions are shown in Table 1.

[0392] Table 1

[0393]

[0394] Clinical Research

[0395] Infant Participants

[0396] The infants included in the study were extracted from a larger longitudinal study of normal brain and behavioral development: the Brown University Assessment of Myelination and Behavior during Maturation (BAMBAM). In order to focus on neurotypical development, children with known potential risk factors for learning, neurological, or psychiatric disorders were specifically excluded during recruitment and enrollment. Therefore, children with in utero alcohol or illicit substance exposure, premature birth (<37 weeks of gestation) or multiple births, fetal ultrasound abnormalities, complicated pregnancies (e.g., preeclampsia), APGAR scores <8, admission to the NICU, neurological disorders (e.g., head injury, epilepsy), psychiatric or developmental disorders in the infant, parents, or siblings (including maternal depression requiring medication) were excluded. Ongoing screening (such as the Autism MCAT, or the Behavior Problems CBCL) was further used to remove enrolled children with clinically concerning behaviors or obvious medical conditions (such as autism spectrum disorders).

[0397] A combination of retrospective and prospective data was obtained from parents via detailed medical records and parent interviews to understand the type of infant formula used, the percentage of breastfeeding versus formula feeding, and the length of time of exclusive breastfeeding. This information was updated at each study visit, which was conducted approximately every 6 months for children under 2 years of age, and once a year for older children. Using this information, children were classified into 2 groups: No. 1, complete formula feeding; and No. 2, complete breastfeeding for at least 90 days (3 months). Children who were fed a combination of breast milk and formula within 3 months were excluded from our analysis. Infants in the complete formula feeding group were further subdivided according to parental reports of the main infant formula used throughout the first 3 months. The main formula was defined as given 90% of the time or more (e.g., in the case where parents use alternative brands during vacation).

[0398] Using these criteria, 94 infants who were exclusively formula-fed were selected to be included in Group 1. These children included 13 children who received Formula 2; 28 children who received Formula 5; 8 children who received Formula 3; 39 children who received Formula 4; 5 children who received Formula 1; and 1 child who received Formula 6. A sample of 52 exclusively breast-fed infants was also selected and matched to the formula-fed groups with respect to mean age, duration of pregnancy, birth weight, sex ratio, ethnicity ratio, maternal education, family size, and the number of languages ​​(other than English) spoken at home. The groupings for each formula are provided in Table 1a.

[0399] Table 1a Details of data used for longitudinal and nutritional analyses

[0400]

[0401] Imaging methods and analysis

[0402] Using mcDESPOT(T 1 and T 2 Each infant was scanned using the multicomponent driven balanced single pulse observation (MDESP) white matter imaging technique, Deoni et al. (Magn. Reson. Med. 2008, 60: 1372-1387), which provides quantitative measurements of myelin water fraction (MWF)—a measure of myelin content—at every point throughout the brain. All infants were scanned during natural (i.e., non-sedated) sleep using the acoustically anechoic mcDESPOT imaging protocol. Total imaging time ranged from 19 minutes for the youngest toddlers to 24 hours for the older 4-year-olds.

[0403] All data are acquired on the Siemens 3T Tim Trio scanner equipped with 12 channel head RF arrays. In order to minimize the internal motion of the scan, children are wrapped with pediatric MedVac vacuum fixation bags (CFI Medical Solutions, USA) and foam pads. By reducing the peak gradient amplitude and conversion rate, and using noise isolation scanner hole inserts (quiet barrier HD composites, UltraBarrier, USA (UltraBarrier, USA)) to reduce scanner noise. MiniMuff pediatric earmuffs and electric headphones (MR Confon, Germany) have also been used. Children are continuously monitored with pediatric pulse oximetry system and infrared camera. All children keep sleeping during the duration of MRI scanning, and there is no motion artifact in the analysis data.

[0404] In image alignment, non-brain signal removal, and the main magnetic field and transmission magnetic field (B 0 and B 1 ) inhomogeneity, a three-cistern signal model (including myelin-associated water; intra-axonal water; and a non-exchangeable free water pool) was fit to the mcDESPOT data to derive voxel-based MWF maps.

[0405] Each child's map was then nonlinearly aligned to a study-specific template. White matter masks corresponding to five bilateral regions (frontal, temporal, occipital, parietal, and cerebellar WM) and the body, genu, and splenium of the corpus callosum were created from a common database, registered to a common template, and superimposed on each child's MWF map. The mean value for each region was then determined for each child and used in subsequent developmental analyses and trajectory modeling.

[0406] Developmental Differences:

[0407] To examine developmental differences between breast-fed and formula-fed infants, and between infants fed different formulas, a nonlinear mixed-effects modeling approach was used. Modified Gompertz growth models were fit independently to Groups 1 and 2, and to each formula subgroup. Each of the four Gompertz model parameters was then compared between the breast-fed and formula-fed groups using unpaired t tests, and between the 4 formula subgroups using analysis of variance, followed by post hoc Tukey tests to determine which differed within the formula groups.

[0408] Cognitive Assessment and Analysis

[0409] In addition to MR imaging, general cognitive abilities and skills were assessed for each child within 7 days of scanning using the Mullen Scales of Early Learning (MSEL) (Mullen EM, 1995). The MSEL provides a broad assessment of behavioral development in the areas of fine and gross motor control, receptive and expressive language, and visual reception. Age-standardized T scores from these domains can be combined into three composite scores: the Early Learning Composite (ELC, which includes fine motor, visual reception, expressive, and receptive language); the Nonverbal Developmental Quotient (NVDQ, which includes fine motor and visual reception scores); and the Verbal Developmental Quotient (VDQ, which includes expressive and receptive language scores).

[0410] As with the MWF MRI data, potential group mean differences in ELC, VDQ, and NVDQ between breast-fed and formula-fed infants and between the different formula subgroups were examined. In addition to mean comparisons, mixed-effects modeling assuming linear trends was used to investigate longitudinal changes in these three composite values.

[0411] Example 1

[0412] Identification of nutritional drivers from cross-sectional analyses

[0413] From the above cohort, children up to 5 years old who were fed different infant formulas during infancy were included in a large correlation analysis to examine the relationship between the nutritional composition of the formulas and brain myelination. The 6 most commonly used formulas in this cohort were analyzed for their nutritional composition. A single general linear model (GLM) simulating all quantitative nutrients and children's age was constructed.

[0414] The Spearman rank correlation between nutrient content and myelin content values ​​(adjusted for children's age) was then calculated at each image voxel or point in the brain. Using a cluster-based correction method, significance was defined as p<0.05 corrected for the first type of error. Association or trend was defined as p<0.15. In the initial analysis, all 22 nutrients shown in Table 1 led to an underpowered model. In order to reduce the number of nutritional components in the model, we checked the correlation between nutrients. Using a conservative threshold of 0.9, we excluded nutritional components that were highly correlated to each other in various formula foods. This produced a final model, which included iron, sphingomyelin, folic acid, choline, DHA, zinc and phosphatidylcholine.

[0415] P<0.05: iron, sphingomyelin, folate, choline, and DHA.

[0416] P < 0.15: zinc and phosphatidylcholine.

[0417] The nutritional components found to be highly correlated with each other were:

[0418] Folic acid and vitamin B12.

[0419] DHA and AA.

[0420] Zinc, calcium, magnesium, copper and phosphorus.

[0421] Phosphatidylcholine, phosphatidylserine and phosphatidylinositol.

[0422] For folic acid, an association with myelination (myelin water fraction) was observed over time in the brain, particularly in the cerebellum, motor cortex, and visual cortex. Results are reported in Figure 1b middle.

[0423] For vitamin B12, an association with myelination (myelin water fraction) was observed over time in the brain, particularly in the cerebellum, visual cortex, motor and somatosensory cortex. Results are reported in Figure 2 middle.

[0424] For iron, an association with myelination (myelin water fraction) was observed over time in the brain, particularly in the cerebellum, visual cortex, internal capsule, motor and somatosensory cortex, corpus callosum, frontal cortex, temporal lobe white matter. Results are reported in Figure 2a middle.

[0425] For zinc, an association with myelination (myelin water fraction) was observed over time in the brain, particularly in the cerebellum, visual cortex, internal capsule, motor and somatosensory cortex, corpus callosum, frontal cortex, temporal lobe white matter. Results are reported in Figure 2b middle.

[0426] For calcium, an association with myelination (myelin water fraction) was observed over time in the brain, particularly in the cerebellum, visual cortex, motor and somatosensory cortex, corpus callosum, frontal cortex, temporal lobe white matter. Results are reported in Figure 2c middle.

[0427] For phosphorus, an association with myelination (myelin water fraction) was observed over time in the brain, particularly in the cerebellum, visual cortex, motor and somatosensory cortex, and prefrontal cortex. Results are reported in Figure 2d middle.

[0428] For magnesium, an association with myelination (myelin water fraction) was observed over time in the brain, particularly in the cerebellum, visual cortex, internal capsule, corpus callosum, frontal cortex, motor cortex. Results are reported in Figure 2e middle.

[0429] For sphingomyelin, an association with myelination (myelin water fraction) was observed over time in the brain, particularly in the cerebellum, visual cortex, internal capsule, frontal lobe, parietal lobe, temporal lobe. Results are reported in Figure 2f middle.

[0430] For phosphatidylinositol, an association with myelination (myelin water fraction) was observed over time in the brain, particularly in the cerebellum, visual cortex, motor cortex, frontal cortex. Results are reported in Figure 2g middle.

[0431] For phosphatidylcholine, an association with myelination (myelin water fraction) was observed over time in the brain, particularly in the cerebellum, visual cortex, internal capsule, frontal lobe, parietal lobe, temporal lobe. Results are reported in Figure 2h middle.

[0432] For choline, an association with myelination (myelin water fraction) was observed over time in the brain, particularly in the cerebellum, visual cortex, thalamus, parietal cortex, and frontal lobe. Results are reported in Figure 2i middle.

[0433] For DHA, an association with myelination (myelin water fraction) was observed over time in the brain, particularly in the cerebellum, primary and secondary motor cortex, internal capsule, visual cortex, frontal cortex. Results are reported in Figure 2j middle.

[0434] For AA, an association with myelination (myelin water fraction) was observed over time in the brain, particularly in the cerebellum, internal capsule, parietal lobe, motor and sensory cortices, visual cortex, frontal cortex. Results are reported in Figure 2k middle.

[0435] Example 2

[0436] a) Myelination trajectories throughout the brain from a longitudinal study

[0437] From the available data, longitudinal myelin development (remyelination) trajectories were calculated using repeated MWF data from children whose infant formulas (the compositions of such formulas are reported in Table 3 below) contained varying amounts of folic acid and vitamin B12. Trajectories were calculated using a longitudinal nonlinear mixed effects approach. A modified Gompertz growth model was fit to the data for children in each formula group. The results are reported in Figure 1 middle.

[0438] Table 3 :

[0439] (Low in folate / B12) (High in folate / B12) Folic acid 107mcg / 100g 306mcg / 100g Vitamin B12 4.93mcg / 100g 8.34mcg / 100g

[0440] b) Average regional myelination trajectories from a longitudinal study

[0441] From the available data, mean regional trajectories of longitudinal myelin development (remyelination) were calculated using repeated MWF data from children whose infant formulas (the compositions of such formulas are reported in Table 2a below) contained varying amounts of folic acid and vitamin B12. Trajectories were calculated using a longitudinal nonlinear mixed effects approach, and a modified Gompertz growth model was fit to the data for children in each formula group. The results are presented in Table 2a. Figure 1a Report in.

[0442] Table 3a

[0443]

[0444]

[0445] Example 3

[0446] Suppliers and Stock Solutions

[0447]

[0448] Vehicle and dosage

[0449]

[0450] Culture medium composition and culture method

[0451] 1) Neural Basal Complete Medium

[0452] Neurobasal medium (Life Technologies Corp., No. 21103-049)

[0453] 50X B27 Supplement (LIFE TECHNOLOGIES CORP, No. 12587-010)

[0454] 2 mM L-glutamine (Life Technologies Corp., No. 25030-149)

[0455] 1X Penicillin-Streptomycin (Life Technologies Corp., No. 15140-122)

[0456] 2) Neural basal medium with growth factors (GF)

[0457] Above recipe with GF blend

[0458] 1M Tris (molecular weight 121.14, Fisher SCI BP152)

[0459] Heparin (sigma H3149)

[0460] BSA (Sigma A7030)

[0461] DNA enzyme, RNA enzyme, protease free water (Fisher SCI AC327390010)

[0462] EGF(GIBCO PHG0311)

[0463] bFGF vial (GIBCO PHG0021)

[0464] 3) Choline-free Neurobasal Medium (Life Technologies, custom formulated, L-free Glutamine, without phenol red)

[0465] NOTE: Finishing and finishing with GF is the same as above.

[0466] Generation of Neural Progenitor Cell (NPC) Banks:

[0467] Dissociation of E14 mouse neocortex

[0468] Required Reagents:

[0469] DPBS (1X) + 10% Penicillin / Streptomycin

[0470] Neurobasal Medium / 10% Penicillin / Streptomycin / 10X Hepes

[0471] Process :

[0472] E14 pup brains were harvested and placed in ice-cold DPBS (1X) + 10% penicillin / streptomycin and then dissected using a dissecting microscope. From each pup, one brain hemisphere was placed in 2 ml of Neurobasal medium / 10% P / S / 10X Hepes and the other brain hemisphere was placed in another tube.

[0473] The tissue from each tube was aseptically and manually dissociated into single cells, Neurobasal complete medium was added and centrifuged at 130G for 5 minutes. The tissue was then resuspended in Neurobasal complete medium with GF and placed in a 100mm×20mm Corning suspension dish (No. 430591). The cells were passaged twice using a 1:3 ratio, after which they were centrifuged (130g, 5 minutes), resuspended in freezing medium (10% DMSO and Neurobasal complete medium, no GF) and frozen in liquid nitrogen (LN2).

[0474] Thawing cells for compound screening

[0475] Remove the vial from LN2, thaw quickly, and transfer the cells dropwise to a 15mL conical flask. Add 10ml of complete neurobasal medium. Transfer the cells to a suspension culture dish and place in an incubator for 2 hours. At 1.5 hours, check the cells. According to health status and number of people, estimate the number of plates required, and warm the appropriate amount of complete neurobasal medium. After 2 hours, place the cells in a 15mL conical tube and spin at 130G for 5 minutes. Then resuspend the cells in complete neurobasal medium with GF (3ul of GF per 10mL culture medium). Then grow the cells overnight and use them in the experiment.

[0476] Plate cells in 96-well plates for neurosphere count and diameter only

[0477] Corning Costar 3474, 96-well plate, ultra-thin attachment

[0478] Dissociation and plating of cells

[0479] Remove 3-4 mL of cells from the tilted plate and add to a 15 ml cone. Use some of the remaining medium to rinse the plate. Pull all remaining medium out and place in a 15 ml conical tube and spin at 130 G for 5 minutes. Remove all medium. Gently resuspend the cells in 5 ml warm PBS and spin again. Then remove the PBS and then gently resuspend the cells in 500 μl Accutase (Corning TM Accutase TMCells were then gently pipetted with a 1000 μl tip to break up clumps and then placed in a shaking water bath for 5-10 minutes, after which they were frequently vortexed by hand.

[0480] Culture media were prepared as indicated below, all with GF :

[0481]

[0482] Control and compound media were prepared with Medium 2 and contained 29uM choline, low (5uM) and medium (70uM) choline media were prepared with Medium 3.

[0483]

[0484] The medium was gently pipetted using a 1000 μl tip, and then a 200 μl tip was used to further disperse the cells.

[0485] Clumps should be no larger than about 3-5 cells. Add 5-10 ml of warm medium (GF) to dilute the enzyme. Add 2 mL of medium. Pipette this with a 1000 ul pipette and then add 3 ml with a serological pipette. Filter cells through a cell culture approved 40 μM filter before plating.

[0486] Remove 1 ml to count the cells. Spin the cells again. Remove the medium from the cell mass and add 1 ml of preparation medium (no GF). Pipette the cells with a 1000 ul pipette. Prepare a cell dilution (24,000 cells / well) in 250 μL of appropriate medium. Vortex the cells every day and grow for 2 days.

[0487] Fixation and staining

[0488] 1. Fix the cells in the hood. For fixation and subsequent immunohistochemical analysis, remove 100 μl of culture medium and add 100 ul of 4% PFA in 1×PBS to fix the cells, count the neurospheres manually, then wash the cells twice with 1×PBS for 5 minutes, and leave in 1×PBS, wrap in foil and place at 4°C overnight, or perform Dapi staining. Remove 100uLPBS and add 100uL antibody (AB) staining solution (1% goat serum, 1×PBS, and 0.1% triton X) block at room temperature for 1 hour. Remove AB staining solution. Then stain the cells with Dapi 1:5000 AB staining solution, 100 μl per well, and then incubate the cells in the dark at room temperature for 15 minutes. Then wash the cells twice in AB staining solution for five minutes. Imaged using GE Cytell imager or LSM 710, Zeiss confocal microscope, and analyze the diameter of neurospheres with ImageJ software (National Institutes of Health).

[0489] Plate cells in 24-well plates for monolayer differentiation or EdU incorporation assays

[0490]

[0491] Prior to use in the following assays, 24-well glass bottom plates (Mat Tek P24G-1.0-13-F Case, Glass Bottom 24 Well Plates) were coated with poly-L-ornithine (Sigma P4957) and fibronectin (Sigma F1141).

[0492] See above for dissociation and plating of cells.

[0493] Cells were plated (10,000 cells per well) in complete media with GF for 24 hours (500ul per well). Once cells were attached, they were switched to choline-deficient media, other compound media, or appropriate media.

[0494] Differentiation assays: quantification of neuronal, glial, and NPC marker expression

[0495] After 24 hours, ensure that the cells are attached to the plate and then carefully remove the culture medium.

[0496] Add 500 μL of 2% Nu serum (serum replacement) (Corning TM Nu-Serum Growth Medium Supplement, No. CB55004), control, compound medium with low choline or medium choline medium. Note: The medium does not contain GF.

[0497] Control and compound media were prepared with Medium 2 and contained 29uM choline, low (5uM) and medium (70uM) choline media were prepared with Medium 3.

[0498] The cells were cultured in medium supplemented with 2% Nu serum for 9 days, with the medium changed every 2 days. For fixation and subsequent immunohistochemical analysis, the medium was removed, the cells were rinsed with 1× PBS for 5 min, rinsed once, and fixed with 4% PFA in 1× PBS for 15 min at 4°C. The cells were then washed twice with 1× PBS for 5 min, left in 1× PBS, wrapped in foil and placed at 4°C overnight, or they were immediately stained with primary antibodies.

[0499] Staining for differentiation

[0500] Remove PBS and add enough AB staining solution (1% goat serum, 1× PBS, and 0.1% triton X) to cover the bottom, and keep the block at room temperature for 1 hour.

[0501] Prepare primary antibody dilutions in an appropriate amount of AB staining solution, 250ul per well (antibodies are only kept on ice for a short time, mouse anti-MAP2 or TUJ1 1:500 (neuronal markers), rabbit anti-GFAP (glial marker) 1:1000, chicken anti-nestin CFP (EGFP antibody (progenitor cell marker)) 1:1000). Remove AB staining solution and add solution of primary antibodies to each chamber. Wrap cells in foil and keep at 4°C overnight. Then, in 400ul AB staining solution

[0502] Wash cells once for 5 minutes to remove primary antibodies. Prepare secondary antibody solution (250ul is sufficient for each chamber) (goat anti-mouse Alexa 488 1:2000, anti-rabbit Cy3 (1:500), anti-chicken Alexa 647 1:500, and 1:5000 Dapi).

[0503] The cells were incubated at room temperature for 1 hour in the dark and washed twice for five minutes in AB staining solution. They were then kept at 4°C or imaged using a GE Cytell imager or LSM710, Zeiss confocal microscope and analyzed with ImageJ software (National Institutes of Health, USA).

[0504] Microtubule-associated protein 2 (MAP2), neuronal β-tubulin III (TuJ1), glial fibrillary acidic protein (GFAP) and Nestin CFP (EGFP antibody).

[0505] Each marker expression was measured on the collected images (integrated density measurement in ImageJ) and normalized to DAPI fluorescence, labeling all nuclei (integrated density measurement).

[0506] Octanoic acid was labeled with neuronal β-tubulin III (TuJ1), and subsequent compounds were labeled with microtubule-associated protein 2 (MAP2).

[0507] NPC proliferation assay in monolayer culture (incorporation of EdU-S phase marker)

[0508] After 24 hours, ensure that cells have attached to the plate and then carefully remove the medium. Add 500 μL of compound medium plus GF. Culture cells in appropriate medium for 3 days.

[0509] Control and compound media were prepared with Medium 2 and contained 29uM choline, low (5uM) and medium (70uM) choline media were prepared with Medium 3.

[0510] use EdU Alexa EdU incorporation was measured using the 555 Imaging Kit (Life Technologies, No. c10338).

[0511] At the end of day 3, EdU was added to each well at 10 μM for 30 minutes prior to fixation. For fixation and subsequent immunohistochemical analysis, the medium was removed, cells were rinsed with 1× PBS for 5 minutes, rinsed once, and fixed with 4% PFA in 1× PBS for 15 minutes at 4°C, then washed twice with 1× PBS for 5 minutes, left in 1× PBS, wrapped in foil and left overnight at 4°C, or stained.

[0512] Remove PBS and add enough AB staining solution (1% goat serum, 1× PBS and 0.1% triton X) to cover the bottom, keep the block at room temperature for 1 hour. Stain the cells for EdU. Incubate the cells at room temperature in the dark for 30 minutes. Wash the cells with 1× PBS and stain with Dapi 1:5000ul for 15 minutes. Wash the cells once with 1× PBS and then place in PBS at 4°C or image immediately using a GE Cytell imager (cell viability application) or LSM 710, Zeiss confocal microscope (analyzed using ImageJ software (National Institutes of Health)).

[0513] The results are shown in Tables 4-8 and Figures 3 to 6 middle.

[0514] Table 4 - Effects of neuraminic acid on neuronal cell density and astrocyte density

[0515] Neurons Astrocytes Control 0.436189 0.642448 Low NA 0.467588 0.621784 Moderate NA 0.56563 0.721512 High NA 0.539448 0.70279

[0516] Table 5 Effect of stearic acid on neuronal cell density and astrocyte density

[0517] Neurons Astrocytes Control 0.44 0.64 Low SA 0.54 0.68 Medium SA 0.66 0.81 High SA 0.64 0.85

[0518] Table 6 Effects of octanoic acid on neuronal cell density and astrocyte density

[0519] Neurons Astrocytes Control 1.1 4.1 Low OA 1.2 3.7 Moderate OA 1.8 6.1 High OA 1.7 7.9

[0520] Table 7 Effect of sphingomyelin on the number of neurospheres

[0521] Sphingomyelin Comparison Low medium high Average (mean) 103 94 121 219

[0522] Table 8 Effects of sphingomyelin on neuronal proliferation

[0523] DAPI Control 262 Low SM 280 Moderate SM 314 High SM 305

[0524] Example 4

[0525] Experimental Section

[0526] sample

[0527] Component C2: whey protein concentrate enriched with alpha lactalbumin (Sample Manager ID: K2Q-00030); first infant milk containing whey protein concentrate enriched with alpha lactalbumin (Sample Manager ID: K2Q-00032); bovine milk (whole milk); human breast milk (quality control pool of 6 individual samples collected after the 4th week after delivery; Lee Biosolutions, St Louis, MI, USA).

[0528] Extraction of phospholipids from dairy products

[0529] milk powder: A 1 g amount of the homogenized powder was weighed into a 50 mL glass flask and diluted into 20 mL of pure distilled water. The solution was heated in a water bath at 40°C for 30 minutes. A volume of 500 μL of this solution was placed in a 10 mL glass tube.

[0530] Cow milk and human milk: 500 μL of the homogenized liquid was aliquoted into 10 mL glass tubes.

[0531] MP post-extraction analytes in human breast milk were quantified in triplicate by UPLC-MS / MS (RDLS-MP-80138-Rev01) using a mixture of 9.5 mL of chloroform / methanol (2+1). Briefly, the tubes were shaken and placed in an ultrasonic bath at 40°C for 15 minutes and then centrifuged at 2500 rpm for 10 minutes. A volume of 2 mL of potassium chloride solution (0.88%, m / m) was added to the liquid phase and then shaken and centrifuged at 2500 rpm for 10 minutes. The lower organic phase was transferred to a glass vial and lysed under gentle N 2 Evaporate to dryness under reduced pressure and reconstitute in 500 μL chloroform / methanol (9+1) before injection into LC-MS.

[0532] Analysis of phospholipids by liquid chromatography coupled to mass spectrometry (LC-MS)

[0533] The analysis was performed on a QExactive plus orbital trap equipped with a Thermo Scientific Dionex UltiMate 3000 rapid separation LC system (Thermo Fisher Scientific, Bremen, Germany). Separation was performed on a HILIC column (100×2.1 (id) mm; 1.7 μm) with a mobile phase composition of (A) ammonium acetate 10 mM and (B) acetonitrile. The injection volume was set to 10 μL, and the gradient started from 95% B to 70% B in 15 minutes, held at 70% B for 1 minute, returned to the initial conditions in 3 minutes and equilibrated for 6 minutes.

[0534] The Q Exactive plus orbital trap was equipped with an atmospheric pressure chemical ionization (APCI) probe operating in positive ion mode. The APCI and MS parameters were as follows: corona discharge current 4.0 μA, sheath gas and auxiliary gas 24 and 5 arbitrary units, respectively; capillary and vaporizer temperatures 320 °C and 390 °C, respectively, sweep gas flow 0 arbitrary units, and s-lens RF level 80. The automatic gain control (AGC) target value was set to 1 × 10 6 The AGC was set to 1 × 10 6 The ion density of the ion was 2400 nm and the ion density was 400 nm. ...

[0535] SM species were extracted from the total ion chromatogram using accurate mass. The parent ion corresponds to the in-source loss of phosphatidylcholine to ceramide. Based on the LipidView database and literature, an inclusion list was used to perform specific fragmentation of 57 SM regioisomers built on the parent ion corresponding to the loss of ceramide to water [Cer-H 2 O+H + ] of m / z (renerry VC, Akbaridoust G., Plozza T., Rochfort S., Wales WJ, Auldist M., Ajilouni S. Ultra-high-performance liquid chromatography-ion trap mass spectrometry characterization of milk polar lipids from dairy cows feddifferent diets. Food Chemistry 2013, 141, 1451-1460); Godzien J., Ciborowski M., Martinez-Alcazar MP, Samczuk P., Kretowski Godzien J., Ciborowski M., Martinez-Alcazar MP, Samczuk P., Kretowski A., Barbas C. Rapid and reliable identification of phospholipids for untargeted metabolomics with LC-ESI-QTOF-MS / MS. Journal of Proteome Research 2015, 14, 3204-3216.

[0536] Analysis of fatty acid methyl esters (FAME) by gas chromatography with flame ionization detector (GC FID)

[0537] SM fractions were collected into glass tubes between 8.5 and 10 min, 5 times per sample. 2 After evaporation of the solvent under the flow, quantification of fatty acids in human milk by gas chromatography after MP was performed in triplicate by FAME analysis (RDLS-MP-8980-00030-Rev01-FAME_Human Milk Fat, 2012, Version 1.0).

[0538] Results and discussion

[0539] Hydrophilic interaction liquid chromatography (HILIC) was used to separate PL classes (i.e., phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylcholine (PC), and SM). The number and degree of unsaturation of carbons within individual SM species were assigned based on the accurate masses of pseudomolecular ions detected in an orbitrap mass spectrometer. The relative abundance of SM species was determined for comparison between ingredients, infant formula, bovine milk, and human milk.

[0540] SM substances in different dairy products

[0541] 45 SM species were detected in the analyzed samples (Table 9).

[0542] Table 9: SM substances (indicated by x) detected in ingredients, infant formula, bovine milk and human milk samples. SM substances detected in human milk are in bold .

[0543]

[0544]

[0545] The substances SM 24:1, SM 38:4, SM 38:3 and SM 42:4 are found only in trace levels in human milk.

[0546] Relative abundance of SM species

[0547] The relative abundance (%) of SM in different dairy products was estimated from the peak area divided by the sum of all peak areas corresponding to SM species in the chromatogram of each sample. Figure 7 The relative abundance of the major SM species in ingredients, infant formula, bovine milk and human milk is shown.

[0548] The relative abundance of SM substances present in ingredients and infant formula is comparable to that in bovine milk, with slight differences in the human milk fraction for some substances (e.g., SM 32:1, SM 32:0, SM 33:1, SM 34:1, SM 38:0, SM39:1, SM 39:0, and SM 41:1), being lower in human milk than in ingredients, infant formula, and bovine milk, whereas SM 36:2, SM 36:1, SM 36:0, SM 37:1, SM 38:2, SM 38:1, SM 40:1, SM 42:2, and SM 42:1 have higher relative abundance in human milk than in other dairy products.

[0549] Human milk samples included a quality control pool of 6 individual samples collected within or after 4 weeks of life. Knowing that SM abundance in human milk varies with diet and duration of lactation, this may partially explain the observed differences. However, despite differences in the relative abundance of some SM species, >85% of the SM species detected in human milk were also found in infant formula and bovine milk.

[0550] It is noteworthy that for a given m / z extracted from the MS trace, different LCB FA combinations can be suggested (e.g., SM34:1 can correspond to SM d18:1 / 16:0, d18:0 / 16:1, d16:1 / 18:0, etc.). Therefore, we evaluated the GC FA profiles to gather more information about the molecular structure of SM between different dairy products.

[0551] Fatty acid profiles in SM fractions from different milk products

[0552] The regioisomeric structure of SM was investigated by first fractionating SM and then analyzing the FAs present in the fractions by GC-FID. Fractionation of SM for LC-MS analysis was performed as described above, but in this case the effluent was directed into 5 mL glass tubes instead of MS. Each fraction was then subjected to a methylation procedure prior to subsequent GC analysis. The relative abundance of FAs within the SM fractions was quantified in Figure 8 Indicated in.

[0553] like Figure 8 As shown in Table 10, the SM fraction contains mainly saturated FA (i.e., myristic acid 14:0, pentadecanoic acid 15:0, palmitic acid 16:0, stearic acid 18:0, arachidic acid 20:0, behenic acid 22:0, tricosanoic acid 23:0 and tetracosanoic acid 24:0). A higher proportion of SFA was observed in the SM fractions from all dairy products (Table 10). This is consistent with the literature, revealing a high distribution of SFA with carbon chains higher than 18 in the SM fraction. This high amount of SFA reflects the structural effect of SM, i.e., reducing the fluidity of the milk fat globule membrane and maintaining rigidity.

[0554] Table 10: Percentages of SFA, MUFA and PUFA detected in SM fractions from different milk products .

[0555]

[0556] Monounsaturated FA (MUFA) accounts for about 4-11% of FA in the SM fraction. Oleic acid 18:1n-9 and nervonic acid 24:1n-9 are 2 MUFA detected. Interestingly, compared with other dairy products, 24:1n-9 is found to have a relatively high ratio in human milk, and this is consistent with the literature. Compared with other products, only PUFA linoleic acid 18:2n-6 is found to be relatively high in the infant formula and human milk tested. Finally, ω-3PUFA is not detected in the SM fraction. This is also consistent with the data found in the literature, showing that arachidonic acid (AA, 20:4n-6), eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) are mainly present in PE, PI and PS.

[0557] Example 5

[0558] Examples of synthetic nutritional compositions (infant formulas) according to the invention are listed in Table 10 and Table 10a.

[0559] Table 11

[0560]

[0561]

[0562] The composition may further comprise any additional ingredients normally found in the preparation of infant formula.

[0563] Table 11a

[0564]

[0565]

[0566]

[0567] Example 6

[0568] The two main formulas reported for infant feeding in the cohort study were Infant Formula 3 and Infant Formula 6. Infant Formula 3 was associated with increased overall myelin development during the first 5 years of life compared with Infant Formula 6. Fig. 9 , 10, 11). The trajectories calculated via our longitudinal mixed effects method show that the Gompertz growth curve parameters are different in each brain region investigated. Specific nutrient analysis of myelin-related nutrients for Infant Formula No. 5 and Infant Formula No. 6 is given in Table 12.

[0569] Table 12-Nutrient analysis of myelin-related nutrients in 6 infant formula foods .

[0570] 3 6 α-lactalbumin g / 100g protein ND 0.89 Fat g / 100g 26.6 26.9 AA mg / 100g 162 172 DHA mg / 100g 79.6 81.5 iron mg / 100g 8.42 10.6 calcium mg / 100g 417 430 phosphorus mg / 100g 237 255 sodium mg / 100g 161 135 Potassium mg / 100g 628 593 copper mcg / 100g 477 472 Zinc mg / 100g 4.23 5.75 magnesium mg / 100g 38.4 46.7 manganese mcg / 100g 140.3 122 Vitamin B12 mcg / 100g 5.15 4.66 Folic acid mcg / 100g 158 98.8 choline mg / 100g 111 170 β-lactoglobulin g / 100g ND 3.54 Phosphatidylcholine mg / kg 397 1287 Phosphatidylinositol mg / kg <LQ 788 Phosphatidylserine mg / kg <LQ(149) 977 Phosphatidylethanolamine mg / kg <LQ(174) <LQ(124) Sphingomyelin mg / kg 421 <LQ(100)

[0571] Example 7

[0572] Co-culture of neurons and OLs

[0573] Neurons / oligodendrocytes were cultured as previously described by Charles et al., 2000.

[0574] Pregnant female rats at 17 days of gestation were killed by cervical dislocation (Wistar rats) and the fetuses were removed from the uterus. The forebrain was removed and placed in Leibovitz ice-cold medium (L15) containing 2% penicillin-streptomycin (PS) and 1% bovine serum albumin (BSA). The forebrain was dissociated by trypsinization for 20 minutes at 37°C (trypsin EDTA 1X). The reaction was terminated by adding Dulbecco's modified Eagle's medium (DMEM) containing DNase I grade II (0.1 mg / ml) and 10% fetal calf serum (FCS). The cells were then mechanically dissociated for 3 generations by a 10 ml pipette. The cells were then centrifuged at 180×g for 10 minutes at 4°C on a layer of BSA (3.5%) in L15 medium. The supernatant was discarded and the cells of the mass were resuspended in DMEM containing 10% FCS. The cells were then centrifuged at 515×g for 10 minutes at 4°C. The supernatant was discarded, and the pelleted cells were resuspended in a culture medium consisting of a neurobasal culture medium supplemented with 2% B27, 2mM L-glutamine (L Glu), 2% PS solution, 1% FCS, and 10ng / ml platelet-derived growth factor (PDGF-AA). Live cells were counted in a Neubauer hemocytometer using a trypan blue exclusion test. Cells were seeded in a 96-well plate pre-coated with poly-L-lysine and laminin at a density of 20,000 cells / well.

[0575] One day after seeding (day 1 of culture), cells were incubated with test compounds ( Selected from those listed in Table 13) or estradiol. Control cells were not incubated with the test compound or estradiol. Estradiol was used as a positive control. It is known that estradiol induces OPC proliferation. The positive effect of estradiol on OL differentiation has also been shown because it has an effect on the early myelination process. The positive effect of estradiol on neurite outgrowth has also been published (see Alevaro et al., 2010 for review).

[0576] In a humidified incubator, the plate was maintained at 37°C in an atmosphere of air (95%)-CO2 (5%). Half of the culture medium was replaced with fresh culture medium and test compound or control compound every other day. The test compound or control compound was maintained at a defined concentration during the experimental duration. Compounds were tested on 1 culture (6 wells per condition). Cells were then used to measure OPC proliferation, OPC differentiation to OL and early myelination process (myelin wrapping) at the 12th, 18th or 30th day of culture, or one of the maturation (myelin maturation) and mature myelination process (myelin wrapping) of OL.

[0577] Proliferation of OPCs-Measurement of A2B5-positive cells and total neurite length (NF)

[0578] On day 12 of culture, cells were fixed with a cold mixture of absolute ethanol (95%) and pure acetic acid (5%) for 5 minutes. The cells were then permeabilized and nonspecific sites were blocked with a solution of phosphate buffered saline (PBS) containing 0.1% saponin and 1% FCS at room temperature for 15 minutes.

[0579] The cells were then incubated with monoclonal anti-A2B5 generated in mice and conjugated to Alexa 488 at 1 / 200 dilution in PBS with 1% FCS, 0.1% saponin for 2 hours at room temperature and with anti-NF (phosphorylated and non-phosphorylated neurofilament 200) raised in rabbit at 1 / 500 dilution in PBS with 1% FCS, 0.1% saponin for 2 hours at room temperature. The antibody was revealed with Alexa Fluor 568 goat anti-rabbit at 1 / 400 dilution in PBS with 1% FCS, 0.1% saponin for 1 hour at room temperature.

[0580] The total number of OPCs (number of A2B5 positive cells) was quantified (to assess proliferation) and the axonal network (total neurite length (NF)) was measured to assess the effect of the compounds on the neuronal network (the quality of myelination is directly related to the quality of the axonal network).

[0581] Differentiation from OPC to OL and myelination process (myelin wrapping) - number, area and overlap of MAG-positive cells Measurement of MAG / NF packaging and total neurite length (NF)

[0582] On day 18 of culture, cells were fixed with a cold mixture of absolute ethanol (95%) and pure acetic acid (5%) for 5 minutes. The cells were then permeabilized and nonspecific sites were blocked with a solution of phosphate buffered saline (PBS) containing 0.1% saponin and 1% FCS at room temperature for 15 minutes.

[0583] The cells were then incubated with monoclonal anti-MAG produced in mouse at a 1 / 400 dilution in PBS containing 1% FCS, 0.1% saponin, and with anti-NF (phosphorylated and non-phosphorylated neurofilament 200) produced in rabbit at a 1 / 500 dilution in PBS containing 1% FCS, 0.1% saponin for 2 hours at room temperature. These antibodies were revealed with CF 488A goat anti-mouse at a 1 / 800 dilution in PBS with 1% FCS, 0.1% saponin, and with Alexa Fluor 568 goat anti-rabbit at a 1 / 800 dilution in PBS with 1% FCS, 0.1% saponin for 1 hour at room temperature.

[0584] The total number of OLs (number and area of ​​MAG positive cells) (to assess differentiation process) and the wrapping of OPCs around axons (overlapping MAG / NF wrapping) (myelination process) were quantified. The axonal network (total axon length (NF)) was measured to assess the effect of compounds on neuronal networks.

[0585] OL maturation (myelin maturation) - number and area of ​​MBP-positive cells, overlapping MBP / NF wrapping, and total axis Measurement of protrusion length (NF)

[0586] On the 30th day of culture, cells were fixed with a cold mixture of absolute ethanol (95%) and pure acetic acid (5%) for 5 minutes. The cells were then permeabilized and nonspecific sites were blocked with a solution of phosphate buffered saline (PBS) containing 0.1% saponin and 1% FCS at room temperature for 15 minutes.

[0587] The cells were then incubated with monoclonal anti-MBP produced in mouse at a 1 / 1000 dilution in PBS containing 1% FCS, 0.1% saponin, and with anti-NF (phosphorylated and non-phosphorylated neurofilament 200) produced in rabbit at a 1 / 500 dilution in PBS containing 1% FCS, 0.1% saponin for 2 hours at room temperature. These antibodies were revealed with CF 488A goat anti-mouse at a 1 / 800 dilution in PBS with 1% FCS, 0.1% saponin, and with Alexa Fluor 568 goat anti-rabbit at a 1 / 400 dilution in PBS with 1% FCS, 0.1% saponin for 1 hour at room temperature.

[0588] The total number of OLs (number and area of ​​MBP positive cells) (to assess OL maturation) and the wrapping of myelin around axons (overlap MBP / NF (wrapping)) were assessed. The axonal network (total axon length (NF)) was measured to assess the effect of compounds on neuronal networks.

[0589] For all measurements, one culture (6 wells per condition) was completed. For each test condition, 30 images were collected per well (each image represents one field) and analyzed at 20 times magnification using ImageXpress (Molecular Devices) equipped with LED lights (excitation 360 / 480 / 565 and emission 460 / 535 / 620). The 30 images were automatically taken and accounted for 80% of the total surface of the culture well.

[0590] Results are expressed as the cumulative mean length (in μm) of the neurite network or myelin per field for a given marker (MAG or MBP). The overlap area between NFs and MAG or MBP was measured to assess encapsulation.

[0591] To assess the OPC population, MAG-positive cell population, MBP-positive cell population, an automatic count of the number of positive cells per picture (=field) was performed. The results are expressed as the average number of positive cells per field.

[0592] All images were taken under the same conditions.

[0593] Table 13

[0594]

[0595]

[0596] The results are shown in Figures 12 to 32 middle

[0597] Example 8

[0598] Materials and methods

[0599] 1. Feeding Layer Preparation: Dissociation of Neonatal Cortices and Maintenance of Mixed Glial Cultures

[0600] Freshly dissected brains were added to a 37°C water bath for 3 minutes, and then the cortex was cut by a P1000 pipette tip to produce smaller fragments. 75 μL of OPC papain solution was added to each brain, and the tissue was then incubated in a 37°C water bath for 20 minutes. Mixed glial cultures were then added to the tissue suspension to inactivate the OPC papain solution.

[0601] The tissue was then triturated using a sterile fire-polished glass Pasteur pipette and 4 mL of mixed glial medium was added per brain. The cells were centrifuged at 1200 rpm (approximately 300 g) for 5 minutes and then resuspended in warm mixed glial medium and plated into PLL-coated flasks.

[0602] 4 hours after plating, a complete medium change was performed to remove most of the debris generated by grinding and to promote culture viability. After 3 days of culture, a 2 / 3 medium change was performed and no subsequent medium changes were performed. The cells were then maintained in culture until confluence.

[0603] 2. Hippocampal Neuron Preparation

[0604] Hippocampal neurons were isolated from embryonic (E18) pups of Sprague Dawley rats. Briefly, after animal sacrifice, the brain was isolated, the meninges were removed from the medial aspect of the cerebral hemispheres, and the hippocampus was dissected out and kept at 4°C until the procedure was completed.

[0605] The tissue was then incubated with 2.5% trypsin in a 37°C water bath for 15 minutes and then gently washed and kept in culture medium. Hippocampal dissociation was performed by repeated pipetting of the hippocampus with a functionalized sterile Pasteur pipette. After mechanical dissociation, cells were plated at the desired density in neuronal plating medium, allowed to recover for 4 hours, and then placed in competitive neuronal medium.

[0606] 3. Purification of OPCs from Mixed Glial Cultures to Establish OL / Hippocampal Neuron Cultures

[0607] On day 9 of the mixed glial culture, the flasks were shaken at 50 rpm for 45 minutes on an orbital shaker in a 5% CO2 tissue culture incubator. The purpose of this shaking was to remove any loosely adherent contaminating cells from the monolayer.

[0608] The medium was then changed and replaced with 4 mL of fresh mixed glial medium supplemented with 5 μg / mL insulin. The flask was then placed back on the shaker and equilibrated for approximately 3 hours, followed by shaking at 220 rpm for approximately 16 hours (overnight).

[0609] The next morning, the mixed glial culture medium containing microglia and OPC cells was collected and pre-plated in P100 dishes (untreated) for 30 minutes to purify OPC cells; microglia immediately began to adhere to the dish, while OPC cells remained in the supernatant culture medium.

[0610] 30 minutes after pre-seeding, the culture medium was collected, and OLs were counted and seeded on hippocampal neurons in a final volume of 1 mL OL culture medium.

[0611] A complete OL medium (minus CNTF) exchange was performed and cells were then maintained in culture until the appropriate experimental time.

[0612] For the mature experiment, the experimental procedure is as follows, Fig.54 As shown:

[0613] a. OPCs grown on astrocyte feeder layer at 10 DIV

[0614] b. Isolation of OPCs (Day 0)

[0615] c. Administration of Compounds (Day 3)

[0616] d. Quantitative evaluation of maturity at days 4, 7 and 10.

[0617] For the myelination experiment, the experimental procedure was as follows, Fig.55 As shown:

[0618] a. Growth of hippocampal neurons until complete neuronal network maturity (14 DIV)

[0619] b. OPCs growing on astrocyte feeder layer at 10 DIV

[0620] c. Isolation of OPCs and co-culture with neurons (Day 14)

[0621] d. Administration of Compounds (Day 15)

[0622] e. Quantitative evaluation of myelination on co-culture days 15, 18, 21 / 23 and 28 / 29 (1 day after co-culture plating and before compound treatment) 4. Image acquisition

[0623] All cultures at different experimental time points were fixed in 4% paraformaldehyde and 4% sucrose for 10 minutes at room temperature (RT). Primary and secondary antibodies were applied to GDB buffer (30 mM phosphate buffer, pH 7.4, containing 0.2% gelatin, 0.5% Triton X-100 and 0.8 M NaCl) at room temperature for 2 hours. Cells were stained with appropriate markers (primary antibodies used: anti-A2B5 antibody (ABCAM cat. ab53521), rat anti-MBP (BIO-RAD cat. aa82-87), oligodendrocyte marker O4 antibody (R&D Systems cat. MAB1326), anti-βIII tubulin mAb (Promega cat. G7121); secondary antibodies used: Alexa anti-rat 555 (Life Tech A-21434), Alexa anti-mouse 488 (LifeTech A-11009)). After immunocytochemical staining, all images were acquired with Array Scan XTI (ThermoScientific); the objective was magnified 20 times in 2 × 2 bins. For each condition and replicate (triplicate), at least 15 images were taken.

[0624] To analyze all acquired images, HCS Studio Cell Analysis Software, specifically the "Scan" application, was used.

[0625] OPC papain solution (made in MEM)

[0626] Papain solution 1.54mg / ml

[0627] L-cysteine ​​360 ​​μg / ml

[0628] DNase I 60 μg / ml

[0629] Mixed glial culture medium (made in DMEM)

[0630] FBS10%

[0631] Penicillin / Streptomycin (0.33%, from stock solution) 33 units / mL penicillin and 33 μg / mL streptomycin

[0632] GlutaMAX 1%

[0633] OL medium

[0634] DMEM

[0635] 100X Ol-Supplement

[0636] Bovine insulin (from 1 mg / mL stock solution)

[0637] GlutaMAX

[0638] Transferrin (from 33 mg / mL stock solution)

[0639] B27 Supplements

[0640] FBSCNTF (from 50ng / μL stock solution)

[0641] The results are shown in Figure 34 to Figure 53 middle.

Claims

1. A synthetic nutritional composition comprising vitamins for promoting, supporting or optimizing remyelination, in particular the trajectory of remyelination, and / or brain structure, and / or brain connectivity, and / or intellectual potential, and / or cognitive potential, and / or learning potential and / or cognitive function in an individual, in particular a formula-fed individual, wherein brain structure refers to the amount and / or spatial distribution of myelinated material in the entire brain, and / or in specific brain regions, and wherein cognitive function is optimized if the difference between the individual's score on standardized neurodevelopmental tests and the score of an exclusively breastfed individual of a well-nourished mother is less than one standard deviation.

2. The synthetic nutritional composition according to claim 1, wherein the individual is a human infant or child, and preferably a formula-fed human infant or child.

3. The synthetic nutritional composition according to any one of the preceding claims, wherein the vitamin is vitamin B12 and / or folic acid.

4. The synthetic nutritional composition according to claim 3, wherein the composition comprises folic acid in an amount higher than 50 mcg / 100 g dry weight of the composition and / or vitamin B12 in an amount higher than 0.01 mcg / 100 g dry weight of the composition.

5. The synthetic nutritional composition according to any one of the preceding claims, wherein the composition further comprises one or more of the following ingredients: minerals, and / or choline, and / or phospholipids, and / or fatty acid derivatives, wherein the fatty acid derivatives are compounds containing fatty acids other than phospholipids.

6. The synthetic nutritional composition according to claim 5, wherein the mineral is selected from the group consisting of iron, zinc, calcium, phosphorus, copper and combinations thereof; wherein the fatty acid derivative comprises docosahexaenoic acid and / or arachidonic acid and / or stearic acid and / or nervonic acid, and wherein the phospholipid is a compound of formula (I) or a mixture of compounds of formula (I) in, R 1 is O; X is NH or O; R 2 is a C2-C44 saturated or unsaturated, linear or branched acyl group; R 3 is a substituent of formula (II) or formula (III): Among them, R 5 is a C2-C44 saturated or unsaturated, linear or branched acyl group; and R 6 is a C2-C44 saturated alkyl or alkenyl group; and R 4 Selected from: C5 or C6 substituted or unsubstituted cyclic alkyl or alkenyl groups, or -(CH2)n-R 7 , wherein n is an integer in the range of 1 to 4, in particular 1 to 2, and R 7 is -N(CH3)3+, NH3+ or a substituent of formula (IV), and In particular, R 4 is a C6 cyclic alkyl or alkyl or alkenyl group substituted by one or more hydroxyl groups.

7. The synthetic nutritional composition according to claim 6, wherein the phospholipid is sphingomyelin, phosphatidylcholine, phosphatidylinositol, phosphatidylserine, and any mixture thereof.

8. The synthetic nutritional composition according to claim 6 or 7, wherein if iron is present in said composition, said iron is comprised in an amount higher than 5 mg / 100 g of said composition dry weight, wherein if sphingomyelin is comprised in said composition, said sphingomyelin is comprised in an amount higher than 300 mg / kg of said composition dry weight, wherein if fatty acid derivatives comprising DHA are comprised in said composition, said fatty acid derivatives comprising DHA are comprised in an amount of 60 to 350 mg / 100 g of said composition dry weight, and wherein if fatty acid derivatives comprising arachidonic acid are comprised in said composition, said fatty acid derivatives comprising arachidonic acid are comprised in an amount of 60 to 350 mg / 100 g of said composition dry weight.

9. The synthetic nutritional composition according to any of the preceding claims, wherein the composition is a composition selected from the group consisting of infant formulas, growing-up milks, compositions for infants intended to be added to or diluted with human breast milk, and foodstuffs intended for consumption by infants and / or children alone or in combination with human breast milk.

10. Use of a synthetic nutritional composition according to any of the preceding claims for promoting, supporting or optimizing remyelination, in particular the trajectory of remyelination, and / or brain structure, and / or brain connectivity, and / or intellectual potential, and / or cognitive potential, and / or learning potential and / or cognitive function in a human infant or child, in particular a formula-fed infant or child, wherein brain structure refers to the amount and / or spatial distribution of myelinated material in the whole brain, and / or in specific brain regions, and wherein the cognitive function is optimized if the individual's score on standardized neurodevelopmental tests differs by less than one standard deviation from the score of an exclusively breastfed individual of a well-nourished mother.

11. A vitamin for promoting, supporting or optimizing remyelination, in particular the trajectory of remyelination, and / or brain structure, and / or brain connections, and / or intellectual potential, and / or cognitive potential, and / or learning potential, and / or cognitive function in a human infant or child, in particular a formula-fed infant or child, wherein in particular the vitamin is vitamin B12 and / or folic acid, and wherein brain structure refers to the amount and / or spatial distribution of myelinated material in the entire brain, and / or in specific brain regions, and wherein cognitive function is optimized if the individual's score on a standardized neurodevelopmental test differs by less than one standard deviation from the score of an exclusively breastfed individual of a well-nourished mother.

12. Vitamins according to claim 11, wherein the vitamins are administered to an individual separately, sequentially and / or simultaneously with one or more of the following ingredients: choline; minerals, in particular iron and / or zinc and / or calcium and / or phosphorus and / or magnesium and / or copper; fatty acid derivatives comprising docosahexaenoic acid and / or arachidonic acid and / or nervonic acid and / or stearic acid; and / or phospholipids, wherein the phospholipids are compounds of formula (I) as defined in claim 6.

13. A method for promoting, supporting or optimizing remyelination, in particular remyelination trajectory, and / or brain structure, and / or brain connections, and / or intellectual potential, and / or cognitive potential, and / or learning potential and / or cognitive function in an individual, the method comprising feeding the individual a synthetic nutritional composition as defined in any one of claims 1 to 10 or a vitamin as defined in claim 12 or 13, wherein the individual is a human infant or child, and more preferably a formula-fed human infant or child, and wherein brain structure refers to the amount and / or spatial distribution of myelinated material in the entire brain, and / or in specific brain regions, and wherein the cognitive function is optimized if the difference between the individual's score on standardized neurodevelopmental tests and the score of fully breastfed individuals from well-nourished mothers is less than one standard deviation.

14. A synthetic nutritional composition according to any one of claims 1 to 9, or a vitamin according to claim 11 or 12, for use in the preparation of a synthetic nutritional composition that promotes, supports or optimizes remyelination, in particular the trajectory of remyelination, and / or brain structure, and / or brain connections, and / or intellectual potential and / or cognitive potential and / or learning potential, and / or cognitive function in a human infant or child, in particular a formula-fed human infant or child, wherein brain structure refers to the amount and / or spatial distribution of myelinated material in the entire brain, and / or in specific brain areas, and wherein the cognitive function is optimized if the individual's score on standardized neurodevelopmental tests differs by less than one standard deviation from the score of an exclusively breastfed individual of a well-nourished mother.

15. A synthetic nutritional composition comprising: vitamins, in particular folic acid and / or vitamin B12; and choline; and / or minerals, in particular iron and / or zinc and / or copper and / or magnesium and / or calcium and / or phosphorus; and / or fatty acid derivatives other than phospholipids, including docosahexaenoic acid and / or arachidonic acid and / or nervonic acid and / or stearic acid; and / or phospholipid metabolic precursors or metabolites thereof, in particular phosphatidylcholine and / or phosphatidylserine and / or phosphatidylinositol and / or sphingomyelin; wherein if sphingomyelin is present in the composition, the wherein if phosphatidylcholine is present in the composition, the phosphatidylcholine is present in an amount of at least 1000 mg / kg, wherein if phosphatidylserine is present in the composition, the phosphatidylserine is present in an amount of at least 900 mg / kg, wherein if phosphatidylinositol is present in the composition, the phosphatidylinositol is present in an amount of at least 700 mg / kg, wherein if folic acid is present in the composition, the folic acid is present in an amount of at least 160 mg / kg , wherein if vitamin B12 is present in the composition, the vitamin B12 is present in an amount of at least 7mcg / 100g, wherein if iron is present in the composition, the iron is present in an amount of at least 11.5mg / 100g, wherein if choline is present in the composition, the choline is present in an amount of at least 140mg / kg, wherein if fatty acid derivatives comprising DHA are present in the composition, the fatty acid derivatives comprising DHA are present in an amount of at least 89mg / 100g, wherein if fatty acid derivatives comprising AA are present in the composition, the fatty acid derivatives comprising AA are present in an amount of at least 175mg / 100g, wherein if zinc is present in the composition, the zinc is present in an amount of at least 7mg / 100g, wherein all weights are based on the dry weight of the composition, and wherein the composition is a composition selected from the group consisting of infant formula, growing-up milk, compositions for infants intended to be added to or diluted with human breast milk, and foodstuffs intended for consumption by infants and / or children alone or in combination with human breast milk.

16. A synthetic nutritional composition comprising: minerals, in particular iron and / or zinc and / or copper and / or magnesium and / or calcium and / or phosphorus; and choline; and / or vitamins, in particular folic acid and / or vitamin B12; and / or fatty acid derivatives other than phospholipids comprising docosahexaenoic acid and / or arachidonic acid and / or nervonic acid and / or stearic acid; and / or phospholipids, in particular phosphatidylcholine and / or phosphatidylserine and / or phosphatidylinositol and / or sphingomyelin and / or metabolic precursors or metabolites of any of the foregoing; wherein if sphingomyelin is present in the composition, it is present in an amount of at least 300 mg / kg, wherein if folic acid is present in the composition, it is present in an amount of at least 100 mcg / kg, wherein if vitamin B12 is present in the composition, it is present in an amount of at least 5 mcg / 100g, wherein if iron is present in the composition, the iron is present in an amount of at least 5 mg / 100g, wherein if fatty acid derivatives comprising DHA are present in the composition, the fatty acid derivatives comprising DHA are present in an amount of at least 60 mg / 100g to 350 mg / 100g, wherein if fatty acid derivatives comprising AA are present in the composition, the fatty acid derivatives comprising AA are present in an amount of at least 60 mg / 100g to 350 mg / 100g, wherein all weights are based on the dry weight of the composition, and wherein the composition is a composition selected from the group consisting of infant formulas, growing-up milks, compositions for infants intended to be added to or diluted with human breast milk, and foodstuffs intended for consumption by infants and / or children alone or in combination with human breast milk.

17. The synthetic nutritional composition according to claim 15, wherein the composition comprises fatty acid derivatives comprising DHA at a concentration of 1023 mg / kg, fatty acid derivatives comprising ARA at a concentration of 1023 mg / kg, vitamin B12 at a concentration of 54 mcg / kg, folic acid at a concentration of 1698 mcg / kg, sphingomyelin at a concentration of 814 mg / kg and iron at a concentration of 67 mg / kg.

18. A composition comprising vitamins for improving vision, motor function including coordination and execution of movements, and / or psychomotor function in an individual, wherein the vitamins are vitamin B12 and / or folic acid.

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