Classifications

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  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
  • A23L33/12—Fatty acids or derivatives thereof
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  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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  • A23L33/13—Nucleic acids or derivatives thereof
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  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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  • A23L33/14—Yeasts or derivatives thereof
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  • A23L33/15—Vitamins
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  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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  • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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  • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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Definitions

• the invention relates to a combination of specific components for use in the prevention or treatment of frailty in a mammal, in particular for use in increasing one or more of body weight, body mass index, lean body weight, muscle mass, muscle strenght, or muscle function, especially in an elderly human, more in particular in a human prone to or suffering from cognitive decline or dementia, in particular senile dementia, more in particular Alzheimer's disease.
• the invention also relates to the specific clinically relevant benefits that can be achieved in such persons, like improvement of stamina, an increased degree of activity during daytime and associated change in lifestyle.
• the invention also relates to a composition comprising said specific combination of components, either as a nutritional or pharmaceutical composition, which are suitable for achieving said effects in a frail mammal, especially in an elderly human, most in particular in a human prone to or suffering from dementia, in particular senile dementia, more in particular Alzheimer's disease.
• Body weight of humans is determined by the weight of the different parts in the body, like that of bones, muscle, organs, vessels, adipose tissue, et cetera. During lifetime the contributions of each body part to the total body weight changes. After maturation of the human body has stopped, typically muscle mass will gradually and steadily decrease with time. This decrease results in a decrease of lean body mass (LBM, which is the body mass minus the mass of adipose tissue], despite the fact that total body mass (or body weight] may increase, e.g. due to an increase of the mass of adipose tissue and changed masses of other parts of the body.
• LBM lean body mass
• Ferruci et al. reported about the progression of loss of muscle strength during aging (Ferruci et al.
• the strength of a muscle is considered to be dependent on its mass. Its mass depends on the number of muscle fibers, which decreases only after 55 years of age to about 50 % at the age of about 80 years, their length , which depends on their trophic condition, and the cross-sectional area, which depends on training (Faulkner et al. (2007 ⁇ Proc Au P S, 38; 69-75 ⁇ . Muscle strength (strength of handgrip or quadriceps ⁇ in normal persons appeared to decrease about 0.5 % per year after the 30 th year. Typically, this rate of de- cline of muscle strength increases with age.
• Frailty is a large problem to the individual which experiences it, to the environment and to society. It has a large impact on the patient's life and creates huge costs for medical care. For this reason, the problem is recognized in the prior art as a geriatric syndrome that is distinct from disability and comorbidity. In addition, a relatively low lean body mass and body weight in elderly and especially in persons experiencing neurological problems, is common and a large problem, which has not yet been solved in the prior art.
• a nutritional composition according the invention preferably comply with the regulations for Food of Special Medical Purposes (FSMP], as currently valid in the European Union.
• FSMP Food of Special Medical Purposes
• the invention aims to increase lean body mass or significantly decrease the rate of loss of lean body mass, muscle mass or body weight.
• Involuntary weight loss during aging above 65 years is strongly associated with decreased immuno-competence, impaired mood and low stamina and an increased prevalence of health complications in the same patient. Involuntary weight loss is therefore typically a great concern to the clinical practitioner and has been included in the list of symptoms for diagnosed frailty by Fried and others (Fried et al. (2001 ⁇ J Gerontol, 56, M146-156 ⁇ .
• Weight loss may already be present in the early stages of dementia and increases with the severity and progression of AD.
• the prognosis of developing more diseases, or developing more severe grades of disease, or experiencing a more rapid progression of diseases increases with lower BMI, in particular when it starts to become lower than 23.5 kg/m 2 .
• a neurological problem such as an impairment of brain function or the function of peripheral nerves.
• An example of such neurological dysfunction may be an impaired cognitive function, like a form of cognitive impairment or dementia.
• the efficacy of the composition according to the invention can be represented as done in Figure 1.
• Alzheimer's disease and other dementias a delirium, Parkinson's Disease, hip fracture, incontinence, pneumonia and dehydration, pre-death, and several end stage diseases, frailty has to be considered as an independent state of the body.
• the "nutritional status" in terms of concentrations of nutrients in blood (plasma]
• frail elderly does not comply with the values that are typically measured in the blood of healthy elderly or healthy middle-aged adults.
• bad nutritional status in terms of blood concentrations of specific nutrients is associated with specific diseases, though in most cases causal relationships are difficult to recognize, if present at all.
• This specific improvement of the nutritional status of a frail or prefrail person or elderly person having a relatively low body weight is defined to be the nutritional man- agement of the frail or prefrail consumer.
• Disease-specific requirements, in particular frailty-specific requirements are met, by administering the composition according the invention.
• the nutritional composition according to the invention achieves the nutritional management of frailty and prefrailty. This is done so not by providing nutrients in general which have been attempted in the prior art, but failed or had severe disadvantages.
• the elderly, and especially the elderly with impaired cognitive function and the frail elderly generally experience difficulties with consuming large quantities or volumes of food, may suffer from impairments in body and organ function or from early satiety and low appetite, have practical problems with cooking and with consuming the food products, and are not keen on or capable of applying exercise programs (Holmes (2008 ⁇ Nursing standard, 22 (26 ⁇ , 47-57 ⁇ .
• the composition according the invention achieves all benefits as described above at about the same time. This is observed in elderly in general (above 65 years of age ⁇ , but also in a subgroup thereof, the oldest one (persons above 75 years of age ⁇ .
• the nutritional or pharmaceutical composition according to the invention is to be used for treating at least two symptoms of frailty, i.e. for increasing low body weight or BMI and for improving activities of daily living (ADL ⁇ , especially in persons older than 50 years of age, more in particular those older than 65 years of age (elderly ⁇ and in particular older than 75 years of age (the oldest ⁇ .
• composition according to the invention may also be used to combat other symptoms of frailty, such as exhaustion or fatigue by its effect on muscle power, and thrive or stamina and the effect on neurological performance, in particular cognition, as disclosed before.
• frailty such as exhaustion or fatigue by its effect on muscle power, and thrive or stamina and the effect on neurological performance, in particular cognition, as disclosed before.
• it constitutes a composition which not only solves these symptoms, but also pro- vides superior effectivity against frailty in comparison to prior art compositions, and without adverse effect.
• a composition which comprises DHA or EPA, in combination with uridine or its equivalent and optionally a range of other components to support activities of daily living.
• the composition can be administered to elderly and locomotor function appeared improved by administering these components.
• protein could be included in the composition of the invention, in order to improve muscle strength, when administered to frail elderly. In order to achieve this, in particular 1 to 5 g protein per 100 ml of a liquid composition was included, wherein the protein comprises more than 80 weight% milk-derived proteins.
• WO2010/002257 discloses the use of a nutritional preparation comprising more than 18 energy percent protein (preferably 22 to 32 en%], whey protein, at least 12 g leucine per 100 g proteinaceous matter and a lipid fraction which comprises EPA, (n-3]DPA, DHA, (n-3] ETA for improving muscle function in a mammal.
• the improvement of the function of muscle was in terms of maximum force, maximum contraction velocity and maximum relaxation velocity, all corrected for muscle mass. This improvement was claimed to occur when the patient suffered from specific diseases, in particular cancer or during "aging" and was claimed to result in improving daily activity, physical performance and quality of life. Frail individuals as such were not mentioned and neither were elderly with a low BMI or elderly being frail.
• composition as disclosed comprises preferably the components as mentioned and in addition specific indigestible oligosaccharides, glutamine, cysteine, oligosaccharides, carnitine and taurine. Though soy protein and wheat protein were mentioned the inclusion of casein instead of these vegetable proteins was preferred. Nucleotides and uridine sources were not mentioned.
• WO 2005/060952 relates to a composition comprising in a daily dosage form 14 to 1000 mg panthothenic acid (vitamin B5] for stimulating appetite, whereby body weight and muscle mass is increased in specific groups of diseased humans. This was surprising, since panthothenic acid had been reported before as a hunger suppressant.
• the composition may further comprise folic acid, vitamin C (as antioxidant], and vitamin B6 and B12 as part of a common vitamin premix.
• WO2007/073178 discloses a drink liquid for Alzheimer patients (Example 3 ⁇ comprising a nucleoside equivalent (UMP], fish oil comprising DHA and EPA, vitamin B6, folic acid and vitamin B12, phospholipids, vitamin C (as antioxidant], and choline. The claimed effect is not disclosed.
• WO2004/026294 discloses a nutritional composition which comprises leucine and at least one of isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine or histidine in free or salt form, wherein free leucine is present in an amount of 10 to 35 weight% of the total amount of amino acids.
• Such composition was claimed to be useful for controlling tumour-induced weight loss, for stimulating protein synthesis, ameliorating loss of muscle in a human or for the dietary management of malnutrition.
• lean body mass (LBW] or the body mass index (BMI] can be increased in frail mammals, or frailty can effectively be treated therapeutically or prophylactically by providing a nutritional or pharmaceutical composition comprising a specific combination of active components.
• the present invention relates to a composition
• a composition comprising at least two, preferably three, and more preferably four components (as active ingredients] selected from the group of (i] a nucleoside equivalent, (ii] an ⁇ -3 polyunsaturated fatty acid selected from the group of DHA, DPA and EPA, (iii] a vitamin B, (iv] a phospholipid, (v] an antioxidant and (vi] a choline, with the proviso that at least component (i] or (iii] is present, for use in the prevention or treatment of frailty in a mammal, in particular for use in increasing one or more of body weight, body mass index, and lean body weight, especially in a human, especially in an elderly human.
• active ingredients selected from the group of (i] a nucleoside equivalent, (ii] an ⁇ -3 polyunsaturated fatty acid selected from the group of DHA, DPA and EPA, (iii] a vitamin B, (i
• a nutritional or pharmaceutical composition for use according the invention (hereafter als called “composition according to the inven- tion” ⁇ not only has an effect on LBW or the BMI in (frail] elderly, or may be used to treat frailty, especially in an elderly mammal, but that the administration of a nutritional or pharmaceutical composition of the invention wherein a uridine-source and ⁇ -3 type polyunsaturated fatty acids ( ⁇ -3 PUFAs] are present, results in a further improvement in the amount of activities of daily living that can be performed and an increased muscle mass, muscle strenght or muscle function, when also a specific protein amount is included in the composition according to the invention.
• composition according to the inven- tion not only has an effect on LBW or the BMI in (frail] elderly, or may be used to treat frailty, especially in an elderly mammal, but that the administration of a nutritional or pharmaceutical composition of the invention wherein a uridine-source and ⁇ -3 type polyunsaturated fatty acids ( ⁇ -3
• composition according the invention may be used to improve stamina, to increase degree and frequency of feeling more energetic, to decrease duration, severity or frequency of feeling tired or exhausted or feeling fatigue, or to increase eagerness to demonstrate initiatives and become more active.
• composition according the invention can improve gait.
• mammals physically benefit from treatment with a specific combination of active ingredients such that one or more of body weight, body mass index, or lean body weight are better maintained or even increased without the need to increase the daily caloric intake of said mammals.
• the specific combination of components is simultaneously capable of decreasing other symptoms of frailty, like an improvement of neurological dysfunction or an improvement of longer term muscle use leading to an increase in the amount of activities that are applied during wake time. This is mandatory to the effective treatment of frailty.
• the specific combination of active ingredients may be used for the treatment of frailty or prefrailty, thus resulting in achieving a lower risk of developing frailty in the course of time.
• the components as described above can be combined with a specific protein com- position to obtain a stronger effect on LBM or BMI.
• a noun e.g. a compound, an additive etc.
• the plural is meant to be included, unless specified otherwise.
• an acid e.g. a fatty acid or folic acid
• this term is meant to include the conjugated bases of said acid [e.g. folate], salts of the acids and derivatives of the acid of which the body is capable of converting it into the acid [e.g. fatty acid esters, such as triglycerides], unless specified otherwise.
• dosages these are in particular intended for adult humans.
• the skilled person will be able to determine a suitable dosage for other mammals based on common general knowledge, the information disclosed herein and optionally a limited amount of routine testing.
• the mammal When referring to a mammal, preferably the mammal is a human mammal, more preferably an elderly human mammal.
• frailty which includes the practical approaches of many scientists (like Fried, Ory, and Chin A Paw].
• a person is deemed to be frail when the individual's condition in a recent period of time complies with at least 3 of the following list of (6] classes of symptoms (frailty criterions]:
• the degree of malfunction of each of the mentioned classes of symptoms can be measured by applying recognized methods that are known in the prior art.
• the application of the following methods is preferred :
• Criterion 1 muscle weakness
• a] for muscles of the arm: hand grip strength or quadriceps strength b] for the leg the method as described by B0rsheim et al. (2008] Clin Nutr. 27, 189-195 ; or as described in Pijnappels et al. (2008 ⁇ Eur J Appl Physiol. 102(5 ⁇ : 585-592 can be applied. Belonging to the lower 20% of the group of age and gender matched persons resulted in fulfilment of this frailty criterion.
• Criterion 2 Feeling of exhaustion or fatigue
• a ⁇ mental fatigue b ⁇ the perception of exerting a standardized exercise protocol, muscle capacity or muscle power, or c ⁇ lung capacity.
• method a ⁇ is done by applying a questionnaire as known in the prior art, e.g. the CES-D scale as described by Roberts (1980 ⁇ Psychiatr Res, 2, 125-134, so scoring on statements like "I cannot get going” or "I feel that everything I do is an ef- fort". This measure is strongly related to the degree of stamina of the individual.
• Method b ⁇ is a measure of physical exhaustion and can for example be done by applying the Borg scale for measuring perceived exertion (Borg (1998 ⁇ Human kinetics, Champaign, 111 ; Nybo (2003 ⁇ Med Sci Sports Exerc, 35, 589-594 ⁇ .
• Method c ⁇ is a measure of the capacity of a human being to provide sufficient oxygen (air ⁇ to the body.
• the preferred method for applying it is measuring forced expiratory volume (FEV1 ⁇ in one second, which should be below 30 % of the normal value, for individuals of similar age and gender, in order to meet the criterion.
• FEV1 ⁇ forced expiratory volume
• Measurement of the degree of physical exhaustion or fatigue, as recommended in method b ⁇ can be done in several ways, which all represent ways that reflect the capac- ity of the neuro-muscular system to exert labour and be active.
• the amount of physical activities can be measured, by attachment of devices to the person to be tested, and measuring the amount of physical activity which is voluntarily applied normally during wake time. This amount can also be related to the amount of sleep or rest that is needed to recover from it, and be put in a score.
• the capacity of the muscle to maintain a certain force for a certain time is a useful measure.
• this force that needs to be maintained is at 15 to 80 % of the maximal force the muscle can provide, in order to reflect better the activities as applied in normal life.
• the speed with which physical exhaustion is developed can be determined. For example, the amount of power a muscle can exert in a certain period of time can be determined; e.g. by measuring the force multiplied with the distance (in a movement ⁇ that the force was exerted, e.g. by swinging a leg at a certain velocity. Equipment for measuring these advanced parameters is commercially available. The speed with which a muscle can be- come tired, or in other words, the time that a certain force can be maintained, is a valuable measure of the capability of an organism to apply daily activities. When the measured values for these parameters in the tested person belong to the lower 20% of such values for a group of persons of similar age and gender, the person is deemed to comply with this criterion of frailty.
• muscle capacity or muscle power provides useful information about the state of exhaustion and fatigue, and especially physical exhaustion and fatigue of a patient.
• the force that a skeletal muscle can apply also influences the maximal velocity with which a certain movement can be made.
• a high movement velocity does not automatically result in a large endurance or a good recovery after exercise, which are required for performing a large amount of activities or showing a high mobil- ity during wake time over the day.
• Criterion 3 (physical activity) - For determining the magnitude of physical activity of a human, one or more methods of the following list can be applied: a ⁇ determination of the amount of basic activities as applied during daily life (as described above ⁇ , and b ⁇ determination of the amount of instrumental activities, as applied during daily life. Especially the measurement of instrumental activities is a valuable measure. A reliable method to do this is assessment of the "Physical Activity Scale for the Elderly” (PASE ⁇ , as described by Washburn et al. (1999 ⁇ J Clin Epidemiol 52, 643-651; "The physical activity scale for the elderly; evidence for validity". For men, a score of less than 30 and belonging to lowest 20 % part fulfilled this criterion for frailty. For women, the threshold value was ⁇ 27.5 (Graham et al. (2009 ⁇ Gerontol, 55, 644-651 ⁇ .
• Criterion 4 For determining the gait of a human, tests can be applied, like those described in the "Modified Physical Performance Test” (PTT ⁇ , as disclosed by Binder et al. (1999 ⁇ J Gerontol, 54, M428-432, like the preferred a] measure of "balance", as e.g. done by determining the way how a frail person is capable of taking a penny from the floor, or b ⁇ time and way to walk 5 to 15 meters, or c ⁇ time and way to raise from a chair. For example, for method b ⁇ the criterion for frailty was fulfilled when the person belonged to 20 % of persons with regard to the time needed.
• the threshold values per gender as mentioned in Graham et al. (2009 ⁇ Gerontol, 55, 644-651 can suitably be applied.
• Criterion 5 For determining the presence of undesired weight loss, it is important to avoid confusion with acute weight loss as caused by a (serious] disease or trauma or an underlying pre-death syndrome.
• frailty as the result of cachexia is excluded from the group of persons wherein the composition according to the invention is effective. In one embodiment of the invention, this exclusion of persons who have become frail because of cachexia is preferred. In this way, frail individuals which comply with the definition as given above differ from the individuals which have developed a frailty that results from these diagnosed conditions, related to acute phases during diseases and briefly before death.
• BMI BMI
• a BMI value between 20 to 25 kg per square meter is considered to be most healthy
• a BMI below 23.5 is considered to be undesirable
• the preferred list of diagnostic tools for establishing a too low body weight, lean body mass or muscle mass aims to be suitable for the aged population.
• the inventors feel that it is desirable to look carefully at the metabolic condition of the individual who suffers from a low BMI, body weight or muscle capacity.
• the metabolic condition of the patient differs on essential points from that of a person who experiences a more generalized metabolic problem.
• This difference has also been made by others, for example for Alzheimer patients (Guerin et al. (2005 ⁇ Am J Clin Nutr, 82 (2 ⁇ , 435-441 ⁇ . Part of the Alzheimer patients appear to experience sudden and severe weight loss as a result of intercurrent events, like institutionalization, a major change in life style, a trauma or the presence of a major disease, while a different part suffered from a more chronic weight loss.
• the BMI value as proposed as a limit for meeting one criterion of frailty, is assessed in the absence of an acute phase condition, i.e. the absence of a diagnosed disease selected from a cancer, AIDS, a COPD, an infection, pre-death, pre-death associated with anorexia, surgery, an accident and similar major trauma, or in an alternative embodiment the acute phases during these diseases or conditions.
• an acute phase condition i.e. the absence of a diagnosed disease selected from a cancer, AIDS, a COPD, an infection, pre-death, pre-death associated with anorexia, surgery, an accident and similar major trauma, or in an alternative embodiment the acute phases during these diseases or conditions.
• the presence of the acute phase during these diseases can be determined by measuring a biomarker as known in the prior art, e.g.
• cytokines which are representative of acute infections or severely progressed disease, like IL-1, IL-6 or TNF-a.
• a disease like cancer, chronic obstructive pulmonary diseases, AIDS and other diseases or pre-death, at some stage can cause a frailty condition that is acute and severe.
• the inventors find that the metabolic condition of such individual is com- pletely different from that of an individual suffering from a frailty that origins from a generalized metabolic inability to cope with the daily stresses from the outside world.
• frailty which is treated and solved by administering the nutritional or pharmaceutical composition according the invention, is not this acute -, and disease- or trauma-related type of advanced weight loss or frailty.
• frailty is the frailty as defined below and caused by a general and complex deterioration of the body to adapt the external stresses, as can have been acquired during life e.g., by applying bad life style including bad dietary habits, exposure to toxicants or as a result of time, as occurs during aging, in particular by aging after 65 years of age and more in particular the frailty as caused by a chronic deterioration of adaptive responses.
• Method b ⁇ for establishing undesired progressed weight loss is applying the criterion of 4.5 kg undesired weight loss in the previous year.
• Method c ⁇ applies the criterion of 6 kg undesired or unexplainable weight loss during previous 2 years.
• a pre-death condition can be diagnosed by a physician. Measurement of transthyretin and al- acid glycoprotein in blood plasma of both genders and the determination of low blood albumin and high C-reactive protein in blood of males, as applied by Carriere (POLA Group] et al. (1998 ⁇ Arch Ophthalmology, 116, 1031 ⁇ is recommended for establishing predeath risk.
• Criterion 6 (Neurological dysfunction) - For determining the degree of neurological dysfunction application of the following list is preferred: a] establishment of a tremor or a locomotor dysfunction different from the balance and performance tests applied in measuring gait performance ; b ⁇ measurement of cognitive function (impair- ment ⁇ ; c ⁇ determionation of verbal fluency ; d ⁇ measurement of speed of conductance of electrical signals over nerves ; e ⁇ analyses of sensory functioning, to establish a problem related to hearing, vision, tasting, smelling and touch] ; f) measurement of a emotional or psychological condition, like establishing the presence of major depression, an affect disorder or an anxiety disorder ; g ⁇ determination of incontinence or the daily occur- rence of significant involuntary urinary loss, and h ⁇ the presence of a major sleep disorder, like chronic insomnia or sleep apnea.
• a patient is considered to meet this neurological dysfunction criterion of frailty when b ⁇ is met (cognitive impairment ⁇ or, when a combination of at least two of the other criterions has been fulfilled.
• Cognitive impairment can be assessed by methods known in the prior art, for example by applying measures of the domains related to the measurement of verbal memory, visuospatial memory and attention-executive abilities. Preferred methods include application of the ADAS-cog assessment, the MMSE assessment, the Montreal cognition assessment or the CERAD methods.
• the analyses of sensory function can be applied by using methods known in the prior art to determine threshold values for tastes, odours and sounds, or to determine the ability to differentiate between different odours and tastes.
• a person is considered to be mildly frail when it complies with three of the six criterions, and moderately frail when it complies with four criterions or when the score of the three symptoms is so bad, that it seriously impairs the patient's condition, as di- agnosed by the clinician or physician.
• prefrailty A person is considered to be in a prefrail condition or prodromal frail condition, when his or her condition complies with only two of the six frailty criterions.
• composition according to the invention treats prefrailty, it is defined to act in a preven- tive manner on the development of frailty. So, prefrailty and prodromal frailty is defined to be synonymous.
• a person is defined to be a frail elderly when it complies with the above-mentioned criterions for frailty and in addition is older than 65, preferably 75 years of age.
• An individual is defined to be a prefrail elderly when the person's condition com- plies with the criterions of prefrailty and the person is older than 65, preferably 75 years of age.
• composition according the invention aims to have its efficacy only in those patients which comply exactly with the criterions as set above.
• Elderly or the aged population is a group that is defined in different ways in the prior art.
• the inventors have applied the fol- lowing definition.
• Elderly or the aged population is defined to be all persons being older than 65 years of age.
• the "oldest old" are those persons being older than 75 years.
• the claimed combination for use in accordance with the invention is in particular suitable for treatment of a mammal.
• said combination is to be used for the treatment of a human, in particular an elderly person.
• an elderly person is a person of the age of 50 or more, in particular of the age of 55 or more, more in particular of the age of 60 or more, more in particular of the age of 65 or more.
• the composition according the invention may induce a concentration in blood of that nutrient, which is outside the normal range as typically observed in the same tissue of healthy individuals, for example of healthy individuals which consume regular food or a normal diet.
• the composition according to the invention also aims to therapeutically nourish frail or prefrail persons or persons having too low LBM or BMI.
• the composition according to the invention is used in combination with an assessment of malnourishment of a mammal, preferably using MUST or MNA.
• the invention comprises at least the following steps:
• the assessment of nutritional status is applied at least twice in combination and relation to the nutritional intervention. More preferably, the assessment is done at least one time before and at least one time after the intervention to measure any changes in nutritional status.
• the initial nutritional assessment may reveal deficiencies which can be resolved by adapting the intervention composition according to the invention.
• separate tools have been defined which is a specific nutritional assessment tool and a module of food components which allows convenient adapatation and fortification of the nutri- tional intervention composition according to the invention.
• a preferred tool for assessing nutritional status comprises several parts, including a questionnaire, which asks the right questions to assess nutritional status, a database which is filled in by answering the questions, and an algorithm which compares the answers with predefined normal values.
• Optionally conclusions are drawn to arrive at an advice.
• These functionalities can be incorporated into an electronic device like a computer or minicomputer, by loading and running an appropriate software program.
• the questions to ask are at least covering biomarkers for the determination of nutrient status using methods as applied in the state of the prior art clinical chemistry laboratories.
• the inventors Apart from the “nutritional management", the inventors also identify the “therapeutic management” of frailty and prefrailty.
• the management of the individual to be treated comprises at least the following steps:
• step a ⁇ measurement of progress made by assessing at least again the same symptom classes as done in step a ⁇ .
• the assessment of symptoms is done by using the tool, in particular a form or document or an electronic device loaded with appropriate software, as described below.
• the intervention with the nutritional composition according to the invention can be combined with one or more of 1 ⁇ an exercise program, 2 ⁇ a program to improve social interactions, 3 ⁇ a program to become more exposed to sunlight and fresh air, 4 ⁇ an adaptation of the diet or of the general food intake practices of the patient, and 5 ⁇ an intervention with a drug or medicine.
• the therapeutic management comprises at least a program to be exposed to sunlight and fresh air or an exercise program as a fourth and fifth step in the therapeutic management of the condition of the patient.
• the mammal to be treated may suffer from any of the frailty symptoms as defined above.
• the mammal is a human which suffer from at least a neurological or brain problem and one selected from the group of weight loss and an abnormally low physical activity.
• the patient experiences all three types of symptoms.
• this is preferably a form of dementia, in particular senile dementia.
• senile dementia For the purpose of the inven- tion, persons that suffer from "senile dementia" are defined as suffering from one or more dementias.
• Senile dementia or dementia is considered to comprise Alzheimer's disease (AD ⁇ .
• the dementia may be in any stage.
• the mammal may be in a prodromal stage of dementia.
• a "prodromal dementia patient” is a person who does not suffer from a senile dementia as defined above, but has an increased likelihood to develop senile dementia.
• a "prodromal Alzheimer patient” is a person who does not suffer from AD, but has an increased likelihood to develop AD.
• any diagnostic tool for determining prodromal dementia patient may be used.
• Several diagnostic tools that can be used to classify the patients as prodromal dementia patients are described below and include an accurate diagnosis of brain lesions and biochemical problems and careful setting of criteria.
• the invention is independently directed at prodromal dementia patients or prodromal Alzheimer's patients.
• CSF ⁇ Total-tau per litre cerebrospinal fluid
• MTL medial temporal lobe
• F2-IsoP F2- so-prostane
• patients who are in a prodromal state of Alz- heimer's Disease are defined to be in a predementia stage of AD.
• the values of the biomarkers indicate a condition of the body, in particular the central nervous system, wherein the risk of developing Alzheimer's disease is significantly increased, no matter whether the final form of Alzheimer's disease will be typical Alzheimer's disease, atypical Alzheimer's disease or mixed Alzheimer's disease.
• This predementia state of the body can be without significant clinical symptoms, the so called preclinical state of Alzheimer's disease, wherein a patient is asymptomatic at risk for Alzheimer's disease or is experiencing presymptomatic Alzheimer's disease.
• a patient may experience mild cognitive impairment without having an increased risk for developing Alzheimer's disease as determined by measuring the above-mentioned pa- rameters (Dubois et al. (2010] Lancet Neurol, 9, 1118-1127].
• composition according the invention has its effects on body weight and frailty, no matter the patient is a real Alzheimer's disease patient, is a prodromal Alzheimer's disease patient, is a normal elderly which experiences age-associated memory impairment or mild cognitive decline witjhout having increased risk of developing AD, or is in the preclinical state of being at increased risk of developing Alzheimer's disease or a different dementia, like a vascular dementia.
• a prodromal Alzheimer patient can be identified as such because he meets at least the first two criteria (total tau and ratio abeta-42/P-tau- 181 ⁇ . More preferably, one of the three other criteria (MTL atrophy, FTL atrophy, F2- IsoP] also applies.
• PET ⁇ Positron Emission Tomography
• impaired glucose metabolism in the brain as measurable by applying SPECT;
• Abnormalities in the condition of the brain or parts thereof can be established by either taking the person's own condition under healthy circumstances as a reference, or, when this is not available, by taking the average condition of a representative group (so matched for e.g. age] as a reference. The latter will occur most frequently.
• the clini- cian is capable of recognizing a prodromal phase.
• an intermediate situation wherein the patient demonstrates a deviation of x% from the value of a healthy individual in the direction of the pathological conditions is for the purpose of this invention considered to be a prodromal patient.
• the value of x for the determination of blood flow and glucose metabolism is 20% when determined under standardised conditions in terms of feeding and exercise. It is important to notice that the effect of the composition according to the invention on body weight occurs in the presence of relatively little energy and protein in the composition according to the invention and that this effect on body weight occurs simultaneously with an effect on other symptoms of frailty, like neurological or brain function, or the physical activity, in particular instrumental activities, which makes it suitable for the treatment of frailty and prefrailty.
• the composition according the invention is a nutritional or a pharmaceutical composition.
• pharmaceutical composition it is understood that such composition has only a medical effect or benefit, i.e. the composition comprises essentially no ingredients which provide a substantial source of energy, other than the active components.
• nutritional composition it is understood that such composition has both a nutritional and a medical effect or benefit, i.e. the composition com- prises macro nutrients which provide a substantial source of energy, other than the active components, in particular proteinaceous matter, fat, other than component (ii], and digestible carbohydrates.
• It preferably comprises food grade components, which make it suitable for safe oral intake or enteral administration.
• the components can also be dissolved in a matrix which makes it suitable for parenteral administration.
• the composition according to the invention can have any form or physical condition.
• it is a sterile composition or a composition which comprises a defined micro-organism population, like a dairy product, for example which is fermented under controlled conditions or a dry product to which probiotics have been added.
• An example of such fermented product is a yoghurt.
• the composition according the invention can be solid, semi-solid or a drink. Such forms have been widely disclosed in the prior art.
• it is a drink, though for patients which experience dysphagia, a high-viscosity product or a semi-solid form is preferred.
• the composition according to the invention may also be a kit-of-parts comprising the components according to the invention, packed for simultaneous or sequential ad- ministration to a person in need thereof.
• each component may be packed separately, or some may be packed together, for example in a sachet, bottle, etc.
• the composition according the invention is preferably a composition which complies with the criterions as set for the ruling regulations for food for special medical purposes or of a medical food. These regulations are distributed by the Food and Drug Administration or as directives from the European Union or by recognized authorities in other jurisdictions.
• the composition according to the invention provides those nutrients and those amounts as required by the patient because of the specific disease state of the patient. These amounts of the active components cannot be consumed by adapting the normal diet.
• the composition according the invention is meant to therapeu- tically improve one or more of body weight, body mass index, lean body weight, muscle mass, muscle strenght or muscle function. This improvement can occur in elderly, in particular frail elderly.
• the composition according to the invention can suitably be used in the nutritional management of individuals suffering from frailty symptoms or the therapeutic management of frailty (or prefrailty], by providing a certain amount of the active components per day, and preferably per period of about 4 hours.
• a daily amount as described herein means in particular an amount in a daily dosage unit provided by the combination of the invention.
• a daily dosage unit may be a single dosage, but it may also be divided over two or three, or even more daily servings.
• the combination according to a preferred embodiment, is intended for administration as a single unit, the daily amounts as described herein are preferably the amounts present in the (preferably packaged] combination unit.
• composition according to the invention is effective, without needing an increase in caloric intake. Accordingly, in a specific embodiment, the effect of said combination on increasing one or more of body weight, body mass index, or lean body weight is not attributed to an increase in caloric intake.
• composition according to the invention may comprise a nucleoside equivalent.
• nucleosides include nucleosides as such deoxynucleosides as such, and equivalents of nucleosides as such or deoxynuclesides as such. Thus, when referring to a nucleoside, this term is meant to include the corresponding deoxynucleoside.
• Equivalents in particular are compounds comprising a nucleobase, such as mononucleotides (mono-, di- or triphosphates of nucleosides], oligonucleotides, polynucleo- tides, nucleobases and physiologically acceptable derivatives thereof that may be converted into the nucleoside as such or a nucleotide as such in vivo.
• a nucleobase such as mononucleotides (mono-, di- or triphosphates of nucleosides], oligonucleotides, polynucleo- tides, nucleobases and physiologically acceptable derivatives thereof that may be converted into the nucleoside as such or a nucleotide as such in vivo.
• examples of such derivatives include various esters.
• WO 2002/088159 (Trommsdorff GmbH] relates to uridine esters, which may be used in accordance with the present invention. The contents of this publication regarding (deoxy
• nucleoside source e.g. acylated derivatives of the nucleosides, for example triacetyl-uridine.
• the composition according to the invention preferably comprises a pyrimidine nu- cleoside or equivalent thereof, such as cytidine or equivalent thereof or a uridine or equivalent equivalent. More preferably, the composition according to the invention comprises a uridine or an equivalent thereof, preferably at least one uridine or an equivalent thereof selected from the group consisting of uridine (i.e. ribosyl uracil], de- oxyuridine (deoxyribosyl uracil], uridine phosphates (UMP, dUMP, UDP, UTP], nucleo- base uracil and acylated uridine derivatives.
• uridine i.e. ribosyl uracil
• de- oxyuridine deoxyribosyl uracil
• uridine phosphates UMP, dUMP, UDP, UTP
• nucleo- base uracil acylated uridine derivatives.
• the composition according to the invention comprises an uridine phosphate selected from uridine monophosphate (UMP], uridine diphosphate (UDP] and uridine triphosphate (UTP].
• UMP uridine monophosphate
• UDP uridine diphosphate
• UTP uridine triphosphate
• the composition according to the invention comprises UMP, as UMP is most efficiently being taken up by the body after oral administration.
• Uridine derivatives like UDP which is readily formed from dietetic UMP, also appear to be important, in particular for trans- port of glycoproteins and glycolipids within the cell and availability thereof in the cyto- sol and plasma membrane.
• At least 20 weight% of the uridine or an equivalent thereof in the composition according to the invention is provided by UMP, more preferably at least 50 weight%, most preferably at least 90 weight%.
• the present use comprises the daily administration of uridine or an equivalent thereof in a daily dosage of 0.08 to 3 g per day, preferably 0.1 to 2 g per day, more preferably 0.12 to 1 g per day.
• the present use comprises the daily administration of UMP in a daily dosage of 1.3 to 37.5 mg UMP per kilogram body weight of the subject to be treated.
• the required dosages of the equivalents of uridine on a weight basis can be calculated from the daily dosage for UMP by taking equimolar amounts using the molecular weight of the equivalent and of UMP, the latter being 324 Dalton.
• the daily dosage of equivalents is preferably 3 to 115 ⁇ per kg body weight per day, preferably 5 to 35 ⁇ per kg body weight per day, or 0.25 to 9 mmol, preferably 0.3 to 6, most preferably 0.45 to 2.8 mmol per day.
• the present use comprises the daily administration of a combination comprising uridine or an equivalent thereof in an amount of 0.06 to 2.4 g UMP per 100 ml liquid composition, preferably 0.08 to 1.6 g UMP per 100 ml liquid composition, more preferably 0.12 to 0.8 g per 100 ml liquid composition.
• the optimal dose for uridine monophosphate per 100 g dry matter is 0.18 to 7.2 g, preferably 0.24 to 5.4 g and more preferably 0.36 to 2.4 g.
• cytidine equivalent cytidine can be used, for example as free base or as a salt, as an ester, as a phosphate derivative, like CMP, CDP or CTP, as cytosine, and as choline derivative, e.g. as citicoline.
• a cytidine equivalent when both an uridine equivalent and a cytidine equivalent are included simulateously in the composition according to the invention it is preferred that the weight ratio of the sum of uridine and equivalents thereof to the sum of cytidine and equivalents thereof is larger that 1.0, more preferably at least 2.0, most preferably more than 5.0.
• nucleosides include extracts of plant, animal, bacterial, algae or yeast material, e.g. in a composition according to the invention for individuals which don't suffer from a kidney disease. Examples of such extracts include heat-treated aqueous extracts from baker's yeast or brewer's yeast.
• the composition according to the invention preferably does not contain high amounts of other nucleotides.
• the weight ratio sum of uridine and equivalents thereof to adenosine or its equivalents in the composition according to the invention is below 0.1, more preferably below 0.01, most preferably 0.
• the weight ratio of the sum of the amount of uridine and equivalents thereof to the amount of guanosine or its equivalents in the composition according to the invention is below 0.1, more preferably below 0.01, most preferably 0.
• the weight ratio of sum of uridine and equivalents thereof to inosine in the composition according to the invention is below 0.1, more preferably below 0.01, most preferably 0.
• composition according to the invention may comprise an ⁇ -3 polyunsaturated fatty acid ( ⁇ -3 PUFA], in particular an ⁇ -3 long chain polyunsaturated fatty acid (LCPUFA], more in particular selected from the group of docosahexaenoic acid (22:6 ⁇ - 3; DHA], docosapentaenoic acid (22:5 ⁇ -3; DPA] and eicosapentaenoic acid (20:5 ⁇ -3; EPA ⁇ .
• ⁇ -3 PUFA polyunsaturated fatty acid
• LCPUFA long chain polyunsaturated fatty acid
• Useful sources include fish oil, algae oil, eggs lipids and genetically modified organisms.
• the composition according to the invention comprises at least DHA, preferably DHA and EPA. More preferably, the combination comprises DHA and at least one precursor of DHA selected from EPA and DPA. More preferably, the composition according to the invention comprises DHA and EPA.
• the inventors recognized that only a part of the DHA incorporated in the brain originates from orally ingested DHA. An important part of the DHA incorporated in the brain is derived from conversion of DPA to DHA in the brain.
• the composition according to the invention pref- erably contains a significant amount of EPA. EPA is converted to DPA ( ⁇ -3], increasing subsequent conversion of DPA ( ⁇ -3] to DHA in the brain.
• the composition according to the invention preferably also contains a significant amount of EPA, so to fur- ther stimulate in-vivo DHA formation.
• the ⁇ -3 PUFA's in particular the LCPUFA's, more in particular DHA, DPA and EPA, may be provided in any form such as, but not limited to, triglycerides, diglycerides, monoglycerides, free fatty acids or their salts or esters, phospholipids, lysophospho- lipids, glycerol ethers, lipoproteins, ceramides, glycolipids or combinations thereof.
• the composition according to the invention comprises at least DHA in triglyceride form.
• the present method comprises the daily administration of 200 to 5000 mg, more preferably 400 to 3000 mg, most preferably 800 to 2500 mg of the sum of DHA and EPA.
• the proportion of (DHA+EPA] relative to the total amount of fatty acids in the combination is preferably 5 to 50 weight%, more preferably 10 to 45 weight%, most preferably 15 to 40 weight%.
• the present method comprises the daily administration of 100 to 4000 mg, more preferably 120 to 1800 mg of DHA.
• the composition according to the invention comprises 1 to 40 weight% DHA based on total amount of fatty acids, preferably 3 to 36 weight% DHA based on total amount of fatty acids, more preferably 10 to 30 weight% DHA based on total amountof fatty acids in the composition according to the invention.
• the composition according to the invention preferably comprises 0.5 to 20 weight% EPA based on total amount of fatty acids, preferably 2 to 10 weight% EPA based on total amount of fatty acids, more preferably 5 to 10 weight% EPA based on total fatty acids.
• the weight ratio of DHA to the sum of EPA and DPA is preferably larger than 1.0, more preferably 1.2 to 10, more preferably 2 to 8.
• the composition according to the invention contains a low amount of arachidonic acid (AA; 20:4 ⁇ -6 ⁇ .
• Arachidonic acid is believed to counteract the effects of the composition according to the invention.
• the present subjects normally ingest sufficient AA, or precursors thereof, and an excess daily dosage may stimulate inflammatory responses, inhibiting daily activities.
• the weight ratio DHA/AA in the composition according to the invention is at least 5, preferably at least 10, more preferably at least 15, up to e.g. 100.
• the weight ratio EPA/AA is at least 2.
• the present method preferably comprises the administration of a composition comprising less than 5 weight% AA based on total amount of fatty acids, more preferably below 2.5 weight%.
• the ⁇ -6/ ⁇ -3 weight ratio of long-chain polyunsaturated fatty acids with at least 20 carbon atoms in the composition according to the invention is advantageously below 0.5, preferably below 0.2. If the long-chain polyunsaturated fatty acids with 18 carbon atoms are also included in the ratio, the preferred ⁇ -6/ ⁇ -3 weight ratio is 0.05 to 1, more preferably 0.1 to 0.6, most preferably 0.15 to 0.4.
• the composition according to the invention comprises at least one vitamin B.
• the vitamin B is selected from the group of vitamin Bl (thiamine], vitamin B2 (riboflavin], vitamin B3 (niacin or niacinamide], vitamin B5 (pantothenic acid], vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride], vitamin B7 (bio- tin], vitamin B9 (folic acid or folate], and vitamin B12 (various cobalamins].
• at least one vitamin B is selected from the group of vitamin B6, vitamin B12 and vitamin B9.
• good results have been achieved with a combination comprising vitamin B6, vitamin B12 and vitamin B9.
• vitamin B12 and vitamin B9 are included because low plasma B12 or vitamin B9 levels are a risk factor for the develop- ment of Alzheimer's disease.
• the vitamin B is to be administered in an effective dose, which dose depends on the type of vitamin B used.
• a suitable minimum or a maximum dose may be chosen based on known dietary recommendations, for instance as recommended by Institute of Medicine (IOM] of the U.S. National Academy of Sciences or by Scientific Committee on Food (a scientific committee of the EU], the information disclosed herein and optionally a limited amount of routine testing.
• IOM Institute of Medicine
• a minimum dose may be based on the estimated average requirement (EAR], although a lower dose may already be effective.
• a maximum dose usually does not exceed the tolerable upper intake levels (UL], as recommended by IOM.
• the vitamin B6 is usually present in an amount to provide a daily dosage in the range of 0.5 to 100 mg, in particular in the range of 0.75 to 25 mg, more in particular in the range of 0.9 to 5 mg
• the vitamin B12 is usually present in an amount to provide a daily dosage in the range of 0.5 to 1000 ⁇ g, in particular in the range of 1 to 100 ⁇ g, more in particular in the range of 1.5 to 10.
• the vitamin B9 is usually present in an amount to provide a daily dosage in the range of 50 to 5000 ⁇ g, in particular in the range of 150 to 1000 ⁇ g, more in particular in the range of 200 to 1000 ⁇ g
• the active components are included in a drink, preferably having a volume of about 125 ml, or in an alternative preferred em- bodiment in a product having a dry mass content of about 30 g, per packaging each of them being for consumption once a day.
• a drink preferably having a volume of about 125 ml, or in an alternative preferred em- bodiment in a product having a dry mass content of about 30 g, per packaging each of them being for consumption once a day.
• the amounts per daily dose as mentioned above can be recalculated to a concentration per millilitre, by dividing the above-mentioned value with 125, or to a concentration per g dry mass of the product by dividing by 30.
• the composition according to the invention may comprise a phospholipid.
• phospholipid includes lyso-phospholipids, de-acylated phospholipids and glycerophospholipids. It is preferred to include a phospholipid which is capable of increasing chylomicrons formation in elderly after administration of triglyceride lipids and can provide useful fatty acids.
• the phospholipid is selected from the group of phosphatidylcholine(PC], phosphatidylethanolamine (PE], phosphatidylserine (PS], phosphatidic acid (phosphatidate], phosphoinositides (such as phosphatidylinosi- tol (PI], phosphatidylinositol phosphate, phosphatidylinositol bisphosphate, phosphati- dylinositol triphosphate] and sphingomyelin.
• PC phosphatidylcholine
• PE phosphatidylethanolamine
• PS phosphatidylserine
• phosphoinositides such as phosphatidylinosi- tol (PI]
• PI phosphatidylinositol phosphate
• phosphatidylinositol bisphosphate phosphati- dylinositol triphosphat
• the combination according to the invention comprises at least two different phospholipids selected from the group consistingof phosphatidylserine, phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine.
• the combination according to the invention comprises phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine.
• Good results have been achieved with a combination of phosphatidylcholine (PC] and phosphatidyl- serine (PS], preferably in a weight ratio of 3:1.
• lecithin may be used as a source for the phospholipids.
• the phospholipids are fortified with one or more phospholipids, such as a ceramide, a sphin- golipid or a specific phospholipid, such as a phosphatidylcholine.
• the phospholipid is to be administered in an effective dose.
• the total phospholipid daily dosage is in the range of 50 to 5000 mg, in particular in the range of 100 to 2000 mg, more in particular in the range of 150 to 1200 mg
• phospholipids further beneficially improves membrane function, thereby enabling an improved functioning of the different parts of the brain that may be affected in prodromal subjects. Furthermore, the phospholipids improve stability and shelf life of the composition according to the invention. Phospholipids further enable the manufacturing of palatable compositions. Also, phospholipids are a source for choline and prevent the decline in plasma choline levels after exercise. Choline is necessary for the formation of acetylcholine, a neurotransmitter involved in learning and memory and in the activation of muscles. These advantages are already achieved at relatively low phospholipid levels.
• composition according to the invention may comprise an antioxidant, in particular one or more antioxidants selected from the group of vitamin C, vitamin E and selenium.
• the anti-oxidant is to be administered in an effective dose.
• a suitable minimum or a maximum dose may be chosen based on known dietary recom- mendations, for instance as recommended by the Institute of Medicine (IOM] of the U.S. National Academy of Sciences or by the Scientific Committee on Food (a scientific committee of the EU], the information disclosed herein and optionally a limited amount of routine testing.
• a minimum dose may be based on the estimated average requirement (EAR], although a lower dose may already be effective.
• a maximum dose usually does not exceed the tolerable upper intake levels (UL], as recommended by IOM.
• vitamin C is usually present in an amount to provide a daily dosage in the range of 20 to 1200 mg, in particular in the range of 30 to 400 mg, more in particular in the range of 35 tol20 mg.
• vitamin E is usually present in an amount to provide a daily dosage in the range of 8 to 200 mg, in particular in the range of 20 to 140 mg, more in particular in the range of 35 to 100 mg.
• the selenium is usually present in an amount to provide a daily dosage in the range of 40 to 400 ⁇ g, in particular in the range of 50 to 200 ⁇ g, more in particular in the range of 55 to 80 ⁇ g.
• the nutritional or pharmaceutical composition according to the invention may comprise a choline.
• Choline refers to the various quaternary ammonium salts containing the ⁇ , ⁇ , ⁇ -trimethylethanolammonium cation. More specifically, choline is selected from the group of the choline cation, choline salts or esters, such as choline chloride, choline bitartrate, choline stearate or the like, or compounds that dissociate to choline, such as choline alfoscerate, sphingomyelin, cytidine-diphospho-choline or citicoline or CDP- choline, acylglycerophosphocholines, e.g, lecithin, lysolecithin, glycerophosphatidylcho- line, and any mixture thereof. It is preferred to include a choline salt or choline alfoscer- ate into the composition according to the invention.
• choline is to be administered in an amount to provide a daily dosage of 100 to 4000 mg, more in particular of 200 to 2000 mg.
• the nutritional or pharmaceutical composition according to the invention may comprise one or more further micronutrients, for instance one or more micronutrients selected from the group of vitamins, minerals, and trace elements, taurine and inositol.
• the composition preferably the nutritional composition according to the invention allows improvement of BMI, or LBM, or frailty, without demanding to consume large amounts of protein or additional energy.
• the amount of energy in the composition according to the invention can remain limited to a value of less than 400 kcal (1680 kj], preferably less than 280 kcal (1178 kj] or more preferably less than 210 kcal (882 kj], all expressed per daily dose for an adult human.
• the amount of energy is not needed to create the effect (as can be concluded from the experiment, which has an isocaloric control], but is simply the result of incorporating the active components into a small sized food product, which is thus used as a vehicle.
• the components (i] to (v] are included in a pharmaceutical composition according to the invention having an energy content per serving unit of less than 130 kcal (546 kj] or preferably less than 80 kcal (336 kj ⁇ .
• the amount of active components (defined as components (f) to (v ⁇ , which is needed to achieve the effect on BMI, etc, delivers more than 50 %, preferably more than 58 %, most preferably 62 to 88 % of the total amount of calories of the composition as claimed.
• the inventors use 9 kcal (37.8 kj] per g of lipids or phospholipids, zero kilojoule per g of nucleosides, vitamins and a choline equivalent, 4 kcal (16.8 kj] per g of protein and digestible carbohydrate and 2 kcal (8.4 kj] per g of fibre.
• composition according to the invention can remain relatively low, which can have important advantages to the largest part of indi- viduals which suffer from weight loss or symptoms of frailty.
• composition according to the invention should not impair normal eating patterns, allow manufacture of a palatable product and not induce heartburn or gastrointestinal discomfort after consumption thereof.
• the composition according the invention appears effective, also when the concentration of protein in the composition according to the invention remains below 11 g per 100 ml and preferably below 9, more preferably 3 to 8.4 g, and most preferably 5.2 to 8.2 g per 100 ml of the composition according to the invention.
• compositions according to the invention result in good compliance with the feeding protocol with such composition according to the invention and in very little adaptation of the normal diet after the composition according to the invention have been consumed according their recommended use.
• the amount of caseinates preferably is 4.5 weight% or vol% or less for liquid formula, and more preferably 0.5 to 4.0 weight% or vol% or most preferably 0.8 to 3.3 weight% or vol%. Therefore, but also for efficacy reasons, it is preferred to include a non-caseinate in the composition according to the invention, which is elaborated below.
• PUFAs, phospholipids, vitamins and a choline equivalent allows efficacy by administering a nutritional composition according to the invention with the minimum amount of food volume, e.g. less than 150 ml per serving unit, which is also important because elderly, and especially frail elderly experience much earlier satiety when consuming food.
• the actives are provided to the consumer, in a ready to use serving unit which provides 15 to 160 g of the effective composition according to the invention.
• the invention therefore provides a solution for the problem that an undesired amount of additional protein has to be administered for anabolic purposes, i.e. the improvement in BMI of elderly and it increases the improvement of the brain function as observed in frail elderly by consuming the combination of one or more of the active components (i] to (v] according to the invention.
• the protein amount preferably comprises a non-caseinate protein for supporting an effect of the composition according the invention on BMI in frail elderly.
• specific whey protein relatively low in phosphorous, fish proteins, in particular cod protein, or a protein derived from eggs and proteins derived from vegetables, like potato, soy, pea, beans, lupin, quinoa and amaranth appeared suitable.
• the proteins can be in- tact, either heat-treated or non-denatured, or be partially hydrolyzed. Hydrolyses of the intact protein aims to improve its solubility, but degree of hydrolyses should be kept to the minimum, preferably to a degree of hydrolyses between 2 and 12, in order to maintain good organoleptic properties of the ready to use composition according to the invention.
• the amount of non-dairy protein is more than 21 weight%, more preferably more than 25 weight%, most preferably more than 42 weight%, in particular more than 51 weight% of the protein amount.
• Suitable whey proteins include those which have a phosphorous content less than 400 mg/1 when 100 g of the protein is dissolved in one litre of water. Preferably, this phosphorous content is 70 to 340 mg/1.
• the amount of protein can be calculated from the label of the product, or, when this is impossible or not justified by measuring Kjeldahl nitrogen by a method accepted as preferred in the prior art for the specific matrix, and multiplying this by 6.25 for mixtures of proteins and peptides.
• dairy proteins are included, it is preferred to include a whey protein.
• Such protein is preferably enriched in serum albumin or alpha lactalbumin.
• Such dairy amount also preferably comprises a lactoferrin.
• the concentration of alpha-lactalbumin as fraction of all whey proteins is preferably more than 25 weight%, that of serum albumin 5 to 12 weight%.
• the concentration of lactoferrin is preferably in the range 0.25 to 3 weight%, preferably 0.29 to 1.4 weight%, more preferably 0.34 to 1.2 weight% of the protein amount.
• the amount of whey protein is preferably less than 50 weight% of the protein amount, in order to keep the satiating character of the composition according to the invention as low as possible, while maintaining efficacy of the composition according to the invention.
• non-essential amino acids or their salts or esters are also useful to include non-essential amino acids or their salts or esters.
• suitable amino acids include serine and aspartic acid. These amino acids can be administered as L-isomer or as a racemic mixture of L and D isomers of the particular amino acid.
• the amount aspartate plus asparagine in the composition according to the invention is preferably more than 8.4, more preferably 9.0 to 16, most preferably 9.5 to 15 g per 100 g amino acids in the composition according to the invention.
• the amount of serine in the ready to use composition according to the invention is preferably more than 4.1 g per 100 g amino acids.
• the presence of these two amino acids in the formula is thought to be at least partially responsible for the anabolic character of the formula and the observed efficacy in treating symptoms of frailty.
• Increasing the concentrations to the indicated amounts in the preferred embodiment increases their effect.
• the effect on neurological symptoms in the low BMI elderly includes the effect on depressed mood, stamina and the activities of daily living.
• the inventors believe that an effect on metabolic pathways is responsible for this, in particular an effect on glucose metabolism and gene expression and not the amount of calories or amount of protein that are provided by the composition according the invention.
• the protein amount contributes to a better functioning of metabolism in order to support the maintenance of BMI, and lean body mass, and other symptoms of frailty, like exhaustion and fatigue and neurological function. Therefore, the protein preferably comprises a whey protein and more preferably a whey protein and a vegetable protein.
• the osmotic value of the composition according to the invention is as low as possible, in order to facilitate easy stomach emptying.
• the composition according to the invention demonstrates an osmolality below 450 mEq/1.
• the buffer strength of the composition according to the invention pref- erably low, in order to achieve rapid digestion and gut transfer of the composition according to the invention after consumption. This is done by using the amounts and types of proteins as indicated above and by preventing the use of high salt loads, in particular of citrates and phosphates.
• the amount of phosphorous in the composition according to the invention is preferably less than 150 mg, more preferably 20 to 110 mg, most preferably 50 to 72 mg per 100 ml.
• the nucleotides in the composition according to the invention like a uridine phosphate, or cytidine phosphate are replaced by their base.
• the composition according to the invention comprises a nucleobase and a nucleoside or nucleotide.
• the ratio of the weight amount of nucleobase to the sum of the corresponding nucleosides and nucleotides is more than 0.06, preferably 0.2 to 0.9.
• the amount of organic acids, like citrates, is preferably less than 2, more prefera- bly less than 1.2 weight%, most preferably 0.1 to 0.9 weight% of the digestible carbohydrate amount.
• the composition according the invention is a liquid formula having a viscosity of less than 60, more preferably 2 to 30 mPa.s, measured at 20 degrees °C.
• the viscosity is the viscosity as measurable using a Anton Paar Physica MCR301 rheometer with aCP50-l/PC cone (diameter 50 mm, 1° difference between middle and outside] at 20 °C at 100s 1 .
• one or more additional ingredients may be present that are commonly used in the prior art, dependent on the form - nutritional or pharmaceutical composition - in which the combination is provided.
• the pharmaceutical composi- tion may comprise one or more excipients known in the prior art to provide a pharmaceutical composition in a dosage form of choice.
• the pharmaceutical composition is preferably for enteral application (orally or via tube-feeding ⁇ .
• solid formulations are tablets, capsules [e.g. hard or soft shell gelatine capsules], pills, sachets, powders, granules and the like which contain the active ingredients together with a conven- tional carrier.
• Any conventional carrier material can be utilized.
• the carrier material can be organic or inorganic inert carrier material suitable for oral administration.
• Suitable carriers include water, gelatine, gum Arabic, lactose, starch, magnesium stearate, talc, vegetable oils, and the like. Additionally, additives such as flavouring agents, preservatives, stabilizers, emulsifying agents, pH-buffers and the like may be added in accordance with accepted practices of pharmaceutical compounding. While the individual active ingredients are suitably administered in a single composition they may also be administered in individual dosage units.
• the composition generally comprises at least one macronutrient for providing (additional] energetic value to the nutritional composition.
• the macronutrient may suitably be selected from the group of pro- teinaceous matter (proteins, peptides, amino acids], fat, other than component (ii], and digestible carbohydrates.
• Suitable proteinaceous matter, lipids and carbohydrates, and suitable concentrations of the macronutrients may be based on known dietary guidelines for food products, in particular for food products for the elderly.
• Suitable formulations may e.g. be based on known commercially available clinical foods, or foods advertised for feeding elderly people or for feeding people suffering from dementia.
• lipid preferably one or more triglycerides are present. These may be selected from vegetable oils and fats and animal oils and fats.
• digestible carbohydrates these may in particular be selected from digestible pentoses, digestible hexoses digestible oligosaccharides, e.g. digestible disac- charides and digestible trisaccharides. and digestible polysaccharides [e.g. starch]. More specifically one or more digestible carbohydrates may be chosen selected from the group of galactose, mannose, ribose sucrose, trehalose, palatinose, lactose, maltodex- trose, maltose, glucose, fructose, including oligomers and polymers thereof.
• a nutritional composition according to the invention comprises one or more non-digestible carbohydrates (dietary fibres] such as oligosaccharides.
• oligosaccharides in particular refers to saccharides comprising 3 to 25 monosaccharide units per molecule.
• the oligosaccharide ⁇ ] may in particular be selected from the group of fructo-oligosaccharides (FOS], galacto-oligosaccharides (GOS], trans-galacto-oligosaccharides (TOS], xylo-oligosaccharides (XOS], soy oligosaccharides, and the like.
• FOS fructo-oligosaccharides
• TOS trans-galacto-oligosaccharides
• XOS xylo-oligosaccharides
• soy oligosaccharides and the like.
• higher molecular weight compounds such as inulin, resistant starch and the like may be incorporated in the composition according to the inven-
• the nutritional composition may comprise a probiotic.
• the nutritional composition may comprise one or more additives commonly used in food technology, such as one or more additives selected from the group of flavourings, stabilisers, preservatives, colourants, emulsifiers, pH-buffers etc.
• the nutritional composition for use in a accordance with the invention may be a solid composition, a semi-solid composition (such as a paste or a gel] or a liquid composition, such as a beverage of a drinkable food product.
• the nutritional composition according to the invention may in particular be in- tended for enteral administration (orally or by tube feeding ⁇ .
• Alternative forms of administration may be applied, in particular parenteral administration.
• the skilled person will be able to formulate a suitable product for parenteral administration, in particular by preventing inclusion of non-endogenous proteinaceous material which may induce an allergic reaction or other adverse effects.
• the administration may be carried out based on a manner known per se for a specific type of nutritional composition.
• the nutritional composition may be selected from the group of spreads; yoghurts, custards, ice-creams, butter, and other dairy products; dairy- substitute products; drinks, such as fruit drinks; candy bars; cookies, cakes and other bakery products; and drinkable foods.
• the total energetic value of the composition may be chosen within wide limits and may range, e.g., from 0.2 to 4 kcal/g.
• the energetic value may be at least 0.4 kcal/g, more in particular at least 0.8 kcal/g.
• the energetic value may be 5 kcal/g or less, more in particular 3 kcal/g or less.
• the nutritional composition in case it is a fluid, it usually has a nutritional value of at least 20 kcal/100 ml, preferably of at least 50 kcal/100 ml, in particular of at least 75 kcal/100 ml or at least 100 kcal/100 ml.
• the nutritional value is usually 300 kcal/100 ml or less, in particular 200 kcal/100 ml or less, more in particular 150 kcal/100 ml or less.
• Suitable dosage forms, active ingredients, further components that may be co- administered and ways of administration are as described for the nutritional or pharmaceutical composition as described herein above, the claims, or the examples herein be- low.
• the vitamin B, the phospolipid , the antioxidant and - if present - further active ingredients may be administered under the supervision of a medical specialist or be self- administered.
• the two diets were isocaloric and differed only with respect to DHA and UMP content
• the amount of fat, carbohydrates and protein was the same between diets.
• During the 3 months of diet intervention body weight was monitored as was food intake.
• mice fed the enriched diet showed - on average - a 17.5% increase in body weight after 3 months compared to 14% for the control mice.
• Food intake was slightly lower in the group which were fed the enriched diet (on average 2.88 gram per day] compared to control mice (on average 3.08 gram per day ⁇ .
• Alzheimer's disease mice showed an increase in body weight when fed with the composition according to the invention (the ⁇ -3 polyunsaturated fatty acid DHA and the nucleoside UMP], not attributed to a caloric increase in body weight.
• the two diets were isocaloric and differed only with respect to B-vitamins, phospholipids and antioxidants content. The amount of fat, carbohydrates and protein was the same between diets. During the 3 months of diet intervention body weight was monitored as was food intake.
• mice fed the B-vitamins+phospholipids+antioxidants enriched diet showed a 18 % increase in body weight after 3 months compared to 14 % for the control mice.
• Alzheimer's disease mice showed an increase in body weight when fed with the composition according to the invention (B vitamins, a phospholipid, and antioxidants], not attributed to a caloric increase in body weight.
• the two diets were isocaloric and differed only with respect to DHA, UMP, B-vitamins and phospholipids content.
• the amount of fat, carbohydrates and protein was the same between diets. During the 3 months of diet intervention, body weight was monitored as was food intake.
• mice fed the enriched diet showed a 20 % increase in body weight after 3 months compared to 14 % for the control mice.
• Food intake was the same in the ⁇ -3 PUFA+nucleoside+B-vitamins+phospholipids group (on average 3.02 gram per day] compared to control mice (on average 3.08 gram per day ⁇ .
• Alzheimer's disease mice showed an increase in body weight when fed with the composition according to the invention ( ⁇ -3 polyunsaturated fatty acids, a nucleo- side, B vitamins, and phospholipids], not attributed to a caloric increase in body weight.
• the two diets were isocaloric. The amount of fat, carbohydrates and protein was the same between diets. During the 3 months of diet intervention, body weight was monitored as was food intake.
• mice fed the nutritional composition showed a 25 % increase in body weight after 3 months compared to 14 % for the control mice.
• Food intake was the same in the group fed the nutritional composition (on average 3.10 gram per day] compared to control mice (on average 3.08 gram per day ⁇ .
• Alzheimer's disease mice showed an increase in body weight when fed with the composition according to the invention (nucleoside : UMP; ⁇ -3 polyunsaturated fatty acids (including DHA]; choline; phospholipids; B vitamins, and antioxidants], not attributed to a caloric increase in body weight.
• compositions of the drinks were as given in Table 1.
• Example 6 Example compositions according to the invention.
• compositions according to the invention may be used for the healthy improvement of body weight in an elderly person experiencing one or more symptoms of frailty, preferably in elderly having a BMI of 23.5 kg/m 2 :
• composition B sip feed, amount per 100 ml
• Vitamin B6 0.3 mg
• Vitamin B12 0.8 ⁇ ⁇
• Composition C Composition D Composition E Composition F
• Protein (g) 8 milk protein + 3 (milk pro10 (ultra fil8 (pea protein, blend soy tein) trated milk procasein, a-lac) prot/a-lac) tein + free leucine)
• Vitamin E (mg a-TE) 16 32 32 25 Components Composition C Composition D Composition E Composition F
• Vitamin C (mg) 32 64 64 50
• Vitamin B12 f ⁇ g 2.4 2.4 2.4 2
• Vitamin B6 (mg) 0.8 0.8 0.8 1
• Potassium (mg) 100-200 150 100-200 100-200
• Vitamin D ( g) 4-7 0.7 0.7 2
• Vitamin K ( g) 14 5.3 5.3 6
• Composition G Product comprising per 1000 litres (about)
• Example 7 Tool for assessing the degree of frailty of a patient
• Consists of answering a fixed set of questions each related to one or more of the aspects of frailty, and scoring the replies by comparison with normal values.
• the questions can be asked by an expert and orally replied to; alternatively they can also be put on a paper or form and the replies written down; however, preferably the ques- tions can be raised on a screen or monitor of an electronic device, like a small computer, tablet or peripheral station of a central computer system.
• the electronic device can have the normal values stored and can be equipped with software which allows automatic calculation of scores per parameter and of the frailty index.
• the algorithm to calculate the final score can be subject to individual medical expertise. However, it is preferred to operate with a common algorithm to allow comparison of diagnosis. In the text of the document, it is described how this can occur. It is preferred to score the value of each individual parameter by comparison with age-matched controls; when the patient scores positive on two of the parameters as given below the pa- tient is defined to be prefrail and can be helped by the composition according to the invention according the invention. When the patient scores positive on at least three parameters, the individual is diagnosed to be frail and to be receptive for improvement by use of the composition according to the invention. Table 6 : Example of a questionnaire for scoring frailty.

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