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WO2014089620A1 - Compositions et procédés pour maintenir/améliorer la fonction cognitive - Google Patents

Compositions et procédés pour maintenir/améliorer la fonction cognitive Download PDF

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Publication number
WO2014089620A1
WO2014089620A1 PCT/AU2013/001447 AU2013001447W WO2014089620A1 WO 2014089620 A1 WO2014089620 A1 WO 2014089620A1 AU 2013001447 W AU2013001447 W AU 2013001447W WO 2014089620 A1 WO2014089620 A1 WO 2014089620A1
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WIPO (PCT)
Prior art keywords
salt
derivative
alternative form
combinations
source
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PCT/AU2013/001447
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English (en)
Inventor
Christopher Oliver
Attila Pataki
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Blackmores Ltd
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Blackmores Ltd
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Publication date
Priority claimed from AU2012905441A external-priority patent/AU2012905441A0/en
Application filed by Blackmores Ltd filed Critical Blackmores Ltd
Priority to CN201380072709.6A priority Critical patent/CN104981244A/zh
Priority to AU2013360021A priority patent/AU2013360021A1/en
Priority to MYUI2015001760A priority patent/MY187748A/en
Publication of WO2014089620A1 publication Critical patent/WO2014089620A1/fr
Anticipated expiration legal-status Critical
Priority to AU2018101460A priority patent/AU2018101460A4/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to compositions comprising a combination of one or more B vitamins and a phospholipid and/or a lipoic acid and/or methods of using the same combination for maintaining/improving cognitive function of adults including elderly adults and/or for maintaining/improving mood in ageing subjects and/or reducing risk markers of cardiovascular disease and/or genetic markers and/or biochemical markers associated with ageing.
  • the compositions include, but are not limited to, dietary supplements e.g., nutritional supplements.
  • a decline in cognitive function is often considered a natural part of ageing.
  • a decline in cognitive function is often considered a natural part of ageing.
  • MCI mild cognitive impairment
  • MCI is considered the prodromal phase of Alzheimer's disease.
  • AD Alzheimer's disease
  • ADCT Alzheimer type
  • the present invention provides a composition comprising an effective amount of a combination of:
  • the present invention provides a method for maintaining/Improving cognitive function and/or slowing age-related decline in cognitive function of an adult subject comprising administering a combination of:
  • the present invention provides use of an effective amount of a combination of:
  • the present invention provides a use of an effective amount of a combination of:
  • phosphatidylserine or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof,
  • adult subjects are contemplated for any aspect and/or example described herein.
  • the age of the adult subjects may vary.
  • Adult subjects may include biological adults, e.g., subjects that have completed puberty and may include any subjects over the age of about 10 e.g., about 10 to 95 years.
  • an adult subject is considered to be a subject over the age of 18, e.g., 18 to 95 years.
  • adult subjects may be between the ages of about 18 to 90 years, or about 20 to 90 years, or about 25 to 90 years, or about 30 to 90 years, or about 35 to 90 years, or about 40 to 90 years, or about 45 to 90 years, or about 50 to 90 years, or about 55 to 90 years, or about 60 to 90 years, or about 65 to 90 years, or about 70 to 90 years, or about 75 to 90 years, or about 80 to 90 years, or about 85 to 90 years, or about 18 to 85 years, or about 18 to 80 years, or about 18 to 75 years, or about 18 to 70 years, or about 18 to 65 years, or about 18 to 60 years, or about 18 to 55 years, or about 18 to 50 years, or about 18 to 45 years, or about 18 to 40 years, or about 8 to 30 years, about 18 to 25 years, or about 25 to 30 years, or about 30 to 35 years, or about 35 to 40 years or about 40 to 45 years, or about 45 to 50 years, or about 50 to 55 years, or about 55 to 60 years, or about 60 to 65 years, or or about
  • the adult subject of any aspect and/or example described herein may also include patients that have Alzheimer's disease, MCI, dementia or other similar neurological impairments.
  • the adult subject of any aspect and/or example described herein may also include those subjects that have a pre-disposition and/or at risk of developing to Alzheimer's disease, MCI, dementia or other similar neurological impairments.
  • subject(s) may be tested for biochemical, genetic, or other risk factors and/or markers that indicate that the subject(s) has a pre-disposition and/or at risk of developing to Alzheimer's disease, MCI, dementia or other similar neurological impairments. Such markers may be identified using any test or assay known in the art for such purposes e.g., as described in Stough et al.
  • Risk factors for Alzheimer's disease, MCI and/or dementia include, but are not limited to those listed in Table 1.
  • Risk markers also include, but are not limited to measuring glycated haemoglobin, insulin levels, blood glucose levels, markers of oxidative stress, markers of inflammation, C-reactive protein, F2-lsoprostanes, inflammatory cytokines including, but not limited to, TNF-alpha, IL-2, IL-4, IL-6, IL-10, and IFN-gamma, liver function, and genetic markers including detecting the presence of Single Nucleotide Polymorphism (SNPs) in DNA samples from subjects.
  • SNPs Single Nucleotide Polymorphism
  • SNPs associated with increased risk of AD, dementia, MCI and cognitive decline in affected and/or normal elderly may also be used.
  • this includes the SNP of APOE allele, which is associated with increased risk of AD and cognitive decline in normal elderly.
  • SNPs associated with increased risk of AD, dementia, MCI and cognitive decline in affected and/or normal elderly may also include any number of SNPs of cytokines, e.g., inflammatory cytokines.
  • Risk factors for Alzheimer's disease, MCI and/or dementia include, but are not limited to measuring cerebral energy metabolism. For example, this includes, but is not limited to measuring insulin levels, insulin function, glucose uptake and metabolism, insulin resistance and downstream effectors of the insulin resistance pathway in the brain e.g., as described in Medhi and Chakrabarty, Neurol Sci (2013) 34: 1719-1725 and/or Cholerton et al., European Journal of Pharmacology (2013) 719: 170-179.
  • the level and/or activity of PI3K/Akt and/or downstream effectors, glucose uptake and metabolism in the brain including intraneuronal and/or extraneuomal glucose, UDPGLcNAc, tau-O-GlcNAc, oxidative stress, advanced glycated end products (AGE) tau phosphorylation, levels of transferrin receptors, iron influx in neurons, PgP Ap clearance may be measured.
  • These parameters may be measured using any test or assay known in the art for measuring energy metabolism and/or insulin resistance e.g., as described in Medhi and Chakrabarty, Neurol Sci (2013) 34: 1719-1725 and/or Cholerton et al., European Journal of Pharmacology (2013) 719: 170-179.
  • the levels and/or activities of each may be measured and compared to a standard known in the art. It will be apparent to a person skilled in the art whether or not a change in the level and/or activity is an indicator of risk for Alzheimer's disease, MCI and/or dementia.
  • Cognitive function is measurable over any time-frame e.g., hours, days, weeks, months or years. Cognitive function which has not changed or has increased over one or more described time-frames, is considered to be maintained or improved in the adult subject, e.g., in any subject described herein. Cognitive function may also decline with increasing age in an adult subject. In this example, cognitive function is measured over longer timeframes, e.g., months or years in ageing subjects as described herein. The cognitive function is measured at two or more time points in an ageing subject. For example, the decline in cognitive function in an ageing subject may be measured between several months or several years to establish a rate of decline. The rate of decline may be compared to a standard known in the art taking into consideration the age of the subject.
  • the rate of decline may also be compared to cognitive function that is then measured again in the same subject, after the subject has aged for a further period of months or years. Age-related decline is considered slowed if the rate of decline that is less compared to the standard or compared to a second measurement is less.
  • a time sufficient to maintain/improve cognitive function and/or slow the age- related decline in cognitive function the adult subject may be determined as required.
  • the time may be 1 month, or 2 months, or 3 months, or 4 months, or 5 months, or 6 months, or 7 months, or 8 months, or 9 months or 10 months, or 11 months, or 12 months.
  • the time may be 1 to 2 years, or 2 to 4 years, or 4 to 6 years, or 6 to 8 years or 8 to 10 years, or greater than 10 year. It will also be apparent that the time of administration may be continued for the life of the adult subject.
  • Cognitive function may be measured using any test or assay known in the art for such purposes e.g., as described in Stough et at. Nutrition Journal 2012, 11 :11.
  • Cognitive function parameters include, but are not limited to, reasoning, decision making, attention span, problem solving, spatial abilities, perceptual-motor and/or cognitive speed, and/or memory.
  • Cerebral energy metabolism is also correlated to cognitive function.
  • a measure of cerebral energy metabolism may also be used as a parameter to indicate changes in cognitive function.
  • measuring cerebral energy metabolism includes, but is not limited to measuring insulin levels, insulin function, glucose uptake and metabolism, insulin resistance and downstream effectors of the insulin resistance pathway in the brain e.g., as described in Medhi and Chakrabarty, Neurol Sci (2013) 34: 1719-1725 and/or Cholerton et al., European Journal of Pharmacology (2013) 719: 170-179.
  • the level and/or activity of PI3K Akt and/or downstream effectors, glucose uptake and metabolism in the brain including intraneuronal and/or extraneuornal glucose, UDPGLcNAc, tau-O-GlcNAc, oxidative stress, advanced glycated end products (AGE) tau phosphorylation, levels of transferrin receptors, iron influx in neurons, PgP ⁇ clearance may be measured.
  • These parameters may be measured using any test or assay known in the art for measuring energy metabolism and/or insulin resistance e.g., as described in Medhi and Chakrabarty, Neurol Sci (2013) 34: 1719-1725 and/or Cholerton et al., European Journal of Pharmacology (2013) 719: 170-179.
  • the levels and/or activities of a parameter described herein may be measured at a time-frame as described according to any aspect, embodiment and/or example herein. It will be apparent to a person skilled in the art whether or not a there is a significant change in the level and/or activity of any one or more parameters described according to any aspect, embodiment and/or example herein.
  • PET Positron emission tomography
  • FDG fluorodeoxyglucose 18-F brain uptake
  • FDG-PET fluorodeoxyglucose
  • the present invention provides a composition comprising an effective amount of a combination of:
  • the present invention provides a method for maintaining/improving mood in an ageing subject and/or slowing the age-related decline in mood of an adult subject comprising administering a combination of:
  • the present invention provides use of an effective amount of a combination of:
  • the present invention provides a use of an effective amount of a combination of:
  • Ageing subjects includes any one or more of the described adult subjects that increase in age. Preferably, ageing subjects includes those adult subjects that are above the age of about 30 or more. Ageing subjects also includes elderly subjects. Preferably, the subjects are healthy adult subjects.
  • Mood may be measured using any test or assay known in the art for such purposes e.g., as described in Stough er a/. Nutrition Journal 2012, 11 :11. Mood parameters include, but are not limited to, depression, anxiety and general mood assessments e.g., happiness, excitement, sadness.
  • Mood is measurable over any time-frame e.g., hours, days, weeks, months or years. Mood which has not changed or has increased over one or more described timeframes, is considered to be maintained or Improved in the adult subject. Mood may also decline with increasing age in an adult subject. In this example, mood may be measured over longer time-frames, e.g., months or years in ageing subjects as described herein. The rate of decline is measured at several time points in an ageing subject. For example, the decline in mood in an ageing subject may be measured between several months or several years to establish a rate of decline. The rate of decline may be compared to a standard known in the art taking into consideration the age of the subject.
  • the rate of decline may also be compared to mood that is then measured again in the same subject, after the subject has aged for a further period of months or years. Age-related decline is considered slowed if the rate of decline that is less compared to the standard or compared to a second measurement is less.
  • a time sufficient to maintain/improve mood in an ageing subject and/or slow the age-related decline in the mood of an adult subject may be determined as required.
  • the time may be 1 month, or 2 months, or 3 months, or 4 months, or 5 months, or 6 months, or 7 months, or 8 months, or 9 months or 10 months, or 11 months, or 12 months.
  • the time may be 1 to 2 years, or 2 to 4 years, or 4 to 6 years, or 6 to 8 years or 8 to 10 years, or greater than 10 year. It will also be apparent that the time of administration may be continued for the life of the adult subject.
  • the present invention provides a composition comprising an effective amount of a combination of: (i) one or more B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and
  • the present invention provides a method for reducing a risk marker of cardiovascular disease and/or a genetic marker and/or a biochemical marker associated with ageing in an adult subject comprising administering a combination of:
  • phosphatidylserine or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof,
  • the present invention provides use of an effective amount of a combination of:
  • phosphatidylserine or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof; and/or lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof
  • the present invention provides use of an effective amount of a combination of:
  • nutraceutical for reducing a risk marker of cardiovascular disease and/or a genetic marker and/or a biochemical marker and/or a biochemical marker associated with ageing in an adult subject.
  • Risk markers of cardiovascular disease associated with ageing in an adult subject may be measured using any test or assay known in the art for such purposes e.g., as described in Stough et al. Nutrition Journal 2012, 1 1 :11. Risk markers are measurable over any time-frame e.g., hours, days, weeks, months or years. A reduction in the presence of one or more risk markers, and/or a reduction in the level of one or more risk markers measured over a time-frame are considered a reduction in the risk markers.
  • Risk markers include, but are not limited to, brachial pressures, aortic pressures and carotid-femoral Pulse Wave Velocity, cardiovascular risk markers, associated with Alzheimer's disease and/or dementia known in the art e.g., as described in Table 1.
  • telomere length is measurable over any timeframe e.g., hours, days, weeks, months or years.
  • Telomere shortening is a marker of genetic damage and associated with ageing. Reduced telomere shortening measured over a timeframe is considered a reduction in a genetic risk marker.
  • Biochemical risk markers associated with ageing in an adult subject may be measured using any test or assay known in the art for such purposes e.g., as described in Stough et al. Nutrition Journal 2012, 11 :11. Risk markers are measurable over any timeframe e.g., hours, days, weeks, months or years. A change in the presence of one or more risk markers, and/or a change in the level of one or more risk markers measured over a time-frame are considered a reduction in the risk markers, depending on the risk marker.
  • Risk markers include, but are not limited to, glycated haemoglobin, insulin levels, blood glucose levels, markers of oxidative stress, markers of inflammation, C-reactive protein, F2- Isoprostanes, inflammatory cytokines including, but not limited to, TNF-alpha, IL-2, IL-4, IL-6, IL-10, and IFN-gamma, liver function tests, and biochemical risk markers associated with Alzheimer's disease and/or dementia known in the art e.g., as described in Table 1.
  • a time sufficient to a reduce risk marker of cardiovascular disease and/or a genetic marker and/or a biochemical marker associated with ageing in an adult subject may be determined as required.
  • the time may be 1 month, or 2 months, or 3 months, or 4 months, or 5 months, or 6 months, or 7 months, or 8 months, or 9 months or 10 months, or 11 months, or 12 months.
  • the time may be 1 to 2 years, or 2 to 4 years, or 4 to 6 years, or 6 to 8 years or 8 to 10 years, or greater than 10 year. It will also be apparent that the time of administration may be continued for the life of the adult subject.
  • the B vitamins of any aspect and/or example described herein may comprise any one or more of B vitamins including B,, B 2 , B 3 , B 5 , ⁇ ⁇ , B 7 , B g, B, 2 .
  • one or more B vitamins are combined with phosphatidylserine.
  • one or more B vitamins are combined with lipoic acid.
  • one or more B vitamins are combined with phosphatidylserine and lipoic acid.
  • the B vitamins comprise any one or more of vitamins ⁇ , B 8 and/or B 12 .
  • vitamin B 6 Is included in any aspect of the invention.
  • vitamin B 9 is included in any aspect of the invention.
  • vitamin Bi 2 is included in any aspect of the invention.
  • vitamins B e , and B 9 are included in any aspect of the invention.
  • vitamins Be, Bg and B 2 are included in any aspect of the invention.
  • any alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, of the B-Vitamins that are known to the skilled artisan are also contemplated.
  • Alternative forms include vitamers.
  • the alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof includes known biologically active forms and/or have measurable activity as described in any known assay used in the art to measure the function of B vitamins.
  • any one or more vitamin B 6 may include, but is not limited to pyridoxine, pyridoxal, pyridoxamine, pyridoxine 5'-phosphate, pyridoxal 5'-phosphate, and pyridoxamine 5'-phosphate, or other alternative forrn(s), derivative(s), or salt(s) thereof, or combinations thereof.
  • any one or more of vitamin B 9 may include, but is not limited to folate, folic acid (folate, vitamin M, vitamin B9, vitamin Be (or folacin), pteroylglutamic acid), or dihydrofolate, tetrahydrofolate, 5-methyltetrahydrofolate (L-methylfolate) or other alternative form(s), derivative(s), or salt(s) thereof (such as the calcium salt of L-5- methyltetrahydrofolate) or other alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof.
  • any one or more form of vitamin B 12 may include, but is not limited to cyanocobalamin, methylcobalamin, hydroxocobalamin, adnenosylcobalamin, or other alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof.
  • Any one or more of the B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof used in the preparation of any aspect and/or example of the invention may be anhydrous, or non-anhydrous.
  • the B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof described herein may be obtained from commercially available sources and/or prepared or derived e.g., from foodstuffs according to methods known in the art.
  • B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof may be derived from unprocessed foods such as, meat, turkey and tuna, liver and meat products, kombucha, whole grains, potatoes, bananas, lentils, chili peppers, tempeh, beans, nutritional yeast, brewer's yeast, and molasses.
  • the B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof may also be chemically synthesized. It will also be apparent to the skilled artisan that any extract or foodstuff rich in B vitamins, or alternative form(s), derivative(s), or salt(s) thereof, may also be used.
  • the phosphatidylserine (Ptd-L-Ser or PS) of any aspect and/or example described herein may be used in pure or purified form from commercially available sources and/or chemically synthesized and/or prepared from PS rich sources, e.g., bovine brain and/or soy bean or combinations thereof, or it may also be provided in the form of an extract or foodstuff rich PS. Any alternative form(s), derivative(s), or salt(s) thereof, of PS that are known to the skilled artisan are also contemplated.
  • the alternative form(s), derivative(s), salt(s) thereof, or combinations thereof includes known biologically active forms and/or have measurable activity as described in any known assay used in the art to measure the function and/or activity of PS,
  • an example of an alternative form of PS includes conjugated phoshpatidylserine-omega-3 compound.
  • Bovine spongiform encephalopathy commonly known as mad-cow disease
  • alternative sources of PS are preferable, e.g., soy derived PS.
  • bovine derived PS may also be used, should such bovine derived PS be found risk-free from BSE pathogen and/or safe for human consumption.
  • the lipoic acid (5-(1,2-dithiolan-3-yl)valeric acid), includes ⁇ -lipoic acid (ALA), thioctic acid or 6,8-Dithioctanoic acid.
  • the lipoic acid of any aspect and/or example described herein may include one or a mixture of both enantiomers (R)-(+)-lipoic acid (RLA) or (S)-(-)-lipoic acid (SLA) at various concentrations including a racemic mixture (R/S)-lipoic acid (R/S-LA).
  • lipoic acid may be used in pure or purified form from commercially available sources and/or chemically synthesized and/or prepared from ALA rich sources e.g., kidney, heart, liver, spinach, broccoli, and yeast extract or combinations thereof, or lipoic acid may also be provided in the form of an extract or foodstuff rich in lipoic acid.
  • Commercially available forms include, but are not limited to, dihydrolipoic acid and salts thereof. Any alternative form(s), derivative(s), or salt(s) thereof, of lipoic acid that are known to the skilled artisan are also contemplated.
  • the alternative form(s), derivative(s), salt(s) thereof, or combinations thereof includes known biologically active forms and/or have measurable activity as described in any known assay used in the art to measure the function and/or activity of lipoic acid.
  • biologically active forms of lipoic acid include lipoate.
  • composition of the invention or the combination of B-vitamins and PS and/or lipoic acid according to any aspect and/or example described herein may be administered by any suitable route.
  • the B-vitamins according to any aspect and/or example described herein may be administered separately, simultaneously or sequentially, in any order with the PS and/or lipoic acid according to any aspect and/or example described herein.
  • the preferred route of administration is oral.
  • the composition of the invention or the combination of B- vitamins and PS and/or lipoic acid according to any aspect and/or example described herein may be administered as a supplement in daily meals or beverages.
  • Administration may also include in a pharmaceutical unit dosage form such as pills, tablets, caplets, tabsules or capsules, for better control of dosing and subject compliance.
  • a pharmaceutical unit dosage form such as pills, tablets, caplets, tabsules or capsules, for better control of dosing and subject compliance.
  • the composition of the invention or the combination of B-vitamins and PS and/or lipoic acid or the unit dosage form according to any aspect and/or example described herein may be administered once, or twice or three times or 4 times a day.
  • administration is 1 or 2 times daily.
  • administration is twice daily.
  • an effective amount of the combination or an administration dosage according to the invention may include about 1 pg to about 200 mg of each B vitamin, or alternative fomn(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 100 pg to about 5 mg of vitamin B 9 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 200 pg to about 5 mg of vitamin B 9 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 400 pg to about 5 mg of vitamin Bg, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 800 pg to about 5 mg of vitamin B 9 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 1.6 mg to about 5 mg of vitamin B 9l or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 3.2 mg to about 5 mg of vitamin B 9 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 100 pg, or about 150 pg, or about 200 pg, or about 250 pg, or about 300 pg, or about 350 pg, or about 400 pg, or about 450 pg, or about 500 pg, or about 550 pg.
  • the effective amount or the administration dosage includes about 200 pg of vitamin B 9 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • Administration may be once, or twice or three times or 4 times a day.
  • administration is twice daily.
  • the effective amount as described herein may be in the form of a single unit dosage.
  • the effective amount, or the single unit dosage may be administered once, twice or three times or 4 times a day.
  • the effective amount, or the single unit dosage is administered twice daily.
  • an effective amount of the combination or an administration dosage according to the invention includes about 1.2 pg to about 1.5 mg of vitamin B 12 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 10 pg to about 1.5 mg of vitamin Bi 2 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 25 pg to about 1.5 mg of vitamin Bi 2 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 50 pg to about 1.5 mg of vitamin B 12l or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 100 pg to about 1.5 mg of vitamin B 2 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 200 pg to about 15 mg of vitamin B 12 , or alternative form(s), derivatlve(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 400 pg to about 1.5 mg of vitamin Bi 2l or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 800 pg to about 1.5 mg of vitamin Bi 2 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 1.2 pg, or about 1.5 g, or about 2.0 pg. or about 2.5 ⁇ g, or about 3.0 pg.
  • vitamin Bi2 or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 250 p9 of vitamin B12, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • Administration may be once, or twice or three times or 4 times a day.
  • administration is twice daily.
  • the effective amount as described herein may be in the form of a single unit dosage.
  • the effective amount, or the single unit dosage may be administered once, twice or three times or 4 times a day.
  • the effective amount, or the single unit dosage is administered twice daily.
  • an effective amount of the combination or an administration dosage according to the invention includes about 0.75 mg to about 200 mg of vitamin B 6j or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 1.5 mg to about 200 mg of vitamin B 6, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 3 mg to about 200 mg of vitamin B 6 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 6 mg to about 200 mg of vitamin B 6 , o f alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 12 mg to about 200 mg of vitamin B 6 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 25 mg to about 200 mg of vitamin B 6 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 50 mg to about 200 mg of vitamin B 6 , or alternative form(s), derivative(s), or saU(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 100 mg to about 200 mg of vitamin B 8 , or alternative form(s), derivative(s), or saltfs) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 0.75 mg, or about 1 mg, or about 5 mg, or about 10 mg, or about 11 mg, or about 12 mg, or about 13 mg, or about 14 mg, or about 15 mg, or about 16 mg, or about 17 mg, or about 18 mg, or about 19 mg, or about 20 mg, or about 25 mg, or about 30 mg, or about 35 mg, or about 40 mg, or about 45 mg, or about 50 mg, or about 55 mg, or about 60 mg, or about 65 mg, or about 70 mg, or about 75 mg, or about 80 mg, or about 85 mg, or about 90 mg, or about 95 mg, or about 100 mg, or about 120 mg, or about 140 mg, or about 160 mg, or about 180 mg, or about 200 mg of vitamin B 6 , or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(S) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 12.5 mg of vitamin B 6p or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • Administration may be once, or twice or three times or 4 times a day.
  • administration is twice daily.
  • the effective amount as described herein may be in the form of a single unit dosage.
  • the effective amount, or the single unit dosage may be administered once, twice or three times or 4 times a day.
  • the effective amount, or the single unit dosage is administered twice daily.
  • an effective amount of the combination or an administration dosage according to the invention may include about 1 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 5 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 10 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 20 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 50 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 100 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 200 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 400 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 800 mg to about 1000 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 1 mg, or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg, or about 8 mg, or about 9 mg, or about 10 mg, or aobut 1 mg, or about 12 mg, or about 13 mg, or about 14 mg, or about 15 mg, or about 16 mg, or about 17 mg, or about 18 mg, or about 19 mg, or about 20 mg, or about 21 mg, or about 22 mg, or about 23 mg, or about 24 mg, or about 25 mg, or about 26 mg, or about 27 mg, or about 28 mg, or about 29 mg, or about 30 mg, or about 35 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg, or about 150 mg, or about 200 mg, or about 250 mg, or about 300 mg, or about 350 mg, or about 400 mg, or about 450 mg, or about 500 mg, or about 550 mg, or about 600 mg,
  • the effective amount or the administration dosage includes about 25 mg of phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • Administration may be once, or twice or three times or 4 times a day.
  • administration is twice daily.
  • the effective amount as described herein may be in the form of a single unit dosage.
  • the effective amount, or the single unit dosage may be administered once, twice or three times or 4 times a day.
  • the effective amount, or the single unit dosage is administered twice daily.
  • an effective amount of the combination or an administration dosage according to the invention may include about 50 mg to about 1200 mg of lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 100 mg to about 1200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 50 mg to about 1200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 200 mg to about 1200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 400 mg to about 200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount, or the administration dosage includes about 600 mg to about 1200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the effective amount or the administration dosage includes about 800 mg to about 200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. In another example, the effective amount or the administration dosage includes about 1000 mg to about 1200 mg of lipoic acid or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention. For example, the effective amount or the administration dosage includes about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 75 mg.
  • the effective amount or the administration dosage includes about 150 mg of lipoic acid, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • Administration may be once, or twice or three times or 4 times a day.
  • administration is twice daily.
  • the effective amount as described herein may be in the form of a single unit dosage.
  • the effective amount, or the single unit dosage may be administered once, twice or three times or 4 times a day.
  • the effective amount, or the single unit dosage is administered twice daily.
  • an effective amount of the combination or arv administration dosage according to the invention may include the ratio of about 1 : 1.9: 11.5 respectively of B- vitamins alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof to phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof to lipoic acid, or alternative form(s), derivative ⁇ ), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the B-vitamins are in a ratio of about 1: 1 to 2.0: 20 to 65 respectively of vitamin B9 to vitamin B12 to vitamin B6.
  • the B-vitamins are in a ratio of about 1 : 1.25: 62.5 respectively of vitamin B9 to vitamin B12 to vitamin B6.
  • an effective amount of the combination or an administration dosage according to the invention may include the ratio of about 1:1.0 to 2.0 :10 to 20 respectively of B-vitamins alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof to phosphatidylserine, or alternative form(s), derivative(s), or salt(s) thereof, or combinations thereof, and/or source(s) thereof to lipoic acid, or alternative form(s), derivative ⁇ ), or salt(s) thereof, or combinations thereof, and/or source(s) thereof described in any aspect and/or example of the invention.
  • the B-vitamins are in a ratio of about 1: 1 to 2.0: 20 to 65 respectively of vitamin B9 to vitamin B12 to vitamin B6.
  • the B-vitamins are in a ratio of about 1 : 1.25: 62.5 respectively of vitamin B9 to vitamin B12 to vitamin B6.
  • the composition of the invention or the combination of B-vitamins and PS and/or Iipoic acid, or the unit dose according to any aspect and/or example described herein may be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, intrathecal, intraperitoneal, intranasal and buccal.
  • the compounds are preferably formulated as either oral, injectable or topical compositions.
  • oral formulation may be a conventional tablet or capsule form.
  • the composition of the invention or the combination of B-vitamins and PS and/or Iipoic acid according to any aspect and/or example described herein may be formulated e.g., as a pharmaceutical, nutraceutical, nutritional supplement and/or dietary supplement.
  • the formulation comprises one or more pharmaceutically acceptable carriers or excipients suitable for each formulation. It will be apparent to the person skilled in the art as to which excipients may be used for each formulation.
  • composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.
  • Treatments directed to cognitive function had the common occurrence of at least folic acid and usually all three major vitamins that are involved in the One Carbon Cycle. Whilst the therapeutic benefits of these vitamins have been linked to aberrant homocysteine levels, the inventors reasoned that it is possible that factors within the One Carbon Cycle affected by the B vitamins are even more important and that homocysteine is a possible non- causal marker.
  • HcyO oxidized homocysteine
  • HycR reduced homocysteine
  • Lipoic acid is known to chelate redox-active transition metals, inhibiting the formation of hydrogen peroxide and hydroxyl radicals, to scavenge reactive oxygen species (ROS), increasing the level of reduced glutathione, down-regulating inflammatory processes, to scavenge lipid peroxidation products and to induce the enzymes of glutathione synthesis and other antioxidant protective enzymes.
  • ROS reactive oxygen species
  • compositions of the invention according to the following formulae and dosage are prepared using standard procedures known in the art.
  • compositions of the invention are prepared as oral nutritional supplements.
  • Fprmula 1- Dosage Two tablets per day
  • Active Amount per unit dosage eg. 1 tablet
  • Active Amount per unit dosage eg. 1 tablet
  • Active Amount per unit dosage eg. 1 tablet
  • Active Amount per unit dosage eg. 1 tablet
  • Active Amount per unit dosage eg. 1 tablet
  • Active Amount per unit dosage eg. 1 tablet
  • Active Amount per unit dosage eg. 1 tablet
  • Active Amount per unit dosage eg. 1 tablet
  • Vitamin B12 500 g Vitamin B6 25 mg
  • Active Amount per unit dosage eg. 1 tablet
  • each active of the combination of one or more B vitamins and phosphatidylserine and/or lipoic acid as described in Example 1 is formulated for oral administration according to standard procedures in the art, wherein each active is in a single unit dosage form and whereby each single unit dosage form is administered either simultaneously or sequentially. In the case of twice daily dosage, these are administered either simultaneously, or sequentially, or once in the morning and once in the evening.
  • a four-arm clinical trial is performed by the Brain Sciences Institute (Melbourne) to determine whether 12 months, 18 months and/or 24 months administration of the composition, or a formulation comprising the same according to any aspect or example described herein, improves cognitive functioning in healthy elderly persons aged between 60 and 75 years.
  • any one or more of the formulae in Example 1 is administered for the described period, and/or any of the doses according to Example 2 is administered for the described period.
  • One arm of the clinical trial comprises subjects that receive placebo.
  • One or more further clinical trials may be performed by administering the composition, or the formulation comprising the same for any length of time and in any subject as described according to any aspect or example herein.
  • the CDR Computerized Cognitive Assessment System is used to measure the cognitive effects of the treatments.
  • a tailored version of the battery is used, similar to that which has previously been found to be sensitive to improved cognitive function as a consequence of ingestion of numerous nutraceuticals.
  • the selection of computer controlled tasks from the system is administered with parallel forms of the tests being presented at each testing session. Presentation is via colour monitors on laptops, and, with the exception of written word recall tasks all responses are recorded via two-button (YES/NO) response boxes.
  • the word recall tasks are performed with pen and paper, and the Tracking task is performed with a joystick. The entire selection of tasks takes approximately 25-30 minutes.
  • the SUCCAB is a battery of screen-based cognitive tasks used to measure cognitive processes that have been found to most likely decline with age. As some cognitive tasks have a motor or decision time component, simple and complex reaction time tasks are also included in the test battery to control for such effects.
  • the tasks forming the battery are described below:
  • the test consists of two congruent and two incongruent trials, presented alternately. Stimulus words are randomly presented (RED, BLUE, GREEN, and YELLOW) in either congruent or incongruent colours for 1.7-seconds, with an ISI of 0.5-seconds. Participants respond by pressing one of four buttons corresponding to the colour of the word, irrespective of what the word reads. This task is used as a measure of executive function and more specifically inhibition; participants are required to inhibit the automatic reading response.
  • each trial participant is presented with a 4 x 4 white grid on a black background, with six grid positions containing white squares. Participants are given 3 seconds to remember where the white squares are located. The grid becomes blank and a series of four white squares are sequentially displayed in various grid positions for 2- seconds each. Participants respond with a yes/no response to indicate whether each square matches a position that is originally filled. In total, participants complete 14 trials, each of which is separated by a blank screen displayed for 2-seconds. Each trial is set such that two out of the four locations in the response series correspond to the original grid locations, and two do not. The task requires participants to hold spatial information in a store that has previously been described as working memory.
  • Contextual Memory A series of 20 everyday images are presented at the top/bottom/left/right of the screen for 3-seconds each with no ISI. On completion of the series the same images are displayed again in randomised order in the centre of the screen for 2-seconds each with no ISI. Participants respond with a top/bottom/left /right button press to indicate the original location of each image. This task requires participants to recall the spatial context of the original presentation and is used as a measure of episodic memory.
  • the Inspection Time task is administered to assess speed of information processing.
  • This task assesses the presentation time that a subject requires to discriminate between two possible stimuli.
  • the task consists of a stimulus with two vertical parallel lines joined at the top by a horizontal line. There are two versions of the stimulus; either the left line is shorter than the right or the right line is shorter than the left. Stimuli are flashed on a computer screen and the participant is instructed to press a key corresponding to the side of the symbol that is shorter.
  • Each stimulus presentation is followed by the presentation of a backward visual mask. This prevents further processing of the stimulus in iconic memory.
  • the speed of stimulus presentation is varied according to the accuracy of the participants' responses.
  • the length of presentation of the backward visual mask also varies to determine the optimal visual encoding time.
  • the objective is to respond as accurately, rather than as quickly, as possible.
  • the duration of stimulus presentation is varied until an 80% accuracy level is obtained by the participant. This is taken as the outcome measure for speed of visual information processing speed.
  • MMSE Mini-Mental State Examination
  • the Mini-Mental State Examination (MMSE) (Folstein et al., 1975) is a brief 30- point test that is commonly used to screen for dementia.
  • the MMSE evaluates six areas of cognitive function: orientation, attention, immediate recall, short-term recall, language, and the ability to follow simple verbal and written commands.
  • the MMSE is divided into two sections. The first part requires vocal responses to the examiner's questions. The participant is asked to repeat a short phrase after the examiner; to count backward from 100 by 7s; to name the current season and similar brief items. It tests the participants' orientation, memory, and attention. The maximum score for this section is 21.
  • the participant is asked to follow verbal and written instructions, write a sentence spontaneously, and copy a geometric figure. The test is not timed but usually takes less than 10 minutes to complete.
  • Mood and health is assessed using the below questionnaires at all time points (e.g., baseline, 3, 6, 9, 12, 18and 24 months).
  • Visual analogue scales is administered as part of the CD system to assess self- reported mood. In total, 16 dimensions of mood are administered. The participant is required to mark, on a 100 mm line to what extent the described state is appropriate to him/her either at that moment in time (“right now") or over the past week.
  • the Bond and Lader VAS discriminates three affective dimensions: alertness, contentment, and calmness.
  • the POMS is a self-report questionnaire designed to measure six dimensions of mood: tension-anxiety; depression-dejection; anger-hostility; vigour-activity; fatigue-inertia; and confusion-bewilderment.
  • the POMS consists of 65 adjectives describing feeling and mood which is answered on a five-point Likert-type scale ranging from not at all to extremely. Respondents are asked to indicate mood reactions for the "past week including today".
  • the SF-36 is a short-form health survey containing.36 questions. It yields an 8- scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures and a preference-based health utility index. It will be used to assess changes in health and general well-being throughout the trial.
  • the BDl-ll is a 21 -item; self-report inventory designed to measure the severity of depressive symptoms.
  • the BDl-ll is one of the most widely used depression inventories in both clinical and research settings.
  • the BDl-ll asks participants to rate how they have felt over the past 2 weeks on a scale of 0 (no symptoms) to 3 (severe symptoms). Higher scores n the BDI-II indicates more severe depressive symptoms, with the maximum total score being 63.
  • the BDI-ll has adequate test-retest reliability and high internal consistency. Furthermore, the BDI-II has been demonstrated to have strong psychometric properties as an assessment tool among older adults in the general population (Segal et al 2008).
  • the STAI consists of two 20-item questionnaires, designed to measure general anxiety (Trait portion) and anxiety at the time of testing (State portion). EBm consumption has previously lead to a significant decrease in state anxiety using this measure (Stough et al 2001 ).
  • the Chalder fatigue Scale (Chalder et al., 1993) is completed by participants to assess physical and mental fatigue.
  • the questionnaire consists of 14 items each rated on a 4-point likert scale.
  • the Chalder Fatigue Sclae has good internal consistency.
  • the Leeds Sleep Evaluation Questionnaire (Parrot & Hindmarch, 1978) is completed by all participants to retrospectively assess aspects of sleep including getting to sleep, quality of sleep, awake following sleep and behaviour following wakening. These four dimensions of sleep are assessed through 10 visual analogue scales.
  • MMSE Mini-Mental State Examination
  • the MMSE (Folstein et al., 1975) is a brief 30-point test that is used to screen for dementia.
  • the MMSE evaluates six areas of cognitive function: orientation, attention, immediate recall, short-term recall, language, and the ability to follow simple verbal and written commands.
  • the MMSE is divided into two sections. The first part requires vocal responses to the examiner's questions. The participant is asked to repeat a short phrase after the examiner; to count backward from 100 by 7s; to name the current season and similar brief items. It tests the participants' orientation, memory, and attention. The maximum score for this section is 21.
  • the participant In the second part of the examination, the participant is asked to follow verbal and written instructions, write a sentence spontaneously, and copy a geometric figure. The test is not timed but usually takes less than 10 minutes to complete.
  • the DRS-II is designed to assess the presence of or the progression towards dementia. Through the administration of 36 tasks and 32-stimulus cards, the DRS-II is a sensitive in differentiating levels of cognitive deficit. Consequently, the DRS-II is used to assess cognitive impairment and or dementia. The rater's cognitive performance is evaluated with respect to scaled scores corrected for age and education as outlined in the manual. The DRS-II is a highly reliable and valid psychometric instrument. The DRS-II will be used to exclude participants with probable dementia.
  • GDS Geriatric Depression Scale
  • the GDS (Yesavage et al. 1982) is a basic screening measure for depression suitable for elderly populations. Although the GDS cannot be used to diagnose clinical depression it provides insight into the severity of depressive symptoms experienced by the rater. The GDS sums 30 questions each of which are answered "yes" or "no". A total score of 0-9 is considered normal, a score of 10-19 indicates mild depressive symptoms and a score of 20-30 indicates severe depressive symptoms. The GDS is a reliable and valid self- rating scale for assessing depressive symptoms in the elderly. The GDS will be used to exclude participants with severe depression.
  • IQ General intelligence
  • WASI scale of intelligence
  • the vocabulary subtest is a 42-itemtask, which requires the examinee to orally define words that are presented visually and orally.
  • the matrix reasoning subtest shows a series of 35 incomplete grid patterns, which the examinee is asked to complete by pointing to, or stating, the correct pattern from five possible choices.
  • the WASI is a reliable measure of intelligence for use in clinical and research settings. Measurement of risk markers
  • Any one or more risk markers e.g., as described in Stough er al. Nutrition Journal 2012, 11 :11 or in Table 1 herein are measured in the subjects of the trial. By way of illustrative example only, the following markers are measured.
  • Brachial pressures, aortic pressures, carotid-femoral Pulse Wave Velocity (PWV) and other cardiovascular risk markers is measured throughout the study. Measurements are conducted according to any standard method in the art. Baseline levels are determined prior to administration of the compositions or formulations to the subjects. Measurements are then repeated during the course of the trial, e.g., at 3 months, 6 months 12 months, 18 months and 24 months. A reduction in the level of one or more of these markers at each time-point relative to baseline indicates administration of the composition or formulation reduces cardiovascular risk markers.
  • Telomere shortening is a marker of genetic damage and associated with ageing. Telomere length is measured according to standard assays known in the art. Telomere length is assessed at baseline and at the end of the study, e.g., 12 months, 18 months or 24 months. Subjects receiving the composition or formulation are compared to controls receiving placebo. Blood is collected at baseline and at 12, 18 or 24 months. DNA is extracted and telomere length is measured according to standard protocols. Reduced telomere shortening in subjects receiving the composition or formulation compared to those receiving a placebo is considered a reduction in a genetic risk marker.
  • HbA1c Glycated haemoglobin
  • blood glucose and insulin levels are measured prior to administration of the composition or formulation. Measurement of these markers provides an indication of glucoregulatory efficiency and control.
  • follow-up measurements are conducted at various time points throughout the study, e.g., weekly or monthly.
  • Measurements of inflammatory cytokines include a measure of cytokine levels, e.g., by ELISA or a measure of mRNA levels. A lower level of these cytokines compared to baseline indicates a lower level of inflammation in the subject after treatment.
  • Cerebral energy metabolism is also measured including insulin levels, insulin function, glucose uptake and metabolism, insulin resistance and downstream effectors of the insulin resistance pathway in the brain .e.g., as described in Medhi and Chakrabarty, Neurol Sci (2013) 34: 1719-1725 and/or Cholerton et a/., European Journal of Pharmacology (2013) 719: 170-179.
  • the level and/or activity of PI3K/Akt and/or downstream effectors, glucose uptake and metabolism in the brain including intraneuronal and/or extraneuomal glucose, UDPGLcNAc, tau-O-GlcNAc, oxidative stress, advanced glycated end products (AGE) tau phosphorylation, levels of transferrin receptors, iron influx in neurons, PgP ⁇ clearance is measured at baseline, and at 12, 18 or 24 months. These parameters are measured e.g., as described in Medhi and Chakrabarty, Neurol Sci (2013) 34: 1719-1725 and/or Cholerton et al., European Journal of Pharmacology (2013) 719: 170- 179.
  • PET Positron emission tomography
  • Glucose uptake and metabolism in the brain and metabolism is used an outcome measure of the clinical trials and may also be used to determine proof of concept early in the trial.
  • a composition of the invention, or a formulation comprising the same according to any aspect or example described herein, is administered as described above in healthy elderly persons aged between 60 and 75 years.
  • any one or more of the formulae in Example 1 is administered for 12, 18 and/or 24 months, and/or any of the doses according to Example 2 is administered for 12, 18 and/or 24 months.
  • One arm of the clinical trial comprises subjects that receive placebo.
  • Glucose uptake and metabolism is measured at all time points (e.g., baseline, 3, 6, 9, 12, 18 and/or 24 months).
  • [18-F]-fluro-D-glucose is administered intravenously.
  • Brain uptake is measured using PET (FDG-PET). Blood glucose concentration is measured before administration of the tracer to ensure that changes in glucose metabolism during FDG-PET are not due to differences in starting blood glucose levels but the intrisinc activity of the brain.
  • PET scanning and imaging is performed on the subject according to standard procedures e.g., as described in Nasrallah and Dubroff, Semin Nucl Med 2013 November;43(6):449-61. Brain scans are analysed to determine overall and regional areas of glucose uptake and metabolism.
  • glucose metabolism in treated subjects is compared to baseline.
  • Glucose metabolism in subjects receiving treatment is also compared to the placebo group. All measurements are compared and a determination is made whereby the maintenance and/or change in glucose metabolism is correlated with maintenance and/or improvement in cognitive function and/or a slowing of the age-related decline in cognitive function in the treated subjects.
  • the primary analysis investigates the effects of treatment on all cognitive outcomes over the course of the trial using Analysis of Variance (ANOVA) techniques. Other techniques may also be used, e.g., linear mixed modelling and intention to treat analysis. Similarly, effects of treatment on secondary outcomes are analysed. Pearson's correlation coefficients are used to investigate whether any improvements in cognition are related to improvements in other variables e.g., biochemical, cardiovascular or mood/health factors and/or cerebral energy including glucose uptake. Correlations and regression models are used to examine baseline associations between variables. Results are considered statistically significant at p ⁇ 0.05 corrected for multiple cognitive factors (primary outcome variables) or p ⁇ 05 for secondary outcome variables.
  • ANOVA Analysis of Variance

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Abstract

La présente invention concerne des compositions comprenant une combinaison de (i) une ou plusieurs vitamines B ou d'autres formes, dérivés ou sels de celles-ci, ou des combinaisons de ceux-ci et/ou sources de ceux-ci ; et (ii) de la phosphatidylsérine, ou d'autres formes, dérivés ou sels de celle-ci, ou des combinaisons de ceux-ci et/ou sources de ceux-ci ; et/ou de l'acide lipoïque ou d'autres formes, dérivés ou sels de celui-ci, ou des combinaisons de ceux-ci et/ou sources de ceux-ci, et/ou des procédés d'utilisation de la même combinaison pour maintenir/améliorer la fonction cognitive d'adultes, notamment d'adultes âgés et/ou pour maintenir/améliorer l'humeur de sujets vieillissants et/ou réduire les marqueurs de risque de maladie cardiovasculaire et/ou les marqueurs génétiques et/ou les marqueurs biochimiques associés au vieillissement. Les compositions comprennent, sans s'y limiter, des compléments alimentaires, par exemple des compléments nutritionnels.
PCT/AU2013/001447 2012-12-11 2013-12-11 Compositions et procédés pour maintenir/améliorer la fonction cognitive Ceased WO2014089620A1 (fr)

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CN201380072709.6A CN104981244A (zh) 2012-12-11 2013-12-11 维持/改善认知功能的组合物及方法
AU2013360021A AU2013360021A1 (en) 2012-12-11 2013-12-11 Compositions and method for maintaining/improving cognitive function
MYUI2015001760A MY187748A (en) 2012-12-11 2013-12-11 Compositions and method for maintaining/improving cognitive function
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PL422153A1 (pl) * 2017-07-06 2019-01-14 Cięciara Mariusz Stabilna płynna kompozycja zawierająca witaminy i kwas foliowy oraz zastosowanie kompozycji

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PL422153A1 (pl) * 2017-07-06 2019-01-14 Cięciara Mariusz Stabilna płynna kompozycja zawierająca witaminy i kwas foliowy oraz zastosowanie kompozycji

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