FIELD OF THE INVENTION

This invention is directed to methods and compositions for improving cognition or rejuvenating the brain of an individual using an active combination of at least one phospholipid and at least one substance selected from the group consisting of a ginseng, green tea, catechin, ginsenoside, essential fatty acid, and combinations thereof. The present invention is further directed to methods and compositions for treating a neurodegenerative disease or neurological disorder in a patient using an active combination of at least one phospholipid and at least one substance selected from the group consisting of a ginseng, green tea, catechin, ginsenoside, essential fatty acid, and combinations thereof. The present invention is further directed to methods and compositions for increasing bioavailability of ginseng or ginsenoside in the brain of an individual using an active combination of at least one phospholipid complexed to at least one ginseng or ginsenoside.

BACKGROUND AND SUMMARY

The chemical constituents of ginseng from Panax and other genuses can be categorized as saponins, polysaccharides, flavonoids and volatile oils. Most biological activity of ginseng has been attributed to the saponin (i.e. ginsenoside) constituents and their metabolites. Clinical applications include anti-hyperglycemic, antioxidant, anti-inflammatory, immune stimulating and anti-apoptotic effects. The bioavailability of the bioactive ginseng constituents has been shown to be limited for orally administered doses, with absorption rates of 0.1% of administered dose for Rgl and 1.9% of administered dose for Rg2 {Herbs, Botanicals and Teas, CRC Press 1998 pg. 28 G. Mazza, B.D. Oomah). Limited recovery of ginsenosides from tissues, feces, and urine is likely due to extensive pre-systemic metabolism of ginsenosides (Masami,TAKINO, Yoshio. (1991). Studies on Absorption, Distribution, Excretion and Metabolism of Ginseng Saponins. VII. Comparison of the Decomposition Modes of Ginsenoside-Rbl and -Rb2 in the Digestive Tract of Rats. Chemical and Pharmaceutical Bulletin, 39(9), 2357-2361). Complexing ginsenosides in a phospolipid matrix has been shown to increase oral bioavailability of individual ginsenosides compared to aqueous solutions in animal models. However, studies have shown that brain tissue levels achieved for most of the ginsenosides are very low and that these levels are unlikely to reach the concentrations in the brain necessary to elicit therapeutic effects.

Catechins are biologically active compounds extracted from natural sources such as green tea, etc. Clinical applications of green tea catechins include prevention of cardiovascular disease, cancer prevention, and weight management.

Phospholipids are lipids containing phosphoric acid residue in general, including soybean lecithin, egg yolk lecithin, phosphatidyl choline, phosphatidyl choline, phosphatidyl ethanolamine, and phosphatidyl serine, which are widely present in the nature, including in animals and plants. Phospholipids are found in the cells of the brain and nervous system of mammals and are commonly used in pharmaceutical preparations. Phospholipid molecules have a hydrophilic head and two hydrophobic long chains, and have been used as pharmaceutical excipients.

The aging process results in a decrease in cognitive function, even in middle aged or elderly individuals who do not otherwise suffer from dementia or other neurodegenerative disease. Damage to white matter tracts with aging contributes to decreased brain size which, along with other structural brain changes associated with aging, corresponds to age-related differences in cognitive performance. In addition, the buildup of a small neuronal protein fragments called amyloid beta, which accumulates to form aggregates of various sizes, may contribute to cognitive decline with aging. Aging of the brain in such individuals generally leads to a decrease in cognitive function, including attention, memory, executive function, speed of processing, efficiency of task switching, and decrease in brain activity, with the cognitive decline generally becoming greater with age. For example, studies reveal that when a healthy elderly person performs the same cognitive task as a young adult, there is a decrease in fMRI signals, and therefore brain activity, in the frontal brain regions of the elderly person as compared to the young adult, suggesting reduced brain activity in the elderly person.

Selective neuronal cell death is the common hallmark of various neurodegenerative diseases and neurological disorders. Sporadic forms of Alzheimer's disease, Parkinson's disease, and Lou Gehrig's disease (amyotrophic lateral sclerosis (ALS)) have been linked to environmental factors that cause neuronal cell death by excitotoxicity, oxidative stress, inhibition of parts of the electron transport chain, cellular and mitochondrial membrane disruption, alterations in cellular organelles, alterations in chromatin, general and specific genotoxic action, and inhibition and/or hyperactivation of cell surface protein receptors and effectors. The experimental and clinical literature supports a potential role for excitotoxins in some forms of neurodegeneration, notably ALS and Alzheimer's disease. In particular, abnormalities in glutamate transport have been linked to ALS and domoic acid, a kainate receptor (i.e., an ionotrophic glutamate receptor) agonist, has been shown to be a causal factor in some forms of memory loss, much like that reported in Alzheimer's disease. Oxidative stress has also been linked to the same disease states

Currently, there is no cure for ALS, Alzheimer's disease (AD), or Parkinson's disease. Current treatment generally involves efforts by physicians to-manage the symptoms and make patients more comfortable. While there are a number of drugs in development and a limited number that are FDA approved for treatment (Riluzole, for ALS; L-dopa for Parkinson's disease; cognitive enhancers, such as Aricept, for AD), these treatments only mask the progression of neurologic disease and may act to marginally prolong the lives of some patients.

Thus, there is a significant need for methods and compositions directed to treatment of neurodegenerative disease and neurological disorders, and to the improvement of cognition or rejuvenation of the brain in individuals, particularly middle aged and elderly individuals with aging but otherwise healthy brains. There is also a significant need for methods and compositions directed to improving brain bioavailability of ginseng and ginsenosides.

Several embodiments of the invention are described by the following enumerated clauses:

1. A method for improving cognition or rejuvenating the brain of an individual, the method comprising the step of

administering to the individual a composition comprising an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof,

wherein cognition in the individual is improved or the brain of the individual is rejuvenated.

2. The method of claim 1, wherein the individual is an aging individual. 3. The method of claim 1 or 2, wherein the individual is a human or a dog.

4. The method of any one of claims 1 - 3, wherein the cognition is selected from the group consisting of attention, memory, processing speed, psychomotor speed, executive function, functional connectivity of frontal regions of the brain, functional connectivity of medial regions of the brain, functional connectivity of parietal regions of the brain, functional connectivity of frontal and parietal regions of the brain, activation of a frontal region of the brain, activation of a medial region of the brain, and any combination thereof.

5. The method of claim 4, wherein the cognition is memory.

6. The method of claim 4, wherein the cognition is executive function.

7. The method of claim 4, wherein the cognition is activation of a frontal region of the brain or activation of a medial region of the brain.

8. The method of claim 4, wherein the cognition is functional connectivity of frontal regions of the brain.

9. A method for improving cognition or rejuvenating the brain of an individual by modulating functional connectivity of frontal regions of the brain, the method comprising the step of

administering to the individual a composition comprising an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof,

wherein functional connectivity of frontal regions of the brain is modulated and wherein cognition is improved or the brain is rejuvenated in the individual.

10. The method of claim 9, wherein the individual is an aging individual.

11. The method of claim 9 or 10, wherein the individual is a human or a dog.

12. The method of any one of claims 9 to 11, wherein the functional connectivity of the frontal regions of the brain is increased during task performance.

13. The method of claim 12, wherein the frontal regions are task network regions. 14. The method of claim 13, wherein the frontal regions are the anterior cingulate cortex and middle frontal gyrus.

15. The method of any one of claims 9 to 11, wherein the functional connectivity of the frontal regions of the brain is decreased during rest.

16. The method of claim 15, wherein the frontal regions are default mode network regions, task network regions, or any combination thereof.

17. The method of claim 16, wherein the frontal regions are the middle frontal gyrus and precuneus.

18. The method of claim 16, wherein the frontal regions are the precentral gyrus and the medial frontal gyrus.

19. A method of treating a neurodegenerative disease, the method comprising the step of

administering to a patient with a neurodegenerative disease a composition comprising an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, wherein the symptoms of the neurodegenerative disease in the patient are reduced.

20. The method of claim 19, wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.

21. A method of treating a neurological disorder, the method comprising the step of

administering to a patient with a neurological disorder a composition comprising an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, wherein the symptoms of the neurological disorder in the patient are reduced.

22. The method of claim 21 , wherein the neurological disorder is traumatic brain injury, autism, schizophrenia or chronic traumatic encephalopathy.

23. The method of any one of claims 1 - 22, wherein the phospholipid is selected from the group consisting of lecithin, phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphoinositide and phosphosphingolipid.

24. The method of any one of claims 1 - 23, wherein the ginsenoside is selected from the group consisting of Rbl, Rb2, Rb3, Rc, Rd, Re, Rf, Rgl, Rg2, Rg3, Rhl, and Rh2.

25. The method of any one of claims 1 - 24, wherein the catechin is selected from the group consisting of epigallocatechin, epicatechin, epigallocatechin gallate, epicatechin gallate, (+) catechin, (-) catechin, and gallocatechin gallate.

26. The method of any one of claims 1 - 25, wherein the substance is ginseng and catechin or ginseng and green tea.

27. The method of claim 26, wherein the ratio of ginseng to green tea or catechin is about 1 :4 to about 4:1.

28. The method of any one of claims 1 - 27, wherein the composition comprises a pharmaceutically acceptable carrier.

29. The method of any one of claims 1 - 28, wherein the composition is administered by a mode of administration selected from the group consisting of oral administration, intranasal administration, sublingual administration, intracerebral

administration, and parenteral administration.

30. A composition for improving cognition or rejuvenating the brain of an individual, the composition comprising a therapeutic amount of an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, and wherein the therapeutic amount is capable of improving cognition or rejuvenating the brain of the individual.

31. The composition of claim 30, wherein the individual is an aging individual.

32. The composition of claim 30 or 31 , wherein the individual is a dog or a human.

33. The composition of any one of claims 30 - 32, wherein the cognition is selected from the group consisting of attention, memory, processing speed, psychomotor speed, executive function, decision making, functional connectivity of frontal regions of the brain, functional connectivity of parietal regions of the brain, functional connectivity of frontal and parietal regions of the brain, activation of a frontal region of the brain, activation of a medial region of the brain, and any combination thereof.

34. The composition of claim 33, wherein the cognition is memory.

35. The composition of claim 33, wherein the cognition is executive function.

36. The composition of claim 33, wherein the cognition is activation of a frontal region of the brain or activation of a medial region of the brain.

37. The composition of claim 33, wherein the cognition is functional connectivity of frontal regions of the brain.

38. A composition for improving cognition or rejuvenating the brain of an individual by modulating functional connectivity of frontal regions of the brain, the composition comprising a therapeutic amount of an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and

combinations thereof, and wherein the therapeutic amount is capable of modulating functional connectivity of frontal regions of the brain and improving cognition or rejuvenating the brain of the individual.

39. The composition of claim 38, wherein the individual is an aging individual.

40. The composition of claim 38 or 39, wherein the individual is a human or a dog.

41. The composition of any one of claims 38 to 40, wherein the functional connectivity of the frontal regions of the brain is increased during task performance.

42. The composition of claim 41 , wherein the frontal regions are task network regions.

43. The composition of claim 42, wherein the frontal regions are the anterior cingulate cortex and middle frontal gyrus.

44. The composition of any one of claims 38 to 40, wherein the functional connectivity of the frontal regions of the brain is decreased during rest.

45. The composition of claim 44, wherein the frontal regions are default mode network regions, task network regions, or any combination thereof. 46. The composition of claim 45, wherein the frontal regions are the middle frontal gyrus and precuneus.

47. The composition of claim 45, wherein the frontal regions are the precentral gyrus and the medial frontal gyrus.

48. A composition for use in treating a neurodegenerative disease in a patient, the composition comprising a therapeutic amount of an active combination at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and

combinations thereof, wherein the therapeutic amount is capable of reducing symptoms of the neurodegenerative disease in the patient.

49. The composition of claim 48, wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.

50. A composition for use in treating a neurological disorder in a patient, the composition comprising a therapeutic amount of an active combination at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and

combinations thereof, wherein the therapeutic amount is capable of reducing symptoms of the neurological disorder in the patient.

51. The composition of claim 50, wherein the neurological disorder is traumatic brain injury, autism, schizophrenia, or chronic traumatic encephalopathy.

52. The composition of any one of claims 30 - 51, wherein the phospholipid is selected from the group consisting of lecithin, phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphoinositide, and phosphosphingolipid.

53. The composition of any one of claims 30 - 52, wherein the ginsenoside is selected from the group consisting of Rbl, Rb2, Rb3, Rc, Rd, Re, Rf, Rgl, Rg2, Rg3, Rhl, and Rh2.

54. The composition of any one of claims 30 - 53, wherein the catechin is selected from the group consisting of epigallo catechin, epicatechin, epigallo catechin gallate, epicatechin gallate, (+) catechin, (-) catechin, and gallocatechin gallate. 55. The composition of any one of claims 30 - 54, wherein the substance is ginseng and catechin or ginseng and green tea.

56. The composition of claim 55, wherein the ratio of ginseng to green tea or catechin is about: 1 :4 to about 4:1.

57. The composition of any one of claims 30 - 56, wherein the

composition comprises a pharmaceutically acceptable carrier.

58. The composition of any one of claims 30 - 57, wherein the

composition is adapted for administration selected from the group consisting of oral administration, sublingual administration, intranasal administration, intracerebral

administration, and parenteral administration.

59. The method or composition of any one of claims 1 - 58, wherein the phospholipid is complexed to the substance.

60. The method or composition of claim 59, wherein the phospholipid is formulated as a nanoparticle.

61. The method or composition of claim 60, wherein the nanoparticle is selected from the group consisting of a nanoemulsion, micelle, or liposome.

62. A composition for use in increasing the bioavailability of a ginseng or ginsenoside in the brain of an individual, comprising a therapeutic amount of an active combination of at least one phospholipid and at least one substance, wherein the substance is a ginseng or ginsenoside, wherein the phospholipid is complexed to the ginseng or ginsenoside, and wherein the therapeutic amount is capable of increasing the bioavailability of the ginseng or ginsenoside in the brain of the individual.

63. The composition of claim 62, wherein the substance is a ginsenoside.

64. The composition of claim 62 or 63, wherein the ginsenoside is selected from the group consisting of Rbl, Rb2, Rb3, Rc, Rd, Re, Rf, Rgl, Rg2, Rg3, Rhl, Rh2, PPT, PPD, and compound K.

65. The composition of any one of claims 62 to 64, wherein the composition comprises one or more catechin, green tea, essential fatty acid, or any combination thereof.

66. The composition of any one of claims 62 to 65, wherein the phospholipid is complexed to the ginseng or ginsenoside by at least one hydrogen bond. 67. The composition of any one of claims 62 to 66, wherein the individual is an aging individual.

68. The composition of any one of claims 62 to 67, wherein the individual is a human or a dog.

69. The composition of claim 68, wherein the individual is a human.

70. The composition of any one of claims 62 to 69, wherein the phospholipid is selected from the group consisting of lecithin, phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphoinositide, and phosphosphingolipid.

71. The composition of any one of claims 62 to 70, wherein the composition comprises a pharmaceutically acceptable carrier.

72. The composition of any one of claims 62 - 71, wherein the

composition is adapted for administration selected from the group consisting of oral administration, sublingual administration, intranasal administration, intracerebral

administration, and parenteral administration.

73. The composition of any one of claims 62 - 72, wherein the at least one phospholipid is formulated as a nanoparticle.

74. The composition of claim 73, wherein the nanoparticle is selected from the group consisting of a nanoemulsion, micelle, or liposome.

75. A method for increasing the bioavailability of a ginseng or ginsenoside in the brain of an individual, the method comprising the steps of

administering to the individual a therapeutic amount of a composition comprising an active combination of at least one phospholipid and at least one substance, wherein the substance is a ginseng or ginsenoside, wherein the phospholipid is complexed to the ginseng or ginsenoside, wherein the bioavailability of the ginseng or ginsenoside in the brain of the individual is increased.

76. The method of claim 75, wherein the substance is a ginsenoside.

77. The method of claim 74 or 75, wherein the ginsenoside is selected from the group consisting of Rbl, Rb2, Rb3, Rc, Rd, Re, Rf, Rgl, Rg2, Rg3, Rhl, Rh2, PPT, PPD, and compound K.

78. The method of any one of claims 75 to 77, wherein the composition comprises one or more catechin, green tea, essential fatty acid, or any combination thereof. 79. The method of any one of claims 75 to 78, wherein the phospholipid is complexed to the ginseng or ginsenoside by at least one hydrogen bond.

80. The method of any one of claims 75 to 79, wherein the individual is an aging individual.

81. The method of any one of claims 75 to 80, wherein the individual is a human or a dog.

82. The method of claim 81, wherein the individual is a human.

83. The method of any one of claims 75 to 82, wherein the phospholipid is selected from the group consisting of lecithin, phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphoinositide, and phosphosphingolipid.

84. The method of any one of claims 75 to 83, wherein the therapeutic amount is administered by a mode of administration selected from the group consisting of oral administration, intranasal administration, sublingual administration, intracerebral administration, and parenteral administration.

85. The method of any one of claims 75 to 84, wherein the at least one phospholipid is formulated as a nanoparticle.

86. The method of claim 85, wherein the nanoparticle is selected from the group consisting of a nanoemulsion, micelle, or liposome.

87. The method or composition of any one of claims 1 to 86, wherein the substance is purified and/or synthetic.

88. The method or composition of any one of claims 1 to 87, wherein the composition comprises a pharmaceutically acceptable carrier.

89. The method of any one of claims 1 - 22, 28 - 29 or the composition of any one of claims 30 - 51, 57 - 59, wherein the substance is ginseng, ginsenosides, green tea, catechins and essential fatty acids.

90. The method or composition of claim 90, wherein the ginseng is Asian ginseng, wherein the green tea is green tea leaf extract, and wherein the essential fatty acids are omega-3 fatty acids, DHA and EPA.

91. The method or composition of claim 91 , wherein the ginseng is complexed to the at least one phospholipid and wherein the green tea is complexed to the at least one phospholipid. 92. The method or composition of any one of claims 89 - 91, wherein the composition comprises Cerbella®.

For all of the embodiments, any applicable combination of embodiments is also contemplated. Any applicable combination of the above-described embodiments is considered to be in accordance with the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: fMRJ activation changes over the course of intervention with the investigational product and placebo were calculated. All maps show differences that are significant at the voxel level at a level of p=.01, and a cluster significance threshold of p=.001 using AlphaSim cluster correction:

Left (Figure 1): fMRJ signal changes among those on placebo included mainly decreases in the fMRI signal, including decreases in a posterior cingulate cortex cluster (shown in blue).

Center (Figure 1): fMRI signal changes among those on the investigational product consisted of a combination of signal increases (shown in orange) and decreases (shown in green).

Right (Figure 1): Locations where the differences in fMRI changes between the investigational product and placebo arms were statistically significant are shown in red. Red regions showed greater increases in activation over the intervention in the investigational product arm compared to the placebo arm. These regions include the posterior and anterior cingulate cortex, regions important to task execution.

Figure 2: Changes in functional connectivity (FC) during task execution in a middle frontal gyrus (MFG) seed location were calculated over the course of each

intervention phase. All maps show differences over time that are significant at the voxel level at a level of p=.01 and a cluster significance threshold of p=.001 using AlphaSim cluster correction [1]:

Left (Figure 2): Task FC changes during treatment with placebo include a combination of increases (cool, green colors) and decreases (hot colors). Centre (Figure 2): Task FC changes during treatment with the investigational product include mainly increases (cool colors).

Right (Figure 2): Task FC between the MFG and locations mainly within the occipital cortex decreased significantly more during treatment with Cerbella® than it did during treatment with placebo (hot colors). However, task FC between the MFG and locations within the cingulate cortex increased significantly more during treatment with Cerbella® than it did during treatment with placebo (cool colors).

Figure 3: Changes in functional connectivity (FC) during rest in the medial frontal gyrus (MeFG, top row), precentral gyrus (PCG, middle row), and precuneus (PREC, bottom row) seed locations were calculated over the course of each intervention phase. All maps show differences over time that are significant at the voxel level at a level of p=.01 and a cluster significance threshold of p=.001 using AlphaSim cluster correction:

Top row (Figure 3): Rest FC between MeFG and an occipital cortex region of interest (ROI) increased significantly during treatment with the investigational product (middle column, cool colors) but was largely unchanged over treatment with placebo (left column).

Middle row (Figure 3): Rest FC between PCG and MeFG increased significantly over the course of treatment with placebo (cool colors, left column) but was largely unchanged over treatment with the investigational product.

Bottom row (Figure 3): Rest FC between PREC and a middle frontal gyrus ROI decreased significantly over the course of treatment with the investigational product (hot colors, middle column) and increased significantly over the course of treatment with placebo (cool colors, left column).

Figure 4 shows ginsenoside concentration in the brains of rats fed one of the following: (I) ginseng - phospholipid complex; (ii) raw ginseng extract; and (iii) water (control). The content of the following ginsenosides was assessed in the brains of the rats: Re, Rgl, Rf, Rg2, Rbl, Rb2, Rc, Rd, PPT, Compound K, and PPD. The results are expressed in ng/g dry brain. Error bars represent Half Distance. DETAILED DESCRIPTION OF THE INVENTION

Methods and compositions are provided for improving cognition in the brain of an individual. In one illustrative embodiment, a method is provided for improving cognition or rejuvenating the brain of an individual by administering to the individual a composition comprising an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, wherein cognition in the individual is improved. Methods and compositions are also provided for treating neurodegenerative disease in a patient. In one illustrative embodiment, a method is provided for treating a neurodegenerative disease in a patient by administering to the patient a composition comprising an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, wherein symptoms of the neurodegenerative disease in the patient are reduced.

Methods and compositions are also provided for treating a neurological disorder in a patient. In one illustrative embodiment, a method is provided for treating a neurological disorder by administering to the patient a composition comprising an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, wherein symptoms of the neurological disorder in the patient are reduced. Methods and compositions are also provided for increasing the bioavailability of a ginseng or ginsenoside in the brain of an individual. In one illustrative embodiment, a method is provided for increasing the bioavailability of a ginseng or ginsenoside in the brain of an individual by administering to the individual a composition comprising an active combination of at least one phospholipid and at least one substance, wherein the substance is a ginseng or ginsenoside, wherein the phospholipid is complexed to the ginseng or ginsenoside, wherein the brain bioavailability of the ginseng or ginsenoside is increased. In another illustrative embodiment, the substance of the preceding embodiment is a ginsenoside. In further illustrative embodiments, in the two preceding embodiments the composition further comprises one or more green tea, catechin, essential fatty acid, or any combination thereof. Methods and compositions are also provided for improving cognition or rejuvenating the brain of an individual by modulating functional connectivity of frontal regions of the brain. In one illustrative embodiment, a method is provided for improving cognition or rejuvenating the brain of an individual by modulating functional connectivity of frontal regions of the brain, said method comprising the step of administering to the individual a composition comprising an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, wherein functional connectivity of the frontal regions of the brain is modulated and cognition in the individual is improved or the brain is rejuvenated. In the preceding embodiment, the functional connectivity of the frontal regions of the brain is modulated by increasing functional connectivity of the frontal regions of the brain during task performance, the functional connectivity of the frontal regions of the brain can be modulated by decreasing functional connectivity of the frontal regions of the during rest, or any combination of the above. In the preceding embodiments, the functional connectivity can be increased in frontal regions of the brain, wherein the frontal regions are task network regions, the functional connectivity can be decreased in frontal regions of the brain, wherein the regions are default mode regions, or any combination thereof. In the preceding embodiment, the default mode network regions can be the medial frontal gyrus and precuneus, and the task network regions can be the anterior cingulate cortex and the middle frontal gyrus.

Methods and compositions are also provided for modulating functional connectivity of frontal regions of the brain. In one illustrative embodiment, a method is provided for modulating functional connectivity of frontal regions of the brain, said method comprising the step of administering to the individual a composition comprising an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, wherein functional connectivity of the frontal regions of the brain is modulated. In the preceding embodiment, the functional connectivity of the frontal regions of the brain is modulated by increasing functional connectivity of the frontal regions of the brain during task performance, the functional connectivity of the frontal regions of the brain can be modulated by decreasing functional connectivity of the frontal regions of the during rest, or any combination of the above. In the preceding embodiments, the functional connectivity can be increased in frontal regions of the brain, wherein the frontal regions are task network regions, the functional connectivity can be decreased in frontal regions of the brain, wherein the regions are default mode regions, or any combination thereof. In the preceding embodiment, the default mode network regions can be the medial frontal gyrus and precuneus, and the task network regions can be the anterior cingulate cortex and the middle frontal gyrus.

In any of the above described method embodiments, the composition can comprise a pharmaceutically acceptable carrier.

As used herein, "task network regions" are frontal regions of the brain that increase activation in a synchronous fashion in response to attention-demanding tasks. Non- limiting examples of task network regions include the anterior cingulate cortex and the middle frontal cortex.

As used herein "default mode network regions" are frontal regions of the brain that activate in a synchronous fashion during periods of rest. Non-limiting examples of default mode network regions include the medial frontal gyrus and precuneus.

As used herein, an individual's brain or regions of the brain are at "rest" or wakeful rest when the individual is not performing an overt cognitive or sensory task. Non- limiting examples of rest include day dreaming and mind wandering.

As used herein, "rejuvenation" of, or to "rejuvenate" a brain or regions of the brain of an individual means to slow or reverse effects of ageing on the brain or regions of the brain. In one illustrative embodiment, the individual is an ageing individual. Non-limiting examples of rejuvenation of the brain include slowing or reversing effects of ageing on the brain, wherein the slowing or reversal of the effects of ageing results in improved cognition. In the preceding embodiment, the improved cognition can be memory, processing speed, attention, psychomotor speed, executive function, functional connectivity of frontal regions of the brain, or any combination thereof.

As used herein, a "complex" is any association or chemical bond between two or more compounds or substances. As used herein, two or more compounds or substances are

"complexed" if there is an association or at least one chemical bond between said compounds or substances. Non-limiting examples of a complex include one or more covalent bonds, ionic bonds, hydrogen bonds, dipolar bonds, and Wan der Waals forces. In various illustrative embodiments, in any of the methods or compositions described herein, the phospholipid is complexed to the substance. In further illustrative embodiments, the substance can be a ginseng or ginsenoside, and the phospholipid can be complexed to the ginseng or ginsenoside by at least one hydrogen bond. In further illustrative embodiments, the substance can be a catechin, and the phospholipid can be complexed to the catechin by at least one hydrogen bond. In further illustrative embodiments, the substance can be a ginseng and catechin, and the phospholipid can be complexed to each of the ginseng and catechin by at least one hydrogen bond.

As used herein, a "phospholipid" refers to any molecule comprising two hydrophobic fatty acid "tails" and a hydrophilic phosphate "head" or group, joined together by a glycerol molecule. In another embodiment, the phosphate group of the phospholipid molecule can be modified with simple organic molecules such as choline. Non- limiting examples of a phospholipid include phosphatidic acid (phosphatidate) (PA), phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS), a phosphoinositide, and a phosphosphingolipid. Non-limiting examples of a phosphoinositide include phosphatidylinositol (PI), phosphatidylinositol phosphate (PIP), Phosphatidylinositol bisphosphate (PIP2) and Phosphatidylinositol triphosphate (PIP3). Non-limiting examples of a phosphosphingolipid include ceramide phosphorylcholine (Sphingomyelin) (SPH), ceramide phosphorylethanolamine (Sphingomyelin) (Cer-PE), and ceramide phosphoryllipid. As used herein, a "phospholipid" can also be lecithin or cephalin. In various illustrative embodiments, the phospholipid of any of the methods or compositions described herein can be selected from the group consisting of lecithin, phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphoinositide, and phosphosphingolipid.

In various illustrative embodiments, the phospholipid or the essential fatty acid of any of the methods or compositions described herein may be formulated as, or form part of a nanoparticle. In the preceding embodiment, the nanoparticle can be selected from the group consisting of a nanoemulsion, liposome or micelle. In the preceding two embodiments, the substance of any of the methods or compositions described herein can be encapsulated within or associate with the nanoparticle. In further illustrative embodiments, the phospholipid and substance of various methods or compositions described herein can be complexed, the phospholipid can be formulated as a nanoparticle, and the substance can be encapsulated within the nanoparticle. As used herein, a "nanoparticle" refers to any nanoparticle or nanoformulation composed wholly or partially of phospholipids, essential fatty acids, or combinations thereof. Non-limiting examples of a nanoparticle include liposomes, micelles, nanoemulsions, ethosomes, solid lipid nanoparticles (SLN), and nanostructured lipid carriers (NLC). Such nanoparticles may be synthesized using methods known in the art and are described in, for example, Multifunctional Nanoparticles for Drug Delivery Applications: Imaging, Targeting, and Delivery, Sonke Svenson, Robert K.

Prud'homme, Springer Science & Business Media, Feb 22, 2012 - Medical - 373 pages, which is incorporated herein by reference.

In various illustrative embodiments, the phospholipid of any of the methods or compositions described herein can be isolated and/or purified from a natural source or can be a synthetic phospholipid that is manufactured. Non-limiting examples of natural sources from which a phospholipid can be isolated and/or purified include plant sources such as soya, rapeseed, sunflower, and animal sources such as chicken eggs, bovine milk, and fish eggs. Methods for manufacturing phospholipids and methods of isolating phospholipids from a natural source are known in the art and are described, for example, at Phospholipids

Handbook, Second Edition 1993 by Gregor Cevc (Editor), Marcel Dekker Inc, NY 997pages, which is incorporated herein by reference.

As used herein, a "substance" refers to a biologically active substance or compound selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and any combination thereof. In various illustrative embodiments, the substance of the methods or compositions described herein can be an essential fatty acid. In another illustrative embodiment, the essential fatty acid can be an omega-3 fatty acid or an omega-6 fatty acid. In another illustrative embodiment, the essential fatty acid can be eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). In further illustrative embodiments, the substance of the methods or compositions described herein can be a ginseng and green tea, a ginseng and catechin, a ginsenoside and green tea, or a ginsenoside and catechin. In further illustrative embodiments, the substance of the methods or

compositions described herein can be a ginseng, green tea, catechin and essential fatty acid.

In further illustrative embodiments, the substance of the methods or compositions described herein can be a ginsenoside, green tea, catechin and essential fatty acid. In further illustrative embodiments, the substance of the methods or compositions described herein can be ginseng, green tea and essential fatty acid. In further illustrative embodiments, the substance of the methods or compositions described herein can be a ginseng, catechin and essential fatty acid. In further illustrative embodiments, the substance of the methods or compositions described herein can be a ginsenoside, green tea and essential fatty acid. In further illustrative embodiments, the substance of the methods or compositions described herein can be a ginsenoside, catechin and essential fatty acid. In further illustrative embodiment, the substance of the methods or compositions described herein can be a ginseng, green tea, catechin and essential fatty acid, wherein the ginseng is from a Panax species, and wherein the essential fatty acid is selected from the group consisting of DHA, EPA, and combinations thereof. In further illustrative embodiments, the ginseng and catechin of any of the methods or compositions described herein can be in a ratio of ginseng to catechin of about 1 :4 to about 4: 1. In further illustrative embodiments, the ginseng and green tea of any of the methods or compositions described herein can be in a ratio of ginseng to catechin of about 1 :4 to about 4:1. In further illustrative embodiments, the ginsenoside and catechin of any of the methods or compositions described herein can be in a ratio of ginseng to catechin of about 1 :4 to about 4:1. In further illustrative embodiments, the ginsenoside and green tea of any of the methods or compositions described herein can be in a ratio of ginseng to catechin of about 1 :4 to about 4:1.

In further illustrative embodiments, the substance of the methods or compositions described herein can be wherein the substance is ginseng, ginsenosides, green tea, catechins and essential fatty acids. In further illustrative embodiments, the ginseng can be Asian ginseng, the green tea can be green tea leaf extract, and the essential fatty acids can be omega-3 fatty acids, DHA and EPA. In further illustrative embodiments, the ginseng can be complexed to at least one phospholipid the green tea can be complexed to at least one phospholipid. In further illustrative embodiments, the composition of the methods or compositions described herein can comprise Cerbella®.

As used herein, a "catechin" refers to any catechin or any pharmaceutically acceptable salt, solvate, ester or isomer thereof, or any combinations thereof. Non-limiting examples of a catechin include (+)-gcatechin (2R, 3S), (-)-catechin (2S,3R), (-)-epicatechin (2R,3R), (+)-epicatechin (2S,3S), epigallocatechin , epigallocatechin gallate, epicatechin gallate, gallocatechin gallate and combinations thereof. In various illustrative embodiments, the catechin of any of the methods or compositions described herein can be a catechin selected from the group consisting of epigallocatechin, epicatechin, epigallocatechin gallate, epicatechin gallate, (+) catechin, (-) catechin, and gallocatechin gallate.

In various illustrative embodiments, the catechin of any of the methods or compositions described herein can be a synthetic catechin that is manufactured or the catechin can be isolated and/or purified from a natural source such as, for example, fruits (e.g. pome fruits, peaches, prunes), tea (e.g. green tea), cocoa (e.g. cocoa beans), acai palm {Euterpe oleracea), argan oil and vinegar. Catechins can be isolated and/or purified from a natural source using methods known in the art, which are disclosed, for example, in Green Tea Polyphenols: Nutraceuticals of Modern Life, edited by Lekh R. Juneja, Mahendra P. Kapoor, Tsutomu Okubo, Theertham Rao, CRC Press 2013, which is incorporated herein by reference. In further illustrative embodiments, the catechin of the methods or compositions described herein can be formulated as or form part of tea extract (e.g. green tea extract). In further illustrative embodiments, the catechin of the methods and compositions described herein can synthetic and manufactured using methods known in the art, which methods are disclosed, for example, at Flavonoids in Health and Disease, Second Edition, edited by Catherine A. Rice-Evans, Lester Packer, Marcel Dekker Inc 2003, which is incorporated herein by reference.

As used herein, "green tea" refers to green tea or green tea extracts from plants. Non-limiting examples of green tea include green tea leaf extract.

As used herein, a "ginseng" refers to extract or raw plant material from a plant or plants belonging to one or more ginseng species. In various illustrative embodiments, a "ginseng" of the methods and compositions described herein can be extracted from a root, leaf, or combinations thereof, of a plant or plants from one or more ginseng species. In further illustrative embodiments, a "ginseng" of the methods and compositions described herein can be a raw leaf, raw root, or combinations thereof, of a plant or plants from one or more ginseng species. In further illustrative embodiments, the ginseng of any of the methods or compositions described herein can belong to the genus Panax. As used herein, "Asian ginseng" refers to ginseng belonging to the genus Panax.

A ginseng extract can be prepared using methods known in the art and disclosed, for example, in: Ginseng, the Genus Panax, edited by William E Court, Harwood academic publishers 2005, which is incorporated herein by reference. As used herein, a "ginseng species" is any species belonging to the genus Panax of the family Araliaceae. Non-limiting examples of a ginseng species include Panax vietnamensis, Panax ginseng, P. quinquefolius, Panax japonicus, Panax notoginseng, Panax bipinnatifidus, Panax wangianus, Panax zingiberensis, Panax

pseudoginseng, Panax stipuleanatus, and Panax trifolius. As used herein, a "ginseng species" also includes Siberian ginseng (Eleutherococcus senticosus) and crown prince ginseng (Pseudostellaria heterophylla).

As used herein, a "ginsenoside" refers to at least one ginsenoside molecule. In one embodiment, the ginsenoside is found naturally occurring in a ginseng. In various illustrative embodiments, the ginsenoside of any of the methods and compositions described herein can be isolated and/or purified from a ginseng, ginseng extract or other plant source, or the ginsenoside can be a syntheticginsenoside that is manufactured. .In further illustrative embodiments, the ginsenoside of the methods and compositions described herein is isolated and/or purified from a ginseng species belonging to the genus Panax, or a ginseng extract thereof. In further illustrative embodiments, the ginsenoside of the methods and compositions described herein is formulated as or forms part of a ginseng extract. Ginsenosides can be isolated and/or purified from ginseng or another plant source using methods known in the art, which are disclosed, for example, in Chemistry and Pharmacology of Natural Products:

Saponins, By K. Hostettmann, A. Marston, Cambridge University Press 1995, which is incorporated herein by reference.

In further illustrative embodiments, the ginsenoside of the compositions or methods described herein is a member of the dammarane family or the oleanane family. In further illustrative embodiments, the ginsenoside of the compositions or methods described herein is a member of a group selected from protopanaxadiols, protopanaxatriols, and pseudoginsenoside Fl 1. In further illustrative embodiments, the ginsenoside of the methods or compositions described herein is selected from the group consisting of Rbl, Rb2, Rb3, Rc, Rd, Re, Rf, Rgl, Rg2, Rg3, Rhl, compound K and Rh2. In further illustrative embodiments, the ginsenoside of the methods or compositions described herein is compound K. As used herein, the term "ginsenoside" also includes a ginsenoside metabolite that is a product of ginsenoside metabolism by mammalian gut bacteria. Non-limiting examples of a ginsenoside metabolite include 20-b-O-glucopyranosyl-20(S)-protopanaxadiol and 20(S)- protopanaxadiol. In a further embodiment, the ginsenoside is a synthetic ginsenoside that is manufactured. Methods of manufacturing ginsenoside synthetically are known in the art and are disclosed, for example, in Organic Synthesis with Enzymes in Non- Aqueous Media, edited by Giacomo Carrea, Sergio Riva, Willey VCH 2008, which is incorporated herein by reference.

As used herein, an "essential fatty acid" refers to at least one molecule of any fatty acid that humans must ingest because the body requires them for good health. In one illustrative embodiment, the essential fatty acid is a polyunsatured fatty acid, e.g. a short- chain polyunsaturated fatty acid (SC-PUFA), a long-chain polyunsaturated fatty acid (LC- PUFA), or any combination thereof. In another illustrative embodiment, the essential fatty acid of any of the methods or compositions described herein is an ω-3 fatty acid, an ω-6 fatty acid, or combinations thereof. In another illustrative embodiment, the essential fatty acid is selected from the group consisting of a-Linolenic acid or ALA, Linoleic acid or LA (18:2n- 6), eicosapentaenoic acid or EPA (20:5n-3), docosahexaenoic acid or DHA (22:6n-3), or combinations thereof. In another illustrative embodiment, the essential fatty acid is EPA. In another embodiment, the essential fatty acid is DHA. In further illustrative embodiments, the essential fatty acid of the methods or compositions described herein can be omega-3 fatty acids, EPA, DHA or any combination thereof. In further illustrative embodiments, the essential fatty acid of any of the methods or compositions disclosed herein is a synthetic essential fatty acid that is manufactured, or the essential fatty acid isolated and/or purified from a natural source such as, for example, fish, shellfish, flaxseed (linseed), flaxseed oil, hemp seed, olive oil, soya oil, canola (rapeseed) oil, chia seeds, pumpkin seeds, sunflower seeds, leafy vegetables, walnuts, and algae. Synthetic essential fatty acids can be

manufactured using methods known in the art and disclosed, for example, at Shahidi, & Wanasundara. (1998). Omega-3 fatty acid concentrates: Nutritional aspects and production technologies. Trends in Food Science & Technology, 9(6), 230-240, which is incorporated herein by reference. In various illustrative embodiments, the essential fatty acid of the methods or compositions described herein is formulated as, or forms part of, fish oil. In another embodiment, the essential fatty acid of the methods or compositions described herein is formulated as, or forms part of, a micelle, nanoemulsion, liposome or other nanoparticle.

As used herein, an "individual" refers to a mammal that does not have any clinically determined neurodegenerative disease. Non-limiting examples of a "mammal" or "mammalian subject" as used herein include a human, a horse or a companion animal (e.g. a dog or a cat). In one illustrative embodiment, the individual is a human. In another illustrative embodiment, the individual is a dog. In another illustrative embodiment, the individual of any of the methods or compositions described herein is an aging individual. In another illustrative embodiment, the aging individual is an aging human. As used herein, an "aging human" refers to a human that is at least 50 years of age. In one illustrative embodiment, the aging human is at least 55 years of age. In another illustrative embodiment, the aging human is at least 60 years of age. In another illustrative embodiment, the aging human is at least 65 years of age. In another illustrative embodiment, the aging human is at least 70 years of age. In another illustrative embodiment, the aging individual is at least 75 years of age. In any of the embodiments disclosed herein, the aging human can be male or female. In a further illustrative embodiment, the aging individual is an aging dog. In a further illustrative embodiment, the aging individual of any of the methods or compositions described herein has a brain that is affected by the normal aging process but is otherwise healthy and does not have any clinically determined neurodegenerative disease.

As used herein, "cognition" refers to a mental action or process through which a mammalian subject acquires and/or makes use of information. Non-limiting examples of cognition include, psychomotor speed, processing speed, task switching, orientation to time- place, executive function, memory, and combinations thereof. As used herein, "cognition" also includes brain activation, functional connectivity between frontal regions of the brain, modulation of functional connectivity of frontal regions of the brain, and combinations thereof.

In one illustrative embodiment, the functional connectivity of frontal regions of the brain of the methods and compositions described herein can be modulated, resulting in improved cognition or rejuvenation of the brain. In a further illustrative embodiment, the functional connectivity of frontal regions of the brain can be modulated by: increasing functional connectivity of frontal regions of the brain during task performance, decreasing functional connectivity of frontal regions of the brain during rest, or any combination thereof. In a further illustrative embodiment, the functional connectivity of frontal regions of the brain can be modulated by: (i) increasing functional connectivity of frontal regions of the brain during task performance, wherein the frontal regions of the brain are task network regions; (ii) decreasing functional connectivity of frontal regions of the brain during rest, wherein the frontal regions are default mode network regions; (iii) or any combination thereof.

As used herein, "brain activation" means increased activity in one or more region of the brain. In one illustrative embodiment, brain activation of the methods and compositions described herein can occur in response to a cognitive task. Non-limiting examples of brain activation include activation of one or more frontal regions of the brain, one or more medial regions of the brain, or any combination thereof. In an illustrative embodiment, brain activation can be activation in a frontal region of the brain, wherein the frontal region is selected from the group consisting of the anterior cingulate cortex, posterior cingulate cortex, and combinations thereof.

As used herein, "executive function" refers to one or more mental processes that enable the cognitive control of behavior. Non- limiting examples of executive function include attention, attentional control, inhibitory control, cognitive flexibility, working memory, reasoning, problem solving, efficiency of task switching, decision making and planning.

As used herein, "functional connectivity" means the integrated functional relationship between two or more distinct regions of the brain. Non-limiting examples of functional connectivity include functional connectivity of two or more frontal regions of the brain, functional connectivity between two or more medial regions of the brain, and functional connectivity between at least one frontal region of the brain and at least one medial region of the brain. In an illustrative embodiment, functional connectivity can be in frontal regions of the brain, wherein the frontal regions are two or more of the left dorsolateral prefrontal cortex, right dorsolateral prefrontal cortex, left inferior lateral parietal cortex, and right inferior lateral parietal cortex, and combinations thereof. In a further illustrative embodiment, functional connectivity can be in task network regions, default mode regions or any combination thereof.

In various illustrative embodiments, the cognition of any of the methods or compositions described herein is selected from the group consisting of memory, processing speed, psychomotor speed, executive function, activation of a frontal region of the brain, activation of a medial region of the brain, functional connectivity between frontal regions of the brain, modulation of functional connectivity of frontal regions of the brain, functional connectivity between parietal regions of the brain, and functional connectivity between frontal regions of brain and parietal regions of the brain. In one illustrative embodiment, the cognition is brain activation. In another illustrative embodiment, the brain activation is activation of a frontal region of the brain. In another illustrative embodiment, the brain activation is activation of a medial region of the brain. In another illustrative embodiment, the cognition is memory. In another illustrative embodiment, the cognition is executive function. In another illustrative embodiment, the executive function is selected from the group consisting of decision making, attention, and working memory. In another illustrative embodiment, the cognition is functional connectivity between frontal regions of the brain and parietal regions of the brain. In another illustrative embodiment, the cognition is functional connectivity of frontal regions of the brain. In another illustrative embodiment, the cognition is modulation of functional connectivity of frontal regions of the brain.

In various illustrative embodiments, the neurodegenerative disease of the compositions and methods described herein can include, but is not limited to, Parkinson's disease, parkinsonisms including progressive supranuclear palsy, Alzheimer's disease, dementia, and motor neuron disease (e.g., amyotrophic lateral sclerosis ("ALS")).

In one illustrative embodiment, the neurodegenerative disease of the methods or compositions described herein is selected from the group consisting of Parkinson's disease, Alzheimer's disease, and ALS. Neurological diseases, including Alzheimer's disease, Parkinson's disease, and ALS, generally result in behavioral deficits that can be observed clinically. These diseases target populations of neurons leading to

neuropathological changes and behavioral symptoms. Alzheimer's disease involves the death of neurons of various regions of the cerebral cortex and the hippocampus and results in the loss of cognitive functions required for memory and learning. Parkinson's disease results in degeneration of portions of the nigro-striatal system. Initial stages involve the loss of terminal projections of dopamine-containing neurons from the substantia nigra. In turn, the neuron cell bodies in the substantia nigra die, impacting motor control and leading to tremor and gait disturbances.

An example of a motor neuron disease is amyotrophic lateral sclerosis (ALS).

ALS primarily involves the progressive loss of motor neurons in the brain and spinal cord, resulting in increasing paralysis and eventually death. Early symptoms of ALS include but are not limited to, footdrop or weakness in a patient's legs, feet, or ankles, hand weakness or clumsiness, muscle cramps and twitching in the arms, shoulders, and tongue. ALS generally affects chewing, swallowing, speaking, and breathing, and eventually leads to paralysis of the muscles required to perform these functions. A review of various neurological diseases is set forth in Shaw et al., Neuroscience and Biobehavioral Reviews, 27: 493 (2003), which is hereby incorporated by reference. The method and compositions of the present invention can be used for both human clinical medicine and veterinary medicine applications. The methods and compositions described herein may be used alone, or in combination with other methods or compositions.

The neurodegenerative disease of the methods or compositions described herein can be heritable, idiopathic, or can be mediated by environmental insult to the patient. The neurodegenerative disease mediated by environmental insult to the patient may be a sporadic disease linked to environmental factors that cause neuronal cell death directly or indirectly by modifying gene expression. In various other illustrative embodiments, the environmental insult is derived from the patient's diet or is the result of endogenous synthesis, or both. In one illustrative embodiment, the environmental insult causes synthesis of a compound that causes a detrimental effect in vivo. The neuronal cell death may occur by any variety of means including, but not limited to, excitotoxicity or oxidative stress. For example, various means by which environmental toxins lead to neuronal cell death are described in U.S. Patent Application Publication No. 2006-0252705, which is hereby incorporated by reference.

In another illustrative embodiment, the neurodegenerative disease state is mediated by an excitotoxin. Excitotoxins are a class of substances that damage neurons through overactivation of receptors, for example, receptors for the excitatory neurotransmitter glutamate, leading to neuronal cell death. Examples of excitotoxins include excitatory amino acids, which can produce lesions in the central nervous system. Additional examples of excitotoxins include, but are not limited to, sterol glucoside, including beta-sitosterol-beta-D- glucoside and cholesterol glucoside, methionine sulfoximine, and other substances known in the art to induce neuro-excitotoxic reactions in a patient. In one illustrative embodiment, the excitotoxin is a sterol glycoside. In further illustrative embodiments, the sterol glycoside is selected from the group consisting of beta-sitosterol-beta-D-glucoside and cholesterol glucoside, or analogs or derivatives thereof.

In further illustrative embodiments, the neurological disorder of the compositions and methods described herein can include, but is not limited to, traumatic brain injury, post stroke, autism, schizophrenia, and chronic traumatic encephalopathy (CTE). In further illustrative embodiments, the neurological disorder of the compositions or methods described herein neurological disorder can be traumatic brain injury, autism, schizophrenia or chronic traumatic encephalopathy.

In another illustrative embodiment, a composition is provided. The composition comprises therapeutically effective amounts of an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, wherein the therapeutically effective amounts comprise amounts effective for improving cognition in an individual.

In another illustrative embodiment, a composition is provided. The composition comprises therapeutically effective amounts of an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, wherein the therapeutically effective amounts comprise amounts effective for rejuvenating the brain of an individual.

In another illustrative embodiment, a composition is provided. The composition comprises therapeutically effective amounts of an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, wherein the therapeutically effective amounts comprise amounts effective for modulating functional connectivity of frontal regions of the brain of an individual.

In another illustrative embodiment, a composition is provided. The composition comprises therapeutically effective amounts of an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, wherein the therapeutically effective amounts comprise amounts effective for for modulating functional connectivity of frontal regions of the brain of an individual and improving cognition or rejuvenating the brain of the individual.

In another illustrative embodiment, a composition is provided. The composition comprises therapeutically effective amounts of an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, wherein the therapeutically effective amounts comprise amounts effective for treating neurodegenerative disease in a patient.

In another illustrative embodiment, a composition is provided. The composition comprises therapeutically effective amounts of an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and combinations thereof, wherein the therapeutically effective amounts comprise amounts effective for treating a neurological disorder in a patient.

In another illustrative embodiment, a composition is provided. The composition comprises therapeutically effective amounts of an active combination of at least one phospholipid and at least one substance, wherein the substance is a ginseng or ginsenoside, wherein the phospholipid is complexed to the ginseng or ginsenoside, and wherein the therapeutically effective amounts comprise amounts effective for increasing the bioavailability of the ginseng or ginsenoside in the brain of the individual.

In another illustrative embodiment, a composition is provided. The composition comprises therapeutically effective amounts of an active combination of at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, catechin, green tea, essential fatty acid, and

combinations thereof, wherein the therapeutically effective amounts comprise amounts effective for increasing the bioavailability of the ginseng or ginsenoside in the brain of the individual. In the preceding embodiment, the phospholipid can be complexed to the ginseng or ginsenoside.

As used herein, an "active combination" refers to a combination of at least one phospholipid and at least one substance. Any of the substances of the various embodiments described herein can be combined with at least one phospholipid to form an active combination. In various illustrative embodiments, the active combination of the compositions or methods described herein can be at least one phospholipid and at least one substance, wherein the substance is a ginseng or ginsenoside. In further illustrative embodiments, the active combination of the methods and compositions described herein is at least one phospholipid and at least one substance, wherein the substance is selected from the group consisting of a ginseng, ginsenoside, green tea, catechin, essential fatty acid, and

combinations thereof. In the preceding embodiment, the essential fatty acid can be an omega- 3 fatty acid or an omega-6 fatty acid, the omega-3 fatty acid can be DHA or EPA, the ginseng can be from a species belonging to the genus Panax, the ginsenoside can be a ginsenoside selected from the group consisting of Rbl, Rb2, Rb3, Rc, Rd, Re, Rf, Rgl, Rg2, Rg3, Rhl, compound K and Rh2, the phospholipid can be selected from the group consisting of lecithin, phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphoinositide, and phosphosphingolipid, and/or the phospholipid can complexed to the substance. In further illustrative embodiments, the active combination of the methods and compositions described herein is at least one phospholipid and at least one substance, wherein the substance is ginseng and catechin. In the preceding embodiment, the ginseng can be derived from a species belonging to the genus Panax, the ginseng can comprise at least one ginsenoside selected from the group consisting of Rbl, Rb2, Rb3, Rc, Rd, Re, Rf, Rgl, Rg2, Rg3, Rhl, and Rh2, the phospholipid can be selected from the group consisting of lecithin, phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphoinositide, and phosphosphingolipid, and/or the phospholipid can be complexed to the substance. In further illustrative embodiments, the active combination of the methods and compositions described herein is at least one phospholipid and at least one substance, wherein the substance is ginseng, catechin and essential fatty acid. In the preceding embodiment, the ginseng can be belong to the genus Panax, the essential fatty acid can be EPA or DHA, the phospholipid can be selected from the group consisting of lecithin, phosphatidylcholine, phosphatidylinositol,

phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphoinositide, and phosphosphingolipid, and/or the phospholipid can be complexed to the substance.

In further illustrative embodiments, the active combination of the methods or compositions described herein can at least one phospholipid and a substance, wherein the substance is ginseng, ginsenosides, green tea, catechins and essential fatty acids. In further illustrative embodiments, the ginseng can be Asian ginseng, the green tea can be green tea leaf extract, and the essential fatty acids can be omega-3 fatty acids, DHA and EPA. In further illustrative embodiments, the ginseng can be complexed to at least one phospholipid the green tea can be complexed to at least one phospholipid. In further illustrative embodiments, the composition of the methods or compositions described herein can comprise Cerbella®. As used herein, "Cerbella®" or "Cerbella" is a composition comprising the active combination set out in Table 1 :

TABLE 1

The unitary daily dosage of the composition comprising an active combination can vary significantly depending on the condition of the individual or patient being treated, the route of administration of the combination and tissue distribution, and the possibility of co-usage of other therapeutic treatments. The effective amount of an active combination to be administered to the patient or individual is based on body surface area, patient weight, physician assessment of patient or individual condition, and the like. In one illustrative embodiment, an effective dose of an active combination can range from about 1 ng kg of patient or individual body weight to about 1 mg/kg of patient or individual body weight, more preferably from about 1 ng/kg of patient or individual body weight to about 500 ng/kg of patient or individual body weight, and most preferably from about 1 ng/kg of patient or individual body weight to about 100 ng/kg of patient or individual body weight.

In another illustrative embodiment, an effective dose of an active combination can range from about 1 pg/kg of patient or individual body weight to about 1 mg/kg of patient or individual body weight. In various illustrative embodiments, an effective dose can range from about 1 pg/kg of patient or individual body weight to about 500 ng/kg of patient or individual body weight, from about 500 pg/kg of patient or individual body weight to about 500 ng/kg of patient or individual body weight, from about 1 ng/kg of patient or individual body weight to about 500 ng/kg of patient or individual body weight, from about 100 ng/kg of patient or individual body weight to about 500 ng/kg of patient or individual body weight, and from about 1 ng/kg of patient or individual body weight to about 100 ng/kg of patient or individual body weight.

In another illustrative embodiment, an effective dose of an active combination can range from about 1 μ /Τ¾ of patient body weight to about 1 mg/kg of patient or individual body weight. In various illustrative embodiments, an effective dose can range from about 1 μg/kg of patient or individual body weight to about 500 μg/kg of patient or individual body weight, from about 500 ng/kg of patient or individual body weight to about 500 μg/kg of patient or individual body weight, from about 1 μg/kg of patient or individual body weight to about 500 μg/kg of patient or individual body weight, from about 0.1 μg/kg of patient or individual body weight to about 5 μg kg of patient or individual body weight, from about 0.1 μg/kg of patient or individual body weight to about 10 μg/kg of patient or individual body weight, and from about 0.1 μg/kg of patient or individual body weight to about 100 μg/kg of patient or individual body weight.

The composition comprising an active combination is preferably administered to the patient or individual orally. Alternatively, the composition comprising an active combination can be administered to the patient or individual intranasally, intranasally, topically, sublingually, intracerebrally or parenterally, e.g., intradermally, subcutaneously, intramuscularly, intraperitoneally, intravenously, intraventricularly, intrathecally,

intracerebrally or intracordally (spinal). Alternatively, the composition comprising an active combination may be administered to the patient or individual by other medically useful processes, and any effective dose and suitable therapeutic dosage form, including prolonged or sustained release dosage forms, can be used. Administration can be by injection. The composition comprising an active combination can also be delivered using a slow pump.

Examples of parenteral dosage forms include aqueous solutions of the active combination, in an isotonic saline, 5% glucose or other well-known pharmaceutically acceptable liquid carriers such as liquid alcohols, glycols, esters, and amides. The parenteral dosage form in accordance with this invention can be in the form of a reconstitutable lyophilizate comprising a dose of a composition comprising an active combination. In one aspect of the present embodiment, any of a number of prolonged or sustained release dosage forms known in the art can be administered such as, for example, the biodegradable carbohydrate matrices described in U.S. Patent Nos. 4,713,249; 5,266,333; and 5,417,982, the disclosures of which are incorporated herein by reference.

In an illustrative embodiment, pharmaceutical formulations for general use with an active combination for parenteral administration comprising: a) a pharmaceutically active amount of an active combination; b) a pharmaceutically acceptable pH buffering agent to provide a pH in the range of about pH 4.5 to about pH 9; c) an ionic strength modifying agent in the concentration range of about 0 to about 250 millimolar; and d) water soluble viscosity modifying agent in the concentration range of about 0.5% to about 7% total formula weight are described or any combinations of a), b), c) and d).

In various illustrative embodiments, the pH buffering agents for use in the compositions and methods herein described are those agents known to the skilled artisan and include, for example, acetate, borate, carbonate, citrate, and phosphate buffers, as well as hydrochloric acid, sodium hydroxide, magnesium oxide, monopotassium phosphate, bicarbonate, ammonia, carbonic acid, hydrochloric acid, sodium citrate, citric acid, acetic acid, disodium hydrogen phosphate, borax, boric acid, sodium hydroxide, diethyl barbituric acid, and proteins, as well as various biological buffers, for example, TAPS, Bicine, Tris, Tricine, HEPES, TES, MOPS, PIPES, Cacodylate, and MES.

In another illustrative embodiment, the ionic strength modulating agents include those agents known in the art, for example, glycerin, propylene glycol, mannitol, glucose, dextrose, sorbitol, sodium chloride, potassium chloride, and other electrolytes.

Useful viscosity modulating agents include but are not limited to, ionic and non-ionic water soluble polymers; crosslinked acrylic acid polymers such as the "carbomer" family of polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the Carbopol® trademark; hydrophilic polymers such as polyethylene oxides, polyoxyethylene- polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers and cellulosic polymer derivatives such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methyl cellulose, carboxymethyl cellulose, and etherified cellulose; gums such as tragacanth and xanthan gum; sodium alginate; gelatin, hyaluronic acid and salts thereof, chitosans, gellans or any combination thereof. It is preferred that non-acidic viscosity enhancing agents, such as a neutral or basic agent be employed in order to facilitate achieving the desired pH of the formulation. If a uniform gel is desired, dispersing agents such as alcohol, sorbitol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, or stirring, or combinations thereof. In one embodiment, the viscosity enhancing agent can also provide the base, discussed above. In one preferred embodiment, the viscosity modulating agent is cellulose that has been modified such as by etherification or esterification.

In various illustrative embodiments, compositions comprising an active combination are provided that may comprise an active combination, alone or in combination with at least one pharmaceutically acceptable carrier, such as an excipient and/or a stabilizing compound and/or a solubilizing agent, and may be administered in any sterile, biocompatible pharmaceutical carrier, including, but not limited to, saline, buffered saline, dextrose, glucose, and water. Suitable excipients are carbohydrate or protein fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, etc.; celluloses such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium

carboxymethylcellulose; and gums including arabic and tragacanth; and proteins such as gelatin and collagen. Suitable disintegrating or solubilizing agents include agar, alginic acid or a salt thereof such as sodium alginate.

In illustrative embodiments, an active combination can be administered to a patient or individual alone, or in combination with other agents, drugs or hormones or in pharmaceutical compositions mixed with excipient(s) or other pharmaceutically acceptable carriers. In one embodiment, the pharmaceutically acceptable carrier is pharmaceutically inert. In another embodiment, an active combination may be administered alone to a patient suffering from a neurological disorder or neurodegenerative disease or to an individual.

Any effective regimen for administering the composition comprising an active combination can be used. For example, the composition comprising an active combination can be administered as a single dose, or the composition comprising an active combination can be divided and administered as a multiple-dose daily regimen. Further, a staggered regimen, for example, one to three days per week can be used as an alternative to daily treatment, and for the purposes of this invention such intermittent or staggered daily regimen is considered to be equivalent to every day treatment and within the scope of this invention. In one embodiment, the patient or individual is treated with multiple administrations of the composition comprising an active combination. In another embodiment, the patient or individual is administered multiple times (e.g., about 2 up to about 50 times) with the composition comprising active combination, for example, at 12-72 hour intervals or at 48-72 hour intervals. Additional dosages of the composition comprising an active combination can be administered to the patient or individual at an interval of days or months after the initial administration(s). In one embodiment, the initial administration(s) of the composition comprising an active combination may prevent recurrence of a neurodegenerative disease in a patient. In another illustrative embodiment, the initial administration(s) of the composition comprising an active combination may prevent recurrence of a neurological disorder in a patient. In another illustrative embodiment, the composition comprising an active

combination can be administered to an individual without a neurodegenerative disease to prevent the neurodegenerative disease. In another illustrative embodiment, the composition comprising an active combination can be administered to an individual without a neurological disorder to prevent the neurological disorder. In another illustrative embodiment, the initial administration(s) of the composition comprising an active combination can improve cognition in the brain of an individual. In another illustrative embodiment, the initial administration(s) of the composition comprising an active combination can increase bioavailability of ginseng or ginsenoside in the brain of an individual.

In another embodiment, a method is provided for treating a neurodegenerative disease in a patient. The method comprises the step of administering to a patient with a neurodegenerative disease a therapeutically effective amount of an active combination, wherein the amount of the active combination is effective to reduce symptoms of the neurodegenerative disease in the patient.

In another embodiment, a method is provided for treating a neurological disorder in a patient. The method comprises the step of administering to a patient with a neurological disorder a therapeutically effective amount of an active combination, wherein the amount of the active combination is effective to reduce symptoms of the neurological disorder in the patient.

In the above-described embodiments, the composition comprising an active combination can be administered to an individual without a neurodegenerative disease to prevent the neurodegenerative disease, or the composition comprising an active combination can be administered to an individual without a neurological disorder to prevent the neurological disorder.

In another illustrative embodiment, cognition can be improved in an individual by administering to the individual a composition comprising an active combination, wherein administering the composition comprising the active combination to the individual improves cognition in the brain of the individual. Any of the above embodiments using an active combination are applicable to this embodiment.

In another illustrative embodiment, the brain can be rejuvenated in an individual by administering to the individual a composition comprising an active

combination, wherein administering the composition comprising the active combination to the individual rejuvenates the brain of the individual. Any of the above embodiments using an active combination are applicable to this embodiment.

In another illustrative embodiment, functional connectivity of frontal regions of the brain of an individual can be modulated by administering to the individual a composition comprising an active combination, wherein administering the composition comprising the active combination to the individual modulates functional connectivity of the frontal regions of the brain of the individual. Any of the above embodiments using an active combination are applicable to this embodiment.

In another illustrative embodiment, cognition can be improved or the brain can be rejuvenated in an individual by modulating functional connectivity of frontal regions of the brain of the individual by administering to the individual a composition comprising an active combination, wherein administering the composition comprising the active

combination to the individual modulates functional connectivity of the frontal regions of the brain of the individual and improves cognition or rejuvenates the brain of the individual. Any of the above embodiments using an active combination are applicable to this embodiment.

In another illustrative embodiment, a patient with a neurodegenerative disease can be treated by administering to the patient a composition comprising an active combination, wherein treatment of the patient with the composition comprising the active combination reduces the symptoms of the neurodegenerative disease in the patient. Any of the above embodiments using an active combination are applicable to this embodiment.

In another illustrative embodiment, a patient with a neurological disorder can be treated by administering to the patient a composition comprising an active combination, wherein treatment of the patient with the composition comprising the active combination reduces the symptoms of the neurological disorder in the patient. Any of the above embodiments using an active combination are applicable to this embodiment.

In another embodiment, a pharmaceutical composition is provided. The pharmaceutical composition comprises therapeutically effective amounts of an active combination, and a pharmaceutically acceptable carrier, wherein the therapeutically effective amounts comprise amounts capable of improving cognition in an individual. Any of the above embodiments (e.g., formulation embodiments, dose regimen embodiments, treatment regimen embodiments, etc.) using an active combination are applicable to this embodiment.

In another embodiment, a pharmaceutical composition is provided. The pharmaceutical composition comprises therapeutically effective amounts of an active combination, and a pharmaceutically acceptable carrier, wherein the therapeutically effective amounts comprise amounts capable of rejuvenating the brain of an individual. Any of the above embodiments (e.g., formulation embodiments, dose regimen embodiments, treatment regimen embodiments, etc.) using an active combination are applicable to this embodiment.

In another embodiment, a pharmaceutical composition is provided. The pharmaceutical composition comprises therapeutically effective amounts of an active combination, and a pharmaceutically acceptable carrier, wherein the therapeutically effective amounts comprise amounts capable of modulating functional connectivity in frontal regions of the brain of an individual. Any of the above embodiments (e.g., formulation

embodiments, dose regimen embodiments, treatment regimen embodiments, etc.) using an active combination are applicable to this embodiment.

In another embodiment, a pharmaceutical composition is provided. The pharmaceutical composition comprises therapeutically effective amounts of an active combination, and a pharmaceutically acceptable carrier, wherein the therapeutically effective amounts comprise amounts capable of modulating functional connectivity in frontal regions of the brain of an individual and improving cognition or rejuvenating the brain of the individual. Any of the above embodiments (e.g., formulation embodiments, dose regimen embodiments, treatment regimen embodiments, etc.) using an active combination are applicable to this embodiment.

In another embodiment, a pharmaceutical composition is provided. The pharmaceutical composition comprises therapeutically effective amounts of an active combination, and a pharmaceutically acceptable carrier, wherein the therapeutically effective amounts comprise amounts capable of improving ginseng or ginsenoside bioavailability in the brain of an individual. Any of the above embodiments (e.g., formulation embodiments, dose regimen embodiments, treatment regimen embodiments, etc.) using an active combination are applicable to this embodiment.

In yet another embodiment, a pharmaceutical composition is provided. The pharmaceutical composition comprises therapeutically effective amounts of an active combination, and a pharmaceutically acceptable carrier, wherein the therapeutically effective amounts comprise amounts capable of reducing the symptoms of a neurodegenerative disease in a patient with a neurodegenerative disease. Any of the above embodiments (e.g.

formulation embodiments, dose regimen embodiments, treatment regimen embodiments, etc.) using an active combination are applicable to this embodiment.

In yet another embodiment, a pharmaceutical composition is provided. The pharmaceutical composition comprises therapeutically effective amounts of an active combination, and a pharmaceutically acceptable carrier, wherein the therapeutically effective amounts comprise amounts capable of reducing the symptoms of a neurological disorder in a patient with a neurological disorder. Any of the above embodiments (e.g. formulation embodiments, dose regimen embodiments, treatment regimen embodiments, etc.) using an active combination are applicable to this embodiment.

In yet another embodiment, a pharmaceutical composition is provided. The pharmaceutical composition comprises therapeutically effective amounts of an active combination, and a pharmaceutically acceptable carrier, wherein the therapeutically effective amounts comprise amounts capable of preventing the symptoms of a neurodegenerative disease or in an individual without neurodegenerative disease. Any of the above

embodiments (e.g. formulation embodiments, dose regimen embodiments, treatment regimen embodiments, etc.) using an active combination are applicable to this embodiment. In yet another embodiment, a pharmaceutical composition is provided. The pharmaceutical composition comprises therapeutically effective amounts of an active combination, and a pharmaceutically acceptable carrier, wherein the therapeutically effective amounts comprise amounts capable of preventing the symptoms of a neurological disorder or in an individual without the neurological disorder. Any of the above embodiments (e.g. formulation embodiments, dose regimen embodiments, treatment regimen embodiments, etc.) using an active combination are applicable to this embodiment.

EXAMPLE 1

COGNITIVE IMPROVEMENT STUDY

A study was carried out to determine the feasibility, safety, and tolerability of Cerbella®.

Study Summary

Over the course of approximately 8 months a total of 16 individuals were screened, with 11 individuals randomized and 10 individuals ultimately completing the study. The crossover study design consisted of participants being randomly assigned into either the placebo arm or the intervention arm, followed by a washout period. After the washout period, study participants were placed into the second arm of the study, which involved receiving the treatment not given in the first arm of the study. In this clinical trial, individuals were either on placebo, or active treatment group (Cerbella®), with every individual receiving both placebo and Cerbella® over the course of the study. Each arm of the study involved a 26 +2 day treatment with either placebo or Cerbella®, with the washout period being between at least 30 days. The study was double blinded, meaning that neither the study subject or study staff were aware of which intervention the study subject was receiving at any time during the study. Blinding was designated and controlled by the onsite pharmacist and un-blinding occurred at the time of data analysis.

The Cerbella® intervention consisted of administering Cerbella, which composition is linked to the enhancement of brain health. Both the Cerbella® and placebo were distributed in identical containers. The Cerbella® and placebo were formulated into liquid products which were indistinguishable in appearance, taste, odor and consistency. All participants were instructed how often to consume the liquid product, and when to consume the liquid product, and compliance was measured by diaries and weighing of the liquid at designated visits. Individuals were screened to ensure they were between the ages of 55-75 years of age, non-demented (MMSE >25), had the ability to undergo MRJ, and were able to provide informed consent. In addition, screening involved making sure the study participants were not currently taking vitamins or nutraceuticals related to Cerbella®, were not exhibiting depression (GDS>6), were not diabetic, were not smokers, etc. The primary objective of the study was to test the hypothesis that exposure to the investigational product (Cerbella®) will alter brain activity, as measured by blood oxygenation level dependent (BOLD) imaging and cognitive function in middle aged and older adults. A further objective of the study was to determine the feasibility, tolerability, and safety of using the investigational product

(Cerbella®) in middle aged and older adults.

The 10 individuals completing the study consisted of 6 females and 4 males. These individuals had a mean age of 67.3 years + 2.01 years. The study participants had a mean education of 15.67 years + 0.73 years. The mean weight of participants was 149.8 pounds + 8.21 pounds. The mean body mass index for participants was 23.30 + 0.93. All study participants were compliant in terms of taking the placebo and Cerbella® (each individual > 90% compliant in each arm of the study) based on study subject questioning and the weighing of fluids at designated study visits.

Adverse Events

A total of 6 adverse events were reported over the course of the study including a nasal congestion (1), persistent cold (1), nausea- vomiting (1), and wrist, knee and elbow pain (3). No serious adverse events were reported over the course of the study. No adverse event appeared to be related to treatment with either placebo or Cerbella®. There was no significant difference between placebo and Cerbella® groups in terms of the number of adverse events, indicating that Cerbella® did not significantly increase adverse events as compared to placebo in this study.

Cognitive Findings

A number of cognitive measures were used at the beginning and end of each experimental arm of the study to determine the ability of Cerbella® to alter cognitive function relative to control. This battery of cognitive assessments included the mini-mental state exam (MMSE) as a global measure of cognition (Folstein et al., 1975), the digit symbol (DS) substitution test as a measure of attention and psychomotor speed (Wechsler, 1981), the

Stroop test which as a measure of processing speed and parallel processing (Lamers, 2010), and Logical Memory I and II as measures of immediate and delayed recall (Lezak et al., 2012). The MMSE consists of a series of questions and tasks that examine orientation to time place, working memory, and executive function as a quick snapshot of overall cognitive function. The DS test involves having an individual match a series of incomplete digit and symbol pairs as fast as they can using a designated code. The Stroop test involves having individuals complete the naming of color names under conditions where the color of the word matches, and conditions where the color does not match, the color name. The Logical Memory task involves the reading of a short story and asking the individual to immediately recall as many facts as possible about the story, and to ask them again at a later time to repeat what they remember about the story.

Increases in scores on the MMSE, Stroop, and Digit Symbol tests over the course of treatment with the investigational product were statistically significant (all p<.05, see Table 2). Mean changes in scores on all tests during the placebo phase, as well as changes in scores on the Immediate and Delayed Recall tests during the investigational product phase, were positive, but not significantly different from time 0 (p>.05). While none of the cognitive measures were increased to a statistically significant (p<0.05) degree with Cerbella® treatment, all aspects of cognition other than immediate recall with Logical Memory were elevated by Cerbella® treatment relative to placebo (see Table 2). With regards to the MMSE, individuals receiving Cerebella® exhibited an improvement (0.90 (+ 1.10)) as compared to placebo (0.20 (+ 1.03)) (p= .15). With regards to the Stroop task, treatment with Cerbella® improved cognitive performance (6.60 (+ 8.71)) relative to placebo (4.80 (+7.22)). With regards to the DS, treatment with Cerbella® increased the number of digits completed (3.30 (+2.75)) versus placebo (2.60 (+8.53)).

Table 2: Cognitive Changes

Table 2: Cognitive function summary measures before ("Pre") and after ("Post") the placebo and investigational product phases of the intervention, and change in these measures

("Change") over the course of each intervention phase.

*Cognitive changes significantly differ from 0 at p<.05 level via two-sided one-sample T test.

EXAMPLE 2

FUNCTIONAL MRI SCANNING - ACTIVATION DURING COGNITIVE TASK

The ten trial participants from the study described in Example 1 underwent functional

MRI scanning (fMRI) during each arm of the study. The fMRI was administered at baseline and end of treatment period. The fMRI the participants performed required them to process visual information and make decisions based on the visual information appearing on the screen. There was an easy version of the task and a difficult version; each participant completed both the easy and difficult versions. The primary outcome from each fMRI scan was the difference in fMRI signals observed during performance of the easy and difficult versions of the task. This outcome tells us what parts of the brain become active to complete the difficult version of the task, and how active they become.

Cerbella® and Placebo Groups fMRI Scanning Results

We summarized all fMRI changes over the course of the intervention within

Cerbella® and placebo arms (Figure 1). Those on placebo showed mainly decreases in fMRI responses over the course of the intervention (Figure 1 left) while individuals on Cerbella® showed a combination of increases and decreases in fMRI responses over the course of the intervention (Figure 1 center). The differences in these intervention-related changes between placebo and Cerbella® groups was statistically significant (p<0.01) in multiple important brain regions (Figure 1 right). Many of the brain regions that showed greater increases in fMRI activation in response to Cerbella® are hypothesized to be intimately involved in higher-order cognitive functions, such as the posterior and anterior cingulate cortex (see Table 3). Taken together, these results suggest that both individuals on Cerbella® and individuals on placebo showed fMRI signal changes over the course of the intervention that could plausibly be related to task performance. However, these changes were qualitatively different between groups.

Table 3: fMRI changes within the regions highlighted by cross-hairs in Figure 1.

Table 3: fMRI summary measures before ("Pre") and after ("Post") the placebo and investigational product phases of the intervention, and change in these measures ("Change") over the course of each intervention phase. fMRI summary measures were calculated from sets of voxels identified through a statistical test.

Overall Summary of the Studies of Example 1 and Example 2

Cerbella® was found to be a safe well tolerated intervention that did not significantly increase the number of adverse events relative to placebo. The primary objective of the project was to test the hypothesis that exposure to the investigational product (Cerbella®) will alter brain activity as measured by blood oxygenation level dependent (BOLD) imaging and cognitive function in middle aged and older adults. Statistically significant (p<0.05) increases in cognitive function were observed in the current study, including elevated levels of global cognition, attention and psychomotor speed (DS), and processing speed and parallel processing (Stroop) following Cerbella® treatment. The fact that so many aspects of cognition are elevated in response to Cerbella shows that Cerbella® likely has an impact on multiple cognitive domains in elderly individuals. Individuals on Cerbella® showed qualitatively and quantitatively different brain activity changes while performing a mental task over the course of treatment, compared to placebo. Individuals on Cerbella® largely showed increases in brain activation over the course of the intervention, while those on placebo showed a combination of increases and decreases in this activation. The locations in the brain showing changes during intervention are biologically plausible, including regions implicated in higher order cognition required for this task. Group differences in fMRI changes show that Cerbella® is likely impacting cognitive functioning by modifying how the brain processes information during tasks. Increases in fMRI signals in the Cerbella® arm suggest that after intervention, the brain is able to mount a more vigorous response to the task, reflected in greater fMRI signals. Changes in fMRI signals in the placebo arm, meanwhile, could reflect a placebo effect distinct from Cerbella® effects, or practice effects.

EXAMPLE 3

FUNCTIONAL MRI SCANNING AND FUNCTIONAL CONNECTIVITY

During the human clinical study outlined in Example 1, fMRI functional connectivity analysis was conducted to assess the degree to which the fMRI signal showed synchronicity between distinct locations in the brain. Briefly, a set of regions of interest (ROIs) known to be activated by this task were identified based on prior reports with this task. The ROIs consisted of the left medial frontal gyrus, left middle frontal gyrus, left and right precentral gyri, left and right anterior dorsal premotor cortex, and left superior parietal lobule. For each such task ROI, the mean fMRI time series during task performance blocks was estimated within a 9mm sphere centered on a seed voxel within the ROI. The Pearson correlation between this task mean time series and corresponding task time series in all other brain voxels was estimated to quantify functional connectivity during task execution. Similarly, for each task ROI, the mean fMRI time series during rest blocks was estimated within a 9mm sphere centered on the ROI seed voxel. The Pearson correlation between this mean rest block time series and corresponding rest block time series in all other brain voxels was estimated to quantify functional connectivity during rest. Change in functional connectivity values over the course of each intervention phase were calculated at an individual level. Group level analysis assessed whether such functional connectivity changes over each intervention phase were significantly different from zero and whether such changes differed significantly between the investigational product and placebo phases. These analyses resulted in p value maps that were corrected for multiple comparisons using AlphaSim with a voxel-level p value threshold of .01 and a cluster-level significance threshold of .001. All analyses were performed in SPM12.

Significant decreases in fMRI signal differences between the set of shape-only blocks and color-only blocks on one hand, and the set of alternating blocks on the other hand, over the course of the placebo phase were observed in a cluster of voxels located in the posterior cingulate cortex (Figure 2). Significant changes over the course of the investigational product phase were mixed, including significant increases in a cluster of voxels mainly within the cerebellum and brainstem, as well as significant decreases in small clusters of voxels covering portions of midline white matter tracts. Comparison of placebo and investigational product phases suggested that increases in fMRI signal differences between the set of shape- only blocks and color-only blocks on one hand, and the set of alternating blocks on the other hand, over the course of the investigational product phase were significantly greater than they were over the course of the placebo phase in two clusters of voxels, located in the anterior and posterior cingulate cortex respectively. In both clusters, the average BOLD signal change over the investigational product phase was positive, while the average BOLD signal change over the placebo change was negative (Table 4).

Functional connectivity during rest blocks between the medial frontal gyrus ROI and a voxel cluster in the occipital cortex increased significantly over the course of treatment with the investigational product but was roughly unchanged during treatment with placebo (Figure 3, Table 4). Functional connectivity during rest blocks between the precentral gyrus ROI and a cluster of voxels in the medial frontal gyrus increased significantly over the course of treatment with placebo, and decreased significantly over the course of treatment with Cerbella. Functional connectivity during rest blocks between the precuneus ROI and a cluster of voxels in the middle frontal gyrus also increased significantly over the course of treatment with placebo, and decreased significantly over the course of treatment with the investigational product. Average functional connectivity across all task blocks between the middle frontal gyrus ROI and a cluster of anterior cingulate cortex voxels decreased over the course of treatment with placebo but increased over the course of treatment with the investigational product (Figure 2, Table 4). Table 4: Functional Connectivity (fMRI) During Task Performance and Rest

Table 4: Functional Connectivity (fMRI) summary measures before ("Pre") and after ("Post") the placebo and investigational product phases of the intervention, and change in these measures ("Change") over the course of each intervention phase.

These fMRI functional connectivity findings are consistent with a role for the investigational product in changing the engagement of distributed neural networks during task execution and rest. As mentioned before, execution of the fMRI task requires activation of a task network of brain regions that includes the anterior cingulate cortex and the middle frontal gyrus. In addition, there is a distributed network of regions, commonly referred to as the default mode network, that activates in a synchronous fashion during periods of rest, possibly to facilitate introspective cognition such as re-evaluation of recently perceived series of events. Previous work has suggested that task networks such as the current one show highly structured, temporally synchronous patterns of BOLD signal fluctuations during task performance. Conversely, the default mode network shows highly structured, temporally synchronous patterns of BOLD signal fluctuations in the absence of an overt cognitive or sensory task, and this synchrony reduces markedly during performance of tasks. A large body of research has linked lesser synchrony of the default mode network during rest to poorer cognitive functioning as found in healthy older adults as well as the presence of clinically significant neurological disorders, including AD and Parkinson's disease . In addition, individuals with poorer cognitive function show a reduced ability to modulate functional connectivity between default and task networks. We found that fMRI signal synchrony between two default mode network structures (the medial frontal gyrus and precuneus respectively) and two task network structures (the precentral gyrus and middle frontal gyrus respectively) reduced during rest over the course of treatment with the investigational product. This is consistent with the notion that after a course of treatment with the investigational product, the default mode network is less engaged with the task network during rest. In addition, we found that functional connectivity between a pair of task network structures (anterior cingulate and middle frontal gyri) during task execution increased during treatment with the investigational product. This is consistent with the notion that during treatment with the investigational product, the task network has greater synchrony of activity within the network during task performance. Both of these characteristics— lesser synchrony between task and default mode networks during rest, and greater synchrony within the task network during task execution— have been associated with cognitive health and greater cognitive performance.

EXAMPLE 4

GINSENOSIDE BRAIN BIOAVAILABILITY STUDY

Objective:

To determine if phospholipid complexation of ginseng increases ginsenoside bioavailability in the brain.

Methods:

Rats were fed different formulations of ginseng and their brains were then extracted and analyzed for ginsenoside content. Ginsenoside concentration was determined using LC- MS-MS.

Groups:

1. Ginseng-phospholipid complex in oil (40 mg/kg/day)

2. Raw ginseng extract in water (40 mg/kg/day)

3. Water control For this study only 2 of 6 animals from each of 3 groups were analyzed. The remainder of the animals from these groups as well as animals from an additional 3 groups (complex in water @40 mg/kg/day; extract in water @8 mg/kg/day; and Cerbella® @ 8 mg/kg/day) will be included in the final study report.

Brain Extraction and Analysis Protocol:

Extraction: Approximately 30mg of lyophilized mouse brain was homogenized in 270μ1 water together with digoxin and digoxigenin added as mass spectrometry internal standards. An initial extraction of the homogenate was accomplished using 3 mL

hexane/dichloromethane (2:1) as solvent and the sample, vortex extracted for 30 minutes. Following centrifugation, the upper organic layer was removed and dried by vacuum centrifugation. The aqueous phase was subjected to a second extraction by addition of 1ml acetonitrile followed by vortexing, centrifugation and drying organic phase. The dried residues (combined) were taken up in 50μ1 methanol by vortexing/sonication and the insoluble material was sedimented by centrifugation prior to analysis by LC-MS.

Analysis: High pressure liquid chromatography of the extract was carried out using a biphasic 20-90% methanol gradient containing ammonium fluoride on a Waters BEH CI 8, 2.1x100mm, 1.7μ column. This achieved baseline separation of all ginsenosides and aglycones with overall 18min run length. Mass spectrometric analysis of the separated ginsenosides and aglycones was carried out using a Waters Acquity/Quattro instrument run in electrospray negative (ES-) mode, with m/z of ions and fragments for individual compounds selected for best sensitivity and instrument parameters likewise optimized.

Results:

The results are shown in Figure 4. Brains from the water fed group did not have detectable levels of ginsenosides . In the brains of rats fed raw ginseng extract most of the ginsenosides (with the exception of Re, Rb2 and Rd) were either undetectable or present only at very low levels. In the brains of rats fed the ginseng-phospholipid complex all ginsenosides were detected (with the exception of PPT) and were present at levels much greater than in the brains of the ginseng extract fed group. Of the ginsenosides that were absorbed from the raw extract, the phospholipid complexation increased their absorption 2-13 fold (mean increase of 8.3 fold). This level of absorption-enhancement by complexation is consistent with values reported elsewhere (1).

Discussion: Many of the ginsenosides from the raw extract were poorly absorbed into the brain or not detected at all, but phospholipid complexation increased their absorption, often to high levels. These ginsenosides include Rgl, Rbl, compound K and PPD, all of which have beneficial effects in the CNS (2,3). These results show increased brain bio-availability of complexed ginseng.

EXAMPLE 5

PREPARATION OF COMPOSITIONS COMPRISING A COMBINATION OF PHOSPHOLIPIDS, GINSENG, ESSENTIAL FATTY ACIDS AND CATECHINS

The preparation of compositions that enhance the bioavailability, including brain uptake of the active ingredients, involves three distinct steps, namely, preparation of a ginseng extract - phospholipid complex or ginsenoside(s) - phospholipid complex, preparation of a catechin - phospholipid complex (such as green tea catechin extract), and finally incorporation of these complexes into a stable, omega-3 based liquid emulsion.

To prepare the ginseng - phospholipid complex or catechin - phospholipid complex, lecithin and or other phospholipids are added to a suitable solvent and mixed at room temperature for 30 minutes under nitrogen at a stoichiometric ratio of approximately 1-2 parts phospholipid per part ginseng or catechin. Ginseng and catechin components are slowly added while mixing and increasing temperature to 50-70 °C, then mixed for 1-4 hrs. under nitrogen, followed by cooling to room temperature. The solvent is then removed by evaporation or drying, after which the product is removed from vessel and frozen at -80°C, then milled and desiccated, and finally stored in a dark container under nitrogen.

The individual ginseng - phospholipid and catechin - phospholipid complexes are then added to the emulsifying agent during the emulsification process typical for unsaturated fatty acid emulsification according to Emulsions;Nanotechnology in the Agri-Food Industry Vol 3 Elsevier Inc 2016. Chapter 3 pg. 71-100, which is incorporated herein by reference in its entirety.

Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. In the specification, the word "comprising" is used as an open-ended term, substantially equivalent to the phrase "including, but not limited to," and the word "comprises" has a corresponding meaning. Citation of references herein shall not be construed as an admission that such references are prior art to the present invention. All publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.

REFERENCES

Ferreira, & Busatto. (2013). Resting-state functional connectivity in normal brain aging. Neuroscience and Biohehavioral Reviews, 57(3), 384-400.

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