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PhosphatidylserineThink Smart. Think Sharp.

A Breakthrough Solution for Brain Health

Scientific Summary

2Enzymotec Ltd. Sagi 2000 Industrial Zone | Kfar Baruch. Israel, 23106 | Tel: 972 74 7177177 | Fax: 972 74 7177001

Executive SummaryPhosphatidylserine (PS), a structural component of cells, is

found in all biological membranes of plants, animals and

other forms of life. The human body contains about 30g

of phosphatidylserine, about half (~13 g) of which is found

in the brain. Phosphatidylserine plays a vital role in several

metabolic processes, such as activation of cell-membrane

bound enzymes, and is involved in neuronal signaling.

Pre-clinical and clinical studies demonstrated that oral

administration of phosphatidylserine improves cognitive

functions.

This scientific summary reviews the many facts and

published research findings on phosphatidylserine, and

presents results from Enzymotec’s clinical trial which tested

the effects of its Sharp●PS® product on cognition.

The qualitative and quantitative scientific evidence,

including human and animal data, is sufficient to determine

that phosphatidylserine supplementation is beneficial

to cognition and to establish that consumption of

phosphatidylserine is safe and well tolerated.

3 Enzymotec Ltd. Sagi 2000 Industrial Zone | Kfar Baruch. Israel, 23106 | Tel: 972 74 7177177 | Fax: 972 74 7177001

Background During the last few decades, life expectancy has

been rising sharply and is expected to continue

to rise in nearly all populations worldwide.

According to the United Nations Population

Division, the worldwide proportion of elders,

aged 65 and above, increased from 5% to 7%

from 1950 to 2000, and is expected to grow up

to 16% by 2050. In some countries, China for

example, an even greater extent of population

aging is expected. Due to the Chinese “one

child policy”, which was introduced in 1979 to

alleviate social, economic, and environmental

problems, it is expected that a threefold

increase in the elderly population will occur

between 2000 and 2050, from 7% to 23% of

the population. In Japan, the country with the

highest life expectancy, the elderly population

is projected to increase to more than a third of

the total population by 2050 (figure 1)1.

Aging is not a uniform process, and we must

distinguish between aging and healthy aging. An

increase in life expectancy does not necessarily

mean an increase in the quality of life or health of

the individuals. Therefore, today, one of the main

concerns of the aging population is to maintain

high physical activity and mobility, as well as

mental capacity, all required to maintain high

quality of life and active, healthy, aging.

Among cognitive difficulties of the elderly

population, age associated memory decline,

defined as normal deterioration of memory

which is unrelated to any pathology, may be the

most documented in the scientific literature. In

humans, this decline may start already at 30 years

of age, and may become evident by middle age2,

and experimental findings are in agreement with

people’s subjective reports of memory problems

as they age. Healthy aging is characterized by

slow, but constant, decrease in cognitive functions

Figure 1: Global picture of aging

World USA Japan China

1950 1975 2000 2050

Australia

Perc

ent

of p

opul

atio

n ov

er 6

5

5% 5% 5% 4%

7%8% 8%

9%8%

6%7%

10% 11%

12% 13% 12%

19%

22%

19%

29%

23%

36%

21%

16%

17%

2025

40%

35%

30%

25%

20%

15%

10%

5%

0%


which is completely different from pathological

cognitive deterioration. Pathological deterioration

includes faster changes in brain structure, such

as formation of brain plaques and neuronal

degeneration, manifesting first as Mild Cognitive

Impairment (MCI) and other types of dementia. A

seven year-follow-up clinical study demonstrated

that subjects with subjective memory complaints

had 4.5 times higher risk to further deteriorate to

pathological MCI or dementia than subjects free

of these symptoms3 (figure 2).

Clinical evidence suggests that dietary deficit

of important nutrients may contribute to the

development of brain pathologies during aging.

Thus, supplementation of nutrients with clinically

proven cognitive benefits may give answer to the

customer quest for cognitive enhancers. With better

understanding of the consequences of cognitive

deterioration, aging consumers turn more and

more to nutrition solutions for cognitive support.

This trend is on the rise and, with the aging of the

population, is expected to grow in coming years.

The importance of nutritionGlobalization and industrialization processes have

led to dramatic changes in our daily diet, resulting

in deficiency of many vital minerals, vitamins

and certain lipids. Western diet is characterized

by accumulating more energy than we need

and spending less than we should, by increased

trans-fat consumption and by reduced intake

of vegetables and other food products related

to healthier diets4. In some instances, transition

from traditional diets to Western diets (as in some

Asian countries) resulted in dramatic nutritional

changes which led to severe impact on the health

Cog

nitiv

e D

eclin

e

Mild CognitiveImpairment

Pathological Cognitive Decline

Time (Years)

Mild

Moderate

ModeratelySevereDementia

Severe

Normal Age Associated Memory Decline

Figure 2: Normal gradual decline of cognitive functions during aging (red line) in comparison

with pathological cognitive decline (Adapted and modified from Golomb et al., 2004³).

Our diets today lack many

vitamins, minerals and lipids

which are vital for proper brain

function


in general, and phospholipids in particular, is

affected by our diet. This, in turn, may affect

the structure of the brain. For example, the

hippocampus, a brain region which is responsible

for certain aspects of learning and memory, is

particularly susceptible to disruption by dietary

factors16. Findings that show association between

aging and alterations in brain lipid composition

may explain, at least in part, the deterioration in

cognitive abilities of elderly18.

Phospholipids – The building blocks of cell membranes Phospholipids (PLs) are an important family of lipids

which are distinct from triglycerides, the main

lipid group in our diet, in both form and function.

Phospholipids are the main building blocks of cell

membranes while triglycerides are used by the

human body mainly as a source of energy, or as

energy storage molecules. Both triglycerides and

phospholipids are comprised of fatty acids (FAs)

attached to a glycerol backbone, which is a short

chain of 3 carbons. However, the triglyceride

molecule has three FAs attached to the glycerol

backbone, while a phospholipid molecule has

the glycerol backbone attached to only two FAs

and to a polar, water soluble, head group (Figure

3). Phospholipids are considered amphipathic

of the population5.

Nutrition is known to play a major role in

the function of the nervous system. Thus,

administration of essential brain nutrients, for

support of healthy brain function, is a good

strategy to maintain or restore neuronal functions.

Studies have shown that nutrition affects

cognitive functions and mental performances

early in life6-12, with effects persisting throughout

adulthood and old age13.

Insufficient consumption of important nutrients

may be restored by supplementing it from

external sources. Consequently, more than half

of US adults use dietary supplements to balance

their diets, improve various daily functions and

maintain a healthier lifestyle14.

The brain is influenced by nutritionThe ability of nutrition to affect the brain is limited

by a barrier in the brain known as the Blood-

Brain-Barrier (BBB). Nonetheless, compounds

which are required for proper brain function are

actively transferred from the blood to the brain.

Thus, vitamins, minerals, amino acids and various

lipids are actively carried into the brain by special

protein transporters. The brain is one of the

organs richest in lipid content. Actually, brain lipid

content makes up to 50% of brain dry weight15.

Lipids are an essential component of the diet. Our

diet contains different forms of lipids, such as free

fatty acids, triglycerides, phospholipids and others.

The roles of lipids in our body are diverse, from

structural to functional. In addition to their use

for energy storage, lipids are important building

blocks of the body’s cellular membranes and serve

as precursors for hormones and other biologically

functional molecules. The composition of lipids

Phospholipids are used as cellular

membrane building blocks, unlike

triglycerides which are used for

storage of energy


molecules, meaning they have non-polar FAs on

one side and a polar head group on the other.

This unique characteristic of phospholipids is what

allows their function as building blocks of biological

membranes. The polar head group is comprised of

a phosphate group and an organic molecule linked

to each other. Phospholipids in cellular membrane

differ in composition from one cell type to another,

with phosphatidylcholine (PC) being the most

abundant PL in all cell types. Compared to most

tissues, the brain is enriched with another member

of the phospholipid family, phosphatidylserine (PS).

PhosphatidylserineLevels of PS vary significantly between tissues. In

most tissues, PS accounts for only about 3% of

total membrane phospholipids17, while in brain

tissues its amount is closer to 18%18. Variations

in phospholipid composition from one cell type to

another emphasize the importance of biological

membrane composition for proper function; thus,

the importance of PS to proper brain function is

underlined.

Neuronal cells do not readily regenerate, thus it

is important that these cells will have a superior

survival mechanism. High levels of PS in neuronal

membranes were shown to be important for

neuronal survival by facilitating several important

cellular processes19. Maintaining PS levels in

neuronal tissues has been associated with normal

and efficient signal transduction processes,

efficient neuronal glucose consumption and other

biological pathways which are crucial for normal

and healthy cognitive and mental functions2, 20-22.

Thus, PS is informally characterized as a brain-

specific nutrient because of its possible importance

for proper neuronal function2.

Figure 3: Structure of PS molecule (top), the localization of PS

within the inner layer of cell membrane (middle) and its utilization in

formation of tissues (bottom)


effect of dietary supplementation of PS on cognition Supplementing the diet with PS is known to affect

a large number of cognitive functions, among them

memory, learning and attention. Dietary PS was first

isolated from bovine cortex (BC-PS), and studies

demonstrated its beneficial effects both in pre-

clinical and clinical trials. Based on the large body

of clinical evidence demonstrating the beneficial

effects PS asserts on cognition, the American Food

and Drug Administration (FDA) has authorized in

April 2003 two qualified health claims for PS25:

“Consumption of Phosphatidylserine may reduce

the risk of cognitive dysfunction in the elderly”; and

“Consumption of Phosphatidylserine may reduce

the risk of dementia in the elderly”. However, FDA

also added a disclaimer indicating that “very limited

and preliminary scientific research suggests that

phosphatidylserine may reduce the risk of dementia

in the elderly. FDA concludes that there is little

scientific evidence supporting this claim.”

Phosphatidylserine in the dietPhosphatidylserine is a normal constituent of

human diet23, found in small amounts in human

breast milk and in natural food sources such as:

1) Animals – PS was first identified in bovine

brain which is known to date as a good source for

PS. Other internal animal parts and various fish

are also good sources for PS.

2) Plants – the amount of PS found in plants is

very limited. PS can be found in certain beans,

whole grains and rice, though levels are low.

PS is an example of a nutrient whose intake

levels have dropped in recent years. Changes in

consumer tastes, increased awareness to health

issues (e.g. reduced fat and cholesterol diets, mad

cow disease), as well as advances in technological

processing of fats and oils in the food industry, all

resulted in reduction in the amount of PLs in our

food. PS consumption todays is reduced by nearly

50% (Figure 4) compared to its consumption

during the early 80s’. It is estimated that the current

intake of PS is rather low, about 130 mg per day for

adults consuming “regular” diet, and even lower

for those on a reduced fat or vegetarian diet23.

Figure 4: Dietary trends suggest that PS intake has declined over the

past few decades (adapted from Hamm 200224).

PS is the only cognitive solution with

FDA health claims:

*”Consumption of PS may reduce

the risk of cognitive dysfunction in

the elderly”; and *”Consumption of

PS may reduce the risk of dementia

in the elderly”

Estim

ated

PS

daily

inta

ke (m

g/da

y)

Pre 1980 Current Vegetarian

300

250

200

150

100

50

0


treated with PS for periods of up to 6m, participated

in the studies. The doses used in these trials

ranged from 100 to 800 mg/day, but the most

prevalent regimen was 300 mg/day for 3 months.

The majority of the clinical studies conducted in

the early 80’s, using BC-PS, demonstrated the

clear benefit of PS supplementation on memory30,

concentration31 and other cognitive functions

in elderly population with various degrees of

cognitive deterioration, from Age-Associated

Memory Decline (AAMD) to Alzheimer’s’ disease

(AD)34, 35. Providing BC-PS to elderly patients was

also found to significantly enhance behavioral

parameters33. Importantly, BC-PS supplementation

to patients with AD had positive effect on their

cognitive performance34, 35.

In recent years, due to safety concerns regarding

the risk of contamination by bovine spongiform

encephalopathy prions (“mad cow disease”), BC-

PS is no longer used for human consumption and

alternative sources, such as marine derived PS

or soy PS (S-PS), have been developed. Soybean

derived PS has been available commercially

worldwide for more than a decade and has been

clinically tested during this period.

Clinical evidence of soy derived PSGindin and colleagues36 were the first to test the

cognitive effects of S-PS in a clinical trial. In their

randomized, double blind, placebo controlled

study, 57 elders aged 60-80 with complaints of

memory decline (AAMD) were given 300 mg S-PS

Beneficial effects of PS – Scientific evidence: Pre-clinical studies

PS was shown to have behavioral and cognitive

effects in numerous pre-clinical studies.

Administration of PS to rats was shown to

antagonize the amnesic effects of scopolamine.

The effect was similar regardless of the source

of PS [soy PS (S-PS) and BC-PS]26. Comparable

effects on cognition were also observed in a pre-

clinical study evaluating the cognition-enhancing

properties of S-PS and BC-PS (as well as PS from

eggs) in three different behavioral tests27. Another

study found that dietary supplementation of PS is

able to ameliorate impaired learning behavior28.

Nunzi et al29 demonstrated the capability of BC-

PS treatment to maintain dendritic spine density

(known to reduce with age and neurocognitive

diseases) of neurons in the hippocampus of old

rats. In 27-month-old rats, equal to human elderly

age, spine density showed a significant decrease

in dendrites compared to a 3-month-old animal.

However, in 27-month-old rats treated with BC-PS

values of spine density were not statistically different

when compared to those of 3-month-old animals.

Clinical studies

The clinical database of phosphatidylserine

intake includes over 46 clinical trials of which 27

have been conducted as double-blind, placebo-

controlled studies. The objective of the majority

of these studies was to examine the effects of

PS administration in reducing the symptoms of

dementia and cognitive dysfunction in elderly

individuals. Overall, more than 1500 subjects,


In another study, the clinical effects of 300 mg/day

S-PS were compared to those of BC-PS following 12

weeks of supplementation. The results demonstrated

a similar extent of improvement in cognitive function

following intake of both products37.

Although most of the studies demonstrated the

beneficial effect of PS following consumption of

300 mg/day, several studies suggested that a dose

of 100 mg/day of PS may be effective and sufficient

for demonstrating improvement of cognitive

measures such as memory and concentration.

In a pilot study, with only 12 patients, the

effective dosage of PS was examined. The aim

was to examine whether a dose of 100 mg PS

had a similar effect as 300 mg PS/day. Results of

this study demonstrated that following 12 weeks

of treatment, 100 mg/day PS showed a similar

improvement in various aspects of memory as did

the 300 mg/day dose37.

In a randomized, double-blind, placebo control

study, conducted in 79 Japanese elders with

memory complaints (defined as MCI), the efficacy

of S-PS (100 mg/day or 300 mg/day) was evaluated

over 6 month’s supplementation, followed by 3

months of non-supplemented follow-up period.

PS was found to be safe and no adverse events

were reported. In subjects with relatively low

cognitive score at baseline, the memory scores

following PS treatment were significantly increased

compared to baseline, while memory scores of

the placebo group remained unchanged (Figure

6). The memory improvements in the S-PS-treated

groups were mostly attributed to the increase in

delayed verbal recall and memory abilities38.

per day or placebo for a period of 3 months. Using

the Wechsler test (for memory) and the List of

Depression Symptoms score (for mood), the main

findings of the study were that both memory

and mood were significantly improved following

administration of S-PS (Figure 5).

effect on Memory

effect on Mood

Placebo

Placebo

S-PS

S-PS

Chan

ge in

Wec

hsle

r mem

ory

test

sco

reCh

ange

in L

ist o

f Dep

ress

ion

Sym

ptom

s sc

ore

Figure 5: Effect of soy PS on memory (top, higher score means better

memory) and mood (bottom, higher score means worsening of mood)

in subjects with AAMD supplemented with 300 mg/day PS for 3

months (Gindin 199336).

4

2

0

-2

3

2

1

0


A dose of 100 mg/day PS was also demonstrated

to improve cognitive performance in 120 students

aged 17-18 who were randomized to receive

either 250ml milk supplemented with 100 mg

PS or 250ml un-supplemented milk (placebo)

for 40 days. Memory was assessed by clinical

memory scale with computerized tests. Various

aspects of memory and learning were improved

in the PS supplementation group. Improved

domains included directed memory, associative

learning, free memory of images, recognition of

meaningless figures and portrait features-linked

memory (Figure 7)39. This study demonstrated

that PS beneficial effect is not limited to the

elderly population but may improve cognitive

performance and academic achievements in

young population as well.

Figure 6: Effect of PS in subjects with MCI. Shown are the effects of 100 mg/day S-PS on demented state (left) and on general

cognitive state (right) (Kato-Kataoka 201038).

0

6

3

9 Follow up

Months oftreatment

3

2

1

0

-1

Test for Dementia (HDS-r)

Chan

ge in

DW

R sc

ore

Placebo PS

2

1

0

-1

Test for Cognitive Function (MMSe)

Chan

ge in

DW

R sc

ore

Placebo PS

Even in teenagers, a group whose

cognitive performance is at its peak,

supplementation of 100 mg/day

PS for 40 days improved cognitive

performance.

* p<0.05

**p<0.01

** *

*****


by a computerized cognitive assessment tool (at

baseline, following 6 weeks of treatment and at

study termination).

Enzymotec’s Sharp●PS® Clinical study Sharp●PS® is a high grade soybean derived

PS produced by Enzymotec. The efficacy of

Sharp●PS® in improving cognitive abilities of

elderly participants was evaluated in an open

label study40. Twenty-six subjects (mean age: 74.6

years, 73% females) with memory complaints

were treated with 300 mg/day Sharp●PS® for 12

weeks. Participants’ cognitive performance was

evaluated by verbal and visual neuropsychological

tests, including Rey Auditory Verbal Learning Test

(AVLT) (at baseline and at study termination) and

*

*

*

*

*

Directedmemory

Associativelearning

Free memoryof images

Recognition of meaningless

figures

Portrait features-linked

memory

40

35

30

25

20

15

10

*p<0.05

Before PS intake

After PS intake

Figure 7: Improvement in cognitive functions of high school students following 40 days supplementation with 100 mg/day

PS in milk (Tang Yong 201139)

Test

Sco

re

Supplementation of Enzymotec’s

Sharp●PS® improves many aspects

of cognition such as memory,

learning and more


respectively). This improvement was enhanced

following 12 weeks of treatment (change

from mean baseline score: +8% and +12%,

respectively). Moreover, after 12 supplementation

weeks, mean scores of executive function and

mental flexibility were improved by 14% and

13%, respectively.

ResultsSeveral parameters of cognitive performance were

improved following Sharp●PS® supplementation

(Figures 8 and 9). The results of the computerized

test (Figure 8) show that following only 6 weeks

of Sharp●PS® administration, memory recognition

and memory recall were significantly improved

(change from mean baseline: +7% and +10%,

Memoryrecognition

Memoryrecall

Executivefunctions

Mentalflexibility

95

90

85

80

75

70

65

60

Figure 8: Effect of Sharp●PS® on memory recognition, memory recall, executive functions and mental flexibility following 6

and 12 weeks of supplementation. Significant improvements are presented (change from baseline to 6 and to 12 treatment

weeks). * p<0.01, ** p<0.006.

Baseline

12 weeks

6 weeks

*p<0.01**p<0.006

**

*

**

** ** *

Mea

n Sc

ore

(Poi

nts)


recognition tasks, though these improvements

did not reach statistical significance (data not

shown). Sharp●PS® treatment was well tolerated

and no major treatment-related adverse events

were reported during the course of the study.

The study findings suggest that Sharp●PS® has

a beneficial impact on cognitive abilities of the

elderly and that it is safe for use.

Similarly, significant beneficial effects were

observed in Rey-AVLT test (Figure 9). Following

12 weeks of Sharp●PS® supplementation, verbal

immediate recall and total learning scores improved

significantly (change from mean baseline: +24%

and +10%, respectively). An improvement was

also detected in the best learning score, in the

performance of the verbal delayed recall and

Figure 9: REY-AVLT results following 12 weeks of Sharp●PS® administration.

*p<0.05, **p<0.01 based on Student’s t-test comparison for dependent samples of the change between baseline and

endpoint.

6

5

4

3

2

1

0

45

43

41

39

37

35

33

**

*

Baseline Baseline12 weeks 12 weeks

immediate recall Total Learning

Mea

n Sc

ore

(# w

ords

cor

rect

ly re

calle

d)


in neuronal cells and tissues, translocation

of Akt to the membrane, resulting in its

activation, is PS-dependent43. Increase in brain

PS was accompanied by reduction of apoptosis

(programed cell death) of neurons which is

critical for the maintaining of normal brain

function43. Humans are equipped with the same

number of neurons in their brains from birth till

adulthood44. Thus, keeping the neurons in good

health is of utmost importance.

• Activation of cellular enzymes such as protein

kinase C (PKC): activation of PKC is known to be

PS-dependent45, and its activity is essential for

cognitive processes such as memory and learning.

PKC is known to phosphorylate a number of

proteins, such as MARCKS, GAP-43, and the

NMDA receptor, all of which are known to be

involved in information storage processes. In a

pre-clinical study, PKC activity within the brain

was found to diminish with age46, parallel to age

associated deterioration in cognitive abilities.

Pharmacologic intervention, with PKC inhibitors

and activators, has been shown to modulate

cognition47. A pre-clinical study demonstrated

that intake of PS increases PKC levels in the brain49,

which may partly explain the positive effects of PS

on memory and cognition. The dependence of

PKC activation on PS is schematically presented

in Figure 10.

Summary and conclusions of clinical studiesStudies using S-PS in elders tested effects of 100-

300 mg PS per day, for a period of up to 6 months

supplementation. Improvement could be seen

within 6 weeks, increasing even more following

longer use. In these studies the main benefit of S-PS

in patients with cognitive decline was improvement

of memory. Additional improvements were found

in learning abilities, mental flexibility, mood and

general improvement of daily life. PS was shown

to be safe for consumption and no adverse events

were reported.

Suggested mechanisms of action of PSUnlike most other phospholipids, PS is a negatively

charged molecule (see Figure 10), and many of

the mechanisms by which PS is thought to act are

based on that fact. PS was shown to participate

in key signaling pathways in the neuronal system.

Furthermore, PS was also shown to function

as a component of the membrane which binds

and activates cytosolic (=intracellular) proteins

involved in neuronal signaling and other functions

of neurons43. There are a number of mechanisms

described in the scientific literature for the function

of PS41, though no conclusive evidence points to a

single mechanism. Suggested mechanisms include:

• Activation of signal molecules such as Akt:

Activity of Akt within neurons is mediated

through PS43, and its activation promotes the

survival of neurons. Studies have shown that


nerve cells and an indicator of brain activity.

Measurements of cerebral metabolic rate of

glucose by Position Emission Tomography (PET)

have shown that PS causes a significant increase

in glucose metabolism of defined cortical and

subcortical structures of the brain52.

• Reduction of cortisol levels: Administration

of PS may counteract stress-induced activation

of the hypothalamic-pituitary-adrenal axis in

humans, as shown by reduction in blood cortisol

and ACTH levels following administration of PS53.

All of these suggested PS mechanisms eventually

impacts the subjects’ cognitive functioning as well

as mood and behavior.

• Influence on synaptic plasticity: As PS directly

activates PKC49, increased phosphorylation of

brain PKC following PS supplementation results in

activation of a PKC substrate called GAP4350. GAP43

is known to be involved directly in synaptic plasticity.

• Effect on brain waves (intensity and

frequencies): Administration of PS was shown

to affect quantitative Electroencephalography

(EEG) measurements and profile51, causing a

15-20 percent average power incrementing at

all frequency bands (except Alpha).

• Improvement of glucose utilization and induction of superior metabolic activation: Glucose is the preferred energy substrate for

Figure 10: PKC activation is PS dependent. PKC activation requires the following steps: 1. Ions of calcium bind to PKC,

charging it with a positive charge and opening a cleft for PS binding; 2. the now positively charged PKC is attracted to the

negatively charged PS. When PS binds to PKC, it anchors it to the membrane; 3. PS-dependent membrane anchoring leads to

binding of another lipid member, DAG, which leads to release of an inhibitory domain of PKC, making it active.


Summary• PS is an essential constituent of brain membranes

and an important player in brain-related

biochemical pathways.

• Clinical studies demonstrate that oral

supplementation of PS leads to improvement

in brain functions such as memory, attention,

mood, behavior and more.

• Sharp●PS® is a high quality soy-derived

phosphatidylserine produced by Enzymotec.

• Sharp●PS® efficacy in improving cognitive

abilities of elderly was demonstrated in a clinical

study.


entrance examination. Pediatric research.

1990;28:235-239

11. Kar BR, Rao SL, Chandramouli BA. Cognitive

development in children with chronic protein

energy malnutrition. Behavioral and brain

functions : BBF. 2008;4:31

12. Mendez MA, Adair LS. Severity and timing

of stunting in the first two years of life

affect performance on cognitive tests in

late childhood. The Journal of nutrition.

1999;129:1555-1562

13. Zhang Z, Gu D, Hayward MD. Childhood

nutritional deprivation and cognitive

impairment among older Chinese people.

Social science & medicine. 2010;71:941-949

14. Bailey RL, Gahche JJ, Miller PE, et al. Why

US adults use dietary supplements. JAMA

internal medicine. 2013;173:355-361

15. Woods AS, Jackson SN. Brain tissue

lipidomics: direct probing using matrix-

assisted laser desorption/ionization

mass spectrometry. The AAPS journal.

2006;8:E391-395

16. Hsu TM, Kanoski SE. Blood-brain barrier

disruption: mechanistic links between

Western diet consumption and dementia.

Frontiers in aging neuroscience. 2014;6:88

17. Vance JE, Tasseva G. Formation and

function of phosphatidylserine and

phosphatidylethanolamine in mammalian

cells. Biochim Biophys Acta. 2013;1831:543-

554

18. Svennerholm L. Distribution and fatty acid

composition of phosphoglycerides in normal

human brain. Journal of lipid research.

1968;9:570-579

19. Parletta N, Milte CM, Meyer BJ. Nutritional

modulation of cognitive function and

mental health. The Journal of nutritional

biochemistry. 2013;24:725-743

references1. UN. World population ageing: 1950-2050.

2002

2. McDaniel MA, Maier SF, Einstein GO. “Brain-

specific” nutrients: a memory cure? Nutrition.

2003;19:957-975

3. Golomb J, Kluger A, Stevens JC. Mild

cognitive impairment: historical development

and summary of research. Dialogues in clinical

neuroscience. 2004;6:351-367

4. WHO. Obesity and overweight. 2013

5. Cordain L, Eaton SB, Sebastian A, et al.

Origins and evolution of the Western diet:

health implications for the 21st century.

The American journal of clinical nutrition.

2005;81:341-354

6. Miranda MC, Sinnes EG, Pompeia S, et

al. A comparative study of performance

in the Conners’ Continuous Performance

Test between Brazilian and North American

children. Journal of attention disorders.

2008;11:588-598

7. Agarwal DK, Awasthy A, Upadhyay SK,

et al. Growth, behavior, development and

intelligence in rural children between 1-3

years of life. Indian pediatrics. 1992;29:467-

480

8. Berkman DS, Lescano AG, Gilman RH, et al.

Effects of stunting, diarrhoeal disease, and

parasitic infection during infancy on cognition

in late childhood: a follow-up study. Lancet.

2002;359:564-571

9. Galler JR, Ramsey FC, Forde V, et al. Long-

term effects of early kwashiorkor compared

with marasmus. II. Intellectual performance.

Journal of pediatric gastroenterology and

nutrition. 1987;6:847-854

10. Galler JR, Ramsey FC, Morley DS,

et al. The long-term effects of early

kwashiorkor compared with marasmus. IV.

Performance on the national high school


Dendritic spine loss in hippocampus of

aged rats. Effect of brain phosphatidylserine

administration. Neurobiology of aging.

1987;8:501-510

30. Crook TH, Tinklenberg J, Yesavage J, et

al. Effects of phosphatidylserine in age-

associated memory impairment. Neurology.

1991;41:644-649

31. Crook TH, 3rd, Feher EP, Larrabee GJ.

Assessment of memory complaint in age-

associated memory impairment: the MAC-Q.

Int Psychogeriatr. 1992;4:165-176

32. Amaducci L. Phosphatidylserine in the

treatment of Alzheimer’s disease: results of

a multicenter study. Psychopharmacology

bulletin. 1988;24:130-134

33. Cenacchi T, Bertoldin T, Farina C, et al.

Cognitive decline in the elderly: a double-

blind, placebo-controlled multicenter

study on efficacy of phosphatidylserine

administration. Aging (Milano). 1993;5:123-

133

34. Amaducci L. Phosphatidylserine in the

treatment of Alzheimer’s disease: results of

a multicenter study. Psychopharmacology

Bulletin. 1988;24:130-134

35. Crook T, Petrie W, Wells C, et al. Effects of

phosphatidylserine in Alzheimer’s disease.

Psychopharmacology bulletin. 1992;28:61-

66

36. Gindin J, Novikov M, Kedar D, et al. Effect of

soy lecithin phosphatidylserine (ps) complex

on memory impairment and mood in the

functioning elderly Unpublished Report.

Lipogen, Ltd.; Israel. . 1993

37. Crook T. Treatment of age-related decline

in cognitive capacities The effects of

phosphatidylserine. In: Katz, RM, Goldman,

eds. Anti-Aging Medical Therapeutics,.

1998:20-28.

20. Mozzi R, Buratta S, Goracci G. Metabolism

and functions of phosphatidylserine

in mammalian brain. Neurochem Res.

2003;28:195-214

21. Pepeu G, Pepeu IM, Amaducci L. A review

of phosphatidylserine pharmacological

and clinical effects. Is phosphatidylserine a

drug for the ageing brain? Pharmacol Res.

1996;33:73-80

22. Vance JE, Steenbergen R. Metabolism and

functions of phosphatidylserine. Prog Lipid

Res. 2005;44:207-234

23. Souci SW FE, Kraut H. . Food Composition

and Nutrition Tables. Medpharm Scientific

Publishers; 2008.

24. Hamm m. Nutritional-scientific statement

on the change of nutritive provision with

phosphatidylserine. 2002

25. FDA. Phosphatidylserine and Cognitive

Dysfunction and Dementia (Qualified Health

Claim: Final Decision Letter). 2003

26. Sakai M, Yamatoya H, Kudo

S. Pharmacological effects of

phosphatidylserine enzymatically synthesized

from soybean lecithin on brain functions

in rodents. J Nutr Sci Vitaminol (Tokyo).

1996;42:47-54

27. Blokland A, Honig W, Brouns F, et al.

Cognition-enhancing properties of

subchronic phosphatidylserine (PS) treatment

in middle-aged rats: comparison of bovine

cortex PS with egg PS and soybean PS.

Nutrition. 1999;15:778-783

28. Furushiro M, Suzuki S, Shishido Y, et

al. Effects of oral administration of

soybean lecithin transphosphatidylated

phosphatidylserine on impaired learning of

passive avoidance in mice. Japanese journal

of pharmacology. 1997;75:447-450

29. Nunzi MG, Milan F, Guidolin D, et al.


46. Sharma D, Sethi P, Hussain E, et al. Curcumin

counteracts the aluminium-induced ageing-

related alterations in oxidative stress, Na+,

K+ ATPase and protein kinase C in adult

and old rat brain regions. Biogerontology.

2009;10:489-502

47. Sun MK, Alkon DL. Pharmacology of protein

kinase C activators: cognition-enhancing and

antidementic therapeutics. Pharmacology &

therapeutics. 2010;127:66-77

48. Babenko NA, Semenova Ia A. [Effect of

exogenous phosphatidylserine on cognitive

function and hippocampus phospholipid

turnover in old rats]. Rossiiskii fiziologicheskii

zhurnal imeni I.M. Sechenova / Rossiiskaia

akademiia nauk. 2009;95:1268-1275

49. Lee MH, Bell RM. Supplementation of the

phosphatidyl-L-serine requirement of protein

kinase C with nonactivating phospholipids.

Biochemistry. 1992;31:5176-5182

50. Gianotti C, Porta A, De Graan PN, et

al. B-50/GAP-43 phosphorylation in

hippocampal slices from aged rats: effects

of phosphatidylserine administration.

Neurobiology of aging. 1993;14:401-406

51. Rosadini G, Sannita WG, Nobili F, et al.

Phosphatidylserine: quantitative EEG effects

in healthy volunteers. Neuropsychobiology.

1990;24:42-48

52. Klinkhammer P, Szelies B, Heiss WD. Effect

of phosphatidylserine on cerebral glucose

metabolism in Alzheimer’s Disease. . Cog.

Deterior. 1990;1:197-201

53. Starks MA, Starks SL, Kingsley M, et al. The

effects of phosphatidylserine on endocrine

response to moderate intensity exercise.

Journal of the International Society of Sports

Nutrition. 2008;5:11

38. Kato-Kataoka A, Sakai M, Ebina R, et

al. Soybean-derived phosphatidylserine

improves memory function of the elderly

Japanese subjects with memory complaints.

Journal of clinical biochemistry and nutrition.

2010;47:246-255

39. Yong T, Zhang Q, Mi M, et al. Research

on human memory enhancement by

phosphatidylserine fortified milk. Chongqing

Medicine. 2011;40:3022-3023

40. Richter Y, Herzog Y, Lifshitz Y, et al. The

effect of soybean-derived phosphatidylserine

on cognitive performance in elderly with

subjective memory complaints: a pilot study.

Clinical interventions in aging. 2013;8:557-563

41. Kim HY, Huang BX, Spector AA.

Phosphatidylserine in the brain: Metabolism

and function. Progress in lipid research.

2014;56C:1-18

42. Tsakiris S, Deliconstantinos G. Influence of

phosphatidylserine on (Na+ + K+)-stimulated

ATPase and acetylcholinesterase activities of

dog brain synaptosomal plasma membranes.

The Biochemical journal. 1984;220:301-307

43. Akbar M, Calderon F, Wen Z, et al.

Docosahexaenoic acid: a positive modulator

of Akt signaling in neuronal survival.

Proceedings of the National Academy of

Sciences of the United States of America.

2005;102:10858-10863

44. Bhardwaj RD, Curtis MA, Spalding KL, et

al. Neocortical neurogenesis in humans is

restricted to development. Proceedings of the

National Academy of Sciences of the United

States of America. 2006;103:12564-12568

45. Newton AC. Protein kinase C: structure,

function, and regulation. The Journal of

biological chemistry. 1995;270:28495-28498

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